79466_FM.

QXD 1/8/08 4:09 PM Page i

MANUAL OF GASTROENTEROLOGY:
DIAGNOSIS AND THERAPY
Fourth Edition
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MANUAL OF GASTROENTEROLOGY:
DIAGNOSIS AND THERAPY
Fourth Edition

Canan Avunduk, M.D., Ph.D.

Bay State Gastroenterology
Melrose, Massachusetts;
Clinical Associate Professor of Medicine
Tufts University Medical School
Boston, Massachusetts
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Avunduk, Canan.
Manual of gastroenterology: diagnosis and therapy/Canan Avunduk.—4th ed.
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To all my teachers and students.

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CONTENTS

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

I. APPROACH TO THE PATIENT WITH A

GASTROENTEROLOGIC DISORDER

1. Social Impact of Digestive Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2. The Patient’s Complaints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

3. Examination of the Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4. Psychological and Emotional Aspects

of Gastroenterologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

II. DIAGNOSTIC AND THERAPEUTIC PROCEDURES

5. Endoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

6. Laparoscopy and Laparoscopic Surgery . . . . . . . . . . . . . . . . . . . . . . . . 25

7. Percutaneous Liver Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

8. Manometric Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

9. Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

III. NUTRITIONAL ASSESSMENT AND MANAGEMENT

10. Nutritional Requirements and Assessment . . . . . . . . . . . . . . . . . . . . . . 45

11. Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

12. Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

IV. GASTROENTEROLOGIC EMERGENCIES

13. The Acute Abdomen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

14. Acute Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

15. Foreign Bodies in the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . 94

VII
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VIII Contents

16. Caustic Ingestion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

17. Fulminant Hepatic Failure and Encephalopathy . . . . . . . . . . . . . . . . . . . 102

18. Gastrointestinal and Hepatobiliary Diseases in Pregnancy . . . . . . . . . . 111

V. SPECIFIC COMPLAINTS AND DISORDERS

19. Esophageal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

20. Gastroesophageal Reflux Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

21. Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

22. Noncardiac Chest Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

23. Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

24. Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

25. Stress Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

26. Helicobacter Pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

27. Gastric Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

28. Postgastrectomy Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

29. Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

30. Viral, Bacterial, and Parasitic Disorders of the Bowel . . . . . . . . . . . . . . 195

31. Malabsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

32. Small-Intestinal Neoplasms and Carcinoid Tumors . . . . . . . . . . . . . . . . 222

33. Irritable Bowel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

34. Intestinal Gas and Bloating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

35. Diverticular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

36. Constipation and Fecal Impaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

37. Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

38. Vascular Disease of the Bowel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

39. Colonic Polyps and Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 269

40. Ostomy Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

41. Hemorrhoids and Other Anorectal Disorders . . . . . . . . . . . . . . . . . . . . . 283

42. Sexually Transmitted Enteric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 288

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Contents IX

43. Gastrointestinal and Hepatobiliary Diseases

in Patients with HIV and AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

44. Occult Obscure Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . 303

45. Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

46. Chronic Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

47. Pancreatic Cancer, Ampullary Cancer, Cystic Tumors, and

Neuroendocrine Tumors of the Pancreas . . . . . . . . . . . . . . . . . . . . . . . . 326

48. Jaundice and Interpretation of Laboratory Liver Tests . . . . . . . . . . . . . 335

49. Gallstones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

50. Viral Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

51. Alcoholic Liver Disease (ALD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

52. Nonalcoholic Fatty Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

53. Drug-Related Hepatic Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

54. Chronic Immune-Mediated Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . 407

55. Inherited Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

56. Cirrhosis and Its Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438

57. Tumors of the Liver and Biliary System . . . . . . . . . . . . . . . . . . . . . . . . . 455

58. Liver Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459

59. Anorexia Nervosa and Bulimia Nervosa . . . . . . . . . . . . . . . . . . . . . . . . . 473

60. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
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PREFACE

T he first, second, and third editions of Manual of Gastroenterology were well

received, both in the United States and abroad. This edition continues the intentions of its
predecessors: to be a concise, practical, up-to-date reference for the clinical diagnosis and
management of diseases and disorders of the digestive system. The content of all the exist-
ing chapters has been carefully reviewed, updated, and supplemented to provide current
treatment information for a wide variety of gastrointestinal disorders. References have also
been updated for each chapter.
As in the first three editions, the manual is divided into five parts: I. Approach to the
Patient with a Gastroenterologic Disorder; II. Diagnostic and Therapeutic Procedures;
III. Nutritional Assessment and Management; IV. Gastroenterologic Emergencies; and
V. Specific Complaints and Disorders. In most chapters, a brief review of background
information or pathophysiology precedes the discussion of diagnosis and treatment.
I believe this book will be particularly useful to primary care physicians, internists,
gastroenterologists, medical students, and resident physicians. We also anticipate that
other physicians and health care professionals will value Manual of Gastroenterology as a
guide to gastroenterologic problems that lie beyond their everyday experiences.
Special thanks to Rana H. Bonnice for typing and organizing the manuscript of this
book.
Special thanks to Carol Plasse for typing the manuscript for the second, third and
fourth editions.
Special thanks to Bill Whall for his unyielding support.

Canan Avunduk, M.D., Ph.D.

MANUAL OF GASTROENTEROLOGY:
DIAGNOSIS AND THERAPY
Fourth Edition

XI
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Approach to the Patient with a I

Gastroenterologic Disorder
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SOCIAL IMPACT OF 1
DIGESTIVE DISEASES

N early everyone has experienced a digestive illness. Perhaps it was a self-limiting bout
of “intestinal flu” or heartburn or a more serious condition such as chronic ulcerative col-
itis, Crohn’s disease, or carcinoma of the colon. Nevertheless, the social impact of digestive
diseases is probably underappreciated.
Cardiovascular disease and cancer are dramatic illnesses that command a great deal
of public attention. These disorders are associated with a high mortality and generally
affect the older segment of the population. On the other hand, digestive disorders afflict a
large number of people in all age groups and are associated with considerable pain, dis-
ability, and time lost from school, work, and other activities and considerable health care
costs.
In a typical year, digestive disorders affect about 40 million people in the United
States. The illnesses are responsible for the long-term inability to pursue ordinary activities,
such as school or work, in about a million people, and exact an enormous toll in dimin-
ished productivity: more than 150 million days with some restriction in activity, nearly 70
million bed-days, and more than 20 million days lost from work per year. These conditions
also result in 40 million annual physician contacts outside the hospital. The illnesses pre-
dominantly affect the young and middle-aged, with 70% occurring between the ages of 15
and 64 years. In addition to the losses caused by these predominantly chronic conditions,
acute digestive disorders annually affect more than 11 million people and result in 48 mil-
lion days of restricted activity, 27 million bed-days, and 9 million days lost from work.
Considering all digestive diseases, there are more than 4 million hospitalizations per
year, resulting in 28 million hospital days and accounting for 13% of all hospitalizations.
Moreover, many digestive diseases are fatal, causing about 9% of all deaths in the United
States, or about 220,000 deaths per year, of which 61% are caused by malignancies and
16% by chronic liver disease and cirrhosis. A conservative estimate of the economic bur-
den from digestive diseases is in excess of $60 billion per year, or roughly 10% of the total
costs of all illnesses.

Selected Readings
Lembo AJ. The clinical and economic burden of irritable bowel syndrome. Pract.
Gastroenterol. 2007;Sept:3–9.
Longstreth GF, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491.
Martin BC, et al. The annual cost of constipation in the U.S. ambulatory and inpatients
settings [abstract]. Gastroenterology. 2005;128(suppl 2):A-283. Abstract M974.
Singh G, et al. Use of healthcare resources and cost of care for adults with constipation.
Clin. Gastroentrol Hepatol. 2007;5:1053–1059.
Spiller K. Clinical update: irritable bowel syndrome. Lancet. 2007;369:1586–1588.

3
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2 THE PATIENT’S COMPLAINTS

S urvival is the most important drive for human existence. Thus, eating, digesting,
and eliminating are very important to human beings. Any disruption of any of these func-
tions causes much concern to the individual.
Patient complaints may be directly related to gastrointestinal (GI) dysfunction, such
as difficulty or painful swallowing, keeping foods down or difficulty in eliminating
(i.e., having diarrhea or constipation). The complaints may be indirectly related to the GI
system, such as pain in the chest from gastroesophageal reflux (GER), or pain in the
abdomen or pelvis or from an intestinal disorder. Change in color, consistency, or shape of
one’s stool, unexplained weight loss, jaundice, or abdominal swelling may bring the patient
to the health care professional.
A patient and a physician may differ in their perspectives on the patient’s complaints.
The physician’s orientation generally is in terms of disease categories. The physician wants
to make as accurate a diagnosis as possible and treat accordingly. On the other hand, the
patient comes to the physician with one or several complaints that usually describe signs
or symptoms perceived as “abnormal.” A patient may complain of food sticking on swal-
lowing; the physician thinks of an esophageal disease. A patient complains of yellow eyes
or jaundice; the physician wonders if the patient has hemolysis or liver disease or biliary
obstruction.
This divergence of orientation is sometimes a help and sometimes a hindrance. It is
a help when the health care professional understands that diagnostic categories are
merely aids to understanding and dealing with disease. It is a hindrance when the health
care provider relies unquestioningly on an established or an apparent diagnosis and
ignores other possibilities. For example, a 55-year-old woman with years of irritable
bowel symptoms who develops pencil-thin stools should not simply be reassured and
sent home; she needs an evaluation for carcinoma of the rectum or colon. On the other
hand, the 45-year-old man with chest pain does not necessarily have coronary heart
disease. His symptoms may be related to GER.
In the past 50 years, because of the diagnostic and therapeutic advances in medicine,
and the wide availability of the Internet, the expectations of both patients and physicians
have changed. Diagnostic tests have become much more sophisticated and accurate and
available in most medical facilities. Special expertise in noninvasive or minimally invasive
interventions has replaced invasive surgery as well as exploratory operations. Drugs
specially designed to act on a specific target have replaced drugs with poorly understood
and general effects. Many patients, before they consult their health care provider, go to the
World Wide Web first and gather information on their complaints. This sophistication
generates a milieu for preventive and early diagnostic and therapeutic measures.
Astute physicians and health care professionals are aware of their orientation and their
shortcomings and listen carefully to patients’ complaints. Sometimes the patient has a hid-
den agenda. A 42-year-old woman complains of recent abdominal pain and constipation.
On additional inquiry, it is learned that her mother died recently of colon cancer. This
patient is afraid that she also has cancer but may be reluctant to disclose that fear unless the
physician asks her directly. In another patient, a 32-year-old man with a positive family
history of early onset heart disease, the recent onset of epigastric or chest pain may be
merely the overt manifestation of nearly overwhelming anxiety, which seems to be related
to difficulties he is having at home and at work or exacerbation of gastroesophageal reflux
disease (GERD) or recent onset of angina. The physician should not only listen carefully but

4
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Chapter 2: The Patient’s Complaints 5

also should be purposely redundant. It is helpful to review the same information several
times, sometimes at different visits: “I know you told me about your abdominal pain last
time, but I would like to go over the information again. When did you first notice the pain
and what was it like?”

Selected Readings
Aziz Q, et al. Brain-gut axis in health and disease. Gastroenterology. 1998;114:599.
Bloomer JR, et al. Intermittent unexplained abdominal pain—is it porphyria? Clin.
Gastroentrol. Hepatol. 2007;5(11):1255–1259.
Drossman DA, et al. Psychosocial factors in the case of patients with GI disorders.
In: Yamada T, ed. Textbook of Gastroenterology. Philadelphia: Lippincott–Raven
Publishers; 2003:636–654.
Knoll BM, et al. 56-year-old man with rash, abdominal pain and orthralgias. Mayo Clin.
Prac. 2007;82(6):745–748.
Zinn W. The emphatic physician. Arch Intern Med. 1994;153:306–312.
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3 EXAMINATION OF THE PATIENT

B ecause you are familiar with examining patients, this chapter is not intended to be
comprehensive, but rather to orient you to the essential components of examining a patient
with digestive complaints.
The physician should be sensitive to the patient’s physical and emotional comfort.
Is the patient in as comfortable a position as possible? Is the patient warm enough? Have
you ensured the patient’s privacy by closing doors and adjusting drapes? How does the
patient feel about others in the room—colleagues, residents, students? Saying “This may be
a little awkward or embarrassing for you” may reassure and relax the patient. As you con-
duct the examination, you should inform the patient of what you intend to do, particularly
with regard to aspects of the examination that may be sensitive and embarrassing.

I. THE GENERAL PHYSICAL EXAMINATION. The physical examination of a patient

with digestive complaints is not limited to the abdomen, although the abdominal
examination is important. A general physical examination, including determination of
vital signs, is indicated during the initial evaluation. In particular, is there pallor of the
nail beds or conjunctivae? Is the tongue of normal color and texture? Is there any
lymphadenopathy? What about changes in the color or texture of the skin? Is edema
evident? Although abnormalities of the heart, lungs, or other organ systems may not
be related directly to the patient’s digestive complaints, they may be important con-
siderations in the subsequent management of the patient.

II. THE ABDOMINAL EXAMINATION. The abdomen conventionally is divided into four
quadrants: right upper, left upper, right lower, and left lower. It is also common,
however, to refer to areas of the abdomen by more specific terms, such as epigastric,
periumbilical, suprapubic, and right or left flank (Fig. 3-1).
A. Patient position. The patient should lie in a supine position, although the head
may be elevated slightly for comfort. Some patients lift their arms over their heads,
which tightens the abdominal wall and makes palpation and interpretation of signs
of peritoneal irritation difficult. The arms should remain at the patient’s side.
Flexion of the knees also may relieve abdominal tightness.
B. Inspection
1. Skin of the abdomen. Are there any scars, dilated veins, rashes, or other
marks?
2. Is the umbilicus normal? Is there an umbilical or abdominal wall hernia?
3. Contour of the abdomen. Is the abdomen protuberant or concave? Are there
any bulges?
4. Can you see peristaltic movements or pulsations?
C. Auscultation. In examining the abdomen, it is probably wise to listen before
performing percussion and palpation because these maneuvers may alter the
quality of bowel sounds.
1. Bowel sounds. What is the character of the bowel sounds? In healthy people,
the character and frequency of bowel sounds vary widely. In people who are
hungry, bowel sounds may be active, whereas after a meal the abdomen typi-
cally becomes rather quiet. Bowel sounds may be increased in frequency and
intensity in diarrheal conditions. Intestinal obstruction is characterized initially
by increased bowel sounds that progress to high-pitched tinkling sounds and

6
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Chapter 3: Examination of the Patient 7

Figure 3-1. Areas of the abdomen.

rushes. On the other hand, bowel sounds become decreased or absent in condi-
tions that cause paralytic ileus, such as peritonitis or electrolyte imbalance.
2. Other abdominal sounds. The physician should listen carefully also for
sounds in the abdomen other than bowel sounds.
a. Arterial bruits may indicate narrowing or turbulence in the aorta or renal,
iliac, or femoral arteries, depending on location. In some patients with renal
artery stenosis, the bruit is heard best over the back in the lumbar area.
b. A venous hum is a soft sound in both systole and diastole that indicates
increased collateral circulation between the portal and systemic venous sys-
tems. This rare finding usually is associated with cirrhosis of the liver.
c. A friction rub may be heard with respiration over the ribs that overlie the liver
or spleen. The grating sound of a friction rub is caused by inflammation of the
peritoneal surface, which may be caused by tumor, infection, or infarction.
D. Percussion and palpation. Most experienced physicians combine percussion and
palpation in the examination of the abdomen. Because patients typically are some-
what tense during the abdominal examination, the examiner should avoid sudden
movements. Much more information can be elicited by proceeding slowly and gen-
tly and sometimes firmly.
First, place one hand gently on the abdomen. This will tell you whether the
abdomen is tense, firm, or soft and whether the patient is made uncomfortable by
light pressure. Percuss the abdomen lightly in all four quadrants to determine tym-
pany and dullness.
1. Liver. The size, shape, and consistency of the liver are best estimated by first
percussing the upper and lower limits of liver dullness and then palpating the
lower edge in both phases of respiration. Remember to feel for the liver not
only in the right upper quadrant but also in the epigastrium. Some patients
with hepatomegaly have predominantly left lobe enlargement, which may be
evident only in the epigastrium. Occasionally, a markedly enlarged left lobe is
mistaken for the spleen.
2. The spleen can be identified as an area of dullness just above the left costal
margin posterior to the midaxillary line. In adults, the normal spleen usually
cannot be palpated, although about 10% of teenagers and young adults have
normal, palpable spleens. When the spleen enlarges, it expands anteriorly and
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8 Part I: Gastroenterologic Disorder

toward the midline. In splenomegaly, the area of dullness moves anteriorly,

therefore, the spleen may be palpated beneath the left ribs. A method of detect-
ing a small degree of splenomegaly is to percuss at the junction of the left
anterior axillary line and the costal margin. Normally the percussion note is
tympanitic in both phases of respiration. Dullness to percussion at this point
during inspiration may indicate early splenomegaly. Another method of palpat-
ing the spleen is to have the patient lie on the right side and lean slightly
forward. This position allows the spleen to drop anteriorly and toward the
midline. The examiner stands behind the patient, with fingers hooked beneath
the ribs, and asks the patient to breathe in, thereby allowing the spleen to move
down against the examining fingers.
3. Other organs and masses should be assessed for size, location, shape, and
consistency. The aorta often is felt as a pulsatile mass in the upper abdomen,
particularly in thin patients. Some estimation of the diameter of the aorta can
be made by pressing firmly but gently on either side of the aorta with one or
two hands. An enlarged, expansile aorta, sometimes accompanied by a bruit,
indicates an aneurysm.
4. Abdominal tenderness may be superficial or deep, localized or focal.
a. Guarding, particularly involuntary guarding, is usually a sign of peritoneal
inflammation.
b. Rebound tenderness, which also results from peritoneal inflammation, is
elicited by slowly pressing the abdomen and quickly releasing the pressure.
The examination for rebound tenderness usually is painful and should not
be repeated by subsequent examiners merely for the purpose of document-
ing an interesting clinical sign.
E. Detection of ascites. A protuberant abdomen with bulging flanks may connote
fluid within the peritoneal cavity. At this stage, however, the detection of ascites
usually is not difficult, except perhaps in obese patients.
1. Shifting dullness is identified by percussing the abdomen and noting the loca-
tion of the border between the dullness of the ascitic fluid and the tympany of
floating loops of bowel when the patient lies in a supine position, when the
patient turns to one side or the other, the border of dullness shifts.
2. A fluid wave is elicited when one flank is tapped briskly and the impulse is felt
on the opposite flank. To prevent transmission of the wave through the fat of
the abdominal wall, the patient or an assistant can press the edge of one hand
firmly down along the midline of the abdomen. Some examiners with large
hands are able to press along the midline with their own thumb and tap the
flank with the small finger of the same hand.
3. The puddle sign, although awkward to elicit, may detect small amounts of
ascites. The patient assumes the knee–chest position on the bed or examining
table. This position allows ascitic fluid to accumulate in the most dependent
position of the abdomen, centering around the umbilicus. Tapping the abdomen
while listening with the stethoscope under the umbilicus may produce a splash-
ing sound. If the skin of the abdomen is scratched lightly, beginning from the
periphery and moving toward the umbilicus, a change in the quality of the aus-
cultated sound occurs at the border of the ascitic fluid.

III. THE ANORECTAL EXAMINATION is an important part of the general physical exam-
ination. It may be uncomfortable for the patient and cause embarrassment, but the
discomfort and embarrassment can be ameliorated greatly by an understanding,
unhurried, gentle attitude on the part of the physician.
A. Patient position. Most physicians ask the patient to lie on the left side with knees
and hips flexed. Others prefer the patient to stand, leaning over an examining
table. The former position is preferred and recommended.
B. Perianal area. The buttocks should be spread apart to allow inspection of the
anus and perianal skin. Protuberant hemorrhoids, anal tags, fissures, or abscesses
may be seen. The perianal area is palpated with a gloved finger. Tenderness and
masses are noted.
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Chapter 3: Examination of the Patient 9

C. Insertion. Before inserting a gloved index finger into the rectum, the physician
lubricates both the finger and the anus well. Sometimes it is helpful to ask the
patient to strain down gently, as if having a bowel movement. This maneuver
relaxes the anal sphincter and allows easier penetration of the finger. The longitu-
dinal axis of the anal canal is aimed roughly to the umbilicus; thus, the examiner
gently presses the finger into the anal canal in the direction of the umbilicus. The
rectum is found to turn posteriorly and open out into the hollow area formed by
the sacrum and coccyx.
D. Examination of the rectum should be gentle. A tender anal canal may result from
proctitis, inflamed or thrombosed hemorrhoids, a stricture, or a fissure. Note the
tone of the anal sphincter. Palpate the lateral, posterior, and anterior walls of the
rectum, noting any tenderness or nodularity. Anteriorly, in male patients, the
prostate is felt as a bilobed structure with a median sulcus. What are the size,
shape, and consistency? Is the prostate tender? Are there any nodules? In female
patients, the cervix (and sometimes a vaginal tampon) can be felt as a firm mass
through the anterior rectal wall.
Although most of the rectal wall that is accessible to the examining finger is
below the peritoneal reflection, most examiners can reach above the peritoneal
reflection anteriorly. Thus, tenderness of peritoneal inflammation or metastatic
nodules may be identified.
E. Stool. On withdrawal of the finger, note the color and consistency of the stool.
Is there any mucus or gross blood? If not, test the stool for occult blood.

Selected Reading
Bates B. The abdomen. In: Bates B, Hoeckelman RA, eds. Guide to Physical Examination
and History Taking. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:339–368.
79466_CH04.QXD 1/2/08 12:00 PM Page 10

PSYCHOLOGICAL AND EMOTIONAL

4 ASPECTS OF GASTROENTEROLOGIC
DISORDERS

T he mind and body are not independent but parallel. “For there are not two
processes, and there are not two entities; there is but one process . . . one entity, seen now
inwardly as mind, now outwardly as matter, but in reality an inextricable mixture and
unity of both. Mind and body do not act upon each other, because they are not other, they
are one.” Baruch Spinoza, as paraphrased by Will Durant, The Story of Philosophy, 1954.
An extensive review of the psychological and emotional aspects of digestive disor-
ders is beyond the scope of this book. Because psychological factors do play an important
role in gastroenterologic disorders, however, and patients certainly react emotionally to
illness, we need to consider at least briefly the psychosomatic component of gastrointesti-
nal disease.
Physicians tend to think of disorders as affecting organ systems and resulting in
observable pathophysiologic changes. Most astute physicians and health care providers,
however, either consciously or intuitively understand that a disorder is a complex interac-
tion among pathophysiologic processes, the patient’s emotional makeup, and the patient’s
perception of the disorder. A large number of factors may affect this interaction, including
the patient’s age, sex, socioeconomic and marital status, other “medical” disorders, emo-
tional stress, family history, and society’s view of the disorder. Additional complicating
influences are the physician’s view of the patient, the patient’s disorders, and the options of
managing the patient’s problems.
There is more than a mere relation between the “psyche” and the “soma.” Although
there is a tendency to separate the psychological and somatic aspects of a disease, attach
labels, and categorize, disorders exist as inseparable entities of psyche and soma. In
some patients the psychological and emotional aspects seem to predominate and exert
profound somatic effects, such as in bulimia, anorexia nervosa, and irritable bowel
syndrome. Also, it is believed that exacerbations of some chronic diseases, such as Crohn’s
disease and ulcerative colitis, may be triggered by emotional factors, yet have their patho-
genesis firmly rooted in the soma. In addition, in these chronic, sometimes devastating ill-
nesses, it is easy to understand that patients also experience psychological trauma due to
their illness.
Finally, no matter what the illness is and no matter how trivial it appears, illness
of any degree represents a threat to the patient’s integrity. An illness is never purely
somatic—there is always a person who must experience the illness.

Selected Readings
DiBaise JK. Psychotherapy and functional dyspepsias: Brain-gut interactions. Am J
Gastroenterol. 2001;96:278.
Drossman DA, et al. Psychosocial factors in the care of patients with GI disorders.
In: Yamada T, ed. Textbook of Gastroenterology. Philadelphia: Lippincott–Raven
Publishers; 2003:636–654.
Drossman DA. The physician-patient relationship. In: Corazziari E, ed. Approach to the
Patient with Chronic Gastrointestinal Disorders. Milan: Messaggi; 1999:133–139.
Longstreth GF, et al. Severe irritable bowel and functional abdominal pain syndromes:
Managing the patient and health care costs. Clin Gastroenterol Hepatol. 2005;3:
397–400.
Talley NJ, et al. Practice Parameters Committee of the American College of Gastroenterology.
Guidelines for the management of dyspepsia. Am J Gastroenterol. 2005;100:2324–2337.

10
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Diagnostic and Therapeutic II

Procedures
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ENDOSCOPY 5

S ince Hirschowitz and colleagues described the first flexible fiberoptic endoscopes,
the technical explosion in fiberoptic endoscopy has produced instruments that are durable,
safe, relatively comfortable, and capable of visualizing the gastrointestinal tract with great
diagnostic accuracy.
The typical modern fiberoptic endoscope is a highly sophisticated instrument
(Fig. 5-1). The shaft is 8 to 12 mm in diameter. The fiberoptic bundles pass through the
shaft to transmit light to the tip and the image to the endoscopist. In the handle of the
endoscope are controls for maneuvering the tip and buttons to regulate irrigation water, air
insufflation, and suction for removing air, secretions, and blood. An instrument channel
allows the passage of biopsy forceps, small brushes for obtaining cytology samples, snares
for removing polyps and foreign bodies, and devices to control bleeding.
The adaptation of endoscopes to video monitoring systems has been developed using
computer chip technology and now is in routine use in all endoscopy suites. The endo-
scopist conducts the examination by viewing the video screen, not by looking directly
through the fiberoptic system of the endoscope. The video screen also allows a variable
number of people, including the patient if desired, to observe what the primary endoscopist
is seeing, and the procedure can be videotaped for clinical and educational purposes.

Figure 5-1. Flexible fiberoptic endoscope for examination of the upper gastrointestinal tract. An
open biopsy forceps is shown at the tip of the endoscope, having been passed through the biopsy
channel in the handle. This instrument also has been adapted to perform endoscopic ultrasonogra-
phy by the addition of an ultrasound transducer at the tip. (GF-UE160-AL5, reprinted with Courtesy
of Olympus®.)

13
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14 Part II: Diagnostic and Therapeutic Procedures

Figure 5-2. Endoscopic ultrasound system. The flexible endoscope on the right of the table has
ultrasound transducers at the tip of imaging and fiberoptics that allow direct visualization of lesions.
(SSD-ALPHA5, reprinted with Courtesy of Olympus®.)

During routine upper gastrointestinal endoscopy, the entire esophagus, stomach, and
proximal duodenum are examined. Several therapeutic endoscopic techniques have been
developed that allow endoscopists to treat bleeding lesions (see Chapter 14) and relieve
esophageal obstruction caused by benign or malignant processes. Endoscopic placement of
gastric feeding tubes—percutaneous endoscopic gastrostomy (PEG)—has largely replaced
surgical gastrostomy.
A variation of upper gastrointestinal endoscopy, endoscopic retrograde cholan-
giopancreatography (ERCP), combines endoscopic and radiologic techniques to visualize
the biliary and pancreatic ductal systems. ERCP methods also have been used therapeuti-
cally to perform sphincterotomy of the sphincter of Oddi, to remove common bile duct
stones, and to place stents that bypass obstructing lesions.
During examination of the lower gastrointestinal tract by colonoscopy, a skilled
endoscopist can reach the cecum in more than 95% of patients, and in many instances the
terminal ileum can also be visualized. The major therapeutic capability of colonoscopy,
popularized in the United States in the mid-1980s by President Ronald Reagan’s experience
with a cancerous polyp, is polypectomy, usually by electrocautery.
An important development in endoscopy is endoscopic ultrasonography (EUS)
(Figs. 5-1–5-3). High-frequency, high-resolution ultrasound transducers that are built into
the tip of the endoscope can be passed to sites that are relatively close to the target organ.
Applications include evaluation of lesions involving the esophagus, mediastinum, stomach,
duodenum, pancreas, colon, and rectum. EUS compares favorably with computerized
tomography in tumor staging and determination of lymph node involvement. Indications
for EUS are summarized in Table 5-1. Also, lymph nodes in the thorax and abdomen may
be biopsied and pancreatic pseudocysts may be drained using EUS.
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Chapter 5: Endoscopy 15

Figure 5-3. Endosonographic view of a villous adenoma (arrows). The tumor is invading the sec-
ond hyperechoic layer ( T2 lesion).
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16 Part II: Diagnostic and Therapeutic Procedures

TABLE 5-1 Indications for Endoscopic Ultrasonography

Esophagus Esophageal cancer diagnosis and staging

Anastomotic recurrence of cancer
Submucosal tumors
Mediastinal lymphadenopathy
Esophageal varices
Stomach Adenocarcinoma and lymphoma diagnosis and staging
Submucosal tumors
Gastric polyps
Anastomotic recurrence of cancer
Gastric ulcer healing
Gastric varices
Duodenum Submucosal tumors
Ampullary carcinoma diagnosis and staging
Pancreas and biliary system Pancreatic and biliary cancer diagnosis and staging
Chronic pancreatitis and pseudocysts
Biliary stone disease
Endocrine tumors
Colon and rectum Rectal and colon cancer diagnosis and staging
Villous adenoma
Recurrent colorectal cancer
Benign perianal and perirectal disease

I. UPPER GASTROINTESTINAL ENDOSCOPY

A. Indications. Several conditions in which upper gastrointestinal endoscopy,
also known as esophagogastroduodenoscopy (EGD), may be useful in making
a diagnosis are listed Table 5-2. Opinions differ among physicians as to whether
and when EGD should be performed for a given condition. For example, some
physicians order an upper gastrointestinal x-ray series initially in the evaluation
of a patient who has dyspeptic complaints. Other physicians treat a patient with
dyspepsia empirically with antacids or some other acid-reducing medication
without obtaining a diagnostic study, unless the patient is elderly or has evidence
of gastrointestinal bleeding, weight loss, or vomiting, suggesting gastric outlet
obstruction. An EGD might subsequently be arranged if the patient does not
respond to treatment in a reasonable time or develops bleeding, weight loss, or
vomiting.
B. Contraindications. EGD should not be performed if a perforated viscus is suspected
or if the patient is in shock, is combative, or is unwilling to cooperate (Table 5-3).
C. Preparation of the patient. Elective EGD should be performed after the patient
has fasted for 6 or more hours to ensure an empty stomach. However, this rule
does not apply to emergent situations such as in acute upper gastrointestinal bleed-
ing or with foreign body impaction of the esophagus or when food and clots may
fill the esophagus and/or stomach and these may need to be immediately removed
endoscopically.
In conscious patients, a topical anesthetic may be applied to the pharynx to
numb the gag reflex. Conscious sedation (i.e., intravenous midazolam [Versed],
meperidine [Demerol], or fentanyl) often is administered as a sedative. Tolerances
for midazolam vary widely. Older and severely ill patients may become sedated or
develop respiratory depression even at low doses. Thus, a test dose of 1 to 2 mg
initially is advisable. Most patients require 2 to 5 mg to achieve adequate relax-
ation. The doses of meperidine and fentanyl also vary depending on the patient.
Most patients require 12.5 to 100 mg. Because patients are likely to feel sleepy for
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Chapter 5: Endoscopy 17

Partial List of Conditions in Which Endoscopy May Be

TABLE 5-2
Useful in Making a Diagnosis

Sigmoidoscopy
Condition EGD ERCP or colonoscopy

Dysphagia X
Caustic or foreign body ingestion X
Dyspepsia X
Persistent nausea and vomiting X
Need to obtain small-intestinal biopsy X
Acute or chronic gastrointestinal bleeding X X
Inflammatory bowel disease X X
Chronic abdominal pain X X X
Suspected polyp or cancer X X X
Obstructive jaundice X
Change in bowel habits X
Diarrhea longer than 1 wk X
EGD, esophagogastroduodenoscopy (upper gastrointestinal endoscopy); ERCP, endoscopic retro-
grade cholangiopancreatography.

TABLE 5-3 Contraindications for Endoscopy

Perforated viscus suspected

Patient in shock
Combative or uncooperative patient
Severe inflammatory bowel disease or toxic megacolon (colonoscopy)

an hour or more after the procedure, it is required that the outpatients arrange for
transportation home with an accompanying person after EGD.
Deep sedation, using Propofol IV, may be used in selective patients with med-
ical or psychiatric comorbid conditions.
D. Therapeutic EGD. A number of methods have been used to treat actively bleeding
lesions of the upper gastrointestinal tract. Endoscopic band ligation and/or
injection sclerotherapy of esophageal varices is the most widely practiced thera-
peutic endoscopic method for the treatment of bleeding esophageal varices.
Sclerotherapy or banding reduces both mortality and the frequency of rebleeding
from esophageal varices. Other methods of controlling actively bleeding ulcers and
erosions include local injection of the bleeding site with epinephrine or hyper-
tonic saline, electrocoagulation, and/or placement of clips on the bleeding
lesion and laser photocoagulation. These methods are described in more detail
in Chapter 14. Endoscopic treatment of gastroesophageal reflux disease (GERD)
will be discussed in Chapter 20.
E. Complications of upper gastrointestinal endoscopy. Endoscopy of the gas-
trointestinal tract is generally regarded as safe, but adverse events do occur (Table 5-4).
Major complications of EGD—perforation of the esophagus or stomach, genera-
tion of new hemorrhage, pulmonary aspiration, serious cardiac arrhythmia—occur
with a frequency of from 1 in 1,000 to 1 in 3,000 instances. Mortality ranges from
1 in 3,000 to 1 in 16,000 endoscopies. Sedation and inhibition of the gag reflex
contribute to the risk of aspiration of blood, secretions, and regurgitated gastric
contents.
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18 Part II: Diagnostic and Therapeutic Procedures

TABLE 5-4 Complications of Endoscopy

Complication EGD Colonoscopy

Perforation of viscus X X
Bleeding X X
Cardiac arrhythmias X X
Medication reactions X X
Vasovagal reactions X X
Pulmonary aspiration X
Cardiac failure (due to overhydration during X
bowel preparation)
Hypotension (due to underhydration during X
bowel preparation)
EGD, esophagogastroduodenoscopy.

Complications related to the topical anesthetic to the pharynx or to the intra-

venous midazolam are unusual. Fatalities reported from these agents usually are
associated with large doses that have caused cardiac or central nervous system
effects. Allergic reactions are rare. The major complication of intravenous midazo-
lam and narcotics is respiratory depression. These drugs also may cause transient
hypotension and obtundation. Patients at the highest risk are the elderly and those
with advanced cardiac, pulmonary, hepatic, or central nervous system disease.
The frequency of complications associated with EGD can be reduced by antic-
ipating problems and taking measures to prevent them. A complete history and
physical examination are important, with special attention to history of allergic
drug reactions, presence of bleeding disorders, and cardiac, pulmonary, renal,
hepatic, or central nervous system disease. If a sedative is used, a small test dose
should be administered initially, particularly in elderly or severely ill patients.
The endoscopy assistant must suction secretions and regurgitated material when
necessary from the pharynx. Nasal oxygen should be used to treat hypoxia, and
resuscitation equipment should be available in the event of adverse cardiopul-
monary reactions. After the procedure is completed, the patient should be observed
for an adequate amount of time and for subsequent development of complications.

II. ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY (ERCP)

A. Evaluation of pancreatic and biliary ductal systems. ERCP usually is
performed as an elective procedure to evaluate the pancreatic and biliary ductal
systems. The endoscopic principles for ERCP are similar to those for routine EGD
except that ERCP usually takes longer, patients are likely to be sedated more heav-
ily, and a side-viewing instrument is used. The endoscope is passed into the second
part of the duodenum, and the ampulla of Vater is visualized. The endoscopist
then passes a catheter through the endoscope and maneuvers it into the orifice of
the ampulla. Additional adjustment of the cannula allows it to enter the pancreatic
duct or the common bile duct. After injection of radiocontrast material through the
cannula, x-ray films are taken to identify the configuration of the biliary and
pancreatic ductal systems (Fig. 5-4).
B. Sphincterotomy and calculus retrieval. In patients who have calculi in the com-
mon duct, endoscopic section (sphincterotomy) of the sphincter of Oddi allows
access to the common duct bile and retrieval of the stones. The sphincterotomy
device consists of a wire electrode within a plastic cannula. After the cannula has
been inserted into the sphincter, the wire is elevated and the sphincter is cut by elec-
trocautery. The stone passes spontaneously or may be crushed and/or extracted
using a basketlike device that is passed through the endoscope.
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Chapter 5: Endoscopy 19

Figure 5-4. Endoscopic retrograde cholangiopancreatogram showing the fiberoptic endoscope in

the second portion of the duodenum, a normal common bile duct (single arrow), and a normal pan-
creatic duct (double arrow). (Courtesy of John F. Erkkinen, M.D.; from Eastwood GL. Gastrointestinal
endoscopy. In: Rippe JM, et al [eds.]. Intensive Care Medicine. Boston: Little, Brown; 1985:67–73.
Reprinted with permission.)

C. Stent insertion. Other techniques may also be used with ERCP to insert short
tubes, or stents, through obstructing lesions, such as pancreatic or biliary cancer or
strictures of the distal bile or pancreatic duct. The stents allow relief of the obstruc-
tion and may be used as definitive therapy in patients with inoperable disease or
temporarily until the obstructive lesion is treated by irradiation or surgery.

III. CAPSULE ENDOSCOPY OR PILLCAM ENDOSCOPY. An orally ingested 2.3-by-0.8-cm

capsule containing a computer chip has become a popular tool to visualize the gastroin-
testinal tract, especially the small intestine, by taking numerous pictures as it travels down
the intestinal tract with peristalsis. The electronically recorded pictures are later reviewed
by an experienced gastroenterologist or technician. This technique is most helpful in diag-
nosis of lesions in the small intestine that may be the cause of occult GI bleeding.

IV. LOWER GASTROINTESTINAL ENDOSCOPY

A. Indications and contraindications. Indications for endoscopic examination of
the lower gastrointestinal tract include active or occult bleeding, inflammatory
bowel disease, suspicion of a polyp or cancer, unexplained abdominal pain, and
change in bowel habits (Table 5-2). The contraindications are the same as those for
EGD with the additional contraindications of active diverticulitis, severe inflam-
matory bowel disease and suspected toxic megacolon (Table 5-3).
B. Proctosigmoidoscopy
1. Instruments. The flexible fiberoptic sigmoidoscope, which measures up to
65 cm in length, is a short colonoscope and has replaced the 25-cm rigid sig-
moidoscope for routine examinations. The flexible instruments are capable of
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20 Part II: Diagnostic and Therapeutic Procedures

reaching the descending colon and may even reach the splenic flexure. Further-
more, patients tolerate flexible sigmoidoscopy better than rigid sigmoidoscopy.
2. Preparation of the patient. Tap water or commercial enemas (i.e., Fleet
enemas) usually are sufficient preparation for either rigid or flexible sigmoi-
doscopy. However, the sigmoidoscopic examination should be performed
without enema preparation when patients have watery diarrhea or suspected
colitis. Most patients do not require conscious sedation. For flexible or rigid sig-
moidoscopy, the patients are usually placed in the left lateral decubitus position.
3. Biopsy and polypectomy. As in EGD, the mucosa and lesions within the rec-
tum or colon can be biopsied through the rigid or flexible instrument. Most
endoscopists avoid biopsy immediately before barium enema because of the
small chance of introducing air and barium into the mucosal defect caused by
biopsy. Also, although polyps can be removed through either the rigid or flexi-
ble sigmoidoscope by standard electrocautery methods, this should not be done
unless the entire colon has been properly prepared to avoid the possibility of
gas ignition or explosion.
C. Colonoscopy
1. Instruments. Modern fiberoptic colonoscopes are similar in design to upper gas-
trointestinal endoscopes but are longer, ranging in length from 120 to 180 cm.
2. Preparation of the patient. Standard bowel preparation for colonoscopy is
similar to the preparation for barium enema x-ray examination: 1 to 2 days of
clear-liquid diet followed by a strong cathartic.
Liquid preparations include a balanced electrolyte polyethylene glycol
(PEG) lavage, exemplified by GoLYTELY or Colyte. Typically about 3.8 L of the
solution must be consumed either orally or through a nasogastric tube over
about 2 to 4 hours. The lavage solution is consumed 6 to 12 hours before the
procedure. The advantages of this preparation are that it is quick, gentle and
very effective in cleansing the bowel. The PEG solution also appears to be safe
to use in anyone in whom it is safe to perform colonoscopy. One drawback is
the difficulty some patients have in consuming a gallon of fluid over a few
hours. Alternatively, 2 L of HalfLytely may be given after 4 Dulcolax tablets.
MoviPrep, a newer, better tasting 2-L PEG solution, may be used instead with-
out additional need for Dulcolax tablets.
An easier colon preparation is Fleet phospho-soda, 1.5 oz. in 4 oz. of
water taken twice, 6–8 hours apart, along with a clear-liquid diet. However, the
safety of this preparation has been questioned due to the possibility of causing
dehydration and renal insufficiency in some patients.
Colon preparation has recently been further simplified by giving patients
28 to 32 tablets containing Fleet phospho-soda (Visicol or Osmo-prep) 6 to 12
hours prior to the procedure, along with a clear-liquid diet.
Because colonoscopy generally takes longer and is more uncomfortable
than flexible sigmoidoscopy, it is customary to administer intravenous medica-
tions such as midazolam ( Versed ), meperidine hydrochloride ( Demerol), or
fentanyl to promote relaxation and diminish discomfort. In some cases, intra-
venous Propofol may be administered by an anesthesiologist for deeper sedation.
3. Biopsy and therapeutic procedures. Colonoscopic biopsies of the mucosa
and colonic lesions are obtained routinely for diagnostic purposes. The most
common colonoscopic therapeutic procedure is polypectomy. Pedunculated
polyps may be removed with a wire snare, which is maneuvered to encircle the
stalk. After the snare is tightened, the stalk is severed directly or by passing
electric current through the snare. Sessile polyps may be removed by polypec-
tomy in several pieces or biopsied through the colonoscope. Raising a bleb with
normal saline injection under a sessile polyp allows more complete removal as
routine polypectomy. Some sessile lesions may require surgical removal.
Bleeding lesions of the colon may be treated during colonoscopy in the same
manner as upper gastrointestinal lesions.
D. Complications of colonoscopy. The two major complications of colonoscopy,
perforation and hemorrhage, occur in less than 1% of instances. These are more
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Chapter 5: Endoscopy 21

likely to occur during colonoscopy with polypectomy. Other complications of

colonoscopy include drug reactions, hypotension, vasovagal reactions, cardiac
arrhythmias, and congestive heart failure complicated by over- or underhydration
of a susceptive patient after bowel preparation (Table 5-4).
Colonoscopic complications are minimized by following most of the rules
indicated for EGD. In addition, the colonoscope or sigmoidoscope should be
advanced with care and overdistention of the colon should be avoided. Finally, the
fluid and electrolyte status of elderly patients and those with renal and cardiac dis-
ease should be tended to during preparation of the bowel.

V. SMALL-INTESTINAL BIOPSY. Small-intestinal mucosal biopsy is a valuable aid in the

evaluation of patients with malabsorption or diarrhea caused by small-intestinal
mucosal disorders. In patients with Whipple’s disease, for example, the biopsy is of
critical importance in establishing the diagnosis. In celiac sprue, the diagnosis can be
confirmed by a histologic appearance that is consistent with sprue. Also, the response
to treatment with a gluten-free diet may be confirmed by subsequent biopsies.
Although the diagnosis of giardiasis often can be made by examination of diarrheal
stool samples, the small-bowel biopsy coupled with examination of luminal secretions
remains the most accurate method of identifying Giardia organisms.
A. Indications and contraindications. Small-bowel mucosal biopsy is indicated in the
evaluation of patients who may have a small-bowel mucosal disorder. These patients
typically have diarrhea and malabsorption and some may present only with gas and
bloating and abdominal pain. In the evaluation of a patient with suspected mucosal
disease, the timing of a small-bowel biopsy is a matter of clinical judgment. Generally,
the initial evaluation of such patients includes routine blood studies and several exam-
inations of the stool for ova and parasites, bacterial pathogens, leukocytes, occult
blood, and qualitative stool fat. Barium contrast studies of the upper and lower gas-
trointestinal tract, a xylose absorption test, and a quantitative stool-fat examination
also may have been performed. The evaluation of specific disorders of the small intes-
tine and the role of mucosal biopsy are discussed in subsequent chapters.
The contraindications to small-intestinal biopsy are few. History and clotting
studies should indicate that there is no bleeding tendency, and the patient should
be able to cooperate during the study.
B. Methods of obtaining small-intestinal mucosal biopsies
1. Endoscopic biopsies. Endoscopic biopsy of the small-intestinal mucosa has
become preferred over the use of suction biopsy tubes. Endoscopic biopsies
obtained with large (8-mm) forceps have been shown to be as diagnostically
accurate as suction biopsies, provided they are taken from the distal duode-
num, which avoids the variations in mucosal architecture that occur normally
in the proximal duodenum, and they are oriented carefully. Also, endoscopic
biopsies generally are technically easier to perform than biopsies using a suc-
tion tube.
2. Suction biopsies. The Rubin tube, also known as the Quinton tube, is one
of several biopsy tubes available for obtaining suction mucosal biopsies of the
small intestine. The tube is radiopaque and can be maneuvered under fluoro-
scopic control to the distal duodenum or proximal jejunum. The design of the
biopsy capsule provides full-thickness mucosal samples without transecting
larger blood vessels of the submucosa. These biopsies are easily oriented, which
facilitates accurate histologic interpretation. This technique is no longer used
except for research purposes.
C. Interpretation of the biopsy
1. Orientation. Proper orientation of the mucosal biopsy is crucial to obtain the
maximal information from the biopsy. Proper orientation means that the plane
of sectioning is along the axis of the villi and crypts (Fig. 5-5). Thus, villous
height, crypt depth, and configuration of surface epithelial cells can be evalu-
ated accurately.
2. Evaluating the biopsy. In evaluating small-bowel mucosal biopsies, one should
look at two aspects: the mucosal architecture and the cellular elements.
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22 Part II: Diagnostic and Therapeutic Procedures

Figure 5-5. Photomicrograph of a normal human small-intestinal biopsy taken from the distal
duodenum. (From Eastwood GL. Core Textbook of Gastroenterology. Philadelphia: Lippincott
Williams & Wilkins; 1984:105. Reprinted with permission.)

a. Architecture. The normal villus-crypt ratio in well-oriented biopsies from the

proximal jejunum of North Americans and Europeans is 4:1 or 5:1 (Fig. 5-4).
Villi should be tall and narrow. A variable amount of submucosa may be
present.
b. Cellular elements. Look carefully at the three elements of the mucosa: the
epithelium, the lamina propria, and the muscularis mucosae.
i. The epithelium is a single layer of columnar cells that lines the crypts
and covers the villi. The four major epithelial cell types are columnar
absorptive cells, mucous (goblet) cells, Paneth’s cells, and enteroendocrine
cells. Columnar absorptive cells are the most numerous. They are covered
by a glycoprotein filamentous matrix, the so-called fuzzy coat seen by
light microscopy, which is the site of many digestive enzymes such as the
disaccharidases. Mucous cells, interspersed between the absorptive cells,
contain abundant mucous granules, which in the aggregate have the
appearance of a goblet and thus commonly are called goblet cells.
Paneth’s cells are found predominantly at the base of the crypts. Their
function is unknown, but they appear to be secretory cells because of the
eosinophilic granules they contain. Finally, the epithelium contains a wide
variety of enteroendocrine cells that secrete numerous hormones, includ-
ing gastrin, secretin, cholecystokinin, vasoactive intestinal peptide,
somatostatin, and neurotensin.
ii. Within the lamina propria, which forms the cores of the villi and lies
between the crypts, are connective tissue elements, wisps of smooth
muscle, lymphatics, blood vessels, macrophages, plasma cells, and
lymphocytes. Normally neutrophils are not found in the lamina propria.
Because increases in the number of cells within the lamina propria are
79466_CH05.QXD 1/2/08 12:01 PM Page 23

Chapter 5: Endoscopy 23

characteristic of several mucosal diseases, some experience is necessary in

viewing normal biopsies to determine whether the cellularity is increased
or not.
iii. The muscularis mucosae is a thin layer of muscle lying beneath the
bases of the crypts and below which lays the submucosa.
3. Diagnostic value. The information that is obtained from the biopsy may make
or refute a specific diagnosis or may be nonspecific but consistent with one or
more diagnoses. The diagnostic value of small-intestinal biopsy can be catego-
rized as follows (modified from Trier).
a. Disorders in which the biopsy is invariably of diagnostic value include the
following:
i. Celiac sprue (the biopsy is nonspecific, but coupled with a clinical
response to the elimination of dietary gluten, it is diagnostic)
ii. Whipple’s disease
iii. Abetalipoproteinemia
iv. Agammaglobulinemia
v. Mycobacterium avium-intracellulare
b. Disorders in which the biopsy may or may not be of specific value. (In these
disorders, the lesion may be distributed in an irregular fashion; thus an
abnormal biopsy may make a specific diagnosis, but a normal biopsy does
not rule out the disorder.)
i. Intestinal lymphoma
ii. Intestinal lymphangiectasia
iii. Eosinophilic enteritis
iv. Systemic mastocytosis
v. Parasitic infestation
vi. Amyloidosis
vii. Hypogammaglobulinemia
viii. Dysgammaglobulinemia
c. Disorders in which the biopsy may be abnormal but not diagnostic. (In these
disorders, the biopsy findings are nonspecific.)
i. Tropical sprue
ii. Folate deficiency
iii. Vitamin B12 deficiency
iv. Irradiation enteritis
v. Zollinger-Ellison syndrome
vi. Small-bowel bacterial overgrowth
vii. Drug-induced lesion
viii. Malnutrition
ix. Graft-versus-host reaction
x. Viral enteritis
d. Disorders in which the biopsy is normal.
i. Pancreatic exocrine insufficiency
ii. Cirrhosis
iii. Postgastrectomy malabsorption (without intestinal disease)
iv. Primary lactase deficiency
v. Irritable bowel syndrome

VI. ENDOSCOPIC OR TRANSGASTRIC SURGERY is a new and very promising trend in

abdominal and pelvic surgery. This technique allows surgical intervention without
laparotomy or laparoscopy, thus much less invasive to the patient. The scope of this
new technique is vast and rapidly expanding.

Selected Readings
Avunduk C, et al. Endoscopic sonography of the duodenum, pancreas, liver and the biliary
tract: Findings in benign and malignant conditions. Appl Radiol. 1997;25–33.
Avunduk C, et al. Endoscopic Sonography of the stomach: Findings in benign and
malignant lesions. Amer J Roentgenol. 1994;163:591–595.
79466_CH05.QXD 1/2/08 12:01 PM Page 24

24 Part II: Diagnostic and Therapeutic Procedures

Chak A, et al. Sedationless upper endoscopy. Rev Gastroenterol Disord. Winter

2006;6:13–21.
Cotton PB, et al. Comparison of virtual colonoscopy and colonoscopy in the detection of
polyps/masses. Gastrointest Endosc. 2005;55:AB98.
Eliakim R, et al. A prospective study of the diagnostic accuracy of PillCam ESO esophageal
capsule endoscopy versus conventional upper endoscopy in patients with chronic
gastroesophageal reflux diseases. J Clin Gastroenterol. 2005;39:572–578.
Gress F. Endoscopic ultrasound-guided plexus neurolysis. Gasterol. Hepatol. 2007;3(4):
279–281.
Johnson JF, et al. A randomized, multicenter study comparing the safety and efficiacy of
sodium phosphate tablets with 26 polyethylene glycol solution plus bisacodyl tablets
for colon cleansing. Am J Gastroenterol. 2007;102:2238–2246.
Kim OH, et al. CT colonography for the detection of advanced neoplasia. N Eng J Med.
2007;357:1403–1412.
Kovalak M, et al. Endoscopic screening for varices in cirrhotic patients: Data from a
national endoscopic data base. Gastrointest Endosc. 2007;65:82–88.
Lamade W, et al. Transgastric surgery in the abdomen: The dawn of a new era?
Gastrointest Endosc. 2005;62:293–296.
Leighton JA, et al. Capsule endoscopy: a meta-analysis for use with obscure
gastrointestinal bleeding and Crohn’s disease. Gastrointest Endosc Clin N Am.
2006;16:229–250.
Liu R. The future of surgical endoscopy. Endoscopy. 2005;37:38–41.
Paulsen SR, et al. CT enterography as a diagnstic tool in evaluating small bowel disorders:
review of clinical experience with over 700 cases. Radiographics. 2006;26:641–57;
discussion 657–62.
Ramirez FC, et al. Feasibility and safety of string, wireless capsule endoscopy in the
diagnosis of Barrett’s esophagus. Gastrointest Endosc. 2005;63:742–746.
Rex DK. Review article: moderate sedation for endoscopy; sedation regimens for non-
anaesthesiologists. Aliment Pharmacol Ther. 2006;24:163–171.
Rockey DC, et al. Analysis of air contrast barium enema, computed tomographic
colonography, and colonoscopy: Prospective comparison. Lancet. 2005;365:305–311.
Rossi A, et al. ASGE guidelines for the appropriate use of upper endoscopy: association
with endoscopic findings. Gastrointest Endosc. 2002;56:714–719.
Sequeiros EV, et al. The role of endoscopic ultrasonography in the diagnosis, staging and
management of pancreatic disease states. Curr Gastroenterol Rep. 2000;2:125.
Sotoudehmanesh R, et al. Role of endoscopic ultrasonography in prevention of unnecessary
endoscopic retrograde cholangiopancreatography: a prospective study of 150 patients.
J Ultrasound Med. 2007;26:455–60.
Sunada K, et al. Clinical outcomes of enteroscopy using the double-balloon method for
strictures of the small intestine. World J Gastroenterol. 2005;11:1087–1089.
79466_CH06.QXD 1/2/08 12:02 PM Page 25

LAPAROSCOPY AND LAPAROSCOPIC 6

SURGERY

E xamination of the abdominal cavity and its organs by means of a laparoscope has
been available for nearly a century. Until recently, laparoscopy was largely a diagnostic
procedure; the instruments were used primarily to visualize and biopsy abdominal organs
and other structures, although some treatment was possible in the form of aspiration of
cysts and abscesses, lysis of adhesions, ligation of the fallopian tubes, and ablation of
endometriosis or cancer by laser. In recent years, rapid and dramatic developments in
operative laparoscopy have made laparoscopic cholecystectomy and appendectomy com-
monplace; other, more complicated operative procedures, such as partial gastrectomy and
partial colectomy, have been described using laparoscopic methods.

I. LAPAROSCOPY
A. Indications. The reliance on diagnostic laparoscopy varies from one medical center
to another. In some centers, laparoscopy is used routinely in evaluation of the
abdominal conditions discussed in this chapter, whereas in other centers it is used
rarely. This variability in the use of diagnostic laparoscopy can be attributed to the
advances in computed tomography (CT) and other imaging techniques of the past
decade, which have provided alternatives to laparoscopy that are either less invasive
or more readily available. In hospitals and medical centers where diagnostic
laparoscopy is available, it is usually performed for the following indications.
1. Biopsy of the liver. This procedure may be done to evaluate a diffuse condi-
tion of the liver, such as cirrhosis or an infiltrating disease, or to biopsy a focal
defect of the liver that has been identified by CT or ultrasound examination.
During laparoscopy, the appearance of the liver also can be assessed; for exam-
ple, the collateral vessels of portal hypertension or nodularity of cirrhosis or
neoplasm may be evident.
2. Determination of cause of ascites. When the cause of ascites is unknown,
laparoscopic examination of the abdominal organs, the omentum, and the peri-
toneum may provide an answer. The most common causes are disseminated
cancer, usually ovarian, and cirrhosis.
3. Staging of Hodgkin’s disease and non-Hodgkin’s lymphoma.
4. Evaluation of patients with fever of unknown origin.
5. Evaluation of patients with chronic or intermittent abdominal pain.
Diagnoses include abdominal adhesions, Crohn’s disease, appendicitis, and
endometriosis.
B. Contraindications include a perforated viscus, abdominal wall infections, diffuse
peritonitis, and clinically significant coagulopathy. Chronic lung disease and con-
gestive heart failure are relative contraindications. If laparoscopy is necessary in
those instances, sedation should be minimized and the patient should have pulse
oximetry and cardiovascular monitoring. Tense ascites interferes with adequate
visualization and should be treated before attempting laparoscopy.
C. Technique. Most diagnostic laparoscopic procedures are performed electively in
patients who have fasted and are under sedation and local anesthesia. A small skin
incision is made, usually above and to the left of the umbilicus, avoiding surgical
scars and abdominal masses. Nitrous oxide or carbon dioxide gas is introduced by
a needle to distend the abdomen, and a trocar and cannula are passed through the
incision into the peritoneal cavity. The laparoscope is inserted into the abdomen

25
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26 Part II: Diagnostic and Therapeutic Procedures

and, by maneuvering the instrument or positioning the patient, most of the abdom-
inal contents can be examined. Tissue samples can be obtained by brushes, nee-
dles, or forceps that are passed through the laparoscope. At the conclusion of the
examination, the gas is withdrawn, the instrument is removed, and the small inci-
sion is closed with sutures or clips.
D. Therapeutic laparoscopy. Some conditions can be treated by the laparoscopic
techniques described. These treatments include aspiration of cysts and abscesses,
lysis of adhesions, ligation of the fallopian tubes, and ablation of endometriosis or
cancer by laser. However, the most dramatic advances in therapeutic laparoscopy
have been in the area of operative laparoscopy, described in the following sections.

II. LAPAROSCOPIC SURGERY. The recent advances in laparoscopic surgery have been
the result of two important contemporary factors: (a) the remarkable continuing devel-
opments in fiberoptic technology and (b) the strong economic incentives to minimize
the duration of hospitalization and use of inpatient hospital facilities.
A. Laparoscopic cholecystectomy
1. Indications and contraindications for laparoscopic cholecystectomy are the
same as for traditional operative cholecystectomy (Table 6-1).
2. Technique. The equipment and instruments required to perform laparoscopic
surgery are reviewed in the selected reading by Gadacz and associates. Briefly,
the equipment includes a powerful (xenon) light source, a carbon dioxide insuf-
flator, a high-resolution end-viewing camera with a high-resolution video
monitor, an irrigation device that instills fluid at a high flow rate, and an elec-
trocautery or laser device. A variety of instruments also are needed, including a
Veress needle for insufflation, cannulas with trocars, endoscopes, retractors,
graspers, dissectors, a clip applier, irrigation and aspiration catheters, coagula-
tors, and catheters for performing cholangiography.
Laparoscopic cholangiography and cholecystectomy can be performed
under general or epidural anesthesia. Preoperative antibiotics generally are used
at the discretion of the operator but are indicated in patients with recent chole-
cystitis, heart valve prostheses, and other medical risk factors. Before beginning

Indications and Contraindications for

TABLE 6-1 Laparoscopic Cholecystectomy

Indications Cholelithiasis and biliary colic

Symptomatic gallbladder polyps
Resolved gallstone pancreatitis
Symptomatic chronic cholecystitis
Relative contraindications Acute cholecystitis
Previous upper abdominal operation
Minor bleeding disorder
Common duct stones
Absolute contraindications Acute cholangitis
Severe acute cholecystitis
Acute pancreatitis
Peritonitis
Portal hypertension
Pregnancy
Serious bleeding disorder
Morbid obesity
From Gadacz TR, et al. Laparoscopic cholecystectomy. Surg Clin North Am. 1990;70:1249. Reprinted
with permission.
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Chapter 6: Laparoscopy and Laparoscopic Surgery 27

the procedure, the urinary bladder is drained with a Foley catheter, and the
stomach is decompressed with a nasogastric tube. Two video monitors, one on
each side of the operating table, allow all members of the operating team a view
of the procedure. Several cannulas are inserted through the abdominal wall for
insufflation and surgical manipulation; the surgical laparoscope is inserted just
above the umbilicus. A detailed description of the laparoscopic cholecystectomy
procedure is provided by Gadacz, et al.
3. Results. As experience with laparoscopic cholecystectomy increases, the proce-
dure is recognized to be safe and effective. Operative time is less than 2 hours.
Most patients are able to leave the hospital in fewer than 2 days and are able to
return to work more quickly than after standard operative cholecystectomy.
Thus, there are economic savings both in decreased hospital costs and in
reduced time away from work. Fewer than 5% of patients require standard
laparotomy because of a complication of the laparoscopic procedure, such as
bleeding, bile duct leak, bile duct injury, or technical difficulties.
B. Other laparoscopic operations. Laparoscopic appendectomy and inguinal
herniorrhaphy are performed routinely, and other more extensive abdominal oper-
ations, such as gastrectomy, colectomy, esophageal fundoplication, gastric stapling,
and intestinal bypass are also performed, but require more advanced expertise.
Laparoscopic techniques are also used to treat pulmonary and pericardial lesions
in the chest. Intraluminal laparoscopic surgery via the lumena of the GI tract, e.g.,
stomach, is the promising new era of surgical management of intraabdominal
diseases.

Selected Readings
Anvari M, et al. Five-year comprehensive outcomes evaluation in 181 patients after
laparoscopic Nissen fundoplication. J Am Coll Surg. 2003;196:51–57.
Doherty GM, et al. Current Surgical Diagnosis and Treatment. 12th ed. New York, NY:
McGraw-Hill; 2006:662–667.
Giger U, et al. Laparoscopic cholecystectomy in acute cholecystitis: indication, technique,
risk and outcome. Langenbecks Arch Surg. 2005;390:373–80.
Gurusamy KS, et al. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis.
Cochrane Database Syst Rev. 2006;4:CD005440.
Iannelli A, et al. Therapeutic laparoscopy for blunt abdominal trauma with bowel injuries.
J Laparoendosc Adv Surg Tech A. 2003;13:189–191.
Kalloo An, et al. Flexible transgastric peritoneoscopy: A novel approach to diagnostic and
therapeutic interventions in the peritoneal cavity. Gastrointest Endosc. 2004;60:
114–117.
Kamoz T, Granderath F, Pontner R. Laparoscopic antireflux surgery. Surg Endosc.
2003;17:880–885.
Madan A. Laparoscopic bariatric surgery. US Gastroenterol Rev. 2000;1:29–33.
McQuay N, et al. Laparoscopy in the evaluation of penetrating thoracoabdominal trauma.
Am Surg. 2003;69:788–791.
Polanivelu C, et al. Laparoscopic lateral pancreaticojejunostomy: A new remedy for an old
ailment. Surg Endosc. 2006;20:458–461.
Roggin KK, et al. What is the long term safety and efficacy of laparoscopic resection for
gastric and gastrointestinal stroma tumors? Nat Clin Pract Gastroenterol Hepatol.
2007;4:76–78.
Soper NJ, et al. Laparoscopic general surgery. N Engl J Med. 1994;330:409.
Tom J, et al. Laparoscopic surgery for Chron’s disease: a meta analysis. Dis Colon Rectum.
2007;50(5):576–585.
79466_CH07.QXD 1/2/08 12:04 PM Page 28

7 PERCUTANEOUS LIVER BIOPSY

M icroscopic or biochemical examination of liver tissue often provides the

definitive diagnosis and leads to effective management of liver and systemic disorders. The
liver tissue typically is obtained by percutaneous needle biopsy, either in hospitalized
patients or in selected outpatients. The outpatient procedure is reserved for patients who
do not have severe liver disease, a clotting disorder, or some other serious illness. Facilities
must be available to observe the patients for 3 to 5 hours after the biopsy.
In recent years, percutaneous needle aspiration or biopsy of liver lesions under ultra-
sound or computed tomography (CT) scan guidance has obviated the need for obtaining a
traditional “blind” liver biopsy in most patients. Automatic liver biopsy needles are used
to obtain thin core biopsies of liver lesions or for sampling of the liver. Liver biopsy may
also be obtained during laparoscopy.

I. INDICATIONS AND CONTRAINDICATIONS. The major indication for performing a

liver biopsy is to clarify the nature of suspected liver disease. In some instances, liver
biopsy is performed to determine the effect of treatment of known liver disease or to
document the appearance of the liver before initiating therapy (usually for a nonhep-
atic disorder) with a potentially hepatotoxic drug.
Contraindications to percutaneous liver biopsy are listed in Table 7-1; some
may not be absolute. For example, patients with severe liver disease commonly have
clotting disorders. If a liver biopsy is believed to be necessary under those circum-
stances, patients can be prepared with infusions of fresh-frozen plasma and platelets.
In patients with severe liver disease and coagulopathy, a transjugular venous liver
biopsy may be the safer and the only alternative technique for obtaining a liver biopsy.

II. TRADITIONAL METHOD OF PERFORMING THE BIOPSY

A. Prebiopsy care. Patients should fast for at least 6 hours before the biopsy and,
because they will have to remain in bed for several hours after the biopsy, they
should be encouraged to void. Hemoglobin count, hematocrit, white blood cell
count, platelet count, prothrombin time, and partial thromboplastin time should
be determined several days before the biopsy.
B. Choice of biopsy site. The patient lies in a supine position near the right edge of
the bed with the right hand under the head and the head turned toward the left.
If the liver is not enlarged, an intercostal site is chosen that is within the area of

TABLE 7-1 Contraindications to Percutaneous Liver Biopsy

Uncooperative patient
Bleeding disorder
Infection in skin, pleura, right lower lung, or peritoneum overlying the liver
Suspected liver abscess or vascular lesion
Difficulty in determining liver location, as with ascites
Severe extrahepatic obstruction

28
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Chapter 7: Percutaneous Liver Biopsy 29

maximal liver dullness between the anterior and midaxillary lines. If the biopsy is
being done under ultrasound, the site is chosen by the radiologist.
C. Preparation of the biopsy site. Using sterile gloves, cleanse the biopsy site and
surrounding skin with acetone-alcohol and iodine solutions, and arrange sterile
drapes around the biopsy site. Infiltrate the skin with local anesthetic. The anes-
thetic also may be infiltrated beneath the skin to the liver capsule, with care taken
to keep the needle at the upper edge of the rib to avoid the artery that runs below
the rib.
D. Taking the biopsy. Make a 4-mm skin incision at the biopsy site with a no. 11
knife blade. Fill a 20-mL syringe with about 10 mL of sterile saline (avoid bacte-
riostatic preparations if you plan to culture the biopsy tissue), and attach the
biopsy needle. (Generally, this is a Menghini or modified Menghini needle.) Insert
the biopsy needle through the skin incision parallel to the surface of the bed, aim-
ing toward the xiphoid. Advance the needle into the intercostal muscles, and flush
the needle with 0.2 to 0.5 mL of saline.
Have the patient hold the breath at full expiration for the intercostal
approach; at full inspiration for the subcostal approach. It is wise to have the
patient practice this maneuver several times before the biopsy is obtained. Apply
constant suction on the syringe and, in a rapid, smooth motion, advance and

Figure 7-1. Photomicrograph of the liver, showing the central area of a classic lobule with a cen-
tral vein. (From Snell RS. Clinical and Functional Histology for Medical Students. Boston: Little,
Brown; 1984:479. Reprinted with permission.)
79466_CH07.QXD 1/2/08 12:04 PM Page 30

30 Part II: Diagnostic and Therapeutic Procedures

Figure 7-2. Photomicrograph of the liver, showing the peripheral area of a classic lobule with a
branch of the hepatic artery (A), a branch of the portal vein (V), and a small bile duct (D). (From Snell
RS. Clinical and Functional Histology for Medical Students. Boston: Little, Brown; 1984:479.
Reprinted with permission.)

withdraw the needle 4 to 5 cm. The total duration of this movement should not
exceed 1 second. Ask the patient to resume breathing. A second biopsy through
the same incision at a slightly different angle will increase the diagnostic yield in
patients with suspected cancer of the liver. The biopsy may be expelled from the
needle temporarily into saline or directly into 10% formalin. Apply an adhesive
bandage over the biopsy wound.
Percutaneous liver biopsies may also be obtained using automatic biopsy
needles. These automatic needle “guns” are usually preferred by radiologists and

TABLE 7-2 Complications of Percutaneous Liver Biopsy

Hemorrhage Hemothorax
Bile peritonitis Penetration of abdominal viscera
Pneumothorax
79466_CH07.QXD 1/2/08 12:04 PM Page 31

Chapter 7: Percutaneous Liver Biopsy 31

gastroenterologists obtaining liver biopsies under ultrasound or CT-scan guidance.

The steps of the procedure are similar to the traditional biopsy technique.
E. Postbiopsy care. The patient should remain in bed for 4 to 6 hours. Some physi-
cians advise patients to lie on their right side for the first 2 hours. After that time
they may sit up in bed. Blood pressure and pulse should be checked frequently.
One method is to obtain vital signs every 30 minutes for 2 hours, and every hour
for 3 hours. Outpatients should be asked to communicate with a nurse or physi-
cian the next day. Patients may be allowed to drink clear liquids shortly after
biopsy but should avoid solid food for several hours until it is clear that no seri-
ous complication has developed.

III. COMPLICATIONS FROM LIVER BIOPSY are infrequent but may be dramatic
(Table 7-2 on page 30). Deaths have been reported in about 1 in 1,000 biopsies and
major complications in about 3 in 1,000. Complications can be minimized by using a
needle 1.2 mm in diameter or less, avoiding biopsy in high-risk patients, and adhering
strictly to protocol for obtaining the biopsy.

IV. INTERPRETATION OF THE BIOPSY. The spectrum of pathologic changes is broad

and cannot be discussed here at length. However, the approach to interpretation of a
liver biopsy is similar to that for interpretation of a small-bowel mucosal biopsy: The
observer looks for changes in cellularity and architecture.
The liver lobule contains a central (hepatic) vein surrounded by sinusoids (Fig.
7-1 on page 29). At the periphery of the lobule are several portal triads (Fig. 7-2 on
page 30). Within the triads are bile ducts, portal vein, hepatic artery, connective tis-
sue, and round cells. Pathologic changes may include expansion of the portal triads
with inflammatory cells, accumulation of inflammatory cells and fibrosis between
the triads (bridging), destruction of hepatic parenchymal cells, dropout of parenchy-
mal cells, and distortion of the lobular architecture by inflammation and fibrosis.

Selected Readings
Bravo AA, et al. Liver biopsy. N Engl J Med. 2001;344:495.
Brunt EM, et al. Liver biopsy interpretation for the gastroenterologist. Curr Gastroenterol
Rep. 2000;2:27.
Cjaza AJ, et al. Optimizing diagnosis from the medical liver biopsy. Clin Gastroenterol
Hepatol. 2007;5(8):898–907.
Edmison JM, et al. How good is transjugular liver biopsy for the histologic evaluation of
liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:306–308.
LefKowitch JH. Hepatobiliary pathology. Curr Opin. Gastroenterol. 2006;22:198–208.
Schiaro TD, et al. Importance of specimen size in accurate needle biopsy evaluation of
patients with chronic hepatitis. C. Clin Gastroenterol Hepatol. 2005;3:930–935.
Sherman KE, et al. Liver biopsy in cirrhotic patients. AJ Gastroenterol. 2007;102:789–793.
79466_CH08.QXD 1/2/08 12:04 PM Page 32

8 MANOMETRIC STUDIES

T he gastrointestinal tract is a long, muscular tube in which the coordinated relaxation

and contraction of smooth muscle, expressed as peristalsis, actions of various sphincters,
and accommodation to the bulk of ingested food and secretions play an important role in
normal digestive function. Increasingly, abnormalities in gastrointestinal neuromuscular
activity are recognized as being responsible for clinical disorders.

I. ESOPHAGEAL MOTILITY STUDIES. The main purpose of the esophagus is to trans-

port food and secretions to the stomach. It performs this task through a series of coor-
dinated events that begins when a solid or liquid bolus is propelled to the back of the
mouth and into the pharynx by the tongue. Thereafter, the process of swallowing
becomes “automatic.” First, the upper esophageal sphincter (UES), which constricts
the esophagus just below the pharynx, relaxes as the pharynx contracts and the bolus
passes into the upper esophagus. Next, a primary peristaltic contraction propels the
bolus down the esophagus but usually is insufficient to carry the bolus the entire
length of the esophagus.
Secondary peristaltic contractions are initiated when the esophagus is distended
by the bolus, and these contractions finish moving the bolus to the stomach. Finally,
as the bolus reaches the mid-to-lower esophagus, the lower esophageal sphincter (LES)
relaxes to allow the bolus to pass into the stomach. The tonic contraction of the LES,
which relaxes during swallowing, normally presents an effective barrier against reflux
of gastric contents into the esophagus.
A. Indications and contraindications. Esophageal manometry is useful in diagnos-
ing disorders of motility or a dysfunctional UES or LES (Table 8-1). Typically,
patients with motility disorders complain of dysphagia, usually to both liquids and
solids (see Chapter 20). Esophageal manometry also is useful in the evaluation of
patients with noncardiac chest pain (see Chapter 21). Some of these patients can be
shown to have esophageal spasm or a related motility disorder. Finally, esophageal
manometry sometimes is used in the evaluation of patients with severe gastroe-
sophageal reflux to document impairment of peristalsis or LES function (see
Chapter 19). Patients with reflux symptoms usually do not require esophageal
manometry, however.
Esophageal manometry should not be performed in a patient who is unwill-
ing to cooperate in swallowing the tube or in a patient with severe mechanical
esophageal obstruction.
B. Method of performing esophageal manometry. Patients are asked to fast for 6
to 8 hours before the study. Usually no sedatives or topical anesthetics are given
because these medications may interfere with esophageal motor function. If the
patient is unable to swallow the tube, however, a small amount of topical anes-
thetic may be applied to the pharynx or, if the tube is to be passed through the
nose, to the internal nares. Patients may return to their usual activities and diet
after completion of the study.
The typical manometry tube has three recording probes (either perfused
catheter tips or solid-state transducers) arranged linearly toward the distal end of
the tube (Fig. 8-1). The most proximal probe is 5 cm above the middle probe, which
in turn is 5 cm above the distal probe. The tube is passed through either the nose or
the mouth as the patient swallows and is positioned initially so that all three probes

32
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Chapter 8: Manometric Studies 33

TABLE 8-1
Disorders in Which Esophageal Manometry May Be
Useful in Making a Diagnosis

Upper esophageal sphincter (UES) dysfunction

Poor coordination between pharyngeal contraction and UES relaxation
Hypercontracting UES
Motility disorder of the esophageal body
Hypo- or aperistalsis
Hyperperistalsis—“nutcracker” esophagus
Esophageal spasm or variant
Nonspecific motility disorder
Lower esophageal sphincter (LES) dysfunction
Hypercontracting LES that fails to relax completely on swallowing (achalasia)
Weak or absent LES

are within the stomach. As the tube is withdrawn gradually, each probe passes
through the LES. As the probes move up into the body of the esophagus, peristaltic
contractions are recorded sequentially as they pass down the esophagus, first with
the proximal probe, next the middle probe, and last the distal one. When the mid-
dle or distal probe lies within the LES, the relation between esophageal peristaltic
contractions and sphincteric relaxation can be observed (Fig. 8-2). Similarly, when
the upper probe lies in the pharynx and the middle probe is within the UES, the
relation between pharyngeal contractions and UES relaxation can be recorded.

Figure 8-1. The esophageal manometry tube is coiled on a chart recorder. Note the three small
transducers arranged serially, 5 cm apart, beginning 5 cm from the distal end of the tube.
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34 Part II: Diagnostic and Therapeutic Procedures

Figure 8-2. Manometric appearance of normal peristaltic contractions and relaxation of the lower
esophageal sphincter (LES). The upper, middle, and lower probes are each separated by 5 cm.
(From Eastwood GL. Core Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins;
1984:27. Reprinted with permission.)

C. Interpretation of manometric findings and the role manometry plays in the diag-
nosis of specific esophageal disorders are discussed in subsequent chapters. It is
sufficient at this point to say that some conditions may have quite specific diag-
nostic findings by manometry, such as the hypercontracting LES of achalasia,
which fails to relax completely on swallowing, whereas other conditions, such as
esophageal motor disorders causing chest pain, may be accompanied by nonspe-
cific or normal findings at the time of manometry; in these instances, manometry
is of little diagnostic value.

II. PH TESTING. Measurement of esophageal pH by means of an intraesophageal pH

electrode, which usually is positioned 5 cm above the LES, can be determined at the
time of the esophageal motility study or over a 24-hour period.
A. pH measurements after standard motility studies include testing for acid clear-
ance in which 15 mL of 0.1 N HCl is infused into the lower esophagus. The patient
is asked to dry-swallow every 30 seconds until the pH returns to the baseline value,
which should occur within 15 swallows. Ineffective clearance of acid occurs in con-
ditions that cause abnormal esophageal peristalsis, such as scleroderma, achalasia,
and other esophageal motility disorders, and in conditions that decrease the volume
of salivary secretion, such as scleroderma and the sicca complex.
Measurements of lower esophageal pH also can be diagnostic of gastro-
esophageal reflux. Esophageal pH is documented with the patient supine, prone,
and on the left and right sides; when relaxed and after performing the Valsalva
maneuver; and after assuming the knee–chest position. After the patient is posi-
tioned, 300 mL of 0.1 N HCl is instilled into the stomach and pH measurements
are repeated in all the positions. A drop in pH below 4.0 in any position in the
basal state or in two positions after acid instillation is regarded as indicative of
abnormal reflux of acid. Measurement of esophageal peristalsis during acid infu-
sion (see Chapter 22, Section II.B.2.d, Bernstein test) may document a motility dis-
order that is responsible for the chest pain.
B. Ambulatory pH measurements. Several ambulatory pH monitoring systems are
available that allow continuous measurement of esophageal pH for up to 24 hours
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Chapter 8: Manometric Studies 35

under conditions that patients experience during their everyday lives. This proce-
dure is particularly useful in documenting nocturnal reflux symptoms or symptoms
that occur in relation to other experiences or activities. Patients are asked to keep
a record of their symptoms. The best correlations with symptoms appear to be
with total time that pH is less than 4.0 and with the number of times intra-
esophageal pH below 4.0 exceeds 5 minutes.
C. A wireless pH monitoring (Bravo) device has been developed to improve patient
comfort and increase pH test sensitivity. It is placed endoscopically in the distal esoph-
agus and allows for prolonged monitoring (48 hours vs. 24 hours). The extended
monitoring period helps to better understand GER physiology by studying the day-
to-day and moment-by-moment variability of GER. It may also be used to assess the
effectiveness of acid suppressive therapy without the need for repeat testing.
D. Multichannel intraluminal impedance (MII) is a new technique for the evalua-
tion of gastroesophageal reflux disease (GERD) and for esophageal motor function
testing. It can assess esophageal bolus transit similar to barium swallow and the
proximal extent of the reflux event. MII can be used in combination with
esophageal manometry for concurrent assessment of esophageal motor function
and motility.
E. High-resolution manometry (HRM) is solid-state manometry with 36 circumferen-
tial sensors spaced at 1-cm intervals (4.2-mm outer diameter). Each of these sensors
contains 12 circumferentially isolated sensors that detect pressure over a 2.5-mm
length of the esophagus.
The procedure involves placing the catheter in the esophagus and recording
10 swallows, then withdrawing. Pressures detected by each sensor are averaged to
obtain a mean pressure measurement for each sensor, making each of the 36 sen-
sors a circumferential pressure detector. The data obtained are then processed by a
computerized program (ManoScan) to create high-resolution plots or conventual
line traces.
HRM is simpler, faster, and more precise. It provides a complete observation
of the esophageal motor function from the pharynx to the LES without the need
for catheter reposition and gives accurate sphincter pressures and assessment of
peristaltic performance.

III. ANORECTAL MANOMETRY may be useful in the evaluation of patients with consti-
pation or stool incontinence. Measurements include documentation of baseline pres-
sures of the internal and external anal sphincters and the relaxation response of the
internal sphincter to distention of the rectal vault by stool or an inflated balloon. For
example, in Hirschsprung’s disease, the internal anal sphincter does not relax ade-
quately in response to rectal distention.
Incontinence from internal anal sphincteric dysfunction can be caused by hemor-
rhoid surgery or neuromuscular disorders affecting smooth muscle. The internal anal
sphincter is under autonomic control, whereas the external anal sphincter is under vol-
untary control. External sphincteric dysfunction may be related to sacral nerve disease
and disorders of striated muscle.

IV. MANOMETRY OF THE STOMACH, SMALL INTESTINE, AND COLON is available in

some institutions as a research tool to investigate clinical disorders of gut motility;
however, the technique is not generally available. Conditions that may affect motility
of the stomach and intestines include diabetes, autonomic neuropathy, vagotomy,
connective tissue disorders, muscular disorders, and infiltrative disorders (e.g.,
amyloidosis).

Selected Readings
Adler DG, et al. Primary esophageal motility disorders. Mayo Clin Proc. 2001;76:195.
Fox M, et al. High-resolution manometry predicts the success of oesophageal bolus
transport and identifies clinically important abnormalities not detected by conventional
manometry. Neurogastroenterol Motil. 2004;16(5):533–542.
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36 Part II: Diagnostic and Therapeutic Procedures

Kahrilas PJ. Esophageal motility disorders: current concepts of pathogenesis and treatment.
Can J Gastroenterol. 2000;14:221–230.
Pandolfino J. Esophageal monitoring devices. US Gastroenterol Rev. 2007;(1)23–27.
Pandolfino J, et al. AGA medical position statement? Clinical use of esophageal manometry.
Gastroenterology. 2005;128:107–108.
Park W, et al. Esophageal impedance recording: Clinical utility and limitations. Curr
Gastroenterol Rep. 2005;7:182–189.
79466_CH09.QXD 1/2/08 12:05 PM Page 37

IMAGING STUDIES 9

I t is an unusual patient who, complaining of some digestive disorder, does not have a
radiologic or ultrasound study sometime during the course of the evaluation. In the pre-
endoscopic era, many gastroenterologists performed plain and barium-contrast radiographic
studies in their own offices. Now the term gastroenterologist is virtually synonymous with
endoscopist, and roentgenographic studies are performed (appropriately) by a radiologist.
Nevertheless, all physicians who see patients with digestive complaints should be familiar
with the radiologic, ultrasound, and radionuclide studies that are commonly available.

I. RADIOLOGIC AND ULTRASOUND STUDIES

A. Plain chest and abdominal films
1. Chest films. Sometimes physicians overlook the value of the plain chest and
abdominal x-ray films. A widened mediastinum or an air-fluid level in the medi-
astinum may indicate an obstructed and dilated esophagus. Pleural effusions
may accompany ascites or acute pancreatitis. Patients with pneumonia occa-
sionally seek treatment for abdominal pain. In patients with suspected perfora-
tion of an abdominal viscus, the upright chest film is superior to abdominal
films, which usually do not visualize the domes of the diaphragm, in identify-
ing free air under the diaphragm.
2. Abdominal films. A complete set of plain abdominal films includes a supine
view and an upright view. Sometimes the supine film is called the “flat plate,”
a holdover from the early days of radiology when photographic plates instead
of films were used. Another term in the medical jargon is KUB, an acronym for
kidney, ureter, and bladder, although much more than these three organs are
shown.
a. Both the soft tissue densities and the bony structures should be exam-
ined carefully on the abdominal plain film. Accumulations of calcium may
be seen in the pancreas or other organs, signifying chronic inflammatory
disease. In atherosclerotic disease, calcium may outline the aorta and other
vessels; an aortic aneurysm may first be suspected by careful examination
of the abdominal plain film.
b. The distribution of air in the bowel is of importance. Normally air is seen
at various locations in the colon and rectum, and a small amount of air may
appear in the small bowel. The air provides a natural contrast medium,
which sometimes outlines mass lesions. Submucosal collections of blood,
fluid, or inflammatory cells, which also protrude into the bowel lumen,
may give a clue to the presence of a disorder such as ischemic bowel disease,
lymphoma, or Crohn’s disease. Dilatation of the small or large intestine
occurs in bowel obstruction or ileus. A markedly dilated, ahaustral trans-
verse colon is typical of toxic megacolon. Absence of bowel loops in a por-
tion of the abdomen may indicate a large mass; the mass may distort the
appearance of otherwise normal loops of bowel. The upright film (or a lat-
eral decubitus film, if the patient cannot stand) may show air-fluid levels
signifying obstruction or ileus. Rarely, an air-filled loop of bowel in the
scrotum is seen, indicating a large inguinal hernia.
B. The barium swallow most often is ordered to evaluate disorders of swallowing,
although it also may be useful in delineating size and configuration of the heart

37
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38 Part II: Diagnostic and Therapeutic Procedures

chambers and other mediastinal structures. Occasionally an esophageal–tracheal

fistula can be identified in this manner.
Views of the esophagus usually are included in a standard upper gastroin-
testinal (GI) series, but typically are limited to the middle and lower esophagus.
During a barium swallow, the radiologist also obtains views of the pharynx and
upper esophagus and looks carefully under fluoroscopy at the process of swallow-
ing from initiation to completion. This step is facilitated by the use of a videotape
of the swallowing action after the patient swallows both a liquid bolus and a solid
bolus (e.g., barium-impregnated bread). This procedure allows the swallowing
process to be scrutinized closely, using slow motion or stop-action when necessary.
C. Upper gastrointestinal series. The standard upper GI series includes views of
the middle and lower esophagus, stomach, duodenum, and proximal jejunum.
Although the upper GI series has less diagnostic accuracy than endoscopy, it plays
a major role in the evaluation of digestive complaints. Gastrointestinal radiologists
sometimes have the patient also swallow substances that release carbon dioxide,
providing air contrast and improving diagnostic accuracy.
D. Small-bowel series
1. The small-bowel series usually is a continuation of the upper GI series. In most
radiology departments, however, the small-bowel series must be ordered specifi-
cally. After the patient has swallowed the requisite amount of barium to complete
the upper GI series, delayed films are taken for up to 1 to 2 hours to visualize the
loops of small bowel. Particular care is taken to identify the terminal ileum because
of the predilection of Crohn’s disease or lymphoma for that site. Sometimes, a
reasonable view of the cecum and ascending colon can be obtained.
2. An important variant of the small-bowel series is the small-bowel enema, or
enteroclysis. In a small-bowel enema, the patient does not swallow barium;
instead, a small tube is passed by mouth into the duodenum. Barium is injected
through the tube to opacify the small intestine. This procedure has the advan-
tage of allowing a smaller quantity of barium to be used, thereby not obscur-
ing the loops of small intestine and thus focusing more specifically on that
organ. Injection of air after the barium allows air-contrast films to be made and
improves the diagnostic accuracy.
E. Barium enema
1. The standard barium enema is performed after the colon has been evacuated
with a conventional cathartic and enema preparation (usually preceded by a
clear-liquid diet for 1 to 2 days) or a balanced electrolyte lavage solution. These
bowel preparations are similar to those used before colonoscopy (see Chapter 5).
Barium is subsequently allowed to flow by gravity into the colon through the
rectum. Instillation of air improves the contrast. In most patients, barium
refluxes into the terminal ileum.
2. In general, a sigmoidoscopy should precede a barium enema. The two studies
are complementary.
3. In some clinical situations, a limited barium enema is performed without a
bowel preparation. This would be the case when a bowel obstruction is sus-
pected and a limited view of the colon is necessary. If the patient has an intus-
susception of the colon or a sigmoid volvulus, a carefully performed barium
enema without preparation may correct these disorders. Finally, in the evalua-
tion of suspected Hirschsprung’s disease (aganglionosis of the rectum or distal
colon), a limited barium enema in an unprepared colon has a greater likelihood
of providing diagnostic information than examination of a colon empty of stool.
F. Gallbladder and biliary studies. A number of studies have been used to evaluate
the gallbladder and biliary ductal system. These include oral cholecystography,
intravenous cholangiography, percutaneous cholangiography, endoscopic retro-
grade cholangiopancreatography (ERCP) (see Chapter 5), computed tomography
(CT) scan (see Section I.H), ultrasonography (see Section I.J), and the HIDA scan
(see Section II.B).
1. The oral cholecystogram has been available for decades to evaluate gallblad-
der function and diagnose gallstones. However, abdominal ultrasonography
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Chapter 9: Imaging Studies 39

(see Section I.J) has largely replaced oral cholecystography for identifying gall-
stones, although the two studies may be complementary in some patients.
During oral cholecystography, radiopaque iodine-containing dye is ingested in
the form of tablets, absorbed from the intestine, extracted by the liver, and
excreted into bile, where it is concentrated in the gallbladder, which is then visu-
alized radiographically. Usually the biliary ductal system is not opacified. Failure
to see the gallbladder after a double-dose oral cholecystogram is a strong indi-
cator of gallbladder disease. However, failure to opacify the gallbladder may
also result from poor absorption of the dye, intrinsic liver disease, or a serum
bilirubin level in excess of 3 mg/dL. Today, this technique is rarely observed.
2. During intravenous cholangiography, a radiopaque dye is injected by vein
and, like the oral dye, is extracted by the liver and excreted in the bile.
However, unlike oral cholecystography, both the major bile ducts and the gall-
bladder opacify during intravenous cholangiography. The study is severely lim-
ited when the serum bilirubin level is greater than 3 mg/dL. Furthermore, the
extent and clarity of opacification of the bile duct system is considerably less
than that achieved with ERCP or percutaneous cholangiography. Thus, cur-
rently there is little clinical use for intravenous cholangiography.
3. Percutaneous transhepatic cholangiography (PTC) is performed by passing
a long, thin needle (about 23-gauge) through the skin into the liver. As the nee-
dle is withdrawn slowly, small amounts of radiopaque dye are injected until the
bile duct is visualized. Sufficient dye is subsequently injected to opacify the bil-
iary system. This test is more than 90% successful in patients with extrahepatic
obstruction and dilated bile ducts. It is only 50% to 60% successful in patients
with normal-size ducts. The ready availability of ERCP has decreased the fre-
quency with which PTC is used. Often, when one of the two studies is unsuc-
cessful, the other is successful in visualizing an obstructed biliary system.
G. Intravenous pyelogram. Although an intravenous pyelogram (IVP) is most com-
monly used in the evaluation of the genitourinary tract, it can be of help as an
adjunct to the evaluation of some GI and other abdominal disorders. Retro-
peritoneal tumors and the inflammatory masses that occur in Crohn’s disease may
cause deviation or obstruction of the ureters. Similarly, masses may impinge on the
bladder. Rarely, an enterovesical fistula can be visualized by IVP or by retrograde
cystography.
H. Computed tomography scan. The nearly universal availability of computed
tomography (CT) scanning has altered the diagnostic approach to many patients
with abdominal complaints. The CT scan often aids in making a diagnosis quickly,
abbreviating the diagnostic evaluation, shortening hospital stay, and avoiding
unnecessary studies. For example, lesions in locations and in organs within the
abdomen that formerly was obscure, such as the retroperitoneum and pancreas,
now often can be readily visualized by CT scanning.
The CT scan has largely replaced the radionuclide liver–spleen scan for
detecting masses of the liver because of its ability to resolve smaller lesions. In
addition, the CT scan shows the size and shape of the liver more accurately and
provides information about other abdominal organs that is not available by
liver–spleen scan. Furthermore, the relative densities of mass lesions can be esti-
mated by CT scanning to determine whether such lesions are solid or cystic.
The diagnostic accuracy of the CT scan is enhanced by the injection of con-
trast material intravenously to visualize the vascular system and by oral adminis-
tration of contrast to delineate the GI tract.
The ability to obtain tissue samples by fine-needle aspiration has enhanced
the diagnostic capability of CT scanning even more. In this manner, malignant
lesions, abscesses, and benign cysts can be histologically and cytologically con-
firmed. Abscesses and infected cysts also can be drained and treated by CT-guided
placement of drainage catheters.
CT colography has been developed for examination of the colon, especially
for the detection of colonic polyps and neoplasms. The patients are prepared sim-
ilarly as for colonoscopy. At the time of the scanning, air is introduced into the
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40 Part II: Diagnostic and Therapeutic Procedures

colon, and the colon is kept distended during the CT scanning. Patients do not
receive any sedation and thus the procedure may be painful. Polyps larger than
7 to 10 mm are seen with acceptable accuracy; however, smaller polyps may be
missed by this technique. If a polyp is found, patients are then referred for
colonoscopy.
CT enterography is a newer technique gaining popularity used in the exam-
ination of the small intestine, especially for the detection of Crohn’s disease and its
complications. It is able to detect early lesions (i.e., aphthous ulcers, bowel wall
inflammation and thickening, and early stricture and fistula formation).
I. Angiography. Selective arteriography of the celiac axis, superior mesenteric artery,
inferior mesenteric artery, or their branches may reveal vascular tumors, document
the effects of other tumors on abdominal organs, and identify sites of bleeding. For
extravasation of dye to be seen at a bleeding site, it is estimated that the rate of
bleeding must be at least 0.5 to 1.0 mL per minute.
Selective arteriography can also be therapeutic. Autologous clots or
vasopressin can be injected into appropriate vessels. In patients with cancer,
chemotherapeutic drugs can be delivered directly to the tumor. This procedure has
been used particularly in the treatment of malignant lesions in the liver.
J. Ultrasonography, which depends on the reflection of sound waves to create an
image rather than ionizing radiation, can visualize the organs of the abdomen with
high accuracy by means of modern high-resolution equipment. Ultrasonography
usually is less expensive than CT and is better in detecting some conditions, such as
gallstones. Stomach or bowel gas may obscure visualization of the organs beneath.
The inclusion of an ultrasound device in the tip of an endoscope (endo-
scopic ultrasound) has produced a sophisticated technique for the examination
of the GI tract and adjacent structures (see Chapter 5).

II. RADIONUCLIDE STUDIES

A. Liver–spleen scan. When a radiolabeled colloid, such as technetium Tc 99m sul-
fur colloid, is injected intravenously, it is taken up by the reticuloendothelial sys-
tem of the liver, spleen, and bone marrow. Normally little, if any, radioactivity is
detected over the bone marrow of healthy people because most of the colloid has
been “filtered out” through the liver and spleen during the initial passages of the
circulation. In moderate-to-advanced liver disease, however, when blood flow
through the liver is impaired, relatively more colloid is removed in the spleen and
bone marrow. This factor accounts for the increase in density of the spleen and bone
marrow that is typical of chronic parenchymal liver disease. The liver–spleen scan
can give some estimate of the size and shape of the liver and spleen and can indi-
cate whether mass lesions are present. However, the lower limits of resolution for
a mass lesion by radionuclide scan is about 1 to 2 cm, which is poorer than the
resolving power of a CT scan—about 0.5 cm.
Indications for liver–spleen scanning have decreased since abdominal CT
scanning has come into common usage. The liver–spleen scan is still a reasonable
method of estimating the sizes of the liver and the spleen and of determining
whether enough chronic liver disease is present to cause a shift of the colloid to the
spleen and bone marrow.
B. HIDA scan. Technetium Tc 99m—dimethylphenylcarbamylmethyl-iminodiacetic
acid (HIDA) is extracted from blood by liver parenchymal cells and excreted into
bile. In this respect, it resembles oral cholecystography dye; because of nuclear
imaging methods, however, the bile ducts and gallbladder can be visualized when
the serum bilirubin is as high as 7 mg/dL. Other, related radiolabeled agents (i.e.,
PIPP DD) may be used when the serum bilirubin is as high as 10 to 15 mg/dL.
The major use of the HIDA scan is in making the diagnosis of acute chole-
cystitis. In acute cholecystitis, the gallbladder fails to visualize. HIDA scanning
also has been used to implicate common bile duct obstruction when the radiolabel
visualizes the bile ducts, but fails to enter the duodenum. However, other methods
(e.g., ultrasonography, CT scanning, ERCP) are much more accurate in identifying
obstruction of the common duct. Finally, HIDA scanning in conjunction with the
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Chapter 9: Imaging Studies 41

injection of cholecystokinin (CCK) has been used as a test of gallbladder function.

Some patients with an abdominal pain syndrome, but without gallstones, are
believed to suffer from a dysfunctional gallbladder. Injection of CCK normally
causes prompt but painless contraction of the gallbladder and relaxation of the
sphincter of Oddi. If CCK injection during HIDA scanning causes reproduction of
the patient’s clinical pain and a delay in gallbladder emptying, it may indicate that
gallbladder dysfunction is responsible for the patient’s symptoms.
C. Scans using radiolabeled blood cells and blood components
1. Scanning the abdomen after labeling the red blood cells or other blood com-
ponents may indicate the site of bleeding. The rate of blood loss required to be
evident by the scan is estimated to be about 0.1 mL per minute, much less than
that required for selective arteriography. The value of the radionuclide scan for
bleeding is not in making a specific diagnosis, but in suggesting the site of bleed-
ing so that other diagnostic studies can be performed.
2. Labeling the patient’s white blood cells has been used in some institutions to
help locate abscesses or tissue necrosis. A variant, the intravenous injection of
gallium 67, can identify abscesses because of the binding of gallium to white
cells. These techniques have been less useful since high-resolution CT scans
have been available.

III. MAGNETIC RESONANCE IMAGING (MRI) depends on the magnetic properties of

atomic nuclei with unpaired nucleons (i.e., an odd number of protons or neutrons).
For clinical purposes, MRI uses the hydrogen atom, or proton. Protons are compo-
nents of water and, to some extent, fats, which are found in all tissues. The MRI image
is generated by placing the protons (tissue) in a strong magnetic field, which aligns
them parallel to the magnetic field, and energizing the protons by the application of an
appropriate radiowave. As the energized protons return to the former equilibrium
state, they emit radiowaves, which are recorded as the MRI signal. The strength of the
signal depends on the density of the protons, the blood flow, and the relaxation time
constants, which are known as T1 and T2. The advantages of MRI over CT are that
MRI uses no ionizing radiation, there is no bone artifact, and contrast agents usually
are not required. The sensitivity and specificity of MRI is enhanced by intravenous
contrast injection.
MRI has been used most extensively in neurodiagnostics, and its application to
gastroenterology has been limited to imaging of the liver to characterize hepatic
tumors, iron overload, and hepatic venous and portal venous occlusion. For the eval-
uation of the other abdominal organs and the retroperitoneum, CT is superior
to MRI.

IV. POSITRON EMISSION TOMOGRAPHY (PET) uses positively charged electrons

(positrons) that are emitted from natural elements, such as carbon 11, nitrogen 13,
oxygen 15, and fluorine 18, to create images. These natural radioisotopes behave
normally in the body and can be used to synthesize radiopharmaceuticals for specific
purposes. An advantage of PET over CT and MRI is that it is more useful in evaluat-
ing organ function. Its clinical application has been largely in the evaluation of pri-
mary or metastatic cancer, recurrence, and for detection of cancer after surgery and/or
chemoradiation therapy.

Selected Readings
Beebe TJ, et al. Assessing attitudes roward laxative preparation in colorectal cancer
screening and effects on future testing: potential receptivity to computed tomographic
colonography. Mayo Clin Proc. 2007;82:666–671.
Beets-tan R, et al. Preoperative MR imaging of anal fistulas: Does it really help the
surgeon? Radiology. 2001;218:75.
Gourtsoyiannis NC, et al. Magnetic resonance imaging evaluation of small intestinal
Crohn’s disease. Best Pract Res Clin Gastroenterol. 2006;20:137–156.
Kim DH, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia.
N Surg J Med. 2007;357:1403–1412.
79466_CH09.QXD 1/2/08 12:05 PM Page 42

42 Part II: Diagnostic and Therapeutic Procedures

Klapman, JB, et al. Endoscopic ultrasound-guided fine-needle injection. Gastrointest

Endosc Clin North Am. 2005;15(1):169–177.
Kochman, ML. EUS in pancreatic cancer. Gastrointest Endosc. 2002;56(20064):S6–12.
Lin C, et al. EUS for detection of occult cholelithiasis in patients with idiopathic pancreatitis.
Gastrointest Endosc. 2000;51:28.
Paulsen SR, et al. CT enterography as a diagnostic tool in evaluation small bowel disorders:
Review of clinical experience with over 700 cases. Radio Graphics. 2006;26:641–662.
Pickhardt PJ. Colonic preparation for computed tomographic colonography: Under-
standing the relative advantages of a noncathartic approach. Mayo Clin Proc. 2007;
82(6):659–661.
Pickhardt PJ. Screening for colorectal neoplasia with CT colonography: initial experience
from the 1st year of coverage by third-party payers. Radiology. 2006 Nov;241:
417–425. Epub 2006 Sep 18.
Rockey DC, et al. Analysis of air contrast barium enema, computed tomographic
colonography, and colonoscopy: prospective comparison. Lancet. 2005;365:305–311.
Shah JN, et al. Clinical impact of endoscopic ultrasonography on the management of
malignancies. Clin Gastroenterol Hepatol. 2004;2(12):1069–1073.
Valls C, et al. Hepatic metastases from colorectal cancer: Preoperative detection and
assessment of resectability with helical CT. Radiology. 2001;218:55.
Van Dam J, et al. Endosonography of the upper gastrointestinal tract. New Engl J Med.
2000;341:1745.
79466_CH10.QXD 1/2/08 12:06 PM Page 43

Nutritional Assessment III

and Management
79466_CH10.QXD 1/2/08 12:06 PM Page 44
79466_CH10.QXD 1/2/08 12:06 PM Page 45

NUTRITIONAL REQUIREMENTS 10
AND ASSESSMENT

I. METABOLISM
A. Normal energy metabolism. Every day normal adults need roughly 25 to 30 kcal
of fuel/kg of body weight. For a 70-kg person, this is about 2,100 kcal per day. A
typical American derives 40% to 60% of daily calories from carbohydrates, 20%
to 45% from lipids, and 10% to 20% from protein. Glucose is the body’s pre-
ferred source of immediate energy. The healthy body manufactures glucose from
carbohydrates, protein, and the glycerol backbone of triglycerides (TGs). Since
very little carbohydrate can be stored in the body, most of the body’s reserve energy
stores are made up of lipids. There is no storage form of protein. Even though pro-
tein can be metabolized for energy, this results in wasting of lean body mass and
negative nitrogen balance.
B. Metabolism of carbohydrates
1. Glucose. Most of the ingested carbohydrate is broken down to glucose, which
enters the circulation. Glucose is taken up by all cells of the body and burned for
immediate energy. Under normal, well-fed circumstances, the cells of the central
nervous system depend on glucose for energy. However, neurons of the brain
cortex and blood cells can use only glucose as fuel under all circumstances.
2. Glycogen. Glucose, fructose, and galactose can be converted to glycogen, a
polymer of glucose, which is stored mainly in the liver (200 mg) and muscle
(300 mg) as a readily available energy reserve. Liver glycogen can be converted
directly to glucose for systemic distribution. However, muscle glycogen is
burned by muscle itself. Total glycogen stores of the body can meet the body’s
energy needs for 36 to 48 hours.
The body protects its glycogen stores for emergencies. At times of tempo-
rary glucose insufficiency, the body manufactures glucose by gluconeogenesis,
from protein and glycerol of lipids. Also free fatty acids (FFAs) and amino acids
are burned for direct energy. Excess dietary carbohydrate is converted to TGs
for storage in the adipose tissue.
C. Metabolism of lipids. Lipids constitute the body’s main energy reserve. A
nonobese, 70-kg man has 12 to 18 kg of fat stores. This figure is somewhat higher
for women. Fat supplies 9 kcal/g compared to 4 kcal/g from glucose or protein.
Ingested lipids are hydrolyzed in the intestinal lumen, and then absorbed into
enterocytes of the small intestine, where they are resynthesized into TGs. In the
enterocytes, TGs made up of long-chain FFAs form chylomicrons by the addition
of apoproteins. Chylomicrons are secreted into the intercellular space and are
absorbed into the lymphatics. Short- and medium-chain FFAs are directly absorbed
into the portal vein. Lipoprotein lipase of endothelial cells release FFAs from TGs,
and FFAs enter cells of various tissues (e.g., heart and muscle), where they are oxi-
dized for energy, and cells of adipose tissue to form TGs for storage. Adipose tis-
sue can also convert carbohydrates and proteins into TGs by lipogenesis.
Mobilization of TGs for energy by lipolysis begins with the hydrolysis of TGs
into FFAs and glycerol. Glycerol may be either converted into glucose by gluco-
neogenesis or directly oxidized further. FFAs enter some tissue cells, are broken
down to acetyl coenzyme A, and oxidized through the Krebs cycle. At times of
starvation and lack of glucose as fuel, large quantities of FFAs enter tissue cells.
The Krebs cycle may become overloaded, and FFAs may be incompletely oxidized.

45
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46 Part III: Nutritional Assessment and Management

Intermediate products in the form of acids and ketone bodies accumulate in the
blood, leading to ketosis and acidosis.
D. Metabolism of protein. The body of a 70-kg man contains 10 to 14 kg of protein.
Because there is no storage form of protein in the body, the protein compartment
must be maintained by daily intake. A typical adult requires about 0.8 to 1.0 g of pro-
tein/kg of body weight per day. For a 70-kg man, this is about 65 to 70 g.
Ingested protein may be used for protein synthesis or fuel, especially if the
body requires more energy than is supplied by carbohydrate and lipid intake. In
this event, body protein may also be catabolized for energy. One third of the body’s
total protein is potentially available as an energy source in case of dire need.
Further protein catabolism, however, severely jeopardizes health.
If protein is ingested in amounts greater than needed for protein synthesis and
energy production, it is stripped of its nitrogen and converted to glucose, glycogen,
and TGs for storage. Protein, besides being needed for structural purposes, is also
needed for replacement, repair, and growth of tissue (cell components) and main-
tenance of circulating proteins (e.g., albumin, transferrin, coagulation proteins,
enzymes, and antibodies).
E. Nitrogen balance. In a healthy adult, ingested protein must supply enough amino
acids to maintain a constant level of body protein. Thus, the intake of protein
must equal or exceed the breakdown of body protein. The effect of diet on the
body’s protein compartment may be approximated by nitrogen balance. Nitrogen
balance is the difference between nitrogen intake and output.
1. When protein synthesis is equal to protein degradation, one has a neutral
nitrogen balance. In adults, this is a sign of health.
2. Positive nitrogen balance occurs when protein synthesis exceeds protein degra-
dation. This suggests tissue growth. This state is normal and expected in chil-
dren. In adults, it may mean rebuilding of wasted tissue.
3. In negative nitrogen balance, the protein breakdown is in excess of protein
synthesis. This catabolic state usually occurs in sepsis, trauma, and burns, and
when the carbohydrate and lipid intake is less than the body’s energy needs,
necessitating use of the body’s own protein for fuel.
4. Calculation of nitrogen balance. Nitrogen balance can be calculated with
reasonable accuracy. Nitrogen makes up 16% of ingested protein. The division
of protein intake in grams by 6.25 (the reciprocal of 0.16) will give nitrogen
intake. Most of the nitrogen output from the body is into the urine as urea,
which can be measured. Other excreted nitrogen is in feces and urine as
nonurea nitrogen, amounting to about 4 g per day. The addition of 4 g to the
urine nitrogen measured will give the daily nitrogen output. Thus, nitrogen bal-
ance can be calculated by subtracting nitrogen output from nitrogen input.
Nitrogen balance
nitrogen in  nitrogen out

protein intake  [daily urinary nitrogen  4 g 6.25
(for nonurea nitrogen)]
For example, if protein intake is 75 g, urine urea nitrogen is 500% or 5 g/L
with 2,000-mL urine output per 24 hours.
Nitrogen balance
75 g protein
 [(5 g/L  2 L)  4]6.25 g protein/g nitrogen

12 g nitrogen intake  14 g nitrogen output

22 g per day
F. Energy metabolism in starvation. During periods of starvation, when ingested nutri-
ents are unavailable, the body goes through different stages of metabolic adaptation.
Energy requirements are met by metabolism of substrates from the energy reserves,
which are drawn on simultaneously, but not equally, following a careful sequence.
1. For immediate use, the glycogen in the liver is depolymerized to glucose for
systemic use. Muscle glycogen is oxidized locally. The lactate produced may be
converted to glucose in the liver for systemic use. If used up entirely, the glyco-
gen reserves are depleted in 36 to 48 hours.
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Chapter 10: Nutritional Requirements and Assessment 47

2. In early starvation, glucose is produced from gluconeogenesis from amino

acids, lactate, and glycerol, but within a week the amount available for fuel
becomes severely limited. Its use is reserved exclusively for the central nervous
system and glycolytic tissues: erythrocytes, leukocytes, and macrophages.
Maintenance of this basal glucose production is essential. However, because its
main source is amino acids derived from catabolism of the body’s own protein,
it jeopardizes the body’s survival.
3. After the first few days of starvation, an adaptive response takes effect.
Metabolic rate decreases. FFAs become the main source of energy. The heart,
kidneys, and muscle take up and oxidize FFAs directly. Twenty-five percent of
the FFA released from the adipose tissue is partially metabolized in the liver to
form ketone bodies, which are readily used in peripheral tissues. There is also
a recycling of lactate and pyruvate back into glucose by the Cori cycle. These
changes decrease the protein requirements to about one third that of the non-
adapted state.
4. In prolonged starvation, the brain also adapts to the use of ketone bodies for
fuel. This further spares glucose and decreases protein breakdown. As the adi-
pose tissue becomes depleted, the body is forced to use its own essential protein
for energy, leading to loss of protein from muscle, liver, spleen, kidneys, gas-
trointestinal tract, and plasma. The heart, adrenals, and central nervous system
are initially protected. However, weight loss in excess of 20% to 30% seriously
increases mortality due to organ dysfunction, anemia, impaired immunity, inef-
fective wound healing, and decreased resistance to infection.
In contrast, the catabolic state in sepsis and injury induces an increase in
protein requirements. Protein catabolism, as represented by urine urea nitro-
gen, may increase by 50% in patients with sepsis and may nearly double in
those with severe trauma or burns. This increase in protein catabolism occurs
without an adequate compensatory increase in protein synthesis. Mediators of
this catabolic response include glucocorticoid, catecholamines, glucagon, and
perhaps interleukin-1. These substances induce an increase in lipid mobiliza-
tion and oxidation, skeletal muscle catabolism, and hepatic gluconeogenesis;
they also induce a state of insulin resistance. The septic state is highly catabolic,
with net catabolism even in the presence of abundant protein and calories.

II. ASSESSMENT OF NUTRITIONAL STATUS. Protein–calorie starvation is the pro-

gressive loss of lean body mass and adipose tissue because of inadequate intake of
amino acids and calories. Anemia, malabsorption, and hypermetabolism are some of
the causes of malnutrition in patients with a variety of subacute and chronic illnesses.
Protein–calorie malnutrition, which increases morbidity and mortality, can be reversed
by appropriate nutritional support by enteral and parenteral routes.
A. Anthropometric measurements
1. Height, weight, triceps skinfold thickness (for quantitative estimate of adi-
pose tissue stores) and mid–upper arm circumference (for estimate of muscle
mass [somatic protein]) are useful data in nutritional assessment. Each actual
measurement can be compared to the standards (Tables 10-1–10-3) as follows:
% standard
Actual measure/Standard  100
2. Body weight below 90% of ideal is considered as protein–calorie undernutri-
tion. However, due to pre-illness obesity and presence of edema, body weight
may not be subnormal in the malnourished patient.
3. Creatinine height index. The most important laboratory test for detecting pro-
tein–energy undernutrition is the creatinine height index (CHI). The actual daily
urinary creatinine excretion is compared with an ideal value to compute CHI.
Actual urinary creatinine/Ideal urinary creatinine  100
CHI
By expressing this index as a percentage of standards, the severity of the
loss of muscle mass can be graded as mild, moderate, severe, or critical (Tables
10-4 and 10-5).
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48 Part III: Nutritional Assessment and Management

TABLE 10-1 Ideal Weight for Height*

Men

Height (cm) Weight (kg) Height (cm) Weight (kg) Height (cm) Weight (kg)

145 51.9 159 59.9 173 68.7

146 52.4 160 60.5 174 69.4
147 52.9 161 61.1 175 70.1
148 53.5 162 61.7 176 70.8
149 54.0 163 62.3 177 71.6
150 54.5 164 62.9 178 72.4
151 55.0 165 63.5 179 73.3
152 55.6 166 64.0 180 74.2
153 56.1 167 64.6 181 75.0
154 56.6 168 65.2 182 75.8
155 57.2 169 65.9 183 76.5
156 57.9 170 66.6 184 77.3
157 58.6 171 67.3 185 78.1
158 59.3 172 68.0 186 78.9

Women

140 44.9 150 50.4 160 56.2

141 45.4 151 51.0 161 56.9
142 45.9 152 51.5 162 57.6
143 46.4 153 52.0 163 58.3
144 47.0 154 52.5 164 58.9
145 47.5 155 53.1 165 59.5
146 48.0 156 53.7 166 60.1
147 48.6 157 54.3 167 60.7
148 49.2 158 54.9 168 61.4
149 49.8 159 55.5 169 62.1
*This table corrects the 1959 Metropolitan Standards to nude weight and height without shoe heels.

From Blackburn GL, Bistrian BR, Maini BJ. Nutritional and metabolic assessment of the hospitalized
patient. J Parenter Enteral Nutr. 1977;1:14. Reprinted with permission from the American Society for
Parenteral and Enteral Nutrition.

TABLE 10-2 Arm Circumference—Adults

Arm circumference (cm)

90% of 80% of 70% of 60% of

Sex Standard standard standard standard standard

Male 29.3 26.3 23.4 20.5 17.6

Female 28.5 25.7 22.8 20.0 17.1
From Keenan RA. Assessment of malnutrition using body composition analysis. Clin Consult Nutr
Support. 1981;1:10. Reprinted with permission.
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Chapter 10: Nutritional Requirements and Assessment 49

TABLE 10-3 Triceps Skinfold—Adult

Triceps skinfold (mm)

90% of 80% of 70% of 60% of `

Sex standard standard standard standard standard

Male 12.5 11.3 10.0 8.8 7.5

Female 16.5 14.9 13.2 11.6 9.0
From Keenan RA. Assessment of malnutrition using body composition analysis. Clin Consult Nutr
Support. 1981;1:10. Reprinted with permission.

TABLE 10-4 Ideal Urinary Creatinine Values

Mena Womenb

Ideal Ideal

Height (cm) Creatinine (mg) Height (cm) Creatinine (mg)

157.5 1288 147.3 830

160.0 1325 149.9 851
162.6 1359 152.4 875
165.1 1386 154.9 900
167.6 1426 157.5 925
170.2 1467 160.0 949
172.7 1513 162.6 977
175.3 1555 165.1 1006
177.8 1596 167.6 1044
180.3 1642 170.2 1076
182.9 1691 172.7 1109
185.4 1739 175.3 1141
188.0 1785 177.8 1174
190.5 1831 180.3 1206
193.0 1891 182.9 1240
aCreatinine coefficient (men)
23 mg/kg of ideal body weight.
bCreatinine coefficient (women)
18 mg/kg of ideal body weight.

From Blackburn GL, Bistrian BR, Maini BJ. Nutritional and metabolic assessment of the hospitalized
patient. J Parenter Enteral Nutr. 1977;1:15. Reprinted with permission of the American Society for
Parenteral and Enteral Nutrition.

4. Creatinine total arm-length ratio. The measurement of total arm length is an

alternative to height for use in nutritional assessment because of the variability
of height in elderly patients. This measurement works equally well in younger
patients.
B. Biochemical data such as serum albumin, transferrin, total lymphocyte count,
delayed hypersensitivity skin response to common antigens, and nitrogen balance
are useful indices for visceral protein status. Deficiency of visceral protein levels is
found in patients with advanced protein depletion.
The serum albumin concentration may be a simple and reliable measurement
for predicting outcome in critically ill patients in the intensive care unit (ICU) set-
ting. In a study from the Mayo Clinic, serum albumin level correlated with the
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50 Part III: Nutritional Assessment and Management

number of ICU days, with the number of days on a ventilator, and with the num-
ber of hospital days. It was the only measurement that correlated with the devel-
opment of both a new infection and ventilator dependency.
C. Rate of nutritional depletion. Not only is the severity of the protein-intake
depletion important, but also its rate of progression. Ingestion of less than 30 g
per day of protein and less than 1,000 kcal per day means that protein–calorie
undernutrition will progress rapidly. Associated fever, infection, trauma, or mal-
absorption will further accelerate the rate of nutritional depletion. It is important
to note that the stress of sepsis induces an obligatory protein loss regardless of the
provision of nutrients. Thus, nutritional status in these patients needs to be closely
monitored.

III. NUTRITIONAL REQUIREMENTS. The body needs seven groups of nutrients: carbo-
hydrates, lipids, proteins, vitamins, electrolytes, trace elements, and water.
The calorie and energy requirements of healthy individuals vary depending on age, body
size, and level of physical activity. Calorie intake should balance energy expenditure to
maintain body weight. The energy requirements of seriously ill or injured patients are
different than in health and depend on the nature and severity of the illness.
A satisfactory estimate of basal calorie requirement or basic energy expenditure
(BEE) can be calculated from the Harris–Benedict equation, which takes into account
sex, height, age, and weight (Table 10-5). For most patients, the Harris–Benedict
equation provides an adequate estimate of caloric needs. However, in some clinical
situations (e.g., impending respiratory failure, active weaning from mechanical venti-
lation), a more individualized and accurate estimate is needed. Indirect calorimetry is
useful in such instances.
Indirect calorimetry is a method of determining caloric expenditure in different
metabolic situations. The carbon dioxide and oxygen levels in inspired and expired air
are measured and compared. The average of several measurements taken over a 10- to
20-minute period gives a close approximation of caloric expenditure.
Indirect calorimetry also provides the respiratory quotient (RQ), which reflects
the number of carbon dioxide molecules produced per molecule of oxygen consumed.
The RQ varies, depending on the metabolic substrate. For example, the RQ is 1.0 for
pure carbohydrate metabolism, 0.8 for protein, and 0.7 for fat. Because respiratory
effort may decrease as carbon dioxide production drops, patients with respiratory
distress may benefit from a reduction in carbon dioxide production achieved by low-
ering the RQ.
Lowering the RQ involves two principles: avoidance of excess calories and sub-
stitution of fat for carbohydrate. A common error is to assume that providing addi-
tional fat calories will reduce the RQ. On the contrary, excess calories may cause the
RQ to increase above 1.0, possibly to as high as 4.0, depending on the amount of
excess calories.

Harris–Benedict Equations for Calculation of Basal

TABLE 10-5
Energy Expenditure

Women: BEE
655  (9.6  W)  (1.8  H)  (4.7  A)

Men: BEE
66  (13.7  W)  (5  H)  (6.8  A)
Multiply resting energy expenditure value by stress or activity factor (ranging from 1.1 to 1.4)
to obtain daily caloric requirements.
BEE, basal energy expenditure; W, actual or usual weight in kilograms; H, height in centimeters;
A, age in years.

From Blackburn GL, Bistrian BR, Maini BJ. Nutritional and metabolic assessment of the hospitalized
patient. J Parenter Enteral Nutr. 1977;1:14. Reprinted with permission of the American Society for
Parenteral and Enteral Nutrition.
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Chapter 10: Nutritional Requirements and Assessment 51

A. Proper use of indirect calorimetry and the RQ requires recognition of the fol-
lowing factors:
1. Excess calories tend to greatly increase the RQ and production of carbon dioxide.
2. When the RQ is greater than 1.0, total calories should be decreased initially
to approximate the caloric requirement; indirect calorimetry may then be
repeated.
3. When the RQ is less than 1.0 but greater than 0.85 and further reduction of the
RQ is deemed beneficial, fat calories may be substituted for carbohydrate calo-
ries; however, simply adding fat calories is counterproductive.
4. Lowering the RQ is beneficial only when respiratory failure is impending or
when weaning from mechanical ventilation is difficult. Patients undergoing
long-term ventilatory support or who will not undergo weaning for several
days do not benefit from high-fat feedings or a reduction in RQ.
B. If lipid substitution is desired, a dietitian can be helpful in making appropriate
changes in enteral feeding or in adjusting glucose calories and substituting lipid in
parenteral feedings. Although lipid substitution can be beneficial, studies have
shown that intravenous administration of lipid has potentially adverse effects.
Despite these reports, intravenous lipid feedings of 50 g per day or less have no
definitive adverse effects. This amount is present in a standard 500-mL unit of
10% intravenous lipid and provides 450 kcal.

IV. GUIDELINES FOR NUTRITIONAL SUPPORT

A. Calorie and protein requirements
1. Well-nourished patients without sepsis or injury. Nutritional support is not
needed for short-term problems. If normal eating is likely to resume within 5
days, no specialized feeding should be initiated. The risks of nutritional support
outweigh any potential benefit. During observation or diagnostic testing, pro-
viding water and electrolytes is sufficient.
2. In nondepleted, postoperative patients, the goal of nutrition is to prevent
loss of body protein. If the patient is unable to eat after surgery, the patient
should be given 20% more calories than the BEE indicates (1.2  1.5  BEE),
which will provide about 35 to 40 kcal/kg of body weight. In addition, 0.8 to
1.0 g of protein per kg of body weight is required.
3. Malnourished patients without sepsis or injury. In this state of simple starva-
tion, protein and caloric requirements are reduced. Increased nutrient intake is
necessary for repletion, but caution is needed to avoid the refeeding syndrome.
4. Refeeding syndrome. Patients who are malnourished, commonly because of
alcoholism or chronic insufficient protein and caloric intake, are at risk for the
refeeding syndrome. When these patients receive carbohydrate or protein, the
activation of anabolic enzymes and pathways may rapidly deplete the available
cofactors. Profound hypophosphatemia and hypomagnesemia may occur,
requiring prompt repletion. Daily assessment of serum phosphate, calcium,
magnesium, and other electrolytes during the first few days of feeding and pro-
vision of adequate but not excessive calories should prevent the potentially dire
consequences of the refeeding syndrome.
5. In nutritionally depleted patients, the protein intake should correspond to
1.5 to 1.8 g/kg of body weight, and the amount of calories should be 50%
above the estimated BEE, or about 40 to 50 kcal/kg of actual body weight.
6. In hypermetabolic patients, the goal is to provide 2 g of protein per kilogram
of body weight and a total energy intake of twice the BEE, about 50 kcal/kg of
body weight.
7. Well-nourished or malnourished patients with sepsis or injury. An altered
metabolic state exists initially and is characterized by hypermetabolism,
increased endogenous protein breakdown, and a tendency for lipid oxidation
and insulin resistance. Unless adequate calories and protein are provided, pro-
found muscle catabolism and weight loss may result. Well-nourished patients
may do well without feeding for a few days, but malnourished patients should
receive prompt, consistent nutritional support.
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52 Part III: Nutritional Assessment and Management

8. Calorie and nitrogen sources. Calorie sources used in nutritional support

regimens are carbohydrate solutions and lipid emulsions. Intact proteins, pep-
tides, or crystalline amino acid solutions are used as nitrogen sources.
9. Essential amino acids. In addition to the general requirement for protein, the
body needs the daily intake of essential amino acids, which the body cannot
synthesize. These are leucine, isoleucine, lysine, methionine, phenylalanine,
threonine, tryptophan, and valine. Histidine, arginine, and glutamine are con-
sidered essential in infants and possibly for healing in adults.
Glutamine is an amino acid synthesized in most body tissue. However, in
catabolic states in critical illness, it may become an essential amino acid. It func-
tions as a nitrogen transporter, a glycogenic precursor, and a high-energy source.
Oxidation of glutamine yields 30 molecules of adenosine triphosphate (ATP). It
is an important fuel for replicating cells (such as cells involved in immunity and
gastrointestinal mucosal cells) and contributes considerably to gut growth.
During catabolic states, glutamine and alanine are released in large quantities

Recommended Daily Allowances of Essential Nutrients

TABLE 10-6
for Healthy Adults

Nutrient Recommended daily allowance

Water 1 mL/cal
Energy 1,800–2,500 kcal
Protein 45–56 g
Linoleic acid 4–6 g
Vitamin A 2,640–3,000 IU
Vitamin D 200 IU
Vitamin E 8–10 IU
Vitamin K 0.5–1.0 mg/kg
Ascorbic acid 60 mg
Folic acid 400 µg
Niacin 6.6 mg/1,000 kcal
Riboflavin 1.2–1.6 mg
Thiamine 0.5 mg/1,000 kcal
Vitamin B6 (pyridoxine) 2.2 mg
Vitamin B12 3.0 mg
Pantothenic acid 5–10 mg
Biotin 100–200 mg
Calcium 800 mg
Phosphorus 800 mg
Iodine 100–130 µg
Iron 10–18 mg
Magnesium 300–350 mg
Zinc 15 mg
Copper 2 mg
Potassium 2,500 mga
Sodium 2,500 mga
Chloride 2,000 mga
Chromium 50–120 µga
Manganese 6–8 mga
Molybdenum 400 µga
Selenium 50–100 µga
aRecommended daily allowance not established. Values are those provided in a normal diet.

Adapted from Food and Nutrition Board, Recommended Daily Allowances. Washington, D.C., 1974;
National Academy of Sciences, National Research Council.
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Chapter 10: Nutritional Requirements and Assessment 53

from muscle, taken up by the splanchnic bed, and delivered to the gut and liver.
In the gut, glutamine is converted to glutamate and enters the Krebs cycle. The
liver metabolizes it to glucose, ketones, and ammonia. Glutamine supplementa-
tion of external and parenteral solutions seems to improve gut mass function and
limit bacterial translocation from the gut to the circulation in critically ill patients.
B. Fluid and electrolytes. The fluid and electrolyte requirements of individuals vary
depending on the disease process. Therapy should be tailored to the patient’s indi-
vidual needs and requirements based on appropriate clinical and laboratory eval-
uations. In general, the patient should receive maintenance requirements of water
and electrolytes. Previous and ongoing losses should be replaced with attention to
the patient’s cardiopulmonary and renal status. A convenient method for calcu-
lating maintenance fluid requirements is as follows:
1. First 10 kg of body weight
1,000 mL.
2. Next 10 kg of body weight
500 mL.
3. Each kilogram of body weight thereafter
20 mL.
C. Vitamins and trace elements serve as parts of enzymes or coenzymes and are
needed by the body in small quantities each day. These should be included in the
patient’s daily diet (Table 10-6).

Selected Readings
Banh L. Serum Proteins as Markers of Nutrition: What are we treating? Practical
Gastroenterol. 2006;xxx(10):46.
Heller AR, et al. Omega-3 fatty acids improve the diagnosis–related clinical outcome. Crit
Care Med. 2006;34:972–979.
Heyland DK, et al. Antioxidant nutrients: a systematic review of trace elements and
vitamins in the critically ill patient. Intensive Care Med. 2005;31:327–337.
Holick MF, et al. Vitamin D deficiency. N Eng. J Med. 2007;357:266–281.
Krystofiak C. Gastrointestinal Disease. In The A.S.P.E.N. Nutrition Support Core
Curriculum: A Case-Based Approach—The Adult Patient. Edited by Gottschlich MM.
Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2007:163–186.
Ockenga J, et al. Glutamine-enriched total parenteral nutrition in patients with
inflammatory bowel disease. Eur J Clin Nutr. 2005;59:1302–1309.
Wooley JA, et al. In Nutrition Support Core Curriculum, edn 2. Edited by Gottschlich MM.
Silver Spring, MD: ASPEN; 2007:19–32.
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11 ENTERAL NUTRITION

I. PATIENT SELECTION. Patients with established protein–calorie malnutrition or those

whose condition will result in protein–calorie undernutrition are candidates for nutri-
tional support. The enteral route should be preferred in any patient with a functional
gastrointestinal (GI) tract over the parenteral routes because of its relative simplicity,
safety, and economy. Some indications for the use of enteral hyperalimentation are
listed in Table 11-1. Enteral feeding is contraindicated in patients with severely com-
promised GI function, where access to the GI tract is not feasible, and in patients with
severe vomiting, intestinal obstruction, ileus, or GI bleeding.
Nutritional support by the enteral route is not a single entity. It encompasses a
wide range of techniques and products for use in the clinical spectrum of undernutri-
tion. At one extreme, it may be the addition of a nutritional supplement to the
patient’s orally consumed diet; at the other extreme, it may provide the patient with
the complete nutritional requirements. In some cases, a satisfactory level of nutritional
support may not be achievable by the enteral route alone, and combination of this
method with parenteral intravenous alimentation may be necessary.

II. ENTERAL FORMULAS. Three types of enteral mixtures differing in osmolality,

digestibility, caloric density, lactose content, fat content, and cost (Table 11-2) are
available: formulas with intact nutrients, formulas with predigested nutrients (ele-
mental diets), and feeding modules.
A. Formulas with intact nutrients
1. Blenderized feedings are equivalent to a meat-based meal that has been
prepared in a blender. They are nutritionally complete if sufficient calories are
given and generally provide 1 kcal/mL. However, they tend to be viscous and do
not flow well in the newer, narrower, soft feeding tubes, and most contain lactose.

Some Indications for the Use of Enteral

TABLE 11-1
Nutritional Support

Anorexia Major burns

Malabsorption syndromes Severe trauma
Chronic malnutrition Multiple fractures
Gastrointestinal tract fistulas (low) Head and neck surgery
Partial obstruction of the gastrointestinal tract Anorexia nervosa
Ulcerative colitis Hepatic failure
Crohn’s disease Renal failure
Bowel irradiation Prolonged ventilatory support
Pancreatic disease Cerebrovascular accident
Short-bowel syndrome Prolonged coma
Presurgical nutritional replenishment Neurologic trauma
Postoperative nutritional support Organic brain syndrome
Inflammatory bowel disease Sepsis
Carcinoma Multiple organ system failure

54
 TABLE 11-2 Selected Enteral Nutritional Supplements
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meet 100%
1/2/08

Nitrogen for USRDA

Product Protein content CHO Fat % vitamins &
description Calories mOsm/kg g/L (%) g/L (%) g/L (%) g/L (%) MCT minerals Source

Lactose-free
12:08 PM

formulas with
intact nutrients
Isocal 1/mL 300 34 (13) 5 133 (50) 44.3 (37) 20 1,877 Mead
Johnson
Precision 1/mL 300 7.5 5 37.5 (60) 7.8 (28) 28 1,800 Doyle
Page 55

Isotonic
Osmolite 1/mL 300 37 6 145 (55) 38.4 (31.5) 50 2,000 Ross
Enrich 1.1/mL 300 40 — 162 (52) 37.1 (30) — — Ross
(with fiber)
Jevity 1/mL 310 44.3 — 151.4 36.7 — — Ross
(with fiber)
Precision 1.1/mL 530 26 (9.5) 4 248 (89) 1.6 (1.3) — 1,710 Sandoz
(low residue)
Meritine 1/mL 600 (24) 10 (46) (30) — —
Ensure 1/mL 450 37 (14) 6 145 (55) 37 (31.5) — 1,391 Ross
Ensure 1.5/mL 600 (17) 9 (53) (30) — — Ross
Plus HN
Sustacal 1/mL 625 (24) 10 (55) (21) — — Mead
Johnson
Magnacal 2/mL 590 (27) 11 (50) (23) — — Organon

(continued)

55
56
TABLE 11-2 Continued
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meet 100%
Nitrogen for USRDA
Product Protein content CHO Fat % vitamins &
1/2/08

description Calories mOsm/kg g/L (%) g/L (%) g/L (%) g/L (%) MCT minerals Source

Elemental
Vivonex TEN 1/mL 630 38 (15) 7 206 (82) 2.8 (2.5) — 2,000 Norwich
(30% Eaton
12:08 PM

branched-
chain AA)
Travasorb HN 1/mL 560 45 (18) 7 175 (70) 13.5 (12) 60 2,000 Travenol
Criticare HN 1/mL 650 38 (14) 6 222 (83) 3.4 (3) — 1,900 Mead
Johnson
Page 56

Vital HN 1/mL 500 42 (18) 7 185 (78) 10.8 (5) — — Ross

Modular
Casec 3.7/g (95) (5) — — — Mead
Johnson
Propack 4/g (76) (18) (6) — — — Sherwood
Medical
Polycose 3.8/g — — (100) — — — Ross
SLD 3.65/g 20.4 (0.3) (74.2) — — 1,022 Ross
MCT 9.0/g — 100 — — 100 — Ross

CHO, carbohydrates; MCT, medium-chain triglycerides; USRDA, United States Recommended Daily Allowance; AA, amino acids; HN, high nitrogen;
TEN, total enteral nutrition.
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Chapter 11: Enteral Nutrition 57

2. Lactose-free feedings (1 kcal/mL). These products have become the standard

tube-feeding preparations. They are prepared from isolated nutrients rather than
whole foods. They consist of polymeric mixtures of proteins, fats, and carbohy-
drates in high-molecular form. Thus, they are lower in osmolality (300–350 osm/L
isotonic to plasma) than are formulas supplying equivalent amounts of calories
in lower molecular weight substrates. Since these mixtures are prepared from
undigested nutrients, patients who are receiving them must have intact digestive
and absorptive capabilities. They are nutritionally complete if sufficient calories
are given. Their sodium, potassium, lactose, and residue contents are low.
Essential fatty acid insufficiency is not a problem. With these products, 30% to
40% of the calories are provided as fat, 50% to 70% as carbohydrate, and 3%
to 10% as protein. Because these formulas are unflavored and generally taste
like chalk, they are recommended for tube feeding only, not for oral intake. Two
new enteral formulas are available that contain soy polysaccharide as a fiber
source (Jevity and Enrich). These formulations may help decrease the incidence
of diarrhea in tube-fed patients.
3. Nutrient-dense feedings. These formulas are virtually identical in composition
to 1 kcal/mL products except that they are more concentrated and have high
osmolality. They are nutritionally complete and provide 1.5 to 2.0 kcal/mL.
They are also more flavorful and may be used as oral feedings and supplements.
B. Formulas with predigested nutrients (elemental diets)
1. Nutritionally complete feedings. These formulas are prepared from amino
acids or small peptides, simple glucose polymers (oligosaccharides) rather than
complex carbohydrates (polysaccharides), medium-chain triglycerides, and mini-
mal amounts of fat. They are hypertonic and uniformly unpalatable. Elemental
diets, because of their simple nutrients that do not require digestion, have been
recommended for use in patients with digestive or absorptive abnormalities,
such as patients with short-bowel syndrome, low intestinal fistulas, inflamma-
tory bowel disease, acute and chronic pancreatitis, and malabsorptive states.
Recent research has shown that di- and tripeptides are more readily absorbed
than single amino acids by the normal or inflamed intestine. Digestion of fats
containing long-chain triglycerides requires pancreatic lipase for hydrolysis, bile
salts for water solubility, and an intact lymphatic system for intestinal absorp-
tion. Medium-chain triglycerides do not require pancreatic lipase, bile salts, or
lymphatics because they are hydrolyzed by intestinal cell lipase and absorbed
directly into the portal venous system.
The use of oligosaccharides rather than polysaccharides as well as crys-
talline amino acids and small peptides increases the osmotic load of these formu-
las. Hypertonic solutions tend to induce osmotic diarrhea, leading to dehydration
and serum electrolyte abnormalities. The high simple-sugar content increases the
risk of hyperglycemia and hyperosmolar state, especially in patients with glucose
intolerance (overt or latent). Essential fatty acid deficiency may result with pro-
longed use of some formulas with low long free fatty acid content. In such cases,
essential fatty acids and linoleic and linolenic acids should be supplied by another
source and means.
These “elemental” formulas should be restricted to use in patients show-
ing definite evidence of maldigestion and malabsorption.
2. Disease-specific feedings. Some formulas are designed for use in patients
with renal failure, respiratory insufficiency, or hepatic encephalopathy. They
are formulated with amino acid mixtures that are intended to modify the meta-
bolic abnormalities associated with these disease states. Some of these formulas
are nutritionally incomplete and should not be used alone for nutritional sup-
port. Thus, whenever possible, standard formulations are preferable.
a. Renal formulations (e.g., amino-acid) are a mixture of carbohydrates,
fats, and essential amino acids with a minimal amount of electrolytes.
Theoretically, the body can convert the carbohydrate precursors of nonessen-
tial amino acids to the actual amino acids by recycling urea nitrogen, thus
slowing down the rate of rise of blood urea nitrogen.
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58 Part III: Nutritional Assessment and Management

b. Hepatic formulas (e.g., Hepatic-Acid) are enriched with branched-chain

amino acids and are low in aromatic amino acids and methionine. It has been
postulated that alterations in amino acid balance may contribute to
the abnormal central nervous system function in patients with hepatic
encephalopathy.
c. In patients with diabetes mellitus, selection of a product low in simple
sugars and with up to 50% of total calories in complex carbohydrates will
keep insulin needs in moderation.
d. In patients with respiratory disease with carbon dioxide retention, a for-
mula with high-fat content (respiratory quotient [carbon dioxide produced/
oxygen consumed]
0.7 for fats vs. 1.0 for carbohydrate) is preferred. The
complete oxidation of fat produces less carbon dioxide on a per-calorie basis
than does the complete oxidation of either glucose or protein. Replacing car-
bohydrate calories with fat calories has been shown to reduce carbon diox-
ide production, oxygen consumption, and minute ventilation. These effects
may aid in weaning patients from ventilatory support; however, high-fat
enteral diets tend to produce diarrhea in some patients. Thus, initially, a
30% fat polymeric diet may be used; if tolerated, then the fat content may be
raised to 50% of the total calories. In intolerant patients, enteral formulas
may be supplemented with parenteral fat emulsion infusions.
C. Feeding modules are concentrated sources of one nutrient (e.g., fat: Lipomul, MCT
Oil; carbohydrate: Polycose; and protein: Pro-Mix). These modules can be added
to formula diets to increase specific components that are deficient or to yield a small-
volume, high-calorie mixture (1.5–2.0 kcal/mL) for patients in whom fluids should be
restricted.

III. CALORIC REQUIREMENTS

A. Using the Harris-Benedict equation (see Chapter 10, Table 10-6):
1. The enteral maintenance requirement
1.2  basic energy requirements (BEE)
2. The enteral anabolic requirement
1.5  BEE
3. The energy in kilocalories, the nitrogen content, and the protein content of each
enteral feeding formula per milliliter is given in the contents table of the prod-
uct provided by the manufacturer. Once the number of kilocalories and the
required amount of protein per day are determined, the number of milliliters
per day that will yield these amounts can be calculated.

IV. METHODS OF ADMINISTRATION

A. Feeding tubes. Feeding tubes (e.g., Keofeed or Dobbhoff tubes) made of silicone
or polyurethane plastics have several advantages over the polyvinyl plastic naso-
gastric tubes. They are thinner and more flexible and do not stiffen or become brit-
tle in the GI tract. Many of these are weighted at the tip, serving as an anchor or
as a leading end for easier passage of the tube.
1. Nasogastric feeding uses the stomach as a reservoir and the pylorus to con-
trol the entry of the feedings into the intestine, diminishing the risk for diarrhea
from osmotic causes and malabsorption.
2. Nasoduodenal tubes offer more protection for the patient against aspiration
than do nasogastric tubes because of the presence of the pylorus acting as
another sphincter between the area of the tube feeding and the lungs.
3. Surgical placement of feeding tubes may be indicated in some patients who
require long-term enteral nutritional support. Most commonly, gastrostomy,
jejunostomy, or needle–catheter jejunostomy is used.
4. Percutaneous endoscopic gastrostomy (PEG) provides a less invasive alter-
native to laparotomy for placement of a gastrostomy tube. These tubes may be
converted to jejunostomy tubes in selected patients.
Prolonged use (1 month) of nasogastric or nasoduodenal tube feed-
ings is inconvenient, necessitating frequent changes of tubes, and may result
in gastric and esophageal injury due to mechanical trauma from the tube.
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Chapter 11: Enteral Nutrition 59

The same nutrient formulas may be used with PEG tubes as with nasogastric
or nasoduodenal tubes.
B. Types of infusion
1. Continuous drip infusion is the method of choice in initiating tube feedings;
a defined amount is given continuously every hour with the use of an infusion
pump. Although large volumes may be administered over 24 hours, the amount
entering the GI tract at any given time is quite small. This method minimizes
the potential for aspiration, abdominal distention, and diarrhea.
a. For most patients, tube feedings are started at 50 mL/hour using a lactose-
free, 1 kcal/mL formula with intact nutrients. Thereafter, the rate is increased
by increments of 25 mL/hour daily until the desired rate is achieved.
b. If a nutrient-dense or elemental formula is used, the initial starting dilu-
tion should be at least isotonic to plasma. Hypotonic and isotonic solutions
behave almost identically in terms of small intestinal flux of fluid, and thus
there is no advantage to overdiluting a feeding product.
c. When feeding into the small bowel, isotonic solutions (3,000 mOsm) are
started at a continuous rate of 25 to 50 mL/hour every 8 hours until the
needed volume is reached. Osmolarity is then increased until the patient’s
nutrient requirements are reached.
d. Patient position. The patient’s head and shoulders must be kept at a 30- to
45-degree elevation to minimize the risk of aspiration.
2. The “cyclic” method of drip infusion may be used once a patient has been
stabilized on maintenance therapy to provide the patient “flat-in-bed” time by
increasing the rate of infusion per hour during the day and stopping the infu-
sion at night, thus still delivering the same volume of nutrients to the patient
over the 24 hours. The patient’s head and shoulders must be elevated during
feeding and 1 hour after the feeding has been stopped to ensure that gastric
emptying has occurred. Gastric residuals must be measured 2 to 3 hours after
the feeding is stopped.

V. COMPLICATIONS
A. Mechanical complications
1. Tube clogging. Viscous preparations may obstruct the lumen of the feeding
tube. This can be prevented by flushing the tube every 4 to 8 hours with 20 mL
of water or cranberry juice.
2. Pharyngeal irritation and esophageal erosion are rare with the softer tubes.
3. Tracheoesophageal fistula may occur in patients with endotracheal or tra-
cheostomy tubes receiving mechanical ventilation.
4. Aspiration is the most serious problem with tube feedings. It may be mini-
mized by placement of the tube well beyond the pylorus into the duodenum, by
keeping the gastric volumes less than 100 mL, and by elevation of the patient’s
head and shoulders at 30 to 45 degrees while the patient is being fed.
B. Gastrointestinal complications. Patients may have nausea, vomiting, crampy
abdominal pain, distention, flatulence, bloating, and diarrhea.
It is not unusual for tube-fed patients to have no bowel movements for 3 to 5
days because most commercial formulas are low in residue. Likewise, it is not
unusual for patients to have loose stools. As long as the volume of the stools is not
large, this may be tolerated. Diarrhea can result from gut atrophy, osmotic over-
load, malabsorption, lactose intolerance, concurrent medications (e.g., antibiotics,
nonsteroidal antiinflammatory drugs, and magnesium-containing antacids), addi-
tives, or vehicles added to medications and fecal impaction with the liquid feces
escaping around the impaction.
Starting patients on slow, continuous infusion of tube feeding without lac-
tose, with gradual increase in concentration and rate of delivery, or the use of for-
mulas with fiber, minimizes this problem. If diarrhea continues, DTO (deodorized
tincture of opium) may be added to the tube feedings with care that ileus does not
develop.
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60 Part III: Nutritional Assessment and Management

TABLE 11-3 A Protocol for Monitoring Enteral Nutritional Status

1. Confirm placement of feeding tube by abdominal x-ray films before administration of feeding.
2. Elevate head of bed 30 to 45 degrees when feeding into the stomach.
3. Name of formula _________________________ ; volume of formula ____________ mL at
____________ strength to be given over ____________ hour(s); rate of feeding ____________
mL/h.
4. Change administration tubing and feeding bag daily.
5. Irrigate feeding tube with 20 mL water at completion of each intermittent feeding when
tube is disconnected.
6. Check for gastric residual every ____________ hour(s) in patients receiving gastric feedings;
withhold feedings for ____________ hour(s) if residual is 50% greater than ordered volume.
7. Make sure formula does not hang for more than 8 hours.
8. Record intake and output daily; chart volume of formula separately from water or other
oral intake for every shift.
9. Weigh the patient daily; chart on graph.
10. Obtain calorie counts from dietitian daily for 5 d, then once weekly if patient is taking food
by mouth.
11. Order a complete blood count with red blood cell indices, serum chemistries, total iron
binding capacity, and serum iron and magnesium levels weekly.
12. Order serum glucose, electrolytes, BUN, and creatinine.
13. Obtain 24-hour urine collection for volume, creatinine, and urea to start at 8 A.M. weekly.

BUN, blood urea nitrogen.

C. Metabolic complications. Fluid and electrolyte imbalances may occur, especially

in compromised patients. Patients may also develop edema, hyperglycemia, hyper-
ammonemia, azotemia, and essential fatty acid deficiency. Thus, strict monitoring
of patients is mandatory.

VI. MONITORING OF PATIENTS ON TUBE FEEDINGS. Patients on tube feedings should

be continuously monitored for mechanical aspects of the feeding: patient position,
tube position and patency, and gastric residual. In addition, the patient’s daily weight,
serum electrolytes, chemistries, nitrogen balance, nutritional status, and progress need
close attention by both the physicians and the paramedical staff caring for the patient.
A monitoring protocol (Table 11-3) helps ensure that the specified nutritional goals
are met.

Selected Readings
Bruder EA, et al. Colonmetric carbon dioxide detection of enteral feeding tube placement.
US Gastroenterol Rev. 2007;1:17–19.
DeLegge MH, et al. Randomized prospective comparison of direct percutaneous
endoscopic jejunostomy (DPEJ) vs. percutaneous endoscopic gastrostomy with jejunal
extension (PEG-J) feeding tube placement for enteral feeding. Gastrointest Endosc.
2004;59:I58(A).
DeLegge MH. Endoscopic options for enteral feeding. Gastroenterol Hepatol. 2007;3(9):
690–692.
Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients.
J Parenter Enteral Nutr. 2002;26:1–138.
Ho KM, et al. A comparison of early gastric and post pyloric feeding in critically
ill patients: a meta-analysis. Intensive Care Med. 2006;32:639–649.
Javid PJ, et al. The role of enteral nutrition in the reversal of parenteral nutrition-associated
liver dysfunction in infants. J Pediatr Surg. 2005;40:1015–1018.
79466_CH11.QXD 1/2/08 12:08 PM Page 61

Chapter 11: Enteral Nutrition 61

Marin M, et al. Enteral formulations. In: Merritt R, ed. The ASPEN Nutrition Support
Practice Manual. 2nd ed. Silver Spring, Md.: American Society for Parenteral & Enteral
Nutrition; 2005:63–75.
Mizock BA. Risk of aspiration in patients on enteral nutrition: frequency, relevance, relation
of pneumonia, risk factors, and strategies for risk reduction. Curr Gastroenterol Rep.
2007;9(4):338–344.
Uklej A. Gastric versus post-pyloric feeding: relationship to tolerance, pneumonia risk, and
successful delivery of enteral nutrition. Curr Gastroenterol Rep. 2007;9(4):309–316.
Zhou M, et al. Immune-modulating enteral formulations: optimum components,
appropriate patients, and controversial use of arginine in sepsis. Curr Gastroenterol
Rev. 2007;9(4):329–337.
ABLE 11.2
TAB
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12 PARENTERAL NUTRITION

I. DEFINITION. Parenteral nutrition (PN) is defined as the administration of nutrients

directly into the venous system. PN can be given peripherally into the veins of the arm
or centrally into the subclavian or internal jugular vein or vena cava.
The decision to use peripheral parenteral nutrition (PPN) rather than central
or total parenteral nutrition (CPN or TPN, respectively) is based on the number of calo-
ries to be given as well as the duration of the nutritional support. Concentrated solu-
tions of carbohydrates (CHOs) and amino acids (AAs) providing a large number of
calories are hypertonic and cannot be given into the peripheral veins. Due to their small
size and relatively low blood flow, peripheral veins are irritated by hypertonic solutions
and tend to develop thrombophlebitis. In the larger central veins, the hypertonic solu-
tions are quickly diluted by the rapid blood flow, decreasing the risk of inflammation and
venous thrombosis. Both forms of PN can be used in conjunction with enteral feedings.

II. INDICATIONS. PN should be considered in any patient who cannot ingest or absorb
sufficient calories through the gastrointestinal tract. Table 12-1 lists some of the
disease categories with indications for PN.

III. CENTRAL OR TOTAL PARENTERAL NUTRITION

A. Administration. PN is rather complex. To be practiced successfully and safely, it
should be administered by a trained TPN team using a strict protocol. An effective
TPN team consists of a physician, nutritionist, pharmacist, and nurse.
B. Placement of the central venous catheter
1. Percutaneous subclavian or internal jugular catheter is used for short-term
therapy. The placement of the central line should be done by an experienced
physician using standard protocol.
2. Hickman and/or Groshong-Broviac soft catheters for long-term therapy
(
1 month) are silicone (Silastic) catheters with single- or double-lumen tubing
and externally needled Luer-Lok caps, which are inserted by an experienced
physician under fluoroscopy. They are tunneled and anchored subcutaneously
with a polyester (Dacron) cuff.
C. Mechanical complications of central catheterization. Each of the following
complications should be expected and handled expediently by the TPN team:
1. Pneumothorax
2. Hemothorax, hydrothorax, or chylothorax
3. Pericardial effusion with tamponade
4. Arterial puncture
5. Brachial plexus injury
6. Catheter embolism
7. Air embolism
8. Venous thrombosis and thrombophlebitis
D. Catheter care. Patients receiving TPN often have an increased risk of infection. The
predisposing factors include malnutrition, immune incompetence, steroid treatment
or chemotherapy, concomitant infections, broad-spectrum antibiotic therapy, and
presence of a foreign body (the catheter) in the vascular system. TPN-related infection
may result from contamination of the catheter by skin flora, contamination of the
TPN solution or tubing, or bacteremia originating from another source in the body.

62
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Chapter 12: Parenteral Nutrition 63

TABLE 12-1 Indications for Parenteral Nutrition

Gastrointestinal disease
Inflammatory bowel disease
Radiation enteritis
Short-bowel syndrome
Severe malabsorption state
Intestinal fistula
Pancreatitis
Diverticulitis
Intestinal obstruction
Preoperative preparation of malnourished patients
Carcinoma of the head and neck
Esophageal stricture or carcinoma
Tracheoseophageal fistula
Gastric outlet obstruction
Severe peptic ulcer disease
Inflammatory bowel disease
Postoperative surgical complications
Paralytic ileus
Gastrointestinal tract fistula
Enterocutaneous fistula
Pancreatic or biliary fistula
Miscellaneous
Extensive burns or trauma
Cancer patients receiving radiation or chemotherapy
Anorexia nervosa
Some forms of liver disease
Renal failure

Most pathogens responsible for infected catheters originate from superficial sites such
as tracheostomies or abdominal wounds. The most common organisms associated
with catheter infections are: Staphylococcus epidermidis, Staphylococcus aureus,
Klebsiella pneumoniae, and Candida albicans.
A specific procedure using aseptic technique must be followed in the care of
the catheter and dressing. The catheter should be used exclusively for TPN and not
for any other purpose (e.g., blood drawing; central venous pressure measurement;
administration of drugs, antibiotics, or blood products).
E. Caloric requirements. Nutritional support regimens are usually based on estimates
of energy expenditure. These estimates were thought to be increased substantially in
patients with severe trauma or sepsis because of a presumed hypermetabolic state.
However, using actual energy expenditure measurements, a large increase in the
metabolic rate has not been seen in stressed patients. Excessive caloric intake can
produce complications such as hepatomegaly and liver dysfunction due to fatty infil-
tration of the liver, respiratory insufficiency due to excessive carbon dioxide produc-
tion during increased lipogenesis, and hyperglycemia with osmotic diuresis due to
glucose intolerance.
1. A patient’s energy requirements depend on a number of factors, including
age, sex, height, and degree of hypermetabolism. Resting energy expenditure
(REE) may be measured using the principles of indirect calorimetry from mea-
surements of carbon dioxide production and oxygen consumption. If metabolic
nutritional analysis is not available, it is possible to estimate the basal energy
expenditure (BEE) using the Harris–Benedict equation.
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64 Part III: Nutritional Assessment and Management

2. The Harris–Benedict equation offers a reasonable estimate of energy expendi-

ture but generally overestimates at smaller body sizes and smaller body energy
expenditures (W  weight in kilograms, H  height in centimeters, A  age in
years).
a. Men. BEE  66  (13.7  W)  (5  H)  (6.8  A)
b. Women. BEE  655  (9.6  W)  (1.7  H)  (4.7  A)
3. Most studies now suggest that a 12% to 40% increase over estimated BEE is an
appropriate adjustment for septic or injured or critically ill patients requir-
ing mechanical ventilation. One must increase the BEE by an additional 15% to
account for the calories required for utilization of TPN.
4. In summary, if a patient is not stressed by sepsis or trauma, a 15% increase in
BEE is needed to provide the energy necessary to utilize the nutrients provided
by TPN. If the patient requires mechanical ventilation, a 20% to 25% increase
in BEE is needed, and if the patient has evidence of hypermetabolism from sepsis
or injury, an increase of 30% to 40% in BEE may be required.
F. Protein and nitrogen requirements. The healthy individual needs 0.8 g of pro-
tein per kilogram of ideal body weight. Needs may increase up to 2.5 g/kg because
of stress. To replace protein lost because of stress or to promote anabolism, 1.2 to
1.5 g/kg is frequently used.
Another common way of estimating protein needs is to use the nonprotein
calorie-to-nitrogen ratio. The ratios of 100 to 150 kcal:1 g of nitrogen in stressful
conditions to promote anabolism and 250 to 300 kcal:1 g of nitrogen for normal
body maintenance are often used. The nonprotein calorie-to-nitrogen ratio is based
on the premise that sufficient calories must be ingested before protein will be used
for tissue maintenance and repair, that is, 100 to 150 kcal is needed to lay down
1 g of nitrogen.

Ideal calorie–nitrogen ratio  150:1

Protein (gm)/150  6.25  energy requirement in kilocalories
1 g of nitrogen  6.25 g of protein

AAs are administered as a substrate for anabolism rather than as an energy

substrate except in patients with burns or severe sepsis who cannot utilize lipid or
glucose effectively and require AA as a substrate for both energy and anabolism.
AA solutions containing a higher concentration of the branched-chain AAs
(BCAA), leucine, isoleucine, and valine, may be metabolized more effectively in
patients with hypercatabolic states, such as sepsis and trauma. In some studies, it
was noted that septic or injured patients treated with BCAA rather than a conven-
tional AA solution had more rapid improvements in nitrogen balance, total lym-
phocyte count, and delayed hypersensitivity. Because BCAA solutions require a
hypermetabolic state to exert their beneficial effects, they should not be used
routinely.
G. Nutrient sources. Balanced intake of seven groups of nutrients is needed daily.
These are CHOs, lipids, proteins, electrolytes, trace elements, and water. These are
ordered by the physician daily.
Glucose solutions and lipid emulsions are calorie sources (energy substrate)
used in PN except in patients with burns or severe sepsis who are unable to utilize
lipid or glucose effectively. In these patients AAs, preferably BCAAs, are used as
both an energy source and a substrate for anabolism. If glucose is used as the exclu-
sive energy substrate in TPN solutions, carbon dioxide production increases
markedly with increased glucose loading (
40 kcal/kg per day) because there is
increased lipogenesis (net fat synthesis) relative to glucose oxidation. In addition to
increased carbon dioxide production, resulting in an increase of the respiratory
quotient above 1, there is also an increase in oxygen consumption because fat synthe-
sis requires energy. Therefore, large amounts of glucose may constitute a metabolic
stress and cause carbon dioxide retention where respiratory function is impaired.
Using lipids plus glucose, instead of isocaloric amounts of glucose alone, decreases the
respiratory workload in patients with compromised pulmonary function. Fat is
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Chapter 12: Parenteral Nutrition 65

the favored energy source in sepsis, in which glucose utilization is depressed with
increased insulin resistance. It is recommended that in the septic hypermetabolic
patient, glucose intake be restricted to one half or less of the REE.

IV. TPN SOLUTIONS

A. Dextrose solutions (CHO source). Commonly used dextrose solutions are 5%
(170 kcal/L), 10% (340 kcal/ L), 50% (1,700 kcal /L), and 70% (2,380 kcal/L).
B. Protein solutions. Commonly used AA solutions are 3.5%, 8.5%, 10%, and 11.4%.
C. Lipid emulsions. Lipid 10% (500 mL [1.1 kcal/mL]) or 20% (500 mL [2.0 kcal/mL]).

V. CALCULATIONS OF NUTRIENT VALUES FOR TPN

A. CHO
1. CHO (g)  dextrose 50%(mL)  0.5 or dextrose 70%(mL)  0.7
2. CHO (kcal)  3.4  CHO(g) or 3.4 kcal/g of CHO
Dextrose 50%  1.7 kcal/mL or 1,700 kcal/L
Dextrose 70%  2.38 kcal/mL or 2,380 kcal/L
3. Maximum glucose utilization rate  5 mg /kg per minute or 40 kcal/kg per
24 hours
B. Protein
1. Protein (g)  10% AAs  0.1 g protein/mL
 3.5% AAs  0.03 g protein/mL
 8.5% AAs  0.085 g protein/mL
 11.4% Novamine  0.114 g protein/mL
 6.9% FreAmine HBC  0.069 g protein/mL
 8.0% Hepatamine  0.08 g protein/mL
2. 1 g of protein  4.3 kcal
C. Fat
1. Lipids are available as emulsions of cottonseed, soy, and safflower oils and of
glycerol. These emulsions are isotonic and may be administered peripherally or
centrally.
2. The maximum fat allowance  2.5 g/kg per day.
3. Not more than 60% to 70% of total calories per day should be from fat.
4. Lipid is given daily to most patients on TPN to supply 30% to 50% of the total
energy requirements and essential fatty acids. In most medical centers, 20%
lipid solutions are preferred, and the lipid is directly added to the CHO and
protein solutions. The combined mixture is administered to the patient.
5. In a minority of patients, acute respiratory distress, hypoxemia, and cyanosis
may develop at the initial exposure to lipid emulsions. The rate of administra-
tion of the initial dose of lipid should be 1 mL per minute for 30 minutes. If no
problems occur, the infusion rate may be increased up to 100 mL per hour.
Serum triglyceride and cholesterol levels should be determined before and
4 hours after the onset of the infusion to document the utilization of the lipid.
D. TPN nutrient composition is determined by the extent of the patient’s ability to
utilize lipid as an energy source. The TPN solution in a septic or injured patient
should provide an energy–nitrogen ratio of 80 to 200 kcal /g of energy to 13 to
32 kcal/g of protein. An energy–protein ratio of 24 kcal/g of energy to 150 kcal/g
of nitrogen may be ideal in hospitalized patients.
E. Maintenance fluid requirements
1. First 10 kg of body weight  1,000 mL.
2. Next 10 kg of body weight  500 mL.
3. Each kilogram of body weight thereafter  20 mL.
4. In critically ill patients who are receiving TPN, close attention must be given to
the patient’s volume status. Strict monitoring of the intake, output, daily weight,
and hemodynamic status is essential. In most patients, total fluid intake may
be calculated as equal to output plus 500 to 800 mL per day to cover the
insensible losses. This additional amount may not be necessary in patients on
ventilation.
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66 Part III: Nutritional Assessment and Management

VI. EXAMPLES OF CALCULATIONS FOR TPN IN DISEASE STATES

A. Sepsis
1. Calories  BEE
2. Provide 50% of calories as fat and 50% of calories as CHO. Maximum glucose
utilization rate  4 mg/kg per minute or 25 kcal/kg per 24 hours
3. Protein. 100 to 150:1  calorie–nitrogen ratio
4. 2 g protein/kg of ideal body weight
B. Respiratory failure
1. Calories  1.5  BEE
2. Provide 50% of calories as fat and 50% as CHO
3. Maximum glucose utilization rate  4 mg /kg per minute or 25 kcal /kg per
24 hours
4. Protein. 100 to 150:1  calorie–nitrogen ratio
5. 1.5 to 2.0 g protein/kg of ideal body weight
C. Renal failure
1. Calories: maintenance to anabolic as needed
2. Protein
a. Without dialysis, 20 to 60 g per day depending on blood urea nitrogen,
creatinine, and body weight
b. With dialysis, 701 g per day depending on blood urea nitrogen, creatinine,
and body weight
c. 1.0 to 1.2 g protein/kg of ideal body weight can be provided as
i. AA solution
ii. Solution containing essential AAs (e.g., Nephramine)
D. Hepatic failure
1. Calories  1.5  BEE (maintenance requirements)
2. Provide 50% or more of calories as fat and 50% or less as CHO.
3. Protein can be provided as
a. Standard AA solution
b. AA solution containing branched-chain AAs (e.g., Hepatamine) at 701 g of
protein per day

VII. EXAMPLE. Patient is a 30-year-old woman with Crohn’s disease who has an ileocolic
fistula and requires TPN prior to surgery: weight (W)  50 kg (110 lbs), height (H) 
166.4 cm (5 ft 1/2 in.)
A. Energy requirements per day
1. BEE  655  (9.6  W)  (1.7  H)  (4.7  age)
For this patient:
BEE  655  (9.6  50)  (1.7  166.4)  (4.7  30)  1,300 kcal per day
2. Parenteral anabolic requirements  1.8  BEE
 1.8  1,300 kcal per day
 2,300 kcal per day
B. Protein requirements per day
1. Ideal kcal per nitrogen ratio  150:1
2. 1 g nitrogen  6.25 g of protein
3. Protein (g)  6.25  energy requirement per day
150
4. This patient needs
Protein (g)  6.25  2,300 kcal per day
150
 100 g
5. To provide 100 g of protein per day, 1,000 mL of 10% aminosyn solution is needed.
C. Fluid requirements per day
1,000  500  20 (30)  2,100 mL per day
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Chapter 12: Parenteral Nutrition 67

D. Maximum fat allowance per day

2.5  50  9  1,125 kcal per day
For this patient, this is approximately 50% of the total daily calories.
E. Final TPN solution per day
1. Solution Volume (mL) Kcal
10% AA 1,000 01
50% dextrose 1,000 1,7002
20% lipid 300 600
Total 2,300 2,300
2. If more of the calories are to be given as fat, then use
Solution Volume (mL) Kcal
10% AA 1,000 01
50% dextrose 700 1,2002
20% lipid 550 1,100
Distilled water 50 0
Total 2,300 2,300
3. As can be seen in 1 and 2, the volume of CHO and lipid solutions can be
manipulated, and other permutations can be worked out to achieve the total
number of calories and total volume of fluid.
4. When the fluid volume needs to be restricted, as in patients with heart failure
or renal insufficiency, more concentrated solutions, for example, 70% dex-
trose, 11.4% AA, and 20% lipid, may be used.
5. Distilled water can be added to the final solution to bring the volume to the
desired amount.

VIII. ADDITIVES. The basic TPN solution does not contain electrolytes, trace elements, or
vitamins. The electrolyte additives to TPN must be individualized to prevent fluid
and electrolyte abnormalities.
A. Electrolytes (Table 12-2)
1. Sodium (Na), the principal extracellular cation, must be administered in suffi-
cient quantities to provide for maintenance needs and to replace any existing
deficits or ongoing losses. The quantity of Na added to TPN is determined by the
patient’s extracellular fluid volume status and serum Na concentration. Patients

TABLE 12-2 Electrolytes

Additives Usual daily requirements

Sodium chloride
Sodium acetate
60–200 mEq Na

Potassium chloride
Potassium acetate
50–150 mEq K

Sodium phosphate 50–150 mM PO4
Potassium phosphate
Magnesium sulfate 8–24 mEq Mg
Calcium gluconate 8–32 mEq Ca

Na, sodium; K, potassium; Mg, magnesium; Ca, calcium.

1 Calories from AAs are not used in calculation for energy.

2 See section V.A for calculation of CHO calories from dextrose solutions.
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68 Part III: Nutritional Assessment and Management

with hyponatremia should receive larger quantities of Na to limit free water

administration (e.g., 75 to 120 mEq/L of TPN), whereas patients with hyperna-
tremia or extracellular fluid excess require less Na (e.g., 30 mEq/L of TPN). Na
may be administered as the chloride, phosphate, acetate, or bicarbonate salt.
2. Chloride (Cl), the predominant extracellular cation, is given as sodium and potas-
sium salts. Chloride excess in TPN may cause hyperchloremic metabolic acidosis.
3. Acetate is metabolized to bicarbonate in the body and should be included in
the TPN solution to counteract acidosis at doses of 50 to 120 mEq per day.
4. Potassium (K) is the major intracellular cation. It is needed in large amounts
during anabolism. Hypokalemia readily develops in patients receiving TPN. K
is lost with diuresis resulting from hyperglycemia induced by TPN. Increased
plasma insulin concentration during TPN is associated with activation of the
Na-K–ATPase pump, resulting in the shift of K from the extracellular space to
the intracellular space. Beta-adrenergic stimulation and administration of vaso-
pressors and inotropic agents also activate the Na-K–ATPase pump and may
lead to clinically significant hypokalemia mediated by transcellular shifts of K.
Patients with a normal plasma potassium level when TPN is initiated may
receive 20 to 30 mEq of K per liter of TPN initially. Subsequent changes should
be made according to the serum K level. K may be administered as the Cl or the
phosphate salt depending on the serum phosphate concentration.
5. Magnesium (Mg) deficiency may occur in patients with history of alcoholism,
malabsorption, malnutrition, or parathyroid disease and due to magnesia urea
accompanying aminoglycoside therapy. During TPN, Mg is incorporated into
newly synthesized muscle tissue and bone stores. It should be provided in the
TPN solutions with special attention to the patient’s renal status since Mg is
excreted by the kidneys. Patients with mild hypomagnesemia with serum Mg
levels of 1.2 to 1.8 mEq/L should receive 2.5 to 5.0 mEq (1–2 mL) of a 50%
solution of Mg sulfate in each liter of TPN. More severe Mg deficiency needs
additional intravenous (IV) supplementation.
6. Phosphate is a component of nucleic acids, phosphoproteins, and lipids and is
needed to form high energy bonds and 2,3-diphosphoglycerate in red blood
cells and for bone metabolism. Hypophosphatemia and total body phosphate
depletion often complicate stress-starvation and refeeding states. The hyperme-
tabolism seen in sepsis and injury results in skeletal muscle catabolism and
depletion of intracellular phosphate stores. Hypophosphatemia may be exacer-
bated during TPN, with glucose infusions resulting in shifts of phosphate from
extra- to intracellular space, similar to that seen with K.
Phosphate should be included in the daily TPN orders. A reasonable ini-
tial dose of phosphate for septic or injured patients receiving TPN is 15 to 30
mmol per day. Phosphate may be administered as either an Na or a K salt
depending on the serum K concentration.
7. Calcium (Ca), like magnesium, should be provided daily. Hypercatabolic states
(e.g., sepsis or injury) may be associated with increased excretion of Ca.
Mobilization of Ca from bone results in reductions in total body Ca. Vitamin
D deficiency also leads to Ca deficiency. Because Mg is required for the secre-
tion and end-organ effect of parathyroid hormone, hypocalcemia may result
from hypomagnesemia. Approximately 50% to 60% of serum Ca is bound to
albumin. In hypoalbuminemic patients, serum Ca concentrations may be falsely
low. To adjust the measured serum Ca for hypoalbuminemia, the following for-
mula may be used:
Serum Ca  4.0  serum albumin (0.8 g/dL)  corrected serum Ca
Patients with corrected low serum Ca levels should receive 5 mEq of Ca as
the gluconate or the gluceptate salt in each liter of TPN solution.
8. Buffers. Metabolic acidosis may develop during TPN therapy. The oxidation
of cationic and sulfur-containing AAs results in the production of hydrogen
ions. When serum bicarbonate or total carbon dioxide binding capacity falls
below 20 mEq/L, a portion of the Na in the TPN solution (e.g., 25–30 mEq/L)
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Chapter 12: Parenteral Nutrition 69

may be administered as acetate. Acetate is metabolized by the liver to yield

bicarbonate. In patients with hepatic dysfunction, sodium bicarbonate (e.g.,
25–50 mEq/L) may be used to correct the metabolic acidosis.
B. Vitamins. Water-soluble forms of vitamins A, D, and E along with vitamin C, B
vitamins, biotin, folate, and B12 (packaged as multivitamins-12) 5 mL should be
added daily in amounts exceeding the recommended daily allowances to the TPN
solutions. Vitamin K 10 to 25 mg weekly is given intramuscularly separately and
should not be given to patients receiving anticoagulants. Patients requiring
hemodialysis should receive 1 mg/dL of folic acid, because folic acid is removed by
dialysis.
C. Trace elements. Chromium, manganese, copper, selenium, and zinc are needed
daily and should be added to the TPN solution as trace elements (3–5 mL). Some
authors advocate the administration of a unit of plasma every 3 to 4 weeks to pro-
vide undefined cofactors.
D. Heparin. Use of heparin, 1,000 U/L of TPN solution, has been shown to enhance
vein and line patency and is recommended.
E. Albumin. In states of severe protein depletion (serum albumin 2.0 g /dL), the
administration of salt-poor albumin may be helpful.
F. Regular insulin in crystalline form may be added to the TPN solution to cover
patients with persistent hyperglycemia or glycosuria. It is generally not needed as
an additive in the average patient.
Hyperglycemia may develop during TPN therapy even in previously nondia-
betic patients. The serum glucose concentrations should be maintained at 100 to
200 mg /dL. When a patient has hyperglycemia greater than 200 mg /dL, regular
human insulin should be added to the TPN solution in an initial dose of 5 to
10 U/L. The rate of TPN administration should not be altered to treat the
hyperglycemia; rather, the hyperglycemia should be controlled with either IV or
subcutaneous regular insulin, using a sliding scale based on the serum glucose
concentration. Regular insulin may be administered IV every 2 to 3 hours. An
example of a sliding scale is as follows:
Serum Glucose Level Regular Insulin
200 to 300 mg/dL 2 to 3 units
300 to 400 mg/dL 3 to 5 units
400  mg/dL 5 to 10 units
If hyperglycemia cannot be controlled by intermittent IV insulin, insulin may
be infused continuously to control the patient’s serum glucose level. One adds 250
units of insulin to 250 mL of normal saline; infusion may be started at a rate of
3 units per hour and adjusted according to the patient’s serum glucose concentra-
tion. The regular insulin dose may be increased once each day until the serum glu-
cose stabilizes at 100 to 200 mg/dL. The increase in insulin dose may be calculated
as one half the IV dose of the previous 24 hours.

IX. INITIATING, TAPERING, AND DISCONTINUING TPN SOLUTION

A. The initiation of TPN therapy should be done gradually according to the patient’s
glucose tolerance and individual requirements. On the first day, 1,000 mL may be
given, then 2,000 mL the second day, and 3,000 mL or more the third day.
B. When stopping TPN solutions, it is recommended the solution be tapered over
48 hours. However, TPN solutions can be reduced to a drip rate of 50 mL per
hour. After 30 to 60 minutes at this rate, the solution can be discontinued. Rarely,
a patient may experience hypoglycemia.
C. TPN solutions are commonly infused at a continuous rate evenly over 24 hours. If
infusion falls behind, it should not be caught up rapidly. This may cause glyco-
suria and diuresis. It is usually possible to increase the drip rate by 10% to 20%
in catch-up situations.
Example: A 52-year-old man is admitted to the intensive care unit with ileus and
multilobar pneumonia requiring ventilatory support. He has severe protein–calorie
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70 Part III: Nutritional Assessment and Management

malnutrition with a total lymphocyte count of 800 and a serum albumin level
of 1.8 g/dL. His serum chemistries are:
Na: 133 mEq/L Cl: 96 mEq/L Creatinine: 1.1 mg/dL
K: 3.4 mEq/L HCO3: 19 mEq/L BUN: 13
W: 80 kg H: 180 cm Age (A): 52 years
BEE  66  (13.7  W)  (5  H) – (6.8  A)
 66  (13.7  80)  (5  180) – (6.8  52) years
 1,708 kcal
This patient has sepsis and requires mechanical ventilation. REE should exceed
BEE by 30%.
REE  BEE  1.3
 1,708  1.3  2,221 kcal
Minimal protein requirement  1.0 to 1.5 kg per day
TPN Solution
1 L AA 10% 100 g protein (16 g nitrogen)
1 L 50% D/ W 500 g dextrose 175 kcal
500 mL 10% Intralipid 550 kcal
Total kcal per day 2,300 kcal
This formula provides 44.2 kcal/kg (76% glucose, 24% lipid)
Energy–nitrogen ratio  144 kcal/g nitrogen
 23 kcal/g, protein
Electrolytes to be added to each liter of TPN:
Sodium chloride (NaCl): 50 mEq
Potassium chloride (KCl): 20 mEq
Magnesium sulfate (MgSO4): 5 mEq
Na acetate: 25 mEq KPO4: 10 mEq
Administration Orders
Day 1 (infuse over 24 hours)
AA 10% 500 mL
50% D/ W 500 mL
Electrolytes (as above)
Multivitamins 5 mL
Trace elements 5 mL
Lipid emulsion 10% 500 mL
Day 2 (infuse over 24 hours)
AA 10% 1,000 mL
50% D/ W 1,000 mL
Electrolytes (as above)
Multivitamins 5 mL
Trace elements 5 mL
Lipid emulsion 10% 500 mL

X. MONITORING OF THE PATIENT ON TPN

A. Monitor patient’s intake and output.
B. Obtain baseline weight and height. Check weight daily at the same time of day.
C. Check vital signs every 4 hours. If the temperature exceeds 38C, the physician
should be notified.
D. Laboratory evaluation. Obtain baseline laboratory values for 24-hour urine for
creatinine and urea nitrogen, serum chemistries (SMA-12), electrolytes, magnesium,
transferrin, triglycerides, complete blood count with differential, and platelet count.
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Chapter 12: Parenteral Nutrition 71

After the TPN is initiated, the concentrations of serum electrolytes and phosphorus
should be determined twice a day until daily requirements are ascertained. Serum
glucose concentration should be measured every 4 to 6 hours. Serum Ca, Mg,
creatinine, and blood urea nitrogen (BUN) should be determined daily. When the
patient is stabilized on TPN, serum electrolytes, creatinine, and BUN should be
measured every other day. Ca and Mg levels may be measured twice weekly. Serum
transaminase, alkaline phosphate, and bilirubin levels should be measured weekly
to facilitate early diagnosis of hepatic steatosis.
To determine the efficacy of TPN therapy, the total lymphocyte count and
serum albumin and transferrin levels should be measured on a weekly basis. The
optimal method for assessing the adequacy of TPN is through nitrogen balance
studies. A 24-hour urine sample is collected for the urea and creatinine determina-
tions. To calculate a patient’s nitrogen balance see section III.F.
If lipids are given in addition to the TPN on a daily basis, serum triglyceride lev-
els should be measured daily for several days to document that the lipid load is not
exceeding the patient’s metabolic capabilities. Serum triglyceride concentrations may
be measured weekly when patients are on a stable TPN regimen.

XI. COMPLICATIONS OF TPN

A. Hyperglycemia. Patients with overt or latent diabetes, liver disease, or acute or
chronic pancreatitis are at risk of development of hyperglycemia and glycosuria.
This may result in hyperosmolar nonketotic coma and dehydration. Slow infu-
sions of TPN initially with frequent glucose determinations should minimize this
complication.
B. Hypoglycemia. Abrupt cessation of TPN may precipitate this condition. Peripheral
10% glucose should be given for treatment.
C. Hypo- and hyperkalemia, calcemia, magnesemia, and phosphatemia should
be avoided by administration of adequate amounts of these minerals with regular
measurement of serum values.
D. Azotemia. The delivery of a high nitrogen load may lead to a modest elevation of
the blood urea nitrogen. Dehydration and prerenal states should be avoided.
E. Acute thiamine deficiency may complicate TPN in patients with chronic alcohol
abuse, sepsis, or injury who are not receiving multivitamins in the TPN solution.
Acute thiamine deficiency is characterized by severe lactic acidosis refractory to
bicarbonate therapy, high output, cardiac failure, confusion, and hypotension. The
lactic acidosis responds only to thiamine infusions.
F. Adverse reactions to lipid infusions. Long-term adverse reactions to a lipid infu-
sion, especially if it exceeds 2.5 g/kg per day, include lipid accumulation in the
lungs, decreasing oxygen diffusing capacity, and in the liver, impairment of biliary
function. Fat infusions greater than 4 g/kg per day may lead to a bleeding diathe-
sis (fat-overload syndrome). Thrombocytopenia, platelet dysfunction, and bleeding
tendency are reversible with reduction of the infusion rate.
G. Acute fatty infiltration of the liver or hepatic steatosis may complicate TPN
with glucose-predominant regimens. The glucose in such formulations is converted
by the hepatocytes to fat and deposited in the liver parenchyma. Patients with
hepatic steatosis exhibit cholestatic jaundice with elevations of serum alkaline
phosphatase and bilirubin levels. Lipid-predominant or mixed lipid-glucose for-
mulations rarely lead to hepatic steatosis.
Calculous and acalculous cholecystitis occurs in approximately 45% of
patients undergoing long-term TPN. Impaired biliary motor function, stasis, sludge
formation, and stones contribute to the pathogenesis. This complication is more
prevalent in patients with hematologic malignancies.
H. Taurine deficiency. Parenteral solutions do not contain this nonessential AA.
Reduced taurine levels may be found in children and adults on long-term home
TPN. Taurine deficiency causes retinal dysfunction, and its addition to TPN solu-
tions reverses this condition.
I. Carnitine deficiency. Carnitine may be required during metabolic response to
injury. It is required for fatty acid oxidation in skeletal and cardiac muscles. In
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72 Part III: Nutritional Assessment and Management

deficiency states, hyperbilirubinemia, generalized muscle weakness, and reactive

hypoglycemia have been reported. Red cell carnitine and plasma carnitine should
be measured.
J. Biotin deficiency. Hair loss, eczematous dermatitis, waxy pallor of skin, lethargy,
depression, and anemia has been reported with biotin deficiency in patients on
long-term TPN.
K. Selenium deficiency. A dilated cardiomyopathy associated with diffuse focal
myocardial necrosis and conduction defects has been reported due to deficiency of
selenium. Gastrointestinal fluid losses enhance selenium losses.
L. Respiratory complications. Protein–calorie malnutrition may be associated with
respiratory muscle failure. Ventilator-dependent patients are more likely to be
weaned successfully from ventilators after nutritional deficits are corrected.
AA infusions may increase ventilatory responsiveness to carbon dioxide.
High-glucose TPN regimens are associated with an increased respiratory quotient
and carbon dioxide production. These patients should receive TPN regimens that
contain a larger fraction of lipid as energy substrate because lipid has a lower res-
piratory quotient than glucose and results in less carbon dioxide production.
M. Protein-calorie mismatch. Most TPN regimens provide an energy–nitrogen ratio
of 80 to 200 kcal/g of nitrogen or 13 to 32 kcal/g of protein. If inadequate energy
source in the form of glucose or lipid is administered, the patient utilizes AAs as an
energy source. The metabolism of the AAs results in progressive increases in BUN
levels out of proportion to creatinine levels. Protein–calorie mismatch may occur
in patients with burns, severe hypermetabolism, or renal failure. This complication
is managed by increasing the energy–nitrogen ratio either by reducing the
administered amount of AA or increasing the level of nonprotein energy substrate.
N. Catheter infection. Sepsis occurs in fewer than 5% of all patients undergoing
TPN. The incidence is clearly related to the catheter, dressings, and solutions.
Catheter sepsis should be suspected whenever there is unexplained fever and leuko-
cytosis in the absence of other sources. Blood, urine, sputum, and wound cultures
should be obtained. The TPN bottle and tubing should be changed and cultured
with each fever spike. A blood culture should be drawn through the TPN catheter.
The catheter should be removed and the tip cultured if the blood culture is posi-
tive. The catheter should not be reinserted for 24 to 48 hours to allow the blood-
stream to clear. Dextrose 10% should be administered peripherally during this
time. Treatment involves coverage of the patient for the causative organism with
intravenous antimicrobials.

XII. PERIPHERAL PARENTERAL NUTRITION

A. Indications. PPN can be used for
1. Patients in whom a central line is precluded.
2. Patients in whom short-term nutritional support is important (e.g., selected pre-
and postoperative patients).
3. Patients who are eating but not getting sufficient calories.
B. Advantages of PPN
1. Placement of a peripheral intravenous line is safer than the placement of a cen-
tral line.
2. Infection control at infusion site is easier.
3. Nursing care is less complicated.
4. The complications of hyperosmolar glucose are avoided.
C. Disadvantages of PPN
1. Hyperosmolar solutions cannot be used in PPN because they irritate the periph-
eral veins and cause thrombophlebitis.
2. The volume of solution required to deliver an adequate number of calories may
be too high, thus limiting the number of calories given.
3. The number of calories that can be given may be inadequate for long-term
anabolism.
D. PPN solutions. A mixture of dextrose and AA solutions is used. A major portion
of nonprotein calories can be provided by the use of lipid emulsions. Peripheral
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Chapter 12: Parenteral Nutrition 73

vein tolerance for osmolality is about 800 mOsm/L. The osmolality of a solution
can be calculated as follows:
Osm (mOsm/L)  10  protein (g)  6  CHO (g)
 (0.3  mL 20% Intralipid) total fluid (liter)
E. Example. For the patient receiving the TPN solution described in section VII.E
1. The osmolality of the TPN solution can be calculated as follows:
Protein  100 g, CHO  1,700 kcal  500 g3
Osm (mOsm/L)
 10(100)  6(353)  0.3(550)  1,427
2.3
This solution is too hyperosmolar to be used in PPN.
2. The osmolality can be decreased by increasing the total volume of the solu-
tion. Because 800 mOsm/L is the desired osmolality, we can solve for total
volume needed to give osmolality of 800 mOsm/L.
800  10(100)  6(353)  0.3(550)
total fluid volume in liter
Total volume  4 L
3. Most patients cannot tolerate such high volumes of IV fluids; thus PPN can
only deliver maintenance amounts of calories.
4. For this patient the maintenance energy requirement is
BEE  1.5  1.5  1,300  1,900 kcal per day
5. The maintenance protein requirement is
Protein  6.25  1,900  80 g per day
150
6. Maximum fat allowance 1,125 kcal per day
7. Final PPN solution per day:
Solution Volume (mL) Kcal
10% AA 800 —
50% dextrose 4703 800
20% Intralipid 550 1,100
Total 1,820 1,900
8. Total volume to allow 800 mOsm/L
10(80)  6(235)  0.3(550)
3L
800
9. To bring the total volume of PPN solution to 3 L, we need to add 1,180 mL
of distilled water.
10. Adequate electrolytes, vitamins, and trace elements as in TPN are added to the
final solution if the patient is not receiving these nutrients enterally.
In many instances, if the PPN is to be administered for a short time a
more simplified PPN solution may be made from:
Solution Volume (mL) Kcal Amount (g) Osmolality (mOsm/L)
8.5 % AA 1,000 340 85 850
10% Dextrose 1,000 340 100 505
10% Lipid 500 550 50 260
Total 2,500 1,230 235 595
F. Method of administration. The protein and CHO solution may be given simulta-
neously with the lipid emulsion. The infusion sets are connected by a Y-connector

3 CHO (g)
 kcal (see section V.A).
3.4
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74 Part III: Nutritional Assessment and Management

that delivers the lipid emulsion to the vein in a piggybacked fashion. This method
seems to “soothe” the vein and decrease the incidence of phlebitis. In most medical
centers, the PPN solutions contain the lipid, CHO, and protein solutions mixed
together into an emulsion. This eliminates the need for piggybacking of the lipid
emulsion. The management and monitoring of patients receiving PPN are the same
as for those receiving TPN, and the same meticulous care and team approach are
necessary to give the best results.

Selected Readings
Bistrian BR, et al. Nutritional and metabolic support in the adult intensive care unit: Key
controversies. Crit Care Med. 2006;34:1525–1531.
Cheung NW, et al. Hyperglycemia is associated with adverse outcomes in patients receiving
total parenteral nutrition. Diabetes Care. 2005;28:2367–2371.
Heller AR, Rossler S, Litz RJ, et al. Omega-3 fatty acids improve the diagnosis-related
clinical outcome. Crit Care Med. 2006;34:972–979.
Huschak G, et al. Olive oil based nutrition in multiple trauma patients: a pilot study. Intensive
Care Med. 2005;31:1202–1208.
Krein SL, et al. Use of central venous catheter-related bloodstream infection prevention
practices by US hospitals. Mayo Clin Proc. 2007;82:672–678.
Kudsk KA. Immunonutrition in surgery and critical care. Annu Rev Nutr. 2006;26:463–479.
Marik PE. Maximizing efficacy from parenteral nutrition in critical care: appropriate
patient population, supplemental parentral nutrition, glucose control, parenteral
glutamine, and alternative fat sources. Curr Gastroenterol Rep. 2007;9(4):345–353.
Sacks GS, et al. Parenteral nutrition implementation and management. In: Merritt R, ed.
The ASPEN Nutrition Support Practice Manual. 2nd ed. Silver Spring, Md.: American
Society for Parenteral & Enteral Nutrition; 2005:108–117.
van der Voort PH, et al. Intravenous glucose intake independently related to intensive care
unit and hospital mortality: an argument for glucose toxicity in critically ill patients.
Clin Endocrinol. 2006;64:141–145.
Waitzberg DL, et al. Postsurgical infections are reduced with specialized nutrition support.
World J Surg. 2006;30:1592–1604.
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Gastroenterologic Emergencies IV
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THE ACUTE ABDOMEN 13

T he term acute abdomen evokes an image of a patient suffering from sudden, severe
abdominal pain, perhaps accompanied by vomiting, attentively surrounded by physicians
and surgeons who are earnestly deciding whether to take the patient to the operating room.
Indeed, many instances of acute abdomen are surgical emergencies. However, the differen-
tial diagnosis is extensive, and the management of an acute abdomen varies according to
the diagnosis.

I. DIFFERENTIAL DIAGNOSIS. The differential diagnosis in a patient with an acute

abdomen may be broad or narrow, depending on the clinical signs and symptoms. For
example, a 12-year-old boy whose generalized abdominal pain has intensified and
become localized to the right lower quadrant very likely has acute appendicitis, but
acute Crohn’s disease and mesenteric lymphadenitis must also be considered. On the
other hand, severe midabdominal pain in a 65-year-old man with ascites may indicate
spontaneous bacterial peritonitis, intestinal ischemia, a perforated ulcer, or a leaking
aortic aneurysm, among other possibilities.
A partial list of the diagnostic considerations for an acute abdomen is found in
Table 13-1.

II. CLINICAL PRESENTATION

A. History
1. Pain
a. Types. Abdominal pain is an invariable feature of an acute abdomen and
presents as one or a combination of three types.
i. Visceral pain develops from stretching or distending of an abdominal
viscus or from inflammation. The pain is diffuse and poorly localized. It
generally has a gnawing, burning, or cramping quality.
ii. Somatic pain arises from the abdominal wall, the parietal peritoneum,
the root of the mesentery, or the diaphragm. It is more intense and bet-
ter localized than visceral pain.
iii. Referred pain is felt at a site distant from the source of the pain but
shares the same dermatome or neurosegment. Referred pain is usually
sharp and well localized; thus, it resembles somatic pain.
b. The onset of pain may be instantaneous, or the pain may develop over min-
utes or even hours. Sudden severe pain characterizes such events as a perforated
ulcer, a ruptured viscus, a ruptured ectopic pregnancy, a spontaneous pneu-
mothorax, or a dissecting aortic aneurysm. On the other hand, more gradual
development of pain is typical of acute pancreatitis, acute cholecystitis, intesti-
nal obstruction, bowel perforation, diverticulitis, and intraabdominal abscess.
2. Vomiting usually accompanies an acute abdomen to a variable degree. A clinical
rule is that pain precedes vomiting in disorders requiring surgical treatment,
whereas vomiting precedes pain in medically treated disorders. Vomiting can be
persistent, as with intestinal obstruction. Long-standing obstruction may result in
feculent vomiting due to the proximal growth of colonic bacterial flora. Vomiting
of bloody material suggests that the bleeding lesion is above the ligament of Treitz.
3. Other historical aspects. A history of a known disorder, such as pancreatitis
or peptic ulcer, makes that diagnosis more likely as the cause of the current

77
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78 Part IV: Gastroenterologic Emergencies

TABLE 13-1 Diagnostic Considerations in the Acute Abdomen*

Ruptured or perforated viscus

Spontaneous pneumothorax
Ruptured esophagus (Boerhaave’s syndrome)
Ruptured stomach (usually due to trauma)
Perforated peptic ulcer
Ruptured diverticulum (Meckel’s, colonic)
Ruptured spleen
Ruptured ectopic pregnancy
Ruptured or dissecting aortic aneurysm
Ruptured cyst or tumor
Obstruction of a viscus
Intraluminal obstruction of gastrointestinal tract (e.g., peptic stricture, neoplasm,
gallstone ileus)
Intraabdominal adhesions
Intussusception
Intestinal volvulus
Strangulation or torsion of a hernia
Gallstone obstruction of cystic duct (cholecystitis) or common duct
Ureteral stone
Ischemia
Mesenteric infraction
Pulmonary embolus
Myocardial infarction
Inflammation
Appendicitis
Cholecystitis
Pancreatitis
Penetrating ulcer into pancreas
Diverticulitis
Mesenteric lymphadenitis
Abdominal abscess
Cystitis or pyelitis
Pelvic inflammatory disease
Regional enteritis
Toxic megacolon (usually due to ulcerative colitis)
Peritonitis
Spontaneous bacterial peritonitis (in presence of ascites)
Secondary to perforated viscus (e.g., ulcer, diverticulum)
Secondary to inflammatory condition (e.g., cholecystitis, pancreatitis, pelvic inflammatory
disease, toxic megacolon)
Systemic disorders
Narcotic withdrawal
Heavy-metal poisoning
Collagen–vascular disease
Acute porphyria
Familial Mediterranean fever
Hereditary angiodema

* Some diagnoses may fall into more than one category. For example, cholecystitis is an inflammatory
condition of the gallbladder, but it usually develops as a result of obstruction of the cystic duct by a
gallstone.
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Chapter 13: The Acute Abdomen 79

event. If the patient has had abdominal surgery, intraabdominal adhesions

become a consideration. Alcohol abuse may suggest pancreatitis or gallstone
disease.
B. Physical examination
1. Vital signs. Temperature elevation suggests sepsis from intraabdominal inflam-
mation and infection. Tachycardia typically accompanies an acute abdomen.
Blood pressure may also be elevated, although hypotension and shock may
develop in patients with a perforated viscus or severe sepsis.
2. Inspection
a. Patient position. A patient with peritonitis is likely to lie quietly with knees
flexed. A patient with acute pancreatitis finds it uncomfortable to lie on the
back and may assume the fetal position. A patient with colicky pain typi-
cally cannot lie still.
b. The abdomen may be distended due to ascites or intestinal obstruction. In
thin patients with complete obstruction, hyperperistalsis may be visible on the
abdominal wall. Ecchymosis in the flanks (Grey Turner’s sign) or around the
umbilicus (Cullen’s sign) may indicate hemorrhagic pancreatitis or a ruptured
ectopic pregnancy.
3. Auscultation. Peristalsis is increased in partial or complete bowel obstruction;
typically there are rushes and high-pitched sounds. Hypo- or aperistalsis develops
in intestinal ileus from a variety of causes, including peritonitis, electrolyte imbal-
ance, severe inflammation (e.g., toxic megacolon, pancreatitis), and long-standing
intestinal obstruction.
The examiner should listen for vascular bruits and friction rubs. The for-
mer may suggest an aneurysm, whereas the latter can develop after rupture of
the spleen or rupture of a lesion of the liver.
4. Percussion. Tympany typically is present in the distended abdomen of intesti-
nal obstruction or toxic megacolon. Percussion can help in outlining the liver
and may indicate enlargement of other organs.
5. Palpation
a. Patients with an acute abdomen typically have abdominal tenderness. If
peritonitis is present, either localized or generalized, there may be guarding
and rigidity. Localized tenderness may provide a clue to the diagnosis.
Rebound tenderness should be elicited by gently depressing the abdominal
wall with one or two fingers, then quickly releasing the pressure. Sharp pain
on release of the pressure indicates peritoneal inflammation. Because this
maneuver often is so uncomfortable to the patient, it should not be repeated
indiscriminately by subsequent examiners.
One should remember that the signs of peritonitis may be blunted in
elderly or severely ill patients. Thus, presence of little or no tenderness does
not exclude peritonitis in these patients.
b. Gentle palpation also may identify organ enlargement or mass lesions. An
expansile, midabdominal mass may indicate an aortic aneurysm. Patients with
acute Crohn’s disease often have a tender mass in the right lower quadrant.
6. Rectal and pelvic examinations. Examination of the rectum and pelvis may
provide valuable information about the pelvic organs and perirectal tissues.
Tumors, inflammatory masses, abscesses, and pelvic inflammatory disease may
be evident.

III. EVALUATION AND MANAGEMENT OF THE PATIENT

A. Laboratory studies. Laboratory examination of blood and urine may help in estab-
lishing a diagnosis and managing the patient with an acute abdomen (Table 13-2).
1. Complete blood count. White blood cell count (WBC) is usually elevated in
patients with an acute abdomen, particularly in inflammatory and infectious
conditions. WBC may be depressed in severe sepsis, in viremia, and in associa-
tion with immunosuppressive therapy. A low hematocrit and hemoglobin count
may reflect chronic anemia or may result from recent bleeding or rupture of a
blood-filled viscus. Thrombocytopenia may contribute to abdominal bleeding or
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80 Part IV: Gastroenterologic Emergencies

Laboratory and Radiologic Studies in the Evaluation

TABLE 13-2
of the Acute Abdomen

Blood studies
Complete blood count
Electrolytes
Calcium and magnesium
Amylase
Bilirubin, SGOT, SGPT, alkaline phosphatase
Arterial blood gases
Urinalysis
Electrocardiogram
Chest x-ray films
Abdominal x-ray films (flat and upright or decubitus)
Additional studies that may be indicated
Ultrasound scan
CT scan
HIDA scan
Intravenous pyelogram
Diagnostic paracentesis

SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase;

CT, computed tomography; HIDA, hepatoiminodiacetic acid.

result from sepsis. Either thrombocytosis or thrombocytopenia can be associ-

ated with a malignancy.
2. Serum electrolytes (sodium, potassium, chloride, bicarbonate) and calcium
and magnesium levels should be determined periodically because of the fluid
and electrolyte shifts that may occur in patients with an acute abdomen.
3. Arterial blood gases also are important to monitor in acutely ill patients.
4. Serum amylase level may be elevated in acute pancreatitis and in bowel
obstruction and ischemic bowel disease. Other conditions causing hyperamy-
lasemia that are not associated with an acute abdomen include salivary gland
disease, renal insufficiency, and the benign condition macroamylasemia.
5. Elevations in serum bilirubin, aspartate aminotransferase (AST; or serum
glutamic-oxaloacetic transaminase, SGOT), alanine aminotransferase
(ALT; or serum glutamic-pyruvic transaminase, SGPT), and alkaline phos-
phatase levels may indicate liver or biliary disease. Elevations in alkaline phos-
phatase in particular may be an early indicator of obstruction of the biliary tract,
either within the liver or in the extrahepatic bile ducts.
6. Urinalysis may indicate pyuria caused by acute pyelonephritis or hematuria
due to a renal stone.
7. An electrocardiogram should be performed in all patients to establish a base-
line tracing and to look for acute changes of myocardial injury.
B. Radiologic studies (Table 13-2; see also Chapter 9)
1. The chest x-ray should not be omitted. Pneumonia, pulmonary embolus, sub-
diaphragmatic free air, or a widened mediastinum of a dissecting aneurysm
may be evident. Plain films of the abdomen, supine and erect or decubitus may
indicate air-fluid levels, free intraabdominal air, or calcification. Loops of bowel
may be displaced by an abscess or other mass. Marked dilatation of the bowel
may indicate obstruction or toxic megacolon.
2. Ultrasound scan, computed tomography scan, HIDA scan, and intra-
venous pyelography may give additional valuable information. (See Chapter 9
for full descriptions of these studies.)
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Chapter 13: The Acute Abdomen 81

C. Diagnostic paracentesis. In some patients with an acute abdomen, withdrawal of

fluid already within the abdomen or withdrawal of instilled fluid is helpful in mak-
ing a diagnosis. Patients with infected ascites have an elevated ascitic WBC and
often have positive bacterial cultures. Fluid that contains blood suggests hemor-
rhage from a viscus, infarction, or hemorrhagic pancreatitis. An elevated amylase
level may be found in pancreatitis or bowel infarction.
The safest site for a closed (needle) paracentesis is in the midline about
2 cm below the umbilicus, where the abdominal wall is relatively avascular.
However, care should be taken not to puncture a distended urinary bladder. Also,
a midline abdominal wound from previous surgery precludes the use of this site.
An open paracentesis using a small paramedian incision and a dialysis catheter
may be safer and more accurate than a needle paracentesis.
D. Treatment includes measures that are applied to all patients plus specific therapies
that depend on the underlying cause.
1. The general approach to patients with an acute abdomen includes intra-
venous fluids, nothing by mouth, and in most instances nasogastric suction to
decompress the stomach and prevent additional air from entering the bowel. In
some patients, it may be necessary to pass an additional long tube to decom-
press the bowel. Careful attention to volume of fluid intake and urine output is
important. As previously indicated, serum electrolytes and arterial blood gases
should be monitored.
2. Specific treatment depends on the cause of the acute abdomen and is dis-
cussed in the appropriate subsequent chapters. (See particularly Chapter 37 for
management of toxic megacolon, Chapter 44 for management of intestinal
ischemia, Chapter 46 for management of severe pancreatitis, and Chapter 49 for
management of acute cholecystitis.) A major decision in the management of a
patient with an acute abdomen is whether the patient needs surgery. Patients
who have a ruptured viscus need prompt surgical intervention. Unresolved
ischemia, which has progressed or will progress to tissue necrosis as a result
either of vascular infarction or strangulation of a viscus, demands surgical treat-
ment. Some inflammatory conditions, such as acute appendicitis, necrotizing
pancreatitis, necrotizing cholecystitis, and toxic megacolon, which have not
responded to medical therapy within 24 to 48 hours, also require surgical atten-
tion. Finally, some acute conditions, such as acute cholecystitis or acute diverti-
culitis, resolve with medical management but may be treated subsequently under
elective conditions by surgery.

Selected Readings
Al-Salamah SM, et al. Role of ultrasonography, computed tomography and diagnostic
peritoneal lavage in abdominal blunt trauma. Saudi Med J. 2002;23:1350–1355.
Brown TA, et al. Acute appendicitis in the setting of clostridium difficile colitis. Clin
Gastroenterol Hepatol. 2007;5(8):969–971.
Fry LC, et al. The yield of capsule endoscopy in patients with abdominal pain or diarrhea.
Endoscopy. 2006;38:498–502.
Iancelli A, et al. Therapeutic laparoscopy for blunt abdominal trauma with bowel injuries.
J Laparoendosc Adv Surg Tech A. 2003;13:189–191.
Khawaja FJ, et al. 86-year-old woman with abdominal pain and diarrhea. Mayo Clin Proc.
2007;82(4):487–489.
Knoll BM, et al. 56-year-old man with rash, abdominal pain and orthralgias. Mayo Clin
Proc. 2007;82(6):745–748.
Maglinte DD, et al. Current concepts in imaging on small bowel obstruction. Radiol Clin
North Am. 2003;41:263–283.
Ng B, et al. 49 year old woman with acute abdominal pain and nausea. Mayo Clin Proc.
2001;76:649.
Poulin EC, et al. Early laparoscopy to help diagnose acute non-specific abdominal pain.
Lancet. 2000;355:861.
Wolfe JM, et al. Analgesic administration to patients with acute abdomen: A survey of
emergency medicine physicians. Am J Emerg Med. 2000;18:250.
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14 ACUTE GASTROINTESTINAL BLEEDING

A cute gastrointestinal bleeding ranges in severity from a single, nearly inconsequen-

tial bleeding episode, perhaps resulting in vomiting of “coffee-ground” material or the
brief passage of red-colored stool, to massive hemorrhage and shock. Chronic or occult
gastrointestinal bleeding is discussed in Chapter 44.
Gastrointestinal bleeding is generally classified as either upper or lower in origin
(Table 14-1) simply because the source of bleeding is only rarely in the jejunum or ileum
and also because the presenting signs and symptoms frequently are characteristic of either
an upper or a lower gastrointestinal source. Regardless of the source, however, the princi-
ples of the initial management of all patients with acute gastrointestinal bleeding are gen-
erally the same (Table 14-2). Because patients vary in the severity of bleeding, the orderly
sequence of history taking, physical examination, diagnostic evaluation, and treatment
may have to be altered to meet the immediate demands.

I. INITIAL MANAGEMENT
A. History
1. Vomiting or passage of blood per rectum. The action of gastric acid on
blood quickly forms dark particles that resemble coffee grounds. Vomiting of
red blood (hematemesis) or of coffee-ground-appearing material usually signi-
fies a source of bleeding in the esophagus, stomach, or duodenum, but it can
result from swallowed blood from the respiratory tract. On the other hand,
passage of red- or maroon-colored stool per rectum (hematochezia) usually
indicates that the source is in the rectum, colon, or terminal ileum.

Diagnostic Considerations in Acute

TABLE 14-1
Gastrointestinal Bleeding

Upper gastrointestinal bleeding Lower gastrointestinal bleeding

Bleeding from nose or pharynx Hemorrhoids
Hemoptysis Anal fissure
Esophagogastric (Mallory-Weiss) mucosal tear Inflammatory bowel disease (proctitis
Esophageal rupture (Boerhaave’s syndrome) or colitis)
Inflammation and erosions (esophagitis, gastritis, Neoplasm (carcinoma or polyps)
duodenitis) Diverticulosis
Peptic ulcer of esophagus, stomach, duodenum, Ischemic enteritis or colitis
or surgical anastomosis Angiodysplasia
Dieulafoy’s lesion (ruptured mucosal artery) Antibiotic-associated colitis
Varices of esophagus, stomach, or duodenum Radiation colitis
Neoplasm (carcinoma, lymphoma, leiomyoma, Amyloidosis
leiomyosarcoma, polyps) Meckel’s diverticulum
Hemobilia Vascular-enteric fistula
Vascular-enteric fistula (usually from aortic Brisk bleeding from an upper
aneurysm or graft) gastrointestinal source

82
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Chapter 14: Acute Gastrointestinal Bleeding 83

Principles of the Initial Management of Acute

TABLE 14-2
Gastrointestinal Bleeding

I. Perform in order determined by activity of bleeding

A. History
B. Vital signs, including postural signs
C. Physical examination, including rectal examination
D. Insertion of large-bore peripheral venous catheter and, if necessary, a central venous line
E. Withdrawal of blood for initial laboratory studies
F. Administration of intravenous electrolyte solutions and blood
II. Pass a nasogastric tube
A. If clear initially or clears promptly with lavage, remove
B. If bloody, leave in to monitor gastrointestinal bleeding and to provide access to the
gastrointestinal tract
III. Survey for concomitant heart, lung, renal, liver, or central nervous system disease
IV. Consult a gastroenterologist, a surgeon, and, if indicated, a radiologist
V. Make a diagnosis (see section II and Figs. 14-1 and 14-2)

However, an important exception is the upper gastrointestinal lesion that

bleeds profusely, such as a ruptured esophageal varix or an eroded vessel within
a peptic ulcer, in which a large volume of blood passes rapidly through the
intestines and appears as hematochezia. The passage of black stool (melena)
usually indicates a more moderate rate of bleeding from an upper gastroin-
testinal source, sometimes as little as 50 mL per day, although bleeding from
the terminal ileum or ascending colon can result in melena.
2. Age of patient. Advanced age worsens the prognosis of acutely bleeding
patients. The age of the patient also makes some diagnoses more or less likely,
particularly with regard to lower gastrointestinal bleeding. The differential
diagnosis of acute lower gastrointestinal bleeding in people over age 60 includes
ischemic colitis, carcinoma of the colon, arteriovenous malformation, and
diverticulosis, whereas none of these is a serious consideration in a 25-year-old.
On the other hand, bleeding from inflammatory bowel disease or a Meckel’s
diverticulum is more likely in a child or young adult.
3. Ingestion of gastric mucosal irritants. The recent ingestion of aspirin, other
nonsteroidal antiinflammatory drugs, or alcohol raises the possibility that ero-
sive gastritis or other mucosal injury has developed. Aspirin not only causes
direct mucosal injury, but also interferes with platelet adhesion; thus, bleeding
lesions in patients who take aspirin are less likely to clot.
4. Associated medical conditions. The number of associated medical conditions
directly increases the risk of mortality in acute gastrointestinal bleeding. Mortality
in patients with no accompanying medical conditions is about 1%, whereas the
risk of dying in patients with four or more associated illnesses is more than 70%.
Patients with liver disease are at risk to develop esophageal varices, which
could bleed. Although acute upper gastrointestinal bleeding in patients known
to have esophageal varices is most likely caused by the varices, other sources
must be considered.
Previous abdominal or pelvic irradiation raises the possibility that lower gas-
trointestinal bleeding is caused by radiation enteritis or colitis. Gastrointestinal
bleeding may develop from the acute effects of irradiation on the gut, or bleeding
may occur months to years later. The latter situation represents a form of ischemic
colitis that is accelerated by the perivascular inflammation that results from the
effects of irradiation.
Knowledge of serious cardiovascular, pulmonary, liver, renal, or neurologic
disease may be valuable in guiding medical and, if necessary, surgical decisions
during subsequent treatment of the patient.
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84 Part IV: Gastroenterologic Emergencies

B. Physical examination
1. The physical examination is unlikely to indicate a precise cause of bleeding.
However, coolness of the extremities, palmar creases, and pallor of the con-
junctivae, mucous membranes, and nail beds may be evident as a result of blood
loss and peripheral vasoconstriction. The signs of chronic liver disease or
abdominal tenderness may provide relevant information.
2. The rectal examination is important and should not be omitted, even
in seemingly obvious upper gastrointestinal bleeding. The anus, perianal
area, and lower rectum can be assessed, as can the character and color of the
stool.
Occult blood in the stool can be detected with as little as 15 mL of blood
loss per day. Stools may remain positive for occult blood for nearly 2 weeks
after an acute blood loss of 1,000 mL or more from an upper gastrointestinal
source.
3. Postural signs. As the patient loses intravascular volume due to blood loss,
cardiac output and blood pressure fall, and pulse rate increases. Under condi-
tions of severe volume loss, postural compensation of blood pressure and pulse
are inadequate. Thus, so-called postural signs are present if, when the patient
sits from a supine position, the pulse rate increases more than 20 beats per
minute and the systolic blood pressure drops more than 10 mmHg. Under these
circumstances, it is likely that blood loss has exceeded 1 L. However, age, car-
diovascular status, and rate of blood loss all influence the development of pos-
tural signs.
C. Fluid, electrolyte, and blood replacement
1. A large-bore intravenous catheter should be inserted promptly into a peripheral
vein. Blood can be drawn at this time for laboratory studies (see section I.D). In
a profusely bleeding patient, a single peripheral intravenous catheter may not
be sufficient to provide adequate blood replacement; two or more intravenous
catheters may be required. In an acute emergency in which a peripheral vein is
not available, venous access should be established via a jugular, subclavian, or
femoral vein.
2. Infusion of fluids and blood. Normal saline is infused rapidly until blood for
transfusion is available. In patients who have excess body sodium, such as
those with ascites and peripheral edema, the physician may be reluctant to
infuse large amounts of saline. In those instances, the restoration of hemody-
namic stability should take precedence over other considerations. In other
words, if the patient is bleeding profusely and blood for transfusion is not yet
available, saline should be infused without regard for the patient’s sodium bal-
ance. If bleeding is less severe, hypotonic sodium solutions may be infused
until blood for transfusion arrives. Appropriate treatment of acute gastroin-
testinal bleeding includes not only replacement of blood, usually in the form of
packed red cells, but also infusion of supplemental electrolyte solutions and,
when necessary, clotting factors.
3. A central venous pressure catheter or Swan-Ganz catheter may be nec-
essary to evaluate the effects of volume replacement and the need for continued
infusion of blood, particularly in elderly patients or patients with cardio-
vascular disease.
4. Monitoring of urine output provides a reasonable indication of vital organ
perfusion. In severely ill patients, a urinary catheter may be necessary.
D. Laboratory studies
1. Initial blood studies should include a complete blood count (CBC) and levels
of electrolytes, blood urea nitrogen (BUN), creatinine, glucose, calcium, phos-
phate, and magnesium; blood should be drawn for typing. Hemoglobin and
hematocrit levels usually are low, and the level of these measures may have
some relation to the amount of blood loss. However, some patients bleed so
rapidly that there is insufficient time for the blood volume to equilibrate, and
the hemoglobin and hematocrit levels are normal or only slightly reduced. In
acutely bleeding patients, changes in blood pressure and pulse and the direct
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Chapter 14: Acute Gastrointestinal Bleeding 85

evidence of continued bleeding via the nasogastric tube or per rectum are bet-
ter indicators than the hemoglobin and hematocrit levels for determining the
administration of electrolyte solutions and the replacement of blood. Clotting
status should be assessed with platelet count, prothrombin time, and partial
thromboplastin time. Depending on the clinical presentation, other blood stud-
ies may be important, such as serum amylase, liver tests, and cardiac enzymes.
In severely ill patients, arterial blood gases should be monitored.
2. Leukocytosis, usually not in excess of 15,000/
L, can accompany acute gas-
trointestinal bleeding. However, an elevated white blood cell count should not
be attributed to acute blood loss without a search for sources of infection.
3. Elevated BUN in a patient whose BUN has recently been normal or whose
serum creatinine level is normal suggests an upper gastrointestinal bleeding
source. The rise in BUN results from the hypovolemia of acute blood loss, but
digestion of blood proteins in the small intestine and the absorption of
nitrogenous products can also contribute. In patients with impaired liver
function, the increased protein load may be sufficient to induce or aggravate
hepatic encephalopathy. The magnitude of the protein load can be calculated
roughly by multiplying the grams of hemoglobin and serum protein per
deciliter of blood by the estimated volume of blood lost. For example, if a
patient has an initial hemoglobin level of 13 g/dL and serum protein of 7 g /dL
and loses 1,000 mL (or 10 dL) of blood, approximately 200 g of protein is
presented to the small intestine ([13 g  7 g]  10  200 g). Thus, gastric
lavage and control of bleeding are additionally important in patients with
liver disease.
4. Later studies. Because of rapid fluid shifts during gastrointestinal bleeding
and the infusion of blood, blood products, and other fluids, frequent assess-
ment of serum electrolytes, calcium, phosphate, and magnesium levels is neces-
sary. Extensive transfusion dilutes platelets and clotting factors, particularly
factors V and VII. This condition can be treated by infusion of fresh-frozen
plasma and platelets as necessary. Also, a high proportion of patients who bleed
while taking therapeutic anticoagulants do so from a clinically significant
lesion. Thus, it is important to evaluate these patients for gastrointestinal
pathology in addition to correcting their clotting status. Most patients who
receive blood transfusions do not need calcium supplements, although hypocal-
cemia as a result of binding of calcium by anticoagulants in banked blood may
occur after massive transfusions. Patients who receive more than 100 mL of
blood per minute may be given 0.2 g calcium chloride (CaCl2) via another
intravenous line during the time the blood is infusing. Measurement of the ion-
ized calcium and monitoring of the electrocardiographic QT interval are rec-
ommended during the rapid infusion of anticoagulated blood.
E. Nasogastric intubation and gastric lavage. A nasogastric (NG) tube should be
passed in all patients with acute gastrointestinal bleeding unless the source is obvi-
ously the lower gastrointestinal tract. Blood from an esophageal or gastric source
pools in the stomach, and in more than 90% of bleeding duodenal ulcers the blood
refluxes back across the pyloric channel into the stomach. If the aspirate is clear or
clears readily with lavage, the NG tube may be removed. If there is fresh blood or
a large amount of old blood or retained material, the stomach should be lavaged
by means of a large-bore sump tube (20–24 French) or an Ewald tube. Removal of
as much of the gastric contents as possible facilitates subsequent endoscopy and
may contribute to hemostasis by allowing the walls of the stomach to collapse.
Because of its adverse effects, the NG tube should be removed promptly when it
no longer fulfills a useful purpose.
1. Benefits of NG intubation
a. To document the presence of blood
b. To monitor the rate of bleeding
c. To identify recurrence of bleeding after initial control
d. To lavage and decompress the stomach
e. To remove gastric acid
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86 Part IV: Gastroenterologic Emergencies

2. Adverse effects of NG intubation

a. Patient discomfort
b. Predisposition to gastroesophageal reflux and pulmonary aspiration
c. Irritation of the esophageal and gastric mucosae, creating mucosal artifacts
and aggravating existing lesions
F. Consultations. The appropriate management of acute gastrointestinal bleeding
typically involves a team of physicians. Specific diagnostic studies usually require
the expertise of a gastroenterologist or a radiologist. The surgeon, when consulted
early, may offer valuable assistance in managing the patient and is in a much bet-
ter position to make a decision regarding operative intervention.

II. DIAGNOSTIC AND THERAPEUTIC STUDIES. Schemes for the diagnostic evaluation
of acute upper and lower gastrointestinal bleeding are shown in Figs. 14-1 and 14-2,
respectively.
A. Endoscopy. Gastrointestinal endoscopy, of both the upper gastrointestinal tract
and the colon and rectum, is discussed in Chapter 5 with regard to diagnostic
capability and methods of performing the procedures.
1. Upper gastrointestinal bleeding
a. Diagnostic endoscopy. Endoscopy usually is recommended as the initial
diagnostic procedure in acute upper gastrointestinal bleeding because

Figure 14-1. Scheme for the diagnostic evaluation of acute upper gastrointestinal bleeding.
(*Stigmata of recent hemorrhage are a visible vessel, fresh blood clot, black eschar, or active bleeding.)
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Chapter 14: Acute Gastrointestinal Bleeding 87

Figure 14-2. Scheme for the diagnostic evaluation of acute lower gastrointestinal bleeding.

knowledge of the specific diagnosis may dictate a specific treatment regi-

men. For example, the treatment of bleeding esophageal varices (see section
IV.A) is likely to be quite different from the treatment of a bleeding peptic
ulcer, hemorrhagic gastritis, or a Mallory-Weiss tear of the esophagogastric
junction. The appropriate treatment of a peptic ulcer that stops bleeding
includes acid-inhibiting drug therapy for several weeks, whereas hemor-
rhagic gastritis, if caused by aspirin ingestion or alcohol abuse, typically
heals rapidly after withdrawal of the offending agent, and administration of
acid-inhibiting drug therapy. A Mallory-Weiss tear may be expected to heal
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88 Part IV: Gastroenterologic Emergencies

in several days without specific therapy. Furthermore, the endoscopic iden-

tification of the so-called stigmata of recent hemorrhage (SRH) within an
ulcer crater may have some prognostic and therapeutic significance. SRH
include a protruding visible vessel, an adherent clot, a black eschar, and
actual oozing or spurting of blood. Patients with SRH are more likely to
have uncontrolled bleeding or recurrent bleeding and to require interven-
tion by therapeutic endoscopic methods or surgery.
b. Therapeutic endoscopy. Methods of treating peptic ulcer bleeding through
the endoscope have included thermal electrocoagulation, laser photocoagu-
lation, injection of epinephrine, ethanol or hypertonic solutions, and place-
ment of clips on the bleeding vessels or ulcer. Experience to date has shown
the following:
i. Bipolar electrocoagulation, laser photocoagulation, injection of various
agents, and placement of clips all appear to be capable of controlling
acute bleeding. The combination of two of these techniques seems to
yield better and more lasting results (less rebleeding).
ii. Laser photocoagulation and electrocoagulation has been shown to
reduce the need for emergency surgery and improve survival.
iii. Laser therapy is less available and the most difficult to learn, whereas
injection therapy is the least difficult and readily available in most hospitals.
iv. Injection therapy (epinephrine 1/10,000 or normal saline) appears to be
the safest and the least expensive.
v. Combining injection therapy with electrocoagulation may have added
benefits and is currently being widely used (Table 14-3). In the endo-
scopic treatment of bleeding esophageal varices, endoscopic banding is
preferred over injection sclerosis (see section IV.A).
2. Lower gastrointestinal bleeding. The initial diagnostic procedure for acute
lower gastrointestinal bleeding is proctosigmoidoscopy, preferably with a flexi-
ble fiberoptic instrument. If the bleeding seems to be occurring above the reach
of the sigmoidoscope, emergency colonoscopy may be performed after the colon
is cleaned with osmotically balanced electrolyte solutions (e.g., GoLYTELY or
Colyte) administered orally or by nasogastric tube. If colonoscopy is not feasi-
ble, selective arteriography may be performed both for diagnostic and possible
therapeutic measures.
B. Radionuclide scanning of the abdomen after labeling of the patient’s red blood
cells or other blood components may indicate the site of bleeding (see Chapter 9,
section II.C). A positive scan may point the way to more definitive diagnostic or
therapeutic procedures. The radionuclide scan appears to be more sensitive than

TABLE 14-3 Endoscopic Treatment of Bleeding Ulcers

Laser Injection
Characteristic Electrocoagulation photocoagulation therapy

Controls bleeding Yes Yes Yes

Reduces need for Yes Yes ?
surgery
Reduces mortality Yes Yes ?
Difficulty to learn Intermediate Most Least
Safety Intermediate Least Most
Expense Intermediate Most Least

From Eastwood GL. Endoscopy in gastrointestinal bleeding: Are we beginning to realize the dream?
J Clin Gastroenterol. 1992;14:187. Reprinted with permission.
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Chapter 14: Acute Gastrointestinal Bleeding 89

selective arteriography in detecting active bleeding; a “positive” scan requires a

lower rate of bleeding (0.1 mL per minute vs. 0.5–1.0 mL per minute) but is less
specific than arteriography in locating the site of bleeding.
C. Selective arteriography of the celiac axis, superior mesenteric artery, inferior
mesenteric artery, or their branches can be both diagnostic and therapeutic.
1. Diagnosis. A focal extravasation of dye usually indicates an arterial bleeding
source. A diffuse blush in the region of the stomach may be found in hemor-
rhagic gastritis. During the venous phase, esophageal, gastric, or intestinal
varices may be seen, although actual variceal bleeding cannot be documented
by arteriography.
2. Treatment. Injection of autologous clot or small pieces of gelatin sponge
(Gelfoam) has been used to embolize arteries supplying localized bleeding sites.
Infusion of vasopressin, 0.1 to 0.5 units per minute, into the arterial supply of
the bleeding site also has been effective in controlling bleeding. Variceal bleed-
ing may be controlled by vasopressin infusion into the superior mesenteric
artery, thereby diminishing splanchnic blood flow and reducing portal venous
pressure. Administration of vasopressin by peripheral vein at a rate of 0.3 to
1.0 units per minute is as effective as intraarterial vasopressin in the control of
variceal bleeding. Moreover, the frequency of cardiovascular side effects after
peripheral venous versus arterial vasopressin infusion is similar. In most patients
who receive vasopressin for the control of variceal bleeding, therefore, a periph-
eral venous route is preferred. Intravenous infusion of nitroglycerin may reduce
the hazard of vasopressin in patients at risk for ischemic cardiovascular disease.
Intravenous infusion of octreotide is as effective and safer than vasopressin and
is preferred.
D. Barium-contrast radiographic studies. Upper gastrointestinal series and barium
enema usually provide a lower diagnostic yield than endoscopic studies. In addi-
tion, the presence of barium in the stomach or intestine can make endoscopic visu-
alization of the mucosa difficult and can render an arteriogram uninterpretable.
For these reasons, barium-contrast studies are not recommended in the initial
diagnostic evaluation of patients with acute gastrointestinal bleeding.

III. GASTRIC AND ANTISECRETORY AGENTS. Because gastric acid plays a pathogenic
role in many causes of upper gastrointestinal bleeding, it is reasonable to inhibit acid
secretion with antisecretory agents such as histamine-2 (H2) antagonists, or proton-
pump inhibitors (PPIs). The intent is to maintain the intraluminal gastric pH above
4.0. This is difficult to achieve with the use of H2 antagonists. PPIs inhibit gastric
acid secretion much more effectively and at adequate doses increase the gastric pH to
above 4. In the United States, pantoprazole sodium (Protonix), esomeprazole (Nexium),
and lansoprazole (Prevacid) are available in intravenous form as well as in an oral
formulation.
The reduction of intraluminal acid may be effective in two ways. First, the direct,
harmful effects of acid and pepsin on the bleeding lesion are diminished. Second, a less
acid environment allows platelets to aggregate and thus promotes clotting. After the
NG tube is removed, the patient is treated with an antisecretory agent, preferably with
a PPI. A bolus of 80 mg of intravenous PPI is administered, followed by a continuous
infusion at 80 mg an hour up to 72 hours.

IV. SPECIAL CONSIDERATIONS

A. Esophageal varices. The treatment of bleeding esophageal varices differs sub-
stantially from the treatment of other bleeding lesions of the upper gastrointestinal
tract. Moreover, patients with esophageal varices typically have severe liver disease
and thus are likely to suffer from poor nutrition, blood clotting disorders, and
encephalopathy, all of which can adversely affect morbidity and mortality.
1. Initial treatment. Figure 14-3 outlines a scheme for the management of bleed-
ing esophageal varices. There is no single correct approach to the control of
variceal hemorrhage; although in most institutions endoscopic band ligation or
injection sclerosis are the initial choices of treatment. These procedures are
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90 Part IV: Gastroenterologic Emergencies

Figure 14-3. Scheme for the management of bleeding esophageal varices.

equally effective or better tolerated than surgical procedures such as portosys-

temic shunts and esophageal transection in controlling acute variceal bleeding.
Endoscopic band ligation of esophageal varices has been shown to be as
effective as injection sclerosis in controlling bleeding: It eradicates the varices
more rapidly than sclerosis and reduces the adverse side effects, such as fever,
chest pain, esophageal ulceration, and pleural effusion that have been associated
with sclerotherapy. Infusion of octreotide (a synthetic analog of somato-
statin) has been shown to be effective in controlling esophageal varied bleeding.
Octreotide given as 50
g bolus, then 50
g per hour administered intravenously
for 2 to 5 days has replaced vasopressin as the medical therapy of choice for
acute variceal bleeding. In some studies, the combination of octreotide and
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Chapter 14: Acute Gastrointestinal Bleeding 91

endoscopic therapy has been shown to improve outcome as compared to

endoscopic therapy alone.
2. Balloon tamponade by Sengstaken-Blakemore tube. The triple-lumen
Sengstaken-Blakemore (SB) tube is representative of several tubes that can com-
press gastroesophageal varices by balloon tamponade. One lumen is used to
evacuate the stomach. The second and third lumens lead to the gastric and
esophageal balloons, respectively. Because use of the SB tube has been associ-
ated with serious complications, including occlusion of the airway by the
esophageal balloon, pulmonary aspiration of secretions and blood from the
esophagus, and ischemic necrosis of the esophageal mucosa due to prolonged
compression by the balloon, the following steps are recommended:
a. Use a new SB tube in each patient.
b. Before passing the SB tube, fill the balloons with sufficient air to test for
leaks.
c. Deflate the balloons, lubricate well, and pass the tube through either the
nose or the mouth into the stomach.
d. After inflating the gastric balloon with 100 mL of air, pull it up firmly
against the gastroesophageal junction and inject another 150 to 200 mL of
air into the balloon, bringing the total amount of air to 250 to 300 mL.
e. Secure the SB tube externally by taping the tube to the nose or mouth or to
the bar of a football helmet or baseball catcher’s face mask worn by the
patient. This type of traction may be termed passive traction. It serves to
maintain traction on the gastric balloon but, in the event of deflation, does
not pull the tube up to occlude the airway. Never apply active traction such
as might be accomplished by tying the external end of the SB tube to a
weight hanging over a pulley.
f. Pass an accessory sump tube into the esophagus to suction blood and secre-
tions. (Some SB-type tubes already have a fourth lumen that permits
esophageal suction.) If no fresh blood is aspirated from the esophagus, either
the bleeding originates below the esophagus or bleeding from esophageal
varices has stopped. If no fresh blood is aspirated from the intragastric
lumen of the SB tube under these circumstances, one can presume that the
bleeding originated from varices in the gastric cardia that are being com-
pressed by the gastric balloon.
g. If fresh blood is aspirated from the esophagus, inflate the esophageal balloon
to a pressure of 35 to 40 mmHg. This is accomplished by connecting the
external lumen of the esophageal balloon via a Y-connector to a blood pres-
sure manometer. Continue to suction secretions from the esophagus above
the balloon by means of the accessory sump tube or, if present, the fourth
lumen.
h. Deflate the esophageal balloon for about 30 minutes every 12 hours.
i. Tape a scissors to the wall beside the patient’s head. If the tube needs to be
removed emergently or after it is no longer needed, it can be cut as it exits
the nose or mouth, thereby instantly deflating the balloons and facilitating
prompt removal. The scissors also serve as a visible reminder of the dangers
of the SB tube.
j. In most patients, use of the SB tube does not exceed 48 hours. By that time,
bleeding has been controlled or more definitive therapy by means of endo-
scopic sclerosis or portosystemic shunt surgery has been instituted.
3. Transjugular intrahepatic portosystemic shunt (TIPS). Patients who con-
tinue to bleed despite endoscopic therapy or have bleeding gastric varices may
require a portosystemic shunt. Since surgical morbidity and mortality are very
high in open portosystemic shunt procedures, TIPS has been developed as a less
invasive procedure often performed by interventional radiologists. TIPS has
been shown to decrease rebleeding more effectively than endoscopic therapy,
band ligation, or injection sclerotherapy. However, most patients with TIPS
experience shunt stenosis within 1 to 2 years and require reinstrumentation,
and many patients develop hepatic encephalopathy. Thus, TIPS is preferred for
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92 Part IV: Gastroenterologic Emergencies

patients with severe liver disease and for those who may require liver trans-
plantation. Patients with compensated cirrhosis may be better treated with distal
splenorenal shunt-type portosystemic shunt surgery.
4. Long-term management. After acute variceal bleeding has been controlled by
endoscopic variceal banding or injection sclerosis, octreotide infusion, or bal-
loon tamponade, a decision regarding long-term management of the varices
must be made. Some physicians elect no specific therapy, hoping that bleeding
will not recur. Because the risk of rebleeding is high, however, some form of
treatment usually is indicated. The daily oral administration of beta-blockers
(e.g., nadolol) and nitrates (e.g., isosorbide dinitrate) has been shown to reduce
portal hypertension in patients and decrease the risk of rebleeding. Because
long-term survival appears to be increased after repeated endoscopic band lig-
ation or injection sclerosis to eradicate the varices or portosystemic shunt
surgery, most patients should be considered for one of these treatments. Total
health care costs are probably less and the risk of encephalopathy is lower in
patients who undergo band ligation or injection sclerosis. Thus, repeated
endoscopic band ligation or injection sclerosis, consisting of repeated injections
separated by 1 to 4 weeks for several months, is a reasonable first choice.
Complications of endoscopic band ligation and injection sclerosis
include acute perforation of the esophagus, mucosal ulceration and necrosis,
and stricture formation. Patients who have recurrent variceal bleeding despite
band ligation and injection sclerotherapy and whose risk of surgery is acceptable
may benefit from portosystemic shunt surgery.
B. Mallory-Weiss gastroesophageal tear. Bleeding from a Mallory-Weiss mucosal
tear at the esophagogastric junction traditionally has been associated with repeated
vomiting or retching before the appearance of hematemesis. However, in a large
review of patients with documented Mallory-Weiss lesions, such a history was
obtained in less than one third of the patients. The diagnosis of Mallory-Weiss
mucosal tear must be made by endoscopic visualization of the lesion. Most patients
stop bleeding spontaneously. In those with active bleeding, endoscopic placement of
clips, bipolar electrocautery or injection of epinephrine may be used successfully.
C. Aortoenteric fistula. Patients with an aortoenteric fistula typically have massive
hematemesis or hematochezia. The bleeding may stop abruptly; if it recurs, it often
is fatal. This is a surgical emergency and immediate surgical intervention is necessary.

Selected Readings
Angtuaes TL, et al. The utility of urgent colonoscopy in the evaluation of acute lower
gastrointestinal tract bleeding: A 2-year experience from a single center. Am J Gastroenterol.
2001;96:1782.
Bardou M, et al. Meta-analysis proton pump inhibition in high-risk patients with acute
peptic ulcer bleeding. Aliment Pharmacol Ther. 2005;21:677–686.
Bianco MA, et al. Combined epinephrine and bipolar coagulation vs. bipolar coagulation
alone for bleeding peptic ulcer: A randomized, controlled trial. Gastrointest Endosc.
2004:60:910–915.
Chan FK, et al. Preventing recurrent upper gastrointestinal bleeding in patients with
Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med.
2001;344:967.
Chan FKL, et al. Combination of a cyclo-oxygenase 2 inhibitor and a proton-pump
inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a
double-blind, randomised trial. Lancet. 2007 May 12;369:1621–6.
Cipolletta L, et al. Endoclips versus heater probe in preventing early recurrent bleeding
from peptic ulcer: A prospective and randomized trial. Gastrointest Endosc. 2001;
53:147–151.
Corely DA, et al. Octreotide for acute esophageal variceal bleeding: A meta analysis.
Gastroenterology. 2001;120:946.
A 40-year-old woman with epistaxis, hematemesis, and altered mental status. Case records
of the Massachusetts General Hospital. N Engl J Med. 2007;356:174–182.
Geier A, et al. Profuse rectal bleeding of no visible cause. Lancet. 2007;369:1664.
79466_CH14.QXD 1/2/08 12:10 PM Page 93

Chapter 14: Acute Gastrointestinal Bleeding 93

Gerson LB, et al. Endoscopic band ligation for actively bleeding Dieulafoy’s lesions.
Gastrointest Endosc. 1999;50:454.
Howarth DM. The role of nuclear medicine in the detection of acute gastrointestinal
bleeding. Semin Nucl Med. 2006;36:133–46.
Lau JY, et al. Oweprazole before endoscopy in patients with gastrointestinal bleeding.
N Eng J Med. 2007;356:1631–1640.
Lau JUW, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic
treatment of bleeding ulcers. N Engl J Med. 2000;343:310.
Leontiadis GI. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane
Database Syst Rev. 2006;1:CD002094.
Park JJ. Meckel diverticulum: the Mayo Clinic experience with 1476 patients (1950–2002).
Ann Surg. 2005;241:529–33.
Sanyal AJ. Octreotide and its effects on portal circulation. Gastroenterology. 2001;120:303.
Schmulewitz N, et al. Dieulafoy lesions: A review of 6 years of experience at a tertiary care
center. Am J Gastroenterol. 2001;96:1688.
Sharara AI, et al. Gastroesophageal variceal hemorrhage. N Engl J Med. 2001;345:669,
2001.
Sung JJY, et al. The effect of endoscopic therapy in patients receiving omeprazole for
bleeding ulcers with nonbleeding visible vessels or adherent clots. A randomized
comparison. Ann Intern Med. 2003;139:237–243.
Villanueva C, et al. Endoscopic ligation compared with combined treatment with nadolol
and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med. 2001;
345:647.
79466_CH15.QXD 1/2/08 12:11 PM Page 94

15 FOREIGN BODIES IN THE

GASTROINTESTINAL TRACT

F oreign bodies may be deliberately or accidentally swallowed or introduced into the

lower gastrointestinal tract from the rectum. The most frequent victims are young children,
persons with dentures, and individuals who are inebriated or mentally impaired.
There are no controlled studies for the management of foreign bodies in the gastroin-
testinal tract. Each situation needs to be evaluated depending on the nature of the foreign
body, the symptoms, the condition of the patient, and the organs involved. Most ingested
foreign bodies pass safely through the intestinal tract between 48 hours and 1 month after
ingestion. Some objects may result in obstruction or perforation and may require endo-
scopic or surgical intervention. Sharp objects such as pins, toothpicks, and bones may
cause perforation, especially in the esophagus and the ileocecal area. Patients may have
pain, sepsis, mediastinitis, peritonitis, hemorrhage, abscess, or abdominal mass.

I. ESOPHAGUS. Foreign bodies may cause obstruction above the upper esophageal
sphincter and may compromise the airway. These patients should be urgently handled
by ear, nose, and throat specialists.
Most obstructions from foreign body ingestions involve the esophagus; many
occur above a benign or malignant stricture, web, or ring. The four areas of physio-
logic narrowing in the esophagus—the cricopharyngeal muscle, the aortic arch, the
left main-stem bronchus, and the gastroesophageal junction—are also common sites
for obstruction. Sharp objects such as fish or poultry bones, pins, or toothpicks
may perforate the esophagus, resulting in sepsis or hemorrhage. Button (miniature,
7.9–11.6 mm) battery ingestions are not uncommon in children. Most of these spon-
taneously pass; however, those with larger diameters (15.6–23.0 mm) may impact in
the esophagus, causing tissue necrosis, perforation, or hemorrhage.
A. Clinical findings
1. Signs and symptoms. Acute esophageal obstruction may result in substernal pain
at the level of obstruction or be referred to the sternal notch. The pain may be mild
or severe or may mimic a myocardial infarction. There may be profuse salivation
and regurgitation. In patients who have ingested a sharp object like a fish bone,
odynophagia and a sensation of the object lodged in the esophagus may be present.
2. Physical examination is usually unrewarding. When perforation is suspected,
subcutaneous air in the soft tissues should be sought by looking for crepitus by
palpation of the upper thorax and neck.
B. Diagnostic tests
1. Radiographic techniques
a. Photographic densities. Plain x-rays are frequently used in the detection of
foreign bodies. However, not all foreign bodies are radiopaque due to differ-
ences in their densities.
i. Foreign bodies of high density are highly radiopaque and have low
photographic density on a radiograph. If the object is of adequate size,
it is easily differentiated from the surrounding tissues. Common exam-
ples include objects made of iron, steel, and some alloys, as in nails,
screws, chips, bullets, and many coins.
ii. Foreign bodies with physical densities somewhat higher than body
tissues (e.g., glass, aluminum, chicken bones, plastics) have photographic
densities slightly less than body tissues and form more subtle images.

94
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Chapter 15: Foreign Bodies in the Gastrointestinal Tract 95

iii. Body-density foreign bodies possess the same photographic density

as the surrounding body tissues and are virtually impossible to detect in
radiographs. Thorns, cactus needles, sea- and freshwater animal spines,
some plastics, and wood that has been in the body for more than 48 hours
are common examples.
iv. When the density of the object is less than the density of surround-
ing body tissues, it appears darker. Some examples of this type of
foreign body are wood immediately after introduction into the body,
materials containing air, and some plastics.
v. Glass, contrary to the general assumption that it is radiolucent, is in
fact radiopaque compared to body tissues. Leaded crystal and optical
glass are highly radiopaque.
vi. Aluminum is of low physical density and may be difficult to detect radi-
ographically. Aluminum alloy, pennies, and pull-top rings of aluminum
soda cans are commonly ingested and may not be detected in plain films.
vii. Wood, when dry, immediately after ingestion appears radiolucent due
to its lower physical density than body tissues. However, within 24 to
48 hours it absorbs water, becomes isodense to body tissues, and may
not be visible on the plain films.
b. X-ray views. When the location of a foreign body is to be determined radi-
ographically, two views at 90 degrees to each other (e.g., anteroposterior and
lateral films) are recommended with techniques used for evaluation of bones.
Additional tangential views may be obtained to gain more information about
the depth of the foreign body.
c. Contrast studies. When the information from the plain radiographs is inad-
equate, the use of contrast media may be required. Water-soluble contrast
agents or barium may be used. Because barium may interfere with proper
visualization of the object at endoscopy, however, a water-soluble contrast
agent such as Gastrografin is preferred. If perforation is suspected, the leak
may also be evaluated using a water-soluble contrast study.
2. Endoscopy. Esophageal foreign bodies may be directly visualized by flexible
endoscopy after adequate sedation of the patient. Intravenous glucagon may be
necessary to relax the esophagus.
C. Management
1. Esophageal relaxation. After a detailed history regarding the nature and tim-
ing of the ingestion is obtained, if no complications are suspected, mild sedation
and esophageal relaxation with intravenous glucagon may allow spontaneous
passage of the foreign body. The patient should be kept in an upright posture,
or the head of the bed should be elevated. In cases of obstruction, a nasogastric
tube may be placed in the esophagus above the object, and secretions may be
suctioned to decrease the risk of aspiration. Intravenous fluids should be used
to prevent dehydration of the patient.
2. When a meat bolus is lodged in the distal esophagus, enzymatic dissolution
with papain has been used (e.g., Adolph’s Meat Tenderizer). Papain, however,
may lead to esophageal wall digestion and perforation or pulmonary aspira-
tion; thus, we do not recommend its use.
3. Endoscopy. Food boluses or other foreign bodies may be removed endoscopi-
cally using forceps, snares, or baskets. An overtube, placed around the intrae-
sophageal portion of the endoscope and the object, will protect the esophageal
mucosa and the airway as the object is pulled out in the endoscope. General
anesthesia may be necessary in children and uncooperative patients. Sharp objects
and those that are embedded in the esophageal wall may require surgical
removal.

II. STOMACH
A. Clinical findings. Foreign bodies in the stomach usually do not cause any symp-
toms. The presence of nausea and vomiting may indicate pyloric obstruction; pain,
bleeding, and fever may suggest mucosal injury or perforation.
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96 Part IV: Gastroenterologic Emergencies

B. Diagnosis
1. Chest and abdominal radiographs help in determining the location and
nature of the swallowed object. Contrast studies may be needed if the object
cannot be visualized by plain films or if there is a question of perforation. The
presence of air under the diaphragm also should be ascertained.
2. Endoscopy visualizes the foreign object, but this may be difficult when the
stomach is full of food.
C. Management. Most ingested objects that have made their way into the stomach
pass through the pylorus and the rest of the gastrointestinal tract. Most coins, such
as dimes and nickels, do not cause obstruction, but quarters may not pass in chil-
dren. With rounded objects, it is thought to be safe to wait several days for the
spontaneous passage of the foreign body. The progress is followed by daily x-rays.
Because objects may become embedded in the wall of the stomach after several
days, endoscopic removal is advised. However, bones, denture fragments, pencils,
toothpicks, needles, razor blades, and other sharp objects should be removed
immediately, endoscopically or surgically. Induced vomiting, especially in intoxi-
cated persons and in children, carries the risk of aspiration of the gastric contents
and the foreign body and is not recommended.

III. SMALL BOWEL

A. Most objects that have passed through the pylorus will also pass through the small
bowel and the ileocecal valve. Long, thin objects may hang up in the angulations
of the duodenum, the angle of Treitz, and the ileocecal area.
B. Management. Objects beyond the second portion of the duodenum cannot be
retrieved endoscopically. Their progress may be followed radiologically. If pain,
fever, distention, vomiting, or bleeding develops, the patient should be surgically
explored. Stimulation of bowel motility by laxatives and cathartics may be harm-
ful, especially when the object is sharp. Mineral oil, stool softeners, or bulking
agents may be useful, but their efficacy has not been studied.

IV. COLON AND RECTUM

A. Occasionally, swallowed objects may hang up in the cecum or the sigmoid colon.
These objects may be retrieved with the colonoscope.
B. Many objects have been inserted into the rectum and sigmoid colon for sexual
stimulation, or by individuals who are mentally impaired. Most of these objects
may be retrieved using flexible or rigid sigmoidoscopic techniques. Patients may
need general anesthesia for cooperation and for relaxation of the anal sphincter. If
perforation or mucosal injury is suspected, surgical intervention may be necessary.

Selected Readings
Athanassiadi K, et al. Management of esophageal foreign bodies: A retrospective review of
400 cases. Eur J Cardio Thorac Surg. 2002;21:653–656.
Focht D, Kaul A. Food impaction and eosinophilic esophagitis. J Ped. 2005;147:540.
Janik JE, et al. Forceps extraction of upper esophageal coins. J Pediatr Surg. 2003;38:
227–229.
Jeen YT, et al. Endoscopic removal of sharp foreign bodies impacted in the esophagus.
Endoscopy. 2001;33:518–522.
Lam HC, et al. Esophageal perforation and neck abscess from ingested foreign bodies:
Treatment outcomes. Ear Nose Throat J. 2003;82:786–794.
Mosca S, et al. Endoscopic management of foreign bodies in the upper gastrointestinal
tract: Report on a series of 414 adult patients. Endoscopy. 2001;33:692–696.
Panda NK, et al. Management of sharp esophageal foreign bodies in young children:
A cause for worry. Int J Pediatr Otorhinolaryngol. 2002;64:243–246.
Soprano JV, et al. Four strategies for the management of esophageal coins in children.
Pediatrics. 2000;105:e5.
Vanelli PM, et al. Exploring the link between eosivephilic esophagitis and esophageal
foreign bodies in the pediatric population. Pract Gastroenterol. 2007;xxx1(10):81–85.
79466_CH16.QXD 1/2/08 12:11 PM Page 97

CAUSTIC INGESTION 16

T he ingestion of caustic chemicals may cause tissue injury on contact with the
oropharynx, esophagus, stomach, and duodenum. Accidental ingestion of these caustic or
corrosive substances is most frequent in small children and inebriated individuals.
Intentional ingestion occurs more commonly in persons who are suicidal.
Caustic substances can be divided into acids and alkalis. Many household and indus-
trial products contain acids or alkalis in liquid or solid form (Tables 16-1 and 16-2).

I. ALKALI INGESTION. Alkalis (e.g., lye–sodium or potassium hydroxide) are ingested

more frequently than acids. Alkalis produce injury by liquefaction necrosis, which
allows deep penetration into the tissues, resulting in full-thickness tissue burns.

TABLE 16-1 Common Alkalis

Sodium or potassium hydroxide (lye)

Detergents and washing powders
Paint removers
Drain cleaners (Drano [granular and liquid], Liquid Plumr, Plunge, Open-Up)
Oven cleaners (Easy-Off, Mr. Muscle)
Clinitest tablets
Denalan denture cleanser (NaOH is formed in vivo)
Sodium hypochlorite
Bleaches (Clorox)
Cleansers
Sodium borates, carbonates, phosphates, and silicates
Detergents
Electric dishwashing preparations
Water softeners
Purex bleach
Ammonia
Toilet bowl cleaners (Lysol)
Metal cleaners and polishers
Hair dyes and tints
Antirust products
Jewelry cleaners
Sodium permanganate
Illegitimate abortifacient medical applications (topical)
Phosphorus
Matches
Rodenticides
Insecticides
Fireworks

NaOH, sodium hydroxide.

97
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98 Part IV: Gastroenterologic Emergencies

TABLE 16-2 Common Acids

Hydrochloric acid (muriatic acid)

Metal cleaners (Quaker House Steam Iron Cleaner)
Toilet bowl cleaners (Lysol liquid toilet bowl cleaner, Sno Bol)
Swimming pool cleaners
Sulfuric acid
Battery acid
Drain cleaners (Mister Plumber, Rooto)
Sodium bisulfite
Toilet bowl cleaners (Sani Flush [granular], Varnish [granular])
Oxalic acid
Disinfectants
Furniture polish
Zud Rust and Stain Remover (granular)
Hydrofluoric acid
Antirust products
Formaldehyde (formic acid)
Deodorizing tablets
Plastic menders
Fumigants
Embalming agents
Carbolic acid (phenol-creosol, creosote)
Antiseptics
Preservatives

A. The severity of the tissue injury after caustic ingestion depends on the nature,
concentration, and quantity of the caustic substance and the duration of tissue
contact. The higher the pH, the more destructive is the alkaline agent. The critical
pH that causes esophageal ulceration is 12.5. Most cases of deep ulceration that
progress to stricture formation involve lye solutions of pH 14.0.
B. Areas of injury. The oropharynx and esophagus are most commonly injured in
alkali ingestions. Twenty to thirty percent of the patients who have esophageal
injury also have gastric injury. The severity of the injury varies from inflammation
and ulceration to necrosis and perforation of the viscera.
1. Solid alkali ingestion. Alkali swallowed in solid form adheres on contact to
mucous membranes of the oropharynx or esophagus, usually sparing the
stomach. If solid alkali is swallowed with water, it is carried further down the
digestive tract.
2. Liquid alkali ingestion, especially of lye, exposes most of the mucosal sur-
face of the oropharynx and upper gastrointestinal tract to the caustic sub-
stance. The esophagus is the most commonly injured organ. The stomach is
also usually injured. In addition to ulceration and necrosis of the affected tis-
sues, bleeding may occur after liquid-lye ingestion. Respiratory distress
secondary to soft-tissue swelling of the epiglottis, larynx, vocal cords, or tra-
chea may occur due to aspiration of lye. Tracheoesophageal fistulas may
develop after severe injury. The most common delayed complication of lye
ingestion is esophageal stricture formation. Strictures may involve a variable
length of the esophagus, ranging from a focal narrowing to complete steno-
sis of the entire esophagus. Antral scarring and pyloric stenosis also have
been reported.
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Chapter 16: Caustic Ingestion 99

II. ACID INGESTION

A. Types of acids. A number of commercially available household substances con-
tain caustic acids (e.g., toilet bowl cleaners, disinfectants, automobile battery
acids, soldering fluxes). These substances may contain hydrochloric, sulfuric,
nitric, phosphoric, and trichloroacetic acids as well as phenol, zinc chloride, mer-
curial salts, and formaldehyde (formic acid). Sulfuric acid is the most corrosive of
these acids. However, hydrochloric and nitric acids are volatile and may predis-
pose the patient to chemical pneumonitis in addition to gastrointestinal tract
injury.
B. Tissue injury. Caustic acids produce coagulation necrosis, forming a firm protec-
tive eschar that may limit deep-tissue injury. They tend to pass rapidly through the
esophagus and usually produce shallow burns, except in cases where there are
anatomic or motility disorders. In the stomach, the acids usually flow along
the lesser curve to the pylorus. Pylorospasm results in pooling of the acid in the
antrum, where the worst of the damage occurs. The range of tissue injury is diffuse
gastritis, hemorrhagic ulceration, and necrosis leading to perforation of the stomach.
Gastric perforation may lead to mediastinitis, peritonitis, and shock.

III. CLINICAL EVALUATION

A. History. A detailed history should be obtained from the patient or family to deter-
mine the type of caustic agent ingested, the time and quantity of ingestion,
whether the patient took anything by mouth before or after the ingestion, and
whether vomiting has occurred. If possible, the container and contents should be
examined and the pH of the substance determined.
B. The physical examination should include vital signs, attention to respiratory
status, and signs pertaining to possible perforation of the esophagus or stomach.
The presence of fever, respiratory distress, subcutaneous air, or signs of peritoneal
irritation should be noted.

IV. INITIAL MANAGEMENT

A. If cardiovascular or respiratory distress is present, a central venous line should
be placed immediately, the airway should be protected, and the patient resusci-
tated. Arterial blood gases and a complete blood count should be obtained, and a
surgeon should be notified.
B. In the event of respiratory distress with swelling of soft tissues of the upper
airway, tracheostomy may be necessary because blind nasotracheal intubation
may cause perforation.
C. Upright x-ray films of the chest and abdomen should be obtained and examined
for signs of aspiration and perforation of the esophagus or stomach.
D. Initially, patients should receive nothing by mouth. Gastric lavage or emesis is
contraindicated due to the risks of aspiration, reexposing the damaged tissues to
the caustic agent, and perforation.
E. The use of diluents is controversial. Neutralization of alkali with acid or acids
with alkali commonly results in an exothermic reaction. The resulting heat may
produce thermal injury and further tissue damage. Water and milk have been
shown to cause minimal temperature elevation, but they may contribute to
increased esophageal and gastric volume and motility and may increase the
already existing tissue damage. Thus, their use and the use of activated charcoal
and cathartics are not recommended.
F. Morphine sulfate or meperidine hydrochloride may be used for pain control
after the patient’s condition is stabilized.

V. DIAGNOSIS OF TISSUE INJURY

A. Barium or soluble contrast studies of the esophagus and stomach do not accu-
rately demonstrate the degree and extent of initial tissue injury. Adherent barium
also may obscure the mucosa from endoscopic observation. Thus, contrast radio-
logic studies are not recommended for initial diagnostic evaluation. If a perforation
is suspected, however, a radiologic study using a soluble contrast material may be
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100 Part IV: Gastroenterologic Emergencies

performed to localize the site of perforation. After 1 to 2 months, the extent of fibro-
sis and stricture formation may be assessed periodically by radiocontrast studies.
B. Endoscopy of the upper gastrointestinal tract within the first 24 hours of inges-
tion is recommended to establish the extent and severity of the tissue damage and
to remove by suction any remaining caustic material from the stomach. Rigid
scopes should not be used. Endoscopes with diameters less than 1 cm are safe in
experienced hands. If esophageal or gastric perforation is suspected clinically or
from plain films, endoscopy should not be performed.
C. The severity of tissue injury is classified by endoscopic appearance.
Grade 0: Normal endoscopic examination
Grade I: Edema and hyperemia of the mucosa
Grade IIa: Friability, hemorrhages, erosions, blisters, whitish membranes or exu-
dates, superficial ulcerations
Grade IIb: Grade IIa plus deep discrete or circumferential ulcerations
Grade IIIa: Grade II plus multiple ulcerations and small scattered areas of necrosis
(areas of brown-black or grayish discolorations)
Grade IIIb: Grade II plus extensive necrosis

VI. THERAPY
A. Patients with grade 0 and grade I injuries are expected to heal with no specific ther-
apy. They should receive nothing by mouth until they can eat without discomfort.
A barium swallow and upper gastrointestinal series may be done after 1 to 2
months to look for scarring and strictures.
B. Patients with grade IIa and some patients with grade IIb injuries recover rapidly
and may be discharged from the hospital within 5 to 12 days. Healing usually
occurs by the third or fourth week without sequelae. Some grade II and all grade
III injuries heal with scarring. Complications such as hemorrhage and perforation
should be carefully looked for in patients with grades IIb and III injuries. Most
patients with grade IIIb injury require immediate surgical attention.
C. Patients with more extensive tissue injury should be treated in the intensive care
unit with special attention to the possibility of viscous perforation. To protect the
injured tissues, the upper gastrointestinal tract should not be used. Total parenteral
nutrition should be started immediately. Intravenous histamine-2 (H2)-blocker therapy
may be used to reduce gastroduodenal acidity to prevent further acid–peptic injury.
D. Steroids. In pharmacologic doses, corticosteroids impair wound healing, depress
immune defense mechanisms, and mask the signs of infection and viscous perfo-
ration. They cannot salvage an already injured organ. Because the risks outweigh
the possible benefits, their use is not recommended.
E. Antibiotics. Serious infections are infrequent with caustic injury. In first- or
second-degree burns, antibiotics should be withheld until evidence of infection is
present. In patients in whom the possibility of perforation exists, antibiotics are
recommended to reduce the risk of infectious mediastinitis or peritonitis.
F. Surgery. The coordinated intensive efforts of both medical and surgical teams are
necessary for the best outcome in patients severely injured with caustic ingestion.
In the event of extensive tissue necrosis, perforation, peritonitis, or severe hemor-
rhage, emergency surgery may be necessary.
In severe gastric burns, antral and pyloric stenosis may require partial or
total gastrectomy. Total gastrectomy and esophageal replacement may be neces-
sary in cases of simultaneous severe esophageal and gastric injury.
G. Stricture formation is usually noted 2 to 8 weeks after a second- or third-degree
caustic injury with circumferential lesions.
1. Dilatation. Single and minor strictures usually respond to repeated dilatation.
However, because early dilatation increases the risk of perforation, it should be
delayed until after the acute injury has healed.
2. Surgery. Extensive esophageal strictures may require surgical resection with
transposition of a segment of jejunum or colon. Placement of an intraluminal
silicone stent under endoscopic guidance for 4 to 6 weeks has been used to pre-
vent severe stricture formation.
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Chapter 16: Caustic Ingestion 101

H. Long-term follow-up. Esophageal and gastric cancer may develop in the scarred
mucosa 10 to 15 years after the initial injury. These patients require ongoing clinical
and endoscopic surveillance and follow-up.

Selected Readings
Bernhardt J, et al. Caustic acid burn of the upper gastrointestinal tract: First use of
endosonography to evaluate the severity of injury. Surg Endosc. 2002;16:1004.
Boukhir S, et al. High doses of steroids in the management of caustic esophageal strictures
in children. Arch Pediatr. 2004;11:13–17.
Erdogan E, et al. Esophageal replacement using the colon: A 15-year review. Pediatr Surg.
2000;16:546–549.
Hamza AF, et al. Caustic esophageal strictures in children: 30-year experience. J Pediatr
Surg. 2003;38:828–833.
Katzka DA, et al. Caustic injury to the esophagus: Current treatment options. Gastroen-
terology. 2001;4:59–66.
Kukkody A, et al. Long-term dilation of caustic strictures of the esophagus. Pediatr Surg Int.
2002;18:486–490.
Nunes AC, et al. Risk factors for stricture development after caustic ingestion. Hepato-
gastroenterology. 2002;49:1563–1566.
Zwischenberger JB, et al. Surgical aspects of esophageal disease. Perforation and caustic
injury. Am J Repir Crit Care Med. 2001;164:1037–1040.
79466_CH17.QXD 1/2/08 12:13 PM Page 102

FULMINANT HEPATIC FAILURE

17 AND ENCEPHALOPATHY

F ulminant hepatic failure (FHF), acute hepatic failure, and fulminant hepatitis
all refer to acute severe impairment of liver function accompanied by coagulopathy,
advanced stages encephalopathy, and coma in patients who have had liver disease for less
than 8 weeks. FHF, in most instances, is complicated by multiorgan failure and cerebral
edema, lasts 1 to 4 weeks, and ends fatally in 60% to 95% of patients. FHF is a rare con-
dition with an incidence of 2,000 cases per year in the United States.
In a subgroup of patients, the duration of illness before the onset of encephalopathy
is more prolonged (subacute FHF) but as in FHF, there is no evidence of previous liver dis-
ease. In patients with late-onset hepatic failure, hepatic encephalopathy and other evidence
of hepatic decompensation appear between 8 and 24 weeks after the first symptoms.
Patients with late-onset disease are significantly older than those who have FHF; median
ages of onset are 44.5 years and 25.5 years, respectively.
Liver transplantation may be the ultimate solution in FHF.
New terminology has been introduced and is based on the interval from the onset of
jaundice to the development of encephalopathy.
Hyperacute liver failure, with an interval of
7 days
Acute liver failure, with an interval of 8–28 days
Subacute liver failure, with an interval of 4–12 weeks.

I. ETIOLOGY. Table 17-1 outlines the numerous causes of FHF.

A. Hepatitis. FHF is most commonly seen with viral and toxic hepatitis. In fact,
viruses are implicated in 75% of instances.
1. FHF is most commonly seen with hepatitis B virus (HBV ) infection; 1% of
patients acutely infected with HBV may develop the syndrome. Thirty to forty
percent of these patients may be infected concomitantly with the hepatitis delta
virus (HDV). Infection with hepatitis A virus (HAV), and rarely hepatitis C virus
(HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), and parvovirus
B19 also may lead to FHF. Enterically transmitted hepatitis E virus may cause
FHF in pregnant women, especially in the third trimester.
2. Acute toxic hepatitis may result from an idiosyncratic hypersensitivity reac-
tion to a drug (e.g., halothane, isoniazid, rifampin, alpha-methyldopa) or from
substances that are intrinsically toxic to the liver (e.g., acetaminophen, hydro-
carbons, white phosphorus, some poisonous mushrooms).
3. These toxic agents and viral infections cause panlobular hepatic necrosis
resulting in FHF.
B. Hepatic ischemia resulting from severe hypoxemia, hypotension, cardiac failure,
or acute Budd-Chiari syndrome may cause extensive centrilobular hepatic necrosis
and FHF.
C. Wilson’s disease may present as FHF accompanied by acute intravascular hemolysis.
D. FHF may result from a group of disorders characterized by acute extensive infil-
tration of hepatocytes with microdroplets of fat and minimal hepatocellular
necrosis. These disorders include Reye’s syndrome, tetracycline induced fatty
liver, fatty liver of pregnancy, fatty liver after jejunoileal bypass surgery, and acute
alcoholic hepatitis. Dideoxyinosine (DDI) used in the treatment of acquired
immunodeficiency syndrome (AIDS) also may cause this condition.

102
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Chapter 17: Fulminant Hepatic Failure and Encephalopathy 103

TABLE 17-1 Causes of Fulminant Hepatic Failure

Viral agents
Hepatitis A virus Herpes viruses
Hepatitis B virus Adenovirus
Hepatitis C virus Cytomegalovirus
Hepatitis D virus Paramyxovirus
Hepatitis E virus Epstein-Barr virus
Toxic substances
Acetaminophen Valproic acid
Halothane Disulfiram
Isoniazid Nortriptyline
Rifampicin White or yellow phosphorus
Amine oxidase inhibitors Emetic toxin of Bacillus cereus
Hydrocarbons Mushroom poisoning (Amanita phalloides)
Carbon tetrachloride Some herbal medicines
Nonsteroidal antiinflammatory drugs Dideoxyinosine
Ischemic liver necrosis
Wilson’s disease with intravascular hemolysis Shock (hypotension hypoxemia)
Acute Budd-Chiari syndrome Autoimmune hepatitis
Congestive heart failure Heat stroke
Acute steatosis syndromes
Reye’s syndrome
Acute fatty liver of pregnancy
Tetracycline
Massive blastic infiltration of the liver Hodgkin’s lymphoma
Lymphoreticular malignancies Burkitt-type lymphoma
Malignant histiocytosis
Non-Hodgkin’s lymphoma
Acute leukemia
Acute phase of chronic myelogenous
leukemia
Acute monoblastic leukemia
Metastatic liver disease from primary lung or breast cancer and melanoma

E. Rarely, FHF may develop in patients who have one of the hematolymphoid malig-
nancies, such as malignant histiocytosis, Burkitt’s lymphoma, the acute phase of
chronic myelogenous leukemia, acute monoblastic leukemia, and Hodgkin’s and
non-Hodgkin’s lymphomas. Massive infiltration of hepatic parenchyma with malig-
nant cells results in infarction and necrosis, leading to FHF.

II. DIAGNOSIS. Serum aminotransferase (aspartate aminotransferase [AST], alanine

aminotransferase [ALT]) and bilirubin levels may provide useful clues regarding the
cause of FHF. In toxic or viral FHF, the serum aminotransferases are significantly ele-
vated due to injury to the hepatocytes. In instances of acute fatty infiltration and mito-
chondrial damage, aminotransferases are only moderately elevated.
The presence in serum of IgM antibody to HAV supports the diagnosis of acute
hepatitis A. The presence of hepatitis B surface antigen (HBsAg) or IgM antibody
to hepatitis B core particle (HBcAb) or both and HBV-DNA in a patient with FHF
favors hepatitis B as the etiologic agent. IgM antibody to the delta virus can be detected
by serologic study only in patients carrying HBsAg. Antibody to hepatitis C may help
in establishing the diagnosis of hepatitis C but may not be detectable in the acute phase
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104 Part IV: Gastroenterologic Emergencies

of the disease. A mutant form of hepatitis B and rarely hepatitis C is implicated in most
instances of late-onset hepatic failure. Determination of viral DNA or RNA titers of
hepatitis B and C viruses by polymerase chain reaction respectively may give informa-
tion that is more accurate in the cases of viral hepatitis B or C.
Liver biopsy may be helpful in establishing a diagnosis but may be difficult to
perform because of the severe coagulopathy, which is not correctable with replace-
ment of clotting factors.

III. PROGNOSIS. Survival from FHF depends on the ability of the liver to regenerate with
restitution of the normal hepatic function. Prothrombin time greater than 100 seconds,
regardless of the stage of encephalopathy or the presence of any three of the following
findings, indicates a poor prognosis in FHF caused by viral hepatitis or drug toxicity
excluding acetaminophen toxicity:
Arterial pH
7.3
Age
10 or 40 years
Jaundice 7 days before the onset of encephalopathy
Prothrombin time 50 seconds
Serum bilirubin 18 mg/dL
Prognosis in FHF depends on the age of the patient, cause of the acute liver
failure, clinical course, occurrence of secondary complications, and duration and
severity of the coma.
A. Causes of death in FHF are neurologic complications (67%), gastrointestinal
hemorrhage (13%), bacterial and/or fungal infection and sepsis (13%), hemody-
namic complications (8%), and progressive respiratory and renal failure.

IV. CLINICAL SYNDROME

A. The encephalopathy of FHF may begin with mild confusion, irrational behavior,
euphoria, or psychosis. It is usually associated with a widely fluctuating but pro-
gressive deterioration of the mental state. Coma may develop rapidly within several
days of onset of symptoms.
1. The pathogenesis of hepatic encephalopathy (HE) is unknown, but there are
several theories. HE is a potentially reversible metabolic disorder of the brain in
the milieu of hepatic failure.
a. “Neurotoxic” substances. The ability of the liver to remove toxic substances
from the circulation is important in the maintenance of normal brain function.
In liver failure, it is assumed that neurotoxic substances normally extracted
from portal venous blood and metabolized in the liver gain access to the sys-
temic circulation and reach the brain parenchyma through a more permeable
blood–brain barrier. These substances may be directly toxic to the neurons or
may modulate neuronal function by causing changes in the metabolism of
neurotransmitters or the functional status of the neurotransmitter receptors.
The toxic substances most commonly implicated in hepatic failure are ammo-
nia (NH3), -aminobutyric acid (GABA), endogenous “benzodiazepines and
opioids,” mercaptans, and fatty acids.
b. “False neurotransmitters.” Another theory implicates the accumulation
of false neurotransmitters in the brain. In liver failure, the plasma ratio of
aromatic amino acids (phenylalanine, tyrosine, and tryptophan) to branched-
chain amino acids increases because of the impaired capacity of the liver to
remove aromatic amino acids. It is thought that this circumstance permits
greater entry of aromatic amino acids into the brain and promotes the
synthesis of serotonin and false neurotransmitters (e.g., octopamine) at the
expense of the true neurotransmitters (e.g., dopamine, norepinephrine) by
competitive inhibition. The increase of inhibitory neurotransmitters and
the deficiency of excitatory neurotransmitters may induce encephalo-
pathic coma.
c. Multifactorial causes. Most likely the cause of HE in FHF is multifactorial
with synergistic interactions among the various factors. Other causes of coma,
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Chapter 17: Fulminant Hepatic Failure and Encephalopathy 105

such as hypoglycemia, hypoperfusion, anoxia, electrolyte disturbances, and

brain edema, may contribute to its pathogenesis.
d. Arterial NH3. It has been customary to use arterial NH3 levels to follow the
course of hepatic encephalopathy. Even though the level of NH3 does not
correlate with the stage of encephalopathy in each patient, the levels help to
establish trends. One must remember, however, that elevation of NH3 may be
an epiphenomenon that reflects the concentration of other neuroactive nitroge-
nous substances such as GABA that are involved in hepatic encephalopathy
and coma.
2. Neurologic assessment. Daily assessment of neurologic function is important
in following the patient’s course and therapy.
a. A clinical coma scale (Tables 17-2 and 17-3) separately appraises the state
of six brain and brainstem functions. There is a high correlation between
best–worst initial coma scores and outcomes and the day-to-day changes in
the score with improvement or deterioration. The presence or absence of
oculovestibular reflexes has been the best predictor of outcome.

TABLE 17-2 A Clinical Coma Profile for Bedside Use

Verbal response
Oculocephalic–oculovestibular reflexes
None
No reaction
Incomprehensible
Partial or dysconjugate
Confused
Full
Normal
Normal
Eye opening
Best motor response
None
None
Noxious stimuli only
Abnormal extensor
Verbal stimuli
Abnormal flexor
Spontaneous
Withdraws or localizes
Pupils Obeys commands
Nonreactive
Respiration
Sluggish
Nil or ventilator
Brisk
Irregular
Regular 22 breaths/min
Regular
22 breaths/min

TABLE 17-3 Hepatic Encephalopathy Scale

Grade Neurologic status

0 No abnormality detected
1 Trivial lack of awareness, shortened attention span, impairment noted on
arithmetic testing
2 Lethargy, disorientation in time, clear personality change, inappropriate
behavior
3 Very drowsy, semicomatose but responsive to stimuli, confused, gross
disorientation in time or space, bizarre behavior
4 Comatose, unresponsive to painful stimuli with or without abnormal
movements (e.g., decorticate or decerebrate posturing)
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106 Part IV: Gastroenterologic Emergencies

b. The electroencephalogram (EEG) pattern changes in a predictable

way parallel with the neurologic state. Initially there is a slowing of the
alpha rhythm. With increasing drowsiness, this phenomenon is replaced
by lower frequency theta activity. As coma deepens, high-amplitude delta
waves become prominent, and the characteristic triphasic waves appear.
Preterminally the amplitude of these waves decreases, and finally the EEG
becomes isoelectric.
c. Visual-evoked potentials have been found to be superior to the EEG in terms
of specificity and ease of quantitation of central neuronal activity associated
with hepatic coma. However, auditory, somatosensory, and visual-evoked
potentials are not widely available clinically.
d. Assessment of cerebral edema. Cerebral edema, which may result in cere-
bellar or uncal herniation or both, is a frequent complication of FHF. The
exact stage at which cerebral edema develops is difficult to determine clini-
cally. Papilledema is seldom present. Findings from computed tomography or
magnetic resonance imaging (MRI) scan of the head are usually normal.
However, loss of definition between gray and white matter may be diagnostic
of early cerebral edema. In advanced disease, the first clinical sign may be
sudden respiratory arrest along with fixed and dilated pupils and absent
brainstem reflexes, indicating tentorial herniation.
B. Renal, electrolyte, and acid-base abnormalities. Microvascular obstruction
with cellular debris from the damaged liver affects most organs and especially the
kidneys.
1. Renal abnormalities. Renal failure is common in patients with FHF. Acute
tubular necrosis with high urine sodium concentration (20 mmol/L) and isos-
molar urine occurs in some patients. Hepatorenal syndrome develops in about
one half of the patients; it is characterized by low urine sodium concentration
(
10 mmol/L), a hyperosmolar urine, and oliguria. This form of renal dys-
function does not improve unless there is simultaneous improvement in hepatic
function. Renal dialysis in FHF has a high frequency of complications.
Peritoneal dialysis is associated with peritonitis and intraperitoneal hemor-
rhage. Hemodialysis may lead to hypotension and gastrointestinal hemorrhage
caused by the use of heparin. The most common indications for dialysis are
volume overload, acidosis, and hyperkalemia.
2. Electrolyte abnormalities are common in FHF. Hypokalemia is seen in the
early stages. Hyponatremia is often associated with high renal retention
of sodium and water and decreased free water clearance. Hypernatremia
may follow multiple transfusions of fresh-frozen plasma or the use of osmotic
diuretics.
3. Alkalosis. Respiratory alkalosis is common in FHF and is thought to be central
in origin. Metabolic alkalosis may be caused by hypokalemia. Gastric aspiration
may potentiate this problem.
4. Lactic acidosis is common, especially in patients with peripheral circulatory
failure. If it is also associated with hypoglycemia, it may be caused by both fail-
ure of hepatic gluconeogenesis and increased anaerobic metabolism.
C. Respiratory disorders. Acute respiratory distress syndrome (ARDS) and unex-
pected respiratory arrest may occur at any time in FHF. Endotracheal intubation
may facilitate delivery of oxygen when hypoxia supervenes and protect the airway
from aspiration.
D. Cardiovascular disorders. An increased cardiac output is common. Central
vasomotor depression with hypotension, cardiac arrhythmias including ventricular
ectopy, heart block, and bradycardia may also occur.
E. Coagulation disorders. In FHF, hepatic protein synthesis is impaired. The syn-
thesis of the proteins of the clotting cascade, the fibrinolytic proteins, and the
inhibitors of the activated factors are all deranged. Because hepatic clearance is
also impaired, coagulopathy is nearly impossible to correct with factor repletion.
Disseminated intravascular coagulation (DIC) also occurs and may be accentuated
by infection and endotoxemia.
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Chapter 17: Fulminant Hepatic Failure and Encephalopathy 107

F. Gastrointestinal and other bleeding. More than half of the patients with FHF
have severe gastrointestinal bleeding from acute erosions in the stomach and
esophagus. Coagulopathy, thrombocytopenia, abnormal platelet function, and
DIC contribute to the bleeding propensity of these patients. Because gastric acid
plays a major role in the formation of erosions and ulcers, prophylactic use of
intravenous proton pump inhibitors or histamine-2 (H2)-receptor antagonists has
been shown to decrease the frequency of upper gastrointestinal bleeding.
Retroperitoneal hemorrhage, epistaxis, or bleeding into the lungs may also
occur. Prophylactic use of fresh-frozen plasma is not of proven benefit. In bleeding
patients, however, maintenance of the blood volume by the use of blood products
and correction of clotting factor deficiencies should be tried.
G. Hypoglycemia is common in patients with FHF and may lead to abrupt deepen-
ing of coma. Blood sugar needs to be closely monitored.
H. Sepsis usually complicates FHF due to leukocyte and macrophage dysfunction,
bacterial gut translocation, decreased opsonin function and complement, release of
endotoxin and cytokines, as well as iatrogenic causes such as placement of naso-
gastric tubes, catheters, and central lines. Prophylactic antibiotics are not generally
recommended, but if sepsis is suspected, cultures should be obtained and sepsis
promptly treated.

V. MANAGEMENT
A. General measures. If hepatic regeneration occurs, complete recovery from FHF
is theoretically possible. The major factors that affect progression of liver injury
are intercurrent infections and respiratory and hemodynamic instability, resulting
in alterations of cerebral and hepatic perfusion. Vigorous maintenance of vital
functions and prompt identification and treatment of all anticipated complica-
tions, particularly of cerebral edema to prevent brain damage, are essential. The
patient should be treated in an intensive care unit, where monitoring personnel are
in constant attendance and prepared for emergencies.
The patient’s vital signs and cardiac rhythm should be monitored continu-
ously. A nasogastric tube, passed to decompress the stomach and monitor for
gastrointestinal bleeding, may be used as an access to give oral medicines. Close
attention should be given to the patient’s fluid balance. A urinary catheter and a
central venous catheter should be placed. It may be necessary to monitor the
plasma glucose as frequently as hourly. Hemoglobin level, blood urea nitrogen
(BUN), and electrolytes should be checked every 12 hours. Measurement of arter-
ial blood gases is essential in determining the acid–base status and oxygenation.
The usual indications for endotracheal intubation and assisted ventilation should
be observed. Frequent surveillance for infection is necessary. The prophylactic use
of antibiotics is not recommended.
Patients should not be given prophylactic infusions of fresh-frozen plasma or
concentrates of clotting factors to treat the coagulopathy without any evidence of
bleeding. Daily administration of parenteral vitamin K is appropriate. Suppression
of gastric acid secretion, maintaining the intragastric pH above 5.0, has been shown
to be effective in preventing upper gastrointestinal bleeding and reducing the
requirements for blood transfusions in patients with FHF. Hypothermia should be
avoided. In patients with delirium or convulsions, intravenous diazepam may
be used cautiously.
Acetylcysteine may be given intravenously in a dose of 150 mg /kg of
body weight in 250 mL of 5% dextrose over a period of 15 minutes and then in
a dose of 50 mg/kg in 500 mL of 5% dextrose over a period of 4 hours. This
regimen has been shown to increase survival of patients with established liver dam-
age induced by acetaminophen even when administered more than 15 hours after
the acetaminophen overdose. This beneficial effect seems to result from an increase
in tissue oxygen transport (delivery and consumption) in response to acetylcys-
teine. The beneficial effect was also seen in eight persons with FHF from other
causes.
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108 Part IV: Gastroenterologic Emergencies

Penicillin and silibinin infusions may be effective in mushroom poisoning

with Amanita phalloides. Penicillin works as an antagonist of amatoxin and silib-
inin blocks hepatocyte uptake of amatoxin.
Various treatment modalities have proven ineffective in FHF. These include
exchange transfusion, insulin and glucagon infusion, prostaglandin E2 infusion,
and charcoal hemoperfusion and hyperimmune globulin infusion for FHF resulting
from HBV infection.
The use of corticosteroids to reduce hepatic inflammation in patients with
FHF has not been substantiated. Corticosteroids in these patients are associated
with a significant increase in the BUN concentration thought to be caused by
steroid-augmented protein catabolism in the peripheral tissues. This situation results
in increased NH3 formation in the intestine, contributing to the encephalopathy.
The immunosuppressive and ulcerogenic potential of corticosteroids may predispose
these patients to increased risk of sepsis and gastrointestinal bleeding. Currently,
corticosteroid therapy is contraindicated in the management of patients with FHF.
B. Nutritional support. Parenteral nutrition is essential in these very ill patients to
provide adequate calories and to minimize the obligatory protein breakdown (see
Chapter 11, section I.2.b, and Chapter 12, section VI.D). Intravenous lipid prepa-
rations may not be well tolerated. In addition to dextrose, the total parenteral
nutrition (TPN) solutions rich in branched-chain amino acids and low in aromatic
acids and methionine are efficacious and help maintain a positive nitrogen balance.
The usual additives to the TPN solution and supplements of vitamin K (15 mg
daily), thiamine hydrochloride (100 mg twice daily), folic acid (1 mg daily), and
ascorbic acid (500 mg daily) should be given.
C. Treatment of hepatic encephalopathy. The main points in the treatment of
hepatic encephalopathy are to identify, correct, and treat any of the precipitating
factors and to minimize the interactions between nitrogenous substances and the
enteric bacterial flora.
1. Gastrointestinal tract cleansing. No protein or amino acids are given by
mouth. The gastrointestinal tract is evacuated by giving a balanced electrolyte
solution (e.g., GoLYTELY, NuLytely, or Colyte) or cathartics such as oral or
nasogastric instillation of magnesium citrate or lactulose and enemas with
proper positioning of the patient to fill the entire colon. If the patient has ileus,
a balanced electrolyte solution may be instilled into the duodenum via a naso-
gastric tube to clean out the small and large bowel.
2. Oral antibiotics. The enteric bacterial flora may be suppressed by oral admin-
istration of poorly absorbed antibiotics such as neomycin, which also may be
given as an enema. Oral metronidazole also may be used in the treatment of
acute and chronic encephalopathy and may be preferred because of its lack of
nephro- and ototoxicity. The combination of the two antibiotics may be even
more efficacious in some instances. A combination of lactulose and neomycin
has been used when either agent alone was unsatisfactory.
Rifaximin, a nonabsorbable gut specific antibiotic, taken orally, is a safer
and much better tolerated alternative. It compares favorably to other antibi-
otics and lactulose in the treatment of hepatic encepahlopathy.
D. Treatment of cerebral edema. Frequent assessment of the clinical neurologic status
using the criteria outlined in Tables 17-2 and 17-3 is necessary. Early diagnosis and
treatment of cerebral edema is essential. Papilledema is an inconstant sign. Signs of a
deteriorating brainstem, including sluggish pupillary reaction, slow oculovestibular
reflexes, or absent ciliospinal reflexes, should be serially assessed. However, these
signs are not sensitive and may be misinterpreted. Direct monitoring of intracranial
pressure through a burr hole using a stable, drift-free intracranial transducer attached
to a flat-bed recording system is desirable but not possible in all patients. As an alter-
native to direct intracranial pressure monitoring, extradural, epidural, and subdural
catheters may be used. Subdural catheter intracranial pressure monitors are thought
to be more accurate than epidural catheters. Extradural catheters may be safer and
may have fewer complications with infections and hemorrhage. Intravenous glycerol
or corticosteroids are not effective in reducing the cerebral edema of FHF.
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Chapter 17: Fulminant Hepatic Failure and Encephalopathy 109

Intravenous mannitol (0.3–0.4 g/kg body weight) given as a 20% solution

with rapid infusion has been effective in most patients in reducing cerebral edema.
Because the response is variable and at times adverse, mannitol therapy should be
used in conjunction with intracranial pressure monitoring. Renal failure precludes
the use of mannitol in these patients. Thiopental (250 mg) infusion may be used,
but its efficacy is still controversial. When cerebral edema progresses despite med-
ical therapy, decompressive craniectomy may be considered, especially in instances
of Reye’s syndrome and acetaminophen overdose.
E. Temporary hepatic support, if possible, provides a desirable milieu and time for
the massively damaged liver to regenerate and resume normal function. Many dif-
ferent methods have been tried. These include exchange blood transfusions, plasma-
pheresis, and total body washout, cross-circulation with another human or animal,
dialysis using various membranes, hemoperfusion through isolated liver or liver cell
cultures, and hemoperfusion through columns of adsorbents. None of these meth-
ods has been shown to be effective in FHF. The early use of charcoal hemoperfusion
with concomitant infusion of prostacyclin to inhibit platelet aggregation and release
has been beneficial in a few patients. In dogs with acetaminophen-induced FHF, the
use of an extracorporeal liver-assist device has been associated with the reversal of
FHF. This device consists of a highly differentiated human liver cell line cultured in
a hollow fiber cartridge. Even in the presence of severe liver injury, the device used
in this trial was capable of supporting total liver function for 48 hours.
F. Liver transplantation. Liver transplantation may be a lifesaving procedure for
patients with FHF, and delays in implementing this therapy can be fatal. Because
mortality and long-term morbidity of liver transplantation are substantial, early
prognostic indicators and clear guidelines are necessary to select the patients most
likely to benefit at a time in the course of their disease when liver transplantation
is still feasible. A significant relation exists between the survival of patients main-
tained with intensive medical therapy and the cause of FHF. In a study involving
137 patients with FHF, the survival rate for patients with acetaminophen overdose
was 52.9%; hepatitis A, 66.7%; hepatitis B, 38.9%; and halothane or drug reac-
tions, 12.5%. In the last three instances, therefore, liver transplantation should be
considered early in the course of FHF.
In most centers, worsening hepatic encephalopathy, clinical evidence of cerebral
edema, and increasing prolongation of the prothrombin time after 24 to 48 hours of
intensive medical treatment are used as the key factors for recommending liver trans-
plantation. The 1-year survival rate for such patients after liver transplantation is
65%. The outcome of liver transplantation also depends on graft quality, because
grafts from incompatible blood groups, steatotic grafts, or partial or reduced-size
grafts do not produce as favorable results. Unfortunately, in patients infected with
hepatitis B or C viruses, the allograft also becomes infected despite interferon therapy.
Axillary liver transplantation has been introduced as an alternative treatment
option in patients with FHF caused by toxins, drugs, or vascular insufficiency. In these
patients, the native liver, which is left in place, may recover if a transplanted axillary
liver provides temporary support. In those patients who recover, immunosuppression
is withdrawn and the donor liver is left to atrophy or may be removed surgically.
In conclusion, patients with FHF require accurate assessment of their critical
condition and of the cause of the FHF, intensive medical management with strict
and persistent attention to the vital functions and complications of the disease, and
treatment of the complications as early as they are identified. Patients who are can-
didates for liver transplantation need to be identified early and transferred to the
transplantation center for early and appropriate liver transplantation.

Selected Readings
Albataineh H, et al. Acute liver failure secondary to Clarithromyah: A case report and
literature review. Pract Gastroenterol. 2007; xxx1(7):87–89.
Keefe EB. Acute liver failure. In: McQuaid KR, Friedman SL, Grendell JH, eds. Current
Diagnosis and Treatment in Gastroenterology. 2nd ed. New York: Lange Medical
Books/McGraw-Hill; 2003:536–545.
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110 Part IV: Gastroenterologic Emergencies

Khashab M, et al. Epidemiology of acute liver failure. Curr Gastroenterol Rep. 2007;
9:66–73.
Montalti R, et al. Liver transplantation in fulminant hepatic failure: experience with
40 adult patients over a 17-year period. Transplant Proc. 2005;37:1085–1087.
O’Grady JG. Acute liver failure. Post Grad Wed J. 2005;81:148–154.
Ostapowicz G, et al. Results of a prospective study of acute liver failure at 17 tertiary care
centers in the United States. Ann Intern Med. 2002;137:947–954.
Polson JL. AASL position paper: the management of acute liver failure. Hepatology.
2005;41:1179–1197.
Riordan SM, et al. Fulminant hepatic failure. Clin Liver Dis. 2000;4:24–45.
Riordan SM, et al. Use and validation of selection criteria for liver transplantation in acute
liver failure. Liver Transplant. 2000;6:170–173.
Schiodt FV, et al. Etiology and outcome for 295 patients with acute liver failure in the
United States. Liver Transplant Surg. 1999;5:29–34.
Voquero J, et al. Mild Hypothermia for the treatment of acute liver failure. Nat Clin Pract
Gastroenterol Hepatol. 2007;4(10):528–529.
79466_CH18.QXD 1/2/08 12:14 PM Page 111

GASTROINTESTINAL AND HEPATOBILIARY 18

DISEASES IN PREGNANCY

P regnant women may present with specific diseases that occur exclusively during
pregnancy as well as those that are present at the time of pregnancy and those that occur
coincidentally with pregnancy. In this chapter, only the diseases that occur exclusively in
pregnancy will be discussed.

I. HYPEREMESIS GRAVIDARUM
A. Definition and epidemiology. Hyperemesis gravidarum involves intractable vom-
iting during pregnancy that may lead to electrolyte abnormalities, dehydration,
and malnutrition. It is more common in the first trimester, in women younger than
25 years of age, and with multiple gestations. Incidence in the United States may
be as high as 6 in 1,000 deliveries.
B. Clinical findings. Patients usually present with nausea, vomiting, dysphagia,
odynophagia, epigastric pain, and dehydration. Fifty percent of patients may
have elevations in the serum aminotransaminases (alanine aminotransferase and
aspartate aminotransferase) as well as, occasionally, also of bilirubin and alkaline
phosphatase levels. There may be concomitant gastroesophageal reflux disease
(GERD) and in the severely malnourished patient, esophageal candidiasis, or her-
pes simplex virus (HSV) infection. Some patients may have hyperthyroidism.
C. Treatment. Most patients do well with intravenous hydration and antiemetics.
Some patients may require gastric acid suppressive drugs such as proton-pump
inhibitors (PPIs) or histamine receptor blockers to control GERD, and esophagi-
tis. While no formal studies of these drugs have been performed on pregnant
women, there have been no reports of adverse effects to the mothers or fetuses
during clinical use. Prokinetic drugs such as metoclopramide hydrochloride
(Reglan) 10 to 20 mg intravenously or by mouth four times daily may be used
concomitantly with PPIs. Antiemetics (i.e., ondansetron [Zofran] 4–5 mg) may
be given by mouth three to four times a day or 8 mg intravenously every 4 to
8 hours.
In refractory cases, upper gastrointestinal (UGI) endoscopy may be required
to document UGI mucosal injury due to peptic and/or infectious (candida or HSV)
concomitant disease. A minority of patients may require total or peripheral
parenteral nutrition.

II. INTRAHEPATIC CHOLESTASIS OF PREGNANCY

A. Definition and epidemiology. A cholestatic syndrome is more commonly seen
during the second and third trimesters of pregnancy, with elevations in serum bile
acid levels but normal
-glutamyltransferase (GGT) and alkaline phosphatase lev-
els in most cases. It is more common in women with a family history of intrahep-
atic cholestasis of pregnancy (IHCP), with a history of intrahepatic cholestases
during use of estrogen or birth control pills, and with use of progesterone during
pregnancy.
B. Clinical findings. The predominant symptom is pruritus. Patients may present
with skin excoriations due to inadvertent scratching. Jaundice may follow the
onset of pruritus. Elevation of serum transaminase, cholesterol, and triglyceride

111
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112 Part IV: Gastroenterologic Emergencies

levels may be present. For early diagnosis, the specific biochemical marker of the
change of 3-hydroxysteroid-sulfate ratio of progesterone metabolites may be used.
C. Clinical outcome. Mothers do well in nearly in all cases; however, fetal outcome
may be complicated by prematurity, prenatal death, fetal distress, and meconium
staining of the amniotic fluid.
D. Treatment. Symptomatic treatment of pruritus addresses increased serum bile salt
concentration.
1. Cholestyramine resin (Questran) (4 mg, 1–4 times daily before meals) works
by intraluminal binding of bile salts.
2. Ursodeoxycholic acid (Actigall) (300 mg, 3–4 times daily) works by modifi-
cation of the serum bile acid concentrations by inhibiting the absorption of
more hydrophobic bile acids that are thought to be more pruritic.
3. Dexamethasone (2 mg per day) may be used in refractory cases. Its mode of
action is not well delineated.

.
III ACUTE FATTY LIVER OF PREGNANCY
A. Definition and epidemiology. In acute fatty liver of pregnancy (AFLP),
microvascular fatty infiltration of the hepatocytes leads to progressive liver
failure. Incidence in the United States is 1 in 7,000 to 15,000 deliveries. AFLP
is more common in cases of multiple gestations, male fetuses, and in first
pregnancies. It generally occurs in the third trimester, as early as 26 weeks of
gestation.
B. Clinical findings. Presenting symptoms include nausea, vomiting, headache,
malaise, and abdominal pain (diffuse, right upper quadrant, or epigastric). Jaundice
may follow initial symptoms. Serum alkaline phosphatase, bilirubin, and transami-
nase levels are mildly to moderately elevated. Hyperuricemia may occur in 80% of
patients. Hypoglycemia may be present. Preeclampsia may occur in 20% to 40% of
patients. Progressive liver failure may occur with coagulopathy, encephalopathy,
and renal failure.
C. Diagnosis. Diagnosis should be prompt with high clinical awareness. Abdominal
ultrasound shows diffusely increased echogenicity of the liver. Computed tomog-
raphy scan of the abdomen may be more sensitive than abdominal ultrasound.
D. Treatment and outcome. Treatment is rapid delivery of the fetus. If fulminant
hepatic failure develops, liver transplantation may be lifesaving. Maternal mortality
is reported to be 8% to 18% and fetal morality 18% to 23%.

IV. HELLP SYNDROME

A. Definition and epidemiology. Hemolytic anemia elevated liver chemistry tests,
and low platelets. Occurs in the third trimester (25–32 weeks’ gestation) in 0.1%
to 0.6% of pregnancies. It may accompany acute fatty liver of pregnancy, pre-
eclampsia, or eclampsia. It is more common in multiparous women older than
25 years. It also may occur postpartum within 2 days of delivery or later.
B. Clinical findings. Patients may complain of nausea and vomiting, epigastric pain,
headache, edema, and visual changes. Patients usually present with hypertension
microangiopathic hemolytic anemia with decreased haptoglobin levels and
increased indirect bilirubin and lactate dehydrogenase (LDH) levels and protein-
uria. Platelets may be less then 10,000/mm3. In patients with preeclampsia, a pos-
itive d-dimer test may help diagnose the onset of HELLP.
C. Treatment. Initial trial of glucocorticoids maybe attempted; however, in patients
with severe symptoms and/or fetal distress, immediate delivery is indicated. Plasma
exchange may be beneficial in postpartum patients.
D. Outcome. The maternal mortality rate is 1% to 3.5%, and the infant mortality
rate is 10% to 60%. There is increased risk of intrauterine growth retardation,
infant prematurity, disseminated intravascular coagulation (DIC), and thrombo-
cytopenia. There is also increased risk of maternal DIC, abruptio placentae, and
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Chapter 18: Gastrointestinal and Hepatobiliary Diseases in Pregnancy 113

cardiopulmonary, renal, and hepatic failure. HELLP may recur in 4% to 27%

of cases and the risk of preeclampsia increases by 2% to 40% in subsequent
pregnancies.

V. PREECLAMPSIA AND ECLAMPSIA

A. Definition and epidemiology. Preeclampsia is a disease with hepatic hemato-
logic, renal, central nervous system, and placental–fetal involvement, characterized
by hypertension, edema, and proteinuria.
B. Eclampsia. Eclampsia differs from preeclampsia by the added complications of
seizures and/or coma that may occur after delivery. Eclampsia most commonly
occurs in primigravidas, usually in the second or third trimester (after 20 weeks of
gestation). Preeclampsia may occur in 5% to 10% of pregnancies and eclampsia in
1% to 2%. There is an increased incidence in patients younger than 20 and older
than 45 years and in those with obesity, hypertension, or diabetes mellitus.
Additional risk factors include family history of preeclampsia/eclampsia, hydatid-
iform mole, polyhydramnios, fetal hydrops, multiple gestations, inadequate pre-
natal care, and cigarette smoking. There may be a genetic inheritance pattern
involving an autosomal recessive single gene.
C. Clinical findings. Blood pressure is elevated to more than 140/90 mmHg but may
rise above 160/110 mmHg. Patients usually present with headache, visual changes,
congestive heart failure, respiratory distress, abdominal pain, and oliguria. If the
patient develops seizures or coma, eclampsia is diagnosed. Diagnosis is based on
clinical findings including elevated transaminase levels (5–100 times) with a mod-
erate increase in bilirubin level. Microangiopathic hemolytic anemia and throm-
bocytopenia may also be present.
D. Treatment. Management of patients who are remote from term is controversial,
but in those who are near term, rapid delivery is recommended.
E. Outcome. Increased perinatal morbidity and mortality in the mother and fetus
correlate with the severity of the preeclampsia and preexisting maternal medical
conditions. The most common causes of maternal death are cerebral involvement
and hepatic rupture. Risks to the fetus include fetal growth retardation, abruptio
placentae, prematurity, and low birth weight.

VI. HEPATIC RUPTURE

A. Definition and epidemiology. The partial or complete fracture of the maternal
liver is rare (1 in 50,000–250,000 deliveries) and is most commonly seen in the
third trimester of pregnancy and near term. Hepatic rupture may occur in patients
with AFLP, HELLP, preeclampsia, or eclampsia as well as in patients with hepatic,
hemangioma, abscess, adenoma, or hepatocellular carcinoma.
B. Clinical findings. Patients present with a sudden onset of severe right upper quad-
rant or diffuse abdominal pain, abdominal distention, nausea, vomiting, hypoten-
sion, and shock. Serum transaminase levels are elevated (2–100 above normal
range) with concomitant anemia, thrombocytopenia, and coagulopathy. The diag-
nosis is based on clinical findings, which may be supplemented by abdominal
ultrasound and computed tomography.
C. Treatment. Early clinical recognition and diagnosis is essential, followed by deliv-
ery of the infant and additional surgical or radiologic intervention as necessary for
the mother.
D. Outcome. The maternal mortality rate ranges from 50% to 75%, and fetal mor-
tality rate ranges from 50% to 60%.

Selected Readings
Bor S, et al. Association of heartburn during pregnancy and the rise of gastroesophageal
reflux disease. Clin Gastroenterol Hepatol. 2007;5:1035–1039.
Floreami A, et al. Intrahepatic cholestatis of pregnancy: three novel MDR3 gene mutations.
Ailment Pharmacul Ther. 2006;23:1649–1653.
79466_CH18.QXD 1/2/08 12:14 PM Page 114

114 Part IV: Gastroenterologic Emergencies

Lammernt F, et al. Intrahepatic cholestasis of pregnancy: Molecular pathogenesis, diagnosis

and management. J Hepatol. 2000;33:1012–1021.
Mazzella G, et al. Ursodeoxycholic acid administration in patients with cholestasis of
pregnancy: Effects on primary bile acids in babies and mothers. Hepatology. 2001;33:
504–508.
O’Brien J, et al. Impact of high dose corticosteroid therapy for patients with HELLP
(hemolysis, elevated liver enzymes and low platelet count) syndrome. Am J Obstet
Gynecol. 2000;183:921–924.
Pauli-Magnus C, et al. Sequence analysis of bile salt export pump (ABC B11) and multi
drug resistance p-glycoprotein 3 (ABC B4, MDR3) in patients with intrahepatic
cholestasis of pregnancy. Pharmacogenetics. 2004;14:91–102.
Statea T, et al. Orthotopic liver transplantation for complicated HELLP syndrome: Case
report and review of the literature. Arch Gynecol Obstet. 2000;264:108–111.
79466_CH19.QXD 1/2/08 12:14 PM Page 115

Specific Complaints V
and Disorders
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ESOPHAGEAL INFECTIONS 19

T he esophagus is rarely infected in immunocompetent persons but is a common site

of infection in patients with immune defects. Normal host defenses of the esophagus are
the salivary flow, an intact mucosa, normal esophageal motility, and normal gastric acidity
with the absence of excessive gastroesophageal reflux.
Humoral immunity including secretory IgA is important in protecting the mucosal
integrity. However, based on the observation that patients with neutropenia and obvious
defects in cell-mediated immunity have higher rates of esophageal infections, it seems likely
that a major protective mechanism in the esophagus is cell-mediated immunity.
The esophagus can be involved with infections by bacteria, fungi, and viruses. Most
esophageal infections are fungal (Candida albicans) or viral (herpes simplex virus [HSV] or
cytomegalovirus) or a combination of the two. Diagnosis of the specific etiologic agent is
essential because of the availability of effective antiviral, antifungal, and antibacterial therapy.

I. FUNGAL ESOPHAGITIS. C. albicans is the most common fungus recovered from

patients with fungal esophagitis. However, other species have been isolated and impli-
cated as etiologic agents of such infections. These are Candida tropicalis, Candida
parapsilosis, Candida glabrata, Histoplasma capsulatum, Blastomyces dermatitidis,
Aspergillus, and Torulopsis glabrata.
C. albicans is found in the oropharynx of approximately 50% of the healthy
population. It is also found in the skin and the bowel of immunocompetent persons.
Patients with defects in cellular immunity and those treated with antibiotics may have
sufficient alteration in their normal bacterial flora to have luminal candidal over-
growth. It is thought that patients with physical or chemical damage to the esophageal
mucosa (e.g., acid reflux) may be at increased risk for developing candidal overgrowth
and subsequent invasive disease. Indeed, the worst lesions visible in many instances of
Candida esophagitis are in the distal esophagus, the area most likely to suffer from
reflux damage.The mechanisms responsible for permitting mucosal adherence and
subsequent invasion are unknown.
Candidiasis is by far the most common esophageal infection. In fact, it is a rather
common disease with a varying spectrum of severity. It can be an asymptomatic inci-
dental finding during endoscopy as well as an overwhelming infection causing death.
In one study, 90% of the HIV-infected patients with oral thrush who underwent
endoscopy had mucosal lesions caused by Candida. Larger series have not confirmed
this high figure; however, many of the treatments effective for oral thrush are also
effective in most instances of Candida esophagitis, suggesting that diagnostic evalua-
tion such as endoscopy might best be reserved for patients who do not respond to initial
topical antifungal therapy.
In addition to acute manifestations of the disease, late sequelae can develop.
Mucosal sloughing caused by an intense inflammatory response, esophageal perforation,
and stricture formation have been reported.
While Candida esophagitis can occur in any patient, certain conditions seem to
predispose to it.
A. Predisposing factors. These factors include HIV infection, neutropenia, hemato-
logic and other malignancies, organ transplantation, and immunosuppressive agents
including corticosteroids, antineoplastic chemotherapy, radiation therapy, broad-
spectrum antibiotics, diabetes mellitus, renal failure, alcoholism, malnutrition, old

117
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118 Part V: Specific Complaints and Disorders

age, and chronic mucocutaneous candidiasis (CMC). In CMC, esophageal candidi-

asis may occur in addition to the chronic involvement of the nails, skin, and oral
cavity. These patients have defective cellular immunity. However, since the wide use
of highly active antiretroviral therapy (HAART), the incidence of opportunistic
infections has been drastically reduced.
B. Diagnosis
1. Clinical presentation
a. Dysphagia and odynophagia. The most common symptoms of esophageal
candidiasis are dysphagia and odynophagia; fever may be present. Pain may
be substernal and radiate to the back. In some patients, odynophagia may be
experienced only when they drink hot or cold beverages, and in others, it
may be so severe that they may not be able to eat at all. The symptoms may
be absent in 20% to 50% of the patients, especially those with mild infec-
tion, patients who are severely debilitated, and those with CMC.
b. Oral thrush may be present in children and in HIV-infected individuals with
esophageal candidiasis, but it is usually absent in immunocompetent adults.
The plaques adhere to the underlying mucosa but can be dislodged at
endoscopy revealing an inflamed, friable mucosa underneath. Candida can
coexist with other pathogens in up to 30% of patients, and reliance on the
endoscopic appearance alone may result in failure to identify a concomitant
viral or bacterial infection. Multiple biopsies are essential to exclude coex-
isting disorders. During endoscopy, mucosal lesions should be brushed and
submitted for cytologic evaluation and biopsied for histologic examination.
Cytologic examination of brushings is more sensitive than histologic exam-
ination of the biopsy specimens since organisms may be washed off the
mucosa in superficial Candida infections during the processing of the biopsy
specimens.
In addition to cytologic evaluation, material obtained from esophageal
brushings may be placed on a microscopic slide, and a drop of potassium
hydroxide may be added to lyse the epithelial cells. Both yeast and hyphae of
C. albicans can be demonstrated in this manner. Because mycelia are not found
in the normal esophagus, their presence in the brushings strongly suggests the
diagnosis. A Gram’s stain of esophageal brush specimens can also demonstrate
the presence of yeast, hyphae, and bacteria.
Biopsy specimens should be stained with hematoxylin-eosin to assess
the severity of the inflammation. Silver and periodic acid–Schiff stains of
biopsy specimens may confirm the presence of fungal elements.
In patients with AIDS, concomitant infection with viruses (e.g.,
cytomegalovirus, HSV) may be present. Cytoplasmic and nuclear inclusion
bodies and other findings suggestive of viral infection also should be looked
for in both biopsy and brush specimens. Figure 19-1 is an algorithm that
may be used as a diagnostic approach.
2. Diagnostic studies
a. Endoscopy. Fiberoptic endoscopy is the most useful method in the diagno-
sis of Candida esophagitis. Direct observation of the esophageal mucosa
may allow the differentiation of Candida esophagitis from other infections
(e.g., herpes) and from varices, carcinoma, or peptic disease, which may
have a similar radiologic picture. The endoscopic appearance of esophageal
candidiasis is graded on a scale from I to IV. The lesions range from small
raised white plaques to ulceration and confluent plaque formation appear-
ing as friable pseudomembranes.
b. Radiologic studies. If a barium swallow is performed, the esophagram is
normal in most patients. When radiologic abnormalities are found, the
infection is usually severe. A double-contrast esophagram may increase the
yield of positive findings. The esophagus usually has a “shaggy” appear-
ance due to superficial ulcerations, but deep ulcerations may also be
present. Abnormal motility with diminished peristalsis and occasional
spasm may be seen. Esophageal stricture is commonly present in CMC.
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Chapter 19: Esophageal Infections 119

Figure 19-1. Algorithm depicting diagnostic approach in patients with suspected fungal esophagitis.

This may be a focal narrowing in the upper esophagus or may involve the
entire length.
C. Treatment
1. Before the initiation of any specific therapy for esophageal candidiasis, the
underlying predisposing factor should be identified.
2. Patients with AIDS and mild-to-moderate symptoms who have oral thrush may
be treated initially with one of the topical agents such as nystatin (Mycostatin)
suspension, clotrimazole troches, or one of the “azoles” may be an alterna-
tive form of therapy before undergoing a diagnostic procedure (Table 19-1).
3. Patients with leukopenia or with severe symptoms or systemic signs should
undergo endoscopy to obtain biopsy and brushing specimens for fungi, viruses,
and bacteria.
4. Orally administered systemic antifungal agents include the azoles and polyene
antibiotics. The most commonly used azoles include ketoconazole (Nizoral),
fluconazole (Diflucan), and itraconazole (Sporanox). All are effective in treat-
ing esophageal candidiasis.
Ketoconazole may be used at high doses. However, its gastrointestinal
side effects; decreased absorption in achlorhydric patients or patients on acid
antisecretory drugs such as histamine-2 (H2) blockers, proton-pump inhibitors,
and prostaglandin analogs; and hepatotoxicity may limit its usefulness.
Fluconazole is extremely efficacious in treating oral candidiasis and Candida
and other fungal esophagitis with or without tissue invasion. Fluconazole may be
administered via oral or parenteral routes. Its oral absorption is efficient and does
not require the presence of gastric acid. It is minimally metabolized and excreted
by the urine. Drug interactions have been demonstrated between fluconazole
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120 Part V: Specific Complaints and Disorders

TABLE 19-1 Available Agents for the Treatment of Fungal Esophagitis

Agent Treatment schedule

Topical
Nystatin 1–3 million units (10–30 mL) 4–5 times daily; swish
and swallow for 5–10 days
Clotrimazole 1 troche (10 mg) 5 times daily for 5–10 days
Systemic
Amphotericin B 0.3–0.6 mg/kg/d intravenously
Ketoconazole 200–400 mg once daily, orally for 5–10 days
Fluconazole 50–200 mg once daily, orally for 5–10 days
100–200 mg twice daily intravenously for 5–10 days
Itraconazole 200 mg once daily for 5–10 days

(and the other azoles) and other medications, including phenytoin, oral antico-
agulants, sulfonylureas, cyclosporin A, rifampin, and barbiturates. Fluconazole
augments the effects of warfarin, necessitating careful observation of patients
receiving both of these agents. Fluconazole may increase serum levels of
cyclosporin A. Serum cyclosporin A and creatinine levels must be monitored
carefully in patients receiving both of these drugs. Fluconazole and the other
azoles also appear to increase the serum levels of phenytoin and oral hypo-
glycemic agents. Fluconazole appears to have minimal antisteroidogenic effects
in humans at currently recommended doses. This results from fluconazole highly
specific affinity for fungal cytochrome P-450 enzymes, with virtually no affinity
for the mammalian system. This is an important advantage of fluconazole over
ketoconazole in patients with AIDS, who often have adrenal insufficiency sec-
ondary to adrenal cytomegalovirus (CMV) infection.
Itraconazole has a longer half-life than ketoconazole, but its absorption
is also reduced by hypochlorhydria. These two azoles are metabolized by the
liver and excreted in the bile. Dose adjustments are not required in the patient
with renal failure. Total treatment dosage is about 100 to 200 mg.
5. Intravenous (IR) amphotericin B should be considered in symptomatic
patients who fail to respond to the above regimen and in those in whom sys-
temic involvement is suspected. In the absence of systemic Candida infection,
a low-dose regimen of 10 to 20 mg per day for 10 days may be given. The
dosage may be increased if the patient does not respond favorably. If systemic
infection is present, the dosage should be increased gradually to 0.5 mg/kg per
day. Most patients are treated for 6 weeks. The major serious side effect of
amphotericin is renal toxicity, which is usually reversible.
6. A major problem in the treatment of esophageal candidiasis is relapse after
therapy is discontinued, especially in patients with AIDS, in whom immuno-
suppression is unrelenting. If the underlying predisposing factors persist, the
chances for permanent cure are low, and maintenance therapy may be neces-
sary (e.g., fluconazole 100 mg /day). However, in patients with reversible
predisposing conditions (e.g., radiotherapy, steroid use), a single course of
therapy for 10 to 21 days should be successful.
7. Nutritional support of the patient is very important. If the patient can swal-
low, the diet should be supplemented with liquid enteral formulas to ensure
that adequate calories are received. If the patient is unable to swallow, par-
enteral nutrition should be given until the patient can receive enteral feedings.

II. VIRAL ESOPHAGITIS is also a common esophageal disorder, especially in immuno-

compromised patients, which may clinically mimic Candida esophagitis. The herpes
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Chapter 19: Esophageal Infections 121

viruses are the most common etiologic agents of viral esophagitis, with HSV and CMV
predominating. In patients with AIDS, Epstein-Barr virus (EBV), varicella zoster
virus, and HIV-1 also have been implicated in esophageal ulcerations.
A. HSV esophagitis. Herpetic esophagitis may be seen in healthy, normal individu-
als, especially after strenuous physical exertion and stress. The infection in such
individuals is self-limited and resolves in approximately 7 to 10 days. Recovery
generally indicates intact humoral and cellular immunity. Persistence or recurrence
of the disease may be a sign of acquired immunodeficiency, requiring further
workup of the patient.
1. Predisposing factors
a. Immunocompromise
i. Malignancy, mainly of the hematopoietic and lymphoreticular systems
ii. Transplantation
iii. Immunosuppressive drugs, steroids
iv. Antineoplastic chemotherapy
v. AIDS
b. Severe debilitation
i. Elderly
ii. Burns
c. Antecedent trauma
i. Nasogastric tubes
ii. Tracheal intubation
iii. Gastroesophageal reflux disease and peptic esophagitis
2. Diagnosis
a. Clinical presentation. Herpetic infection of the esophagus usually presents
as a triad of fever, odynophagia, and substernal pain that increases with
feeding. The pain may radiate to the back. Patients may complain of pain
on palpation of the xiphoid process. Gingival stomatitis may be present.
Disseminated HSV infection is seen in 30% of the patients. Multiple organ
involvement with the virus (e.g., gastric and respiratory infection) is usually
life-threatening. Simultaneous infection with other organisms (bacteria,
fungi, and other viruses) is common. Severely debilitated patients may not
complain of pain; therefore, a high index of suspicion should be present if
these patients have dysphagia and decreased oral intake.
b. Diagnostic studies
i. Endoscopy. Endoscopic examination of the esophagus is the preferred
diagnostic approach in these patients. Biopsies and brushings of the
affected mucosa should be obtained. Biopsies should be obtained from
the edge of the ulcers.
a) The endoscopic appearance varies according to the stage of the viral
infection.
1) Early—vesicles of various sizes.
2) Mid—small, punched-out superficial ulcers covered with yellow,
fibrinous exudates.
3) Late—coalescing ulcers forming a diffuse, erosive esophagitis
with large areas of shallow ulceration.
b) The lesions often become overgrown with Candida and bacteria.
The virus may be cultured from ulcer margins and vesicles. A smear
of the ulcer base should be processed for Candida. Histologically,
the epithelial cells at the border of the ulcers contain inclusion bod-
ies. The chromatin of the infected nuclei is displaced toward the
periphery of the nucleus, giving a “rim” appearance. Multinucleated
giant cells are often present.
ii. Barium swallow. Double-contrast radiography may show ulcers or
plaques. The picture may be indistinguishable from that of Candida
esophagitis.
c. Diagnosis of herpes esophagitis is often difficult because the characteristic
nuclear inclusions or multinucleate giant cells of HSV infection may be
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122 Part V: Specific Complaints and Disorders

absent in endoscopic biopsy specimens. Immunoperoxidase and in situ

hybridization techniques may be used to detect the HSV when nuclear inclu-
sions are not readily apparent in infected epithelium. In situ hybridization
and immunoperoxidase techniques should be used also to detect other viruses
such as CMV, Epstein-Barr, and HIV-1. The diagnosis of HSV esophagitis
may still be missed when no infected epithelium is present in the biopsy spec-
imen. The presence of aggregates of large mononuclear cells (macrophages)
with convoluted nuclei adjacent to infected epithelium in the exudates of her-
petic esophagitis seems to be a characteristic inflammatory response in ulcer-
ative herpetic esophagitis. The presence of these mononuclear cells in a
biopsy specimen that initially does not show herpetic inclusions warrants
additional studies to rule out herpes virus infection.
d. Both brushings and biopsy specimens may be cultured for HSV to increase
the diagnostic yield.
3. Treatment
a. Supportive measures. Patients may benefit from viscous lidocaine swal-
lows for local anesthesia, especially before eating. Patients who have severe,
unremitting odynophagia may require intravenous hyperalimentation.
b. Acyclovir (Zovirax) has been shown to be effective in the prompt resolution
of symptoms. The dosage used is usually 6.2 mg /kg intravenously every 8
hours, for a 10- to 14-day course. Acyclovir 200 mg, five times a day by
mouth, may be used in mild-to-moderate disease.
Valacyclovir (1,000 mg three times a day for 7 days) and famciclovir
(500 mg orally twice a day for 7 days) seem to have similar efficacy as acy-
clovir, but may be administered three times a day.
B. Cytomegalovirus esophagitis. CMV is one of the most common opportunistic
infectious agents causing disease in patients with AIDS. In the gastrointestinal
tract, it most often infects the colon and esophagus.
1. Clinical presentation. CMV esophagitis may mimic HSV, Candida, and peptic
esophagitis. Patients may seek treatment for odynophagia, dysphagia, fever,
nausea, vomiting, or decreased oral intake. Hemoptysis, hematemesis, melena,
or esophageal perforation and sepsis may occur.
2. Diagnostic studies
a. Endoscopy. The endoscopic appearance of CMV esophagitis may resemble
that of HSV or Candida esophagitis. Discrete, deep ulcers may be present.
Biopsies should be taken from the center of the lesions.
b. Pathology. Histologic diagnosis of CMV infection is made with hema-
toxylin-eosin stain by identifying typically enlarged cells with characteristic
intranuclear and intracytoplasmic inclusion bodies. More sensitive tech-
niques such as in situ DNA hybridization and immune histochemical stain-
ing using CMV-specific antibodies have increased the diagnostic yield.
Infected cells are often identified in the granulation tissue and in stromal
papillae of the mucosa and the endothelium, but never in the squamous
epithelium. Thus, deep biopsies are necessary for diagnosis.
Viral cultures of the brushings and biopsies should be done to increase
the diagnostic accuracy and yield. Because multiple infections may coexist in
these patients, other agents such as bacteria, fungi, and other viruses should
be excluded.
3. Treatment. Ganciclovir sodium (5 mg/kg IV body weight twice daily for 14–21
days) has been used successfully in severely ill patients with improvement in the
symptoms of esophagitis. However, patients may require long-term maintenance
therapy and are subject to the myelosuppressive toxicity of the drug. Foscarnet
(foscavir) (60 mg/kg IV or 90 mg IV twice a day) is used in refractory diseases
or when side effects of gancyclovir sodium are limiting. It is effective in clinically
resistant cases of CMV. Its major side effect is reversible renal insufficiency.
Cidofovir, due to its long half-life, may be administered once weekly. It also
causes reversible renal insufficiency. Relapse rate is 50% in patients with AIDS,
especially those who are not on HAART.
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Chapter 19: Esophageal Infections 123

III. IDIOPATHIC ESOPHAGEAL ULCER (IEU) related to primary HIV infection. Large,
deep ulcers resembling CMV or HSV ulcers may occur in patients with AIDS and,
when other etiologies are excluded are attributed to HIV. Endoscopic cure may be
obtained with treatments with oral prednisone or thalidomide.

IV. BACTERIAL ESOPHAGITIS may be a distinct clinical and pathologic entity in

immunocompromised patients. In a neutropenic patient with either fever or a bac-
teremia of unknown source, esophagitis must be considered as a possible cause. In
some patients with bacteremia, the same organism may be seen on endoscopic biopsy
specimens from the esophagus. Most of the organisms isolated from tissue specimens
and blood in these patients are gram-positive cocci or rods and enteric gram-negative
bacilli. Antibiotics should be directed at the specific pathogen isolated.

V. ESOPHAGEAL TUBERCULOSIS. Involvement of the esophagus with tuberculosis

is rare. The condition may result from reactivated lung disease or direct extension of
the infection from adjacent mediastinal or hilar lymph nodes, vertebral bodies, aortic
aneurysms, pharynx, or larynx. Disease can also occur when a patient with active pul-
monary tuberculosis swallows large numbers of organisms that colonize preexisting
mucosal disease. However, most patients with tuberculous esophagitis have no evi-
dence of active pulmonary involvement on chest x-ray.
A. Clinical presentation. Epigastric pain and dysphagia are the most common pre-
senting symptoms. The symptoms in some patients are vague and nonspecific.
B. Diagnosis
1. Radiologic findings are usually diverse and may include extrinsic compression
by lymph nodes, ulceration, and stricture resembling esophageal malignancy.
2. Endoscopy. The endoscopic lesion is ulcerative, with shallow, smooth edges;
granular with small mucosal miliary granulomas; or hyperplastic, with fibrosis,
luminal narrowing, and stricture formation. Biopsies may show caseating gran-
ulomas with or without acid-fast bacilli.
3. Sputum cultures may grow Mycobacterium tuberculosis even in patients with
normal chest x-rays.
4. An intermediate-strength tuberculin skin test is usually positive and should
be compared with other, control antigens.
C. Treatment. A 9-month course of multidrug regimen including isoniazid, rifampin,
and ethambutol hydrochloride has been used to cure esophageal tuberculosis.

Selected Readings
Bini EJ, et al. Natural history of HIV-associated esophageal disease in the era of protease
inhibitor therapy. Dig Dis Sci. 2000;45:1301–1306.
Denning DW. Echinocardin anti fungal drugs. Lancet. 2003;362:1142–1452.
Kearney DJ, et al. Esophageal disorders caused by infection, systemic illness, medications,
radiation and trauma. In: Feldman M, Freedman LS, Schlessinger MH, eds. Philadelphia:
WB Saunders; 2002:623–646.
Keate RF, et al. Lichen planus: Report of three patients with oral tacrolimus or
intraesophageal corticosteroid injection or both. Dis Esophagus. 2003;16:47–53.
Pappas PG. et al. Guidelines for treatment of candidias. Clin Infect Dis. 2004;38:161–189.
Ramanthan J, et al. Herpes simplex esophagitis in the immunocompetent host: An overview.
Am J Gastroenterol. 2000; 95:2171–2176.
Rebolic AC, et al. Anidula fungia versus flucarazole for invasive candidiasis. N Eng J Med.
2007;356:2472–2482.
Walsh TJ. Echinocardins—an advance in the primary treatment of invasive candidiasis.
N Eng J Med. 2006;354:1215–1256.
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20 GASTROESOPHAGEAL REFLUX DISEASE

I. DEFINITIONS
A. Gastroesophageal reflux (GER) occurs when gastric contents escape into the
esophagus. This process may or may not produce symptoms. The most common
symptoms are heartburn, regurgitation, chest pain, and dysphagia.
B. Reflux esophagitis can be defined as esophageal inflammation caused by refluxed
material.
C. Gastroesophageal reflux disease (GERD) includes the constellation of symp-
toms and consequences to the esophagus from reflux damage.

II. PATHOGENESIS. The extent and severity of esophageal injury due to GER depend on
the frequency and the duration of esophageal exposure to the refluxed material, the
volume and potency of gastric juice available for reflux, and the ability of the
esophageal mucosa to withstand injury and to repair itself.
The pathogenesis of reflux esophagitis or GERD is a multifactorial process. The
following factors all contribute to the development of GERD:
A. Antireflux mechanisms. A positive pressure gradient exists between the abdomen
and the thorax. If there were no physiologic barrier at the area of the gastro-
esophageal junction, GER would occur continuously, especially with increases in
intraabdominal pressure or changes in gravitational position and during events
associated with abdominal muscle contraction, such as coughing, sneezing, strain-
ing, bending, turning in bed, and exercise. The antireflux barrier can be divided
into two categories.
1. Anatomic factors extrinsic to the lower esophageal sphincter (LES) that
augment the LES to prevent GER include a distal esophageal mucosal flap,
the acute esophagogastric angle, compression of the esophagogastric junction
by gastric sling fibers, the diaphragmatic crus acting as pinchcock, a hiatal tun-
nel, the sling action of the right diaphragmatic crus, and the intraabdominal
junction of the esophagus. The longer the intraabdominal segment, the less
likely reflux is to occur.
The presence of hiatal hernia with loss of the abdominal esophageal seg-
ment supported by the diaphragm and the normal acute esophagogastric angle
may lead to GER. However, a direct causal relationship has not been found
between hiatal hernia and GER. Nevertheless, a hiatal hernia generally (90%)
accompanies reflux esophagitis. It is possible that hiatal hernia enhances the
likelihood of LES dysfunction due to the loss of angulation at the esopha-
gogastric junction and the direct transmission of intragastric pressure to the
infrathoracic LES. Also, the hiatal hernia may act as a reservoir of refluxate
and impair esophageal clearance in the recumbent position, thus promoting
esophageal injury.
2. The closure strength and efficacy of LES
a. LES corresponds to the 2- to 4-cm zone of asymmetrically thickened smooth
muscle at the esophagogastric junction.
b. LES maintains a high-pressure tone during resting conditions and relaxes
with swallowing, esophageal distention, and vagal stimulation. These prop-
erties are independent of the diaphragm and persist even when the LES is
in the thorax, as in patients with hiatal hernia.

124
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Chapter 20: Gastroesophageal Reflux Disease 125

c. LES is innervated by both excitatory and inhibitory autonomic nerves

carried in the vagi to the esophageal plexuses. The major function of the
LES inhibitory nerves is to mediate sphincter relaxation in response to
swallowing.
d. LES pressure (LESP) is controlled by neural (most likely cholinergic), hor-
monal, and myogenic factors.
e. Resting LES pressure is not constant and varies from minute to minute in
the awake state. During sleep, this variability is diminished.
f. The intrinsic tone (the resting LESP) is one of the major factors that prevent
spontaneous GER.
g. In general, patients with GER have lower LESPs than controls. A minimum
resting LESP in the range of 6 to 10 mmHg prevents GER even during tran-
sient increases in intraabdominal pressure.
h. Changes in resting LES pressure occur throughout the day, especially during
the postprandial period. In addition, transient episodes of LES relaxation
occur not only in response to swallowing but also spontaneously, a process
referred to as “inappropriate LES relaxation” or “transient LES relaxation”
(TLESR). In “physiologic refluxers,” most reflux events occur during the
relaxation events. In “pathologic refluxers” (i.e., patients with reflux dis-
ease), other mechanisms of reflux also occur, including gradual decreases in
resting pressure and episodes of increased intragastric pressure. However,
most reflux events continue to occur during TLESR.
TLESR appears to represent a physiologic response to increased gastric
distention to relieve intragastric pressure.
i. Some GER occurs in all individuals with normal or lower-than-normal LESP
throughout the day. The frequency of GER increases for 2 hours postpran-
dially. However, patients with esophagitis have significantly more and longer
episodes of GER than controls.
j. Low resting LESP seen in patients with esophagitis may be primary or sec-
ondary to injury from reflux and inflammation.
k. LESP is affected by various drugs and hormones (Table 20-1). Avoidance of
agents that decrease the LESP and use of agents that increase LESP can be
helpful in diminishing GER symptoms and esophageal damage.
B. Gastric factors
1. Gastric volume
a. The occurrence of GER depends on an available reservoir of gastric fluid.
b. The probability and rate of GER are related to gastric volume.
c. The rate of reflux and the volume of the refluxate increase with incre-
mental increases in gastric volume, intragastric pressure, and the pressure
gradient between the stomach and the esophagus.
d. Gastric volume is determined by several factors.
i. Volume and composition of ingested materials
ii. Rate and volume of gastric secretion
iii. Rate and efficiency of gastric emptying
iv. Frequency and volume of duodenogastric reflux
e. One or more of the factors in d that favor an increase in gastric volume also
favor the occurrence of GER.
f. Pyloric channel or duodenal ulcers may result in delayed gastric emptying
and predispose to increased GER and GERD.
g. Delayed gastric emptying due to neuromuscular abnormalities such as in
collagen vascular diseases, diabetes mellitus, and hypothyroidism or mechan-
ical gastric outlet obstruction may also predispose to GERD.
2. Irritant potency of the refluxed material
a. The composition of the material refluxed into the esophagus is important
in determining the nature and extent of esophageal injury.
b. Gastric acid causes esophageal injury by protein denaturation and back dif-
fusion of hydrogen ion into deeper layers of the esophageal wall to cause
deeper injury.
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126 Part V: Specific Complaints and Disorders

TABLE 20-1 Agents Affecting Lower Esophageal Sphincter Pressure

Increase LESP Decrease LESP

Gastrin Secretin
Pitressin Cholecystokinin
Angiotensin II Glucagon
Cholinergics (e.g., bethanechol) Vasoactive intestinal polypeptide
Gastric alkalinization Progesterone (birth control pills)
Metoclopramide Theophylline
Anticholinesterases Caffeine
Protein meal Gastric acidification
Prostaglandin F2
Fatty meals
Chocolate (xanthines)
Carminatives (spearmint, peppermint)
Smoking
Ethanol

-Adrenergic antagonists
-Adrenergic agonists
Anticholinergics
Calcium channel blockers
Nitrates
Prostaglandin E2, prostaglandin A2
Morphine, meperidine
Diazepam, other benzodiazepines

LESP, lower esophageal sphincter pressure.

c. Pepsin, a protease, digests esophageal epithelial intercellular substance,

causing shedding of epithelial cells.
d. Duodenogastric reflux, especially postprandially, introduces bile salts
and pancreatic enzymes into the stomach, which may then reflux into the
esophagus. Bile salts may result in micellar dissolution of the lipids in the
esophageal epithelial cell membranes and increase the permeability of
the esophageal mucosa to hydrogen ion back diffusion. Pancreatic enzymes
may cause proteolytic injury.
e. Pancreatic digestive enzymes and bile salts may be the significant agents
of esophageal injury in patients with gastric hypochlorhydria and near-neu-
tral pH.
C. Esophageal clearance
1. The severity of esophageal injury from GER depends on the irritant potency
of the refluxed material and its contact time with the esophagus.
2. The rate of esophageal clearance determines the duration of the exposure of
the esophageal mucosa to the refluxed material.
3. Esophageal clearance of the refluxed material involves three mechanisms:
a. Volume clearance involves the emptying out of the esophagus of the vol-
ume of the refluxed material. It is facilitated by gravity, esophageal motor
activity, and salivation.
i. Normal esophageal motor activity (peristalsis) is required for
esophageal clearance.
ii. Primary peristalsis is initiated by swallowing, and the contraction
wave progresses in a sequential fashion throughout the entire length of
the esophagus, resulting in esophageal emptying into the stomach.
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Chapter 20: Gastroesophageal Reflux Disease 127

Normally, primary peristalsis occurs about once a minute while an indi-

vidual is awake. It is the main esophageal motor event that clears the
esophagus of refluxed material. The absence of swallowing and esoph-
ageal peristalsis during sleep impedes esophageal clearance of refluxed
material and predisposes to esophageal injury. Similarly in patients with
abnormal esophageal motility, increased nonperistaltic contractions lead
to increased reflux injury to the esophagus.
iii. Secondary peristalsis is elicited with distention of the esophagus by
a bolus of food or refluxed fluid. It has a limited effect on volume
clearance, because it does not result in a complete stripping peristaltic
wave.
b. Acid clearance involves the disappearance of the hydrogen ion from the
esophageal mucosa after the reflux of acid fluid. It is accomplished by a
neutralizing action of swallowed saliva.
c. Saliva is the third factor that contributes to esophageal clearance.
i. Normal awake individuals generate 0.5 mL of saliva per minute.
ii. Salivation stops during sleep.
iii. Salivation stimulates swallowing.
iv. Stimuli that increase salivary secretion include sucking, eating, intu-
bation, and cholinergic agents.
v. Under basal conditions, saliva has a pH of 6 to 7 due to the presence
of bicarbonate ion as the major buffer.
vi. During stimulation, both the salivary volume and the bicarbonate ion
concentration increase.
vii. Normal salivary flow effectively neutralizes small volumes (1 mL)
of refluxed acid.
viii. Salivation, by promoting swallowing and primary stripping peristal-
sis, clears the esophagus of the main volume of the refluxed material.
Subsequently saliva itself clears the acid from the esophageal mucosa
by its neutralizing action.
ix. Diminished salivation, primary (e.g., in Sjögren’s syndrome) or sec-
ondary (e.g., due to anticholinergic drugs) causes delayed acid clear-
ance and promotes esophageal injury.
D. Tissue resistance of the esophageal mucosa. The esophageal mucosa itself
has intrinsic protective mechanisms that resist and limit mucosal injury.
1. Preepithelial defenses
a. The luminal surface of esophageal epithelium is lined by a layer of mucus
that serves as both a lubricant and a protective barrier against noxious and
irritant luminal contents. This viscous gel layer prevents large protein mole-
cules like pepsin from contacting the underlying epithelium directly and
slows down hydrogen ion back diffusion.
b. Underneath the mucous layer, there is an area of low turbulence called the
unstirred water layer, which is rich in bicarbonate. This layer establishes a
protective alkaline microenvironment on the epithelial surface, neutralizing
the hydrogen ion that penetrates the mucous layer.
c. Mucus and bicarbonate are secreted by salivary glands and submucosal
glands located just below the upper esophageal sphincter and near the
esophagogastric junction. The rate of secretion of these glands increases
with vagal stimulation and with prostaglandins.
2. Postepithelial defenses. As in all tissues, adequate blood flow and normal
tissue acid–base status are essential for the maintenance of a healthy epithelium.
Blood flow provides the epithelium with oxygen, nutrients, and bicarbonate
(HCO3) as buffer and removes injurious waste products.
E. Epithelial regeneration. Despite the intrinsic ability of the esophageal mucosa to
resist injury, prolonged exposure to noxious substances results in epithelial cell
necrosis. Cell death further increases epithelial permeability, setting up a vicious cir-
cle for further damage. The replicating cells of the stratum basale along the base-
ment membrane need to be protected for epithelial regeneration. The destruction of
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128 Part V: Specific Complaints and Disorders

this layer appears to be necessary for the development of esophageal ulcers, stric-
tures, and Barrett’s epithelium. There is evidence that epithelial cell turnover and
replication is increased after hydrogen (H+) injury. Basal cell hyperplasia seen in
mucosal biopsies of patients with reflux esophagitis lends further support to this
finding. Normal turnover rate for esophageal epithelium is 5 to 8 days. This rate
seems to be increased to 2 to 4 days with injury. This will allow for epithelial
renewal and repair in a short time if further injury is prevented.
F. Summary. Patients with reflux esophagitis have heterogeneous abnormalities that
contribute to the development of esophagitis. Because patients have different
underlying abnormalities responsible for their reflux esophagitis, correct diagnosis
of the specific abnormalities involved allows for designing and selecting appropri-
ate therapy. Thus, therapy may be individualized and directed toward increasing
the LES pressure, enhancing esophageal clearance, promoting salivary output,
improving gastric emptying, suppressing gastric acidity, binding bile salts and pro-
teolytic enzymes, and promoting intrinsic epithelial defenses. Nighttime GER is
most deleterious to the esophageal mucosa and it should be considered with each
patient and addressed therapeutically.

III. DIAGNOSIS
A. Clinical presentation. The prevalence of heartburn, the most common clinical
manifestation of GER, is difficult to determine. Most people consider this sensa-
tion normal and do not seek medical attention. It is estimated that at least one
third to one half of the U.S. population experience heartburn at least once a month
and up to 20% of the population experience heartburn daily. The most common
symptoms of GERD are as follows:
1. Heartburn (pyrosis). A substernal burning pain, radiating upward. Ingestion
of antacids usually relieves this symptom within 5 minutes.
2. Regurgitation. Reflux of sour or bitter material into the mouth usually at
night, while lying down, or when bending over. It suggests severe reflux.
3. Dysphagia. Difficulty in swallowing. Dysphagia usually indicates a narrowing
or stricture of the esophagus; however, it may occur due to inflammation and
edema, which may resolve with aggressive medical therapy of the GERD.
4. Odynophagia. Pain on swallowing, which sometimes accompanies severe
esophagitis.
5. Water brash. Filling of the mouth suddenly with a clear, slightly salty fluid,
which comes in large quantities. The fluid is not refluxed from the stomach but
is secreted by the salivary glands in response to GER.
6. Chest pain. Resembling angina of cardiac origin, chest pain is an atypical pre-
sentation of GERD. This pain may result from acid-induced irritation of the
nerve endings in the elongated rete pegs protruding into the surface epithelium
or from GER-induced esophageal spasm or GER-induced angina pectoris.
In a study of the cardiovascular effect of reflux, esophageal acid perfusion
produced an increase in cardiac workload in patients with angiographically
proven coronary artery disease. Some patients had ischemic changes on elec-
trocardiography during acid perfusion. This suggests that esophageal and car-
diac disease not only may coexist, but also may interconnect. The standard
clinical approach aimed at distinguishing between esophageal and cardiac pain
may represent a serious oversimplification.
7. Hemorrhage may be the first clinical manifestation of esophagitis. It may be
brisk, bright red, or slow and may result in iron-deficiency anemia.
8. Pulmonary symptoms may be the only manifestation of GER and include
chronic cough, hoarseness of voice, wheezing, hemoptysis, asthma, and recur-
rent aspiration pneumonia. Although it is often assumed by clinicians that pul-
monary symptoms associated with reflux result from aspiration, reflux may
increase airway resistance without aspiration, apparently through vagus-mediated
neural reflexes.
9. Other symptoms such as sleep apnea, poor sleep/insomnia, and daytime
sleepiness may result from nighttime GER.
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Chapter 20: Gastroesophageal Reflux Disease 129

B. Diagnostic studies. When a patient describes recurrent retrosternal burning or

regurgitation that is worse after eating, lying down, or bending but is relieved with
antacids, clinical diagnosis of GERD can easily be made. However, when the pre-
sentation is atypical and GERD is suspected, further testing may be required to
establish the diagnosis and determine the severity and extent of the disease.
1. Usefulness of tests in GERD. The tests of GERD can be divided into three
subgroups.
a. Tests indicating possible GER
i. Barium swallow, upper gastrointestinal (GI) series
ii. Endoscopy
iii. Manometry, measurement of LES pressure
b. Tests showing results of GER
i. Bernstein test
ii. Endoscopy
iii. Mucosal biopsy
iv. Double-contrast barium esophagram
c. Tests measuring actual GER
i. Barium swallow and esophagram
ii. Standard acid reflux test
iii. Prolonged pH monitoring of the esophagus
iv. GE scintiscan
2. Barium esophagram and upper GI series. Radiologic examination of the
esophagus, stomach, and proximal duodenum is one of the first and most
common tests ordered in patients with upper GI complaints. The demonstra-
tion of barium reflux during this study is not specific, and many patients with
GERD may not show reflux during the time of study.
GER damage to the esophageal mucosa is usually not detected by single-
contrast esophagrams. The double-contrast studies may not show mild degrees
of inflammation but are more sensitive for severe grades of esophagitis. Positive
signs include contour irregularity, erosions, ulcerations, longitudinal fold thick-
ening, incomplete esophageal distensibility, and stricture formation. An upper
GI series will also help to rule out other upper gastrointestinal lesions, such as
peptic ulcer disease. It is a poor test in assessing esophageal motor dysfunction
but should be obtained in all patients with dysphagia to look for anatomic
causes.
3. GE scintiscan. In this test, 300 mL of normal saline containing technetium
99m–sulfur colloid is placed into the stomach, and counts over the stomach
and esophagus are measured at 30-second intervals while abdominal pressure
is increased incrementally using an abdominal pressure cuff. A reflux index is
calculated as the number of counts over the esophagus for given 30-second
intervals as a percentage of the number of counts initially present over the
stomach. The sensitivity and specificity are considered to be 90%. Because
external pressure is applied to the abdomen, however, it is not certain that this
technique approximates the physiologic situation.
4. Esophageal manometry has limited usefulness in the routine evaluation of
patients with GERD. It is helpful in evaluating the atypical patient with chest
pain, patients in whom medical therapy has failed, and those being considered
for antireflux surgery. It is a poor test in predicting GER unless the LES pres-
sure is less than 6 mmHg.
5. High-resolution manometry (HRM) offers a more precise and more complete
observation of esophageal motor function from the pharynx to the LES and
more accurate sphincter and peristaltic pressures.
6. Prolonged pH monitoring. In recent years, prolonged esophageal pH moni-
toring has become the gold standard for measurement of acid GER. This test
provides the most physiologic measurement of acid reflux over 12 to 24 hours
in relation to meals, body position, activity, and sleep.
A pH electrode is placed 5 cm above the LES, and the pH is charted elec-
tronically by a system similar to the Holter monitoring of cardiac rhythm.
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130 Part V: Specific Complaints and Disorders

Patients follow a normal diet with the exception of foods with pH below 5.0.
Patients are asked to write down their symptoms and their body position
(upright or supine) during the test period. Reflux is defined as the point at
which the pH drops to less than 4.0. Each patient’s reflux status is assessed by a
composite score that incorporates six components:
a. Percentage of time of total acid exposure of the esophagus.
b. Percentage of acid exposure in upright and recumbent positions.
c. Presence of reflux episodes.
d. Total number of reflux episodes.
e. Number of reflux episodes longer than 5 minutes.
f. The longest reflux (time). This test is excellent in identifying acid GER but
does not detect “alkaline” reflux. Prolonged pH monitoring has also been
helpful in documenting the suspected association between GER and pul-
monary disease.
7. Wireless pH monitoring (Brano) device which is placed endoscopically in
the distal esophagus allows for prolonged monitoring (2–4 days) and better
understanding of the day-to-day variability of GER as well as assessing the
effectiveness of acid suppressive therapy without performing a second test.
8. Multichannel intraluminal impedance (MII) is used to assess GER, esopha-
geal bolus transit (peristaltic function), and the proximal extent of the reflux
event. MII may be used in combination with esophageal manometry and
pH testing. It is helpful in documenting GER regardless of the pH of the
refluxate.
9. Esophagogastroduodenoscopy and mucosal biopsy. Flexible fiberoptic
endoscopy has become the most widely used method to examine the mucosal
surface of the esophagus for evidence of esophagitis. Endoscopic forceps biop-
sies are adequate for evaluating histologic changes of GERD. Even when
endoscopic appearance of the esophagus is normal, histologic examination of
the biopsies may confirm the presence of GERD.
Findings of esophagitis by endoscopy are as follows:
a. Mild. Erythema; edema of the mucosa with obliteration of small, linear
blood vessel; mild friability; and increased irregularity of the Z line.
b. Moderate-severe. Round and longitudinal superficial ulcers or erosions,
diffusely hemorrhagic mucosa with exudates, and deep, punched-out
esophageal ulcers and strictures.
10. Histology. In patients with GERD, there is a hyperplasia of the basal cell layer
of the squamous epithelium. This layer constitutes more than 15% of the
epithelial thickness. The dermal papilla extends more than 65% of the dis-
tance to the epithelial surface. Polymorphonuclear leukocytes and eosinophils
may be seen in the lamina propria and may invade the epithelium. Ingrowth
of capillaries is also seen in the lamina propria.
In about 10% to 20% of the patients with chronic GERD, a specialized
columnar metaplastic epithelium (Barrett’s epithelium) is present. Endoscopic
examination of the stomach and the duodenum can rule out other possible
lesions in these areas.
11. Summary. For the diagnosis of GERD, most patients with the classic symp-
toms of GERD of heartburn or regurgitation are given an empiric trial of
medical therapy without further investigation. Endoscopy and mucosal biop-
sies are recommended in patients with refractory symptoms, odynophagia,
dysphagia, and atypical symptoms and in patients when Barrett’s esophagus is
suspected (e.g., those patients with GER symptoms for more than 5 years).
Prolonged pH monitoring and manometry are reserved for patients with atyp-
ical symptoms and pulmonary complaints.

IV. COMPLICATIONS OF GERD

A. Strictures. An esophageal peptic stricture is thought to result from fibrosis when
inflammation and injury extend below the mucosa as consequences of chronic GER.
Up to 11% of patients with GERD seem to develop strictures. Factors predisposing
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Chapter 20: Gastroesophageal Reflux Disease 131

to stricture formation include prolonged GER, reflux while supine, nasogastric intu-
bation, duodenal ulcer disease, gastric hypersecretory states, postgastrectomy states,
scleroderma, and treated achalasia. Ringlike stricture in the distal esophagus at the
E-G junction is called Schatzki’s ring.
1. Location. Strictures are usually located in the distal third of the esophagus. In
the barium esophagogram, they usually have a smooth, tapered appearance
and are of variable lengths. In some instances of Barrett’s esophagus, the stric-
ture is located in the middle third or, less commonly, in the proximal third of
the esophagus.
2. Symptoms. Peptic strictures usually produce no symptoms until the esophageal
intraluminal diameter is decreased to less than 12 mm. Initially dysphagia is
mostly for solids, but with progressive narrowing, swallowing of liquids also
becomes a problem. It is not uncommon for the patient to notice improvement in
the usual reflux symptoms as dysphagia develops with narrowing of the stric-
tured area. Some patients do not recall even having GER symptoms.
3. Treatment. After appropriate diagnostic tests (barium esophagram, endoscopy,
and biopsies) have been performed to ensure that the stricture is not due to a
malignant process, intensive medical therapy is begun for reflux esophagitis.
With resolution of edema and inflammation, some patients may have relief of
their symptoms. However, most patients require additional therapy in the form
of dilatations, surgery, or both.
a. Dilatation. Progressive dilatations with graded mercury-filled rubber bou-
gies (Maloney or Hurst dilators) have been used in the past for symptomatic
relief. Savary dilators passed over a guidewire or inflatable balloon dilators
with endoscopic guidance offer safer and more effective means of dilatation.
Savory dilators come in graded sizes. The guide wire is passed
through the biopsy channel of the endoscope and advanced into the stric-
ture, then into the stomach. The endoscope is then removed. The savory
dilator is then “threaded over” the guide wire and gently advanced into the
lumen of the stricture to dilate it. Afterward, it is withdrawn, then a larger-
sized savory dilator is advanced. Similarly, the process is repeated with
larger dilators until the stricture is adequately dilated and/or “blood” is
seen on the dilator. The dilators should never be forced into the stricture to
avoid perforation. Many gastroenterologists use savory dilators with the
aid of fluoroscopy.
Endoscopic balloon dilators allow endoscopic visualization during
the entire procedure of dilatation. Each balloon catheter can be inflated to
three enlarging sizes that allow progressive dilatation with one insertion.
During the EGD the balloon dilatator catheter is introduced via the biopsy
channel into the esophageal lumen, then into the stricture. The balloon at
the end of catheter is then dilated progressively until the stricture is dilated
to the desired size.
The major complications of dilatations are perforation and bleeding.
Perforations are rare but should be suspected if the patient complains of
persistent pain after dilatation. Perforations are identified by a radiologic
contrast study. Patients are treated with intravenous nutrition and antibi-
otics to cover for organisms from the mouth flora. Surgical drainage and
repair should be considered early, since mortality associated with large
esophageal perforations is high.
Dilatation of the stricture and medical therapy for reflux yield good
results in 65% to 85% of patients. The patency of the esophageal lumen is
maintained by additional dilatations at intervals of weeks to months.
b. Surgery. For the 15% to 40% of patients in whom dilatation and medical
therapy fail, surgery is indicated. The preferred surgical approach to stric-
tures is pre- or intraoperative dilatation combined with an antireflux opera-
tion, such as the Nissen fundoplication. If the stricture cannot be dilated or
is too extensive, resection and end-to-end anastomosis or interposition of a
segment of colon or small bowel may be used. These may be combined with
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132 Part V: Specific Complaints and Disorders

a Nissen fundoplication to avoid anastomotic leaks or recurrence of the

strictures.
B. Esophageal ulcers and bleeding. A small percentage of patients with GERD, in
addition to severe esophagitis, have deep peptic ulcers penetrating into the muscu-
lar layers. These ulcers occasionally perforate or cause massive bleeding.
Most of these ulcers respond to intensive medical therapy, but some require
surgery. Often, deep ulcers are found in metaplastic Barrett’s epithelium. These
ulcers should be biopsied prior to therapy to rule out the possibility of malignancy.
C. Pulmonary manifestations. Respiratory problems attributable to GER include
laryngitis, hoarseness, chronic cough, asthma, bronchitis, bronchiectasis, aspira-
tion pneumonitis, atelectasis, and hemoptysis. Although most of these patients
experience GER symptoms, these symptoms are not always present.
1. Diagnosis. Documentation of pulmonary aspiration of gastric contents is diffi-
cult. Radionuclide scintiscanning of the lungs may be used to document pul-
monary aspiration following the placement of technetium 99m–sulfur colloid in
the stomach. If a positive result is found, it may be helpful; however, a negative
result does not rule out aspiration or absence of a relationship between the pul-
monary disease and GER. Prolonged pH monitoring may be helpful in some
patients. Numerous studies have demonstrated an increased frequency of reflux
in patients with acute and chronic obstructive pulmonary disease. It is accepted
that GER with or without aspiration produces an increased airway resistance
often requiring strict antireflux therapy with constant suppression of gastric acid
secretion with the use of high-dose proton-pump inhibitors (PPIs). Fundoplication
may be necessary in some patients (e.g., refractory asthma, GER-related apnea,
recurrent aspiration pneumonitis).
2. Treatment. Intensive therapy of GER may be beneficial in these patients. Many
of the medications used to treat asthma lower LES pressure and increase the
chance for GER. Thus, the medications used in these patients should be closely
monitored. In addition, patients should be discouraged from smoking. Patients
who do not improve with medical therapy with PPIs may require antireflux
surgery.
D. Barrett’s esophagus. In some patients, chronic reflux esophagitis results in
replacement of the normal squamous epithelium of the distal esophagus with
metaplastic specialized columnar epithelium called Barrett’s epithelium.
Depending on the length of the abnormal tissue, Barrett’s esophagus may be
subclassified as short segment (if it is less than 2 cm) or long segment Barrett’s
esophagus. The prevalence of Barrett’s esophagus may be as high as 20%. Even
though Barrett’s esophagus may be seen at any age, most instances come to medical
attention after the fourth decade of life. It is more common in patients with night-
time GER.
Barrett’s epithelium consists of a complex mixture of varying cell types,
glands, and surface architecture that is normally seen in the small bowel with vary-
ing degrees of atrophy.
1. Complications. Peptic ulceration, strictures, and adenocarcinoma are
complications associated with Barrett’s esophagus. Strictures are characteristi-
cally found in the mid to lower esophagus with squamous epithelium above
and columnar epithelium below the stricture.
Dysplasia and adenocarcinoma of the esophagus have been recognized
arising in Barrett’s epithelium with a reported prevalence of 3% to 9%. The
neoplastic changes may be multifocal and may represent a major pathway in
the genesis of adenocarcinoma of the lower esophagus and gastric cardia. The
presence of a malignant lesion should be suspected in any patient with mid-
esophageal narrowing and stricture formation. However, dysplastic and malig-
nant changes may be present in any patient with Barrett’s esophagus. Periodic
(e.g., every 1–5 years) multiple endoscopic biopsies and brush cytology should
be performed in these patients, especially in patients with histologic dysplasia,
to monitor for malignancy. The frequency of endoscopic surveillance of
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Chapter 20: Gastroesophageal Reflux Disease 133

Barrett’s esophagus is controversial. However, if low-grade dysplasia is

found, yearly EGD and biopsies are recommended. If high-grade dysplasia is
found. EGD and biopsies should be repeated every 3 to 6 months. Some experts
even suggest therapeutic modalities to eradicate the highly dysplastic tissue
and/or consider surgery.
2. Treatment. Most patients with Barrett’s esophagus are treated medically for
reflux esophagitis with high-dose PPIs. Despite strict intensive medical therapy,
regression of this metaplastic change has not been documented. Esophagec-
tomy or mucosal ablation therapy is recommended if severe dysplasia is
found. Mucosal ablation may be accomplished by endoscopic mucosal resec-
tions, photodynamic therapy followed by laser ablation, or by laser, or bipolar
heater probe cautery. These procedures are still not widely accepted or available
except in special tertiary medical centers.

V. TREATMENT OF GERD. GERD is a chronic disorder. It is important to educate the

patients to modify their lifestyle and habits that may promote GER and encourage
them to adopt new habits that will bring long-term beneficial results.
A. Medical therapy
1. Dietary and lifestyle changes recommended include the following:
a. Elevation of the head of the bed (15.2 cm [6 in.]), especially for patients
with regurgitation, may be achieved by the placement of 15.2-cm (6-in.)
blocks under the head of the bed or a 15.2-cm (6-in.) foam-rubber wedge in
place of or under the pillow.
b. Avoid
i. Smoking
ii. Fatty and fried foods
iii. Chocolate
iv. Alcohol
v. Tomato products
vi. Citrus juices and fruits
vii. Coffee, tea, and carbonated beverages
viii. Carminatives (spearmint, peppermint)
ix. Large meals that would distend the stomach
c. Encourage
i. High-protein, low-fat diet.
ii. Three small-to-moderate-sized nutritionally balanced meals a day. The
evening meal should be light and easy to digest.
d. No eating 4 to 5 hours prior to reclining or going to sleep.
e. Weight loss, if overweight.
f. Avoid using tight belts or girdles that increase intraabdominal pressure.
g. Avoid drugs that promote GER (reduce LES pressure and esophageal clearing):
i. Progesterone or progesterone-containing birth control pills
ii. Anticholinergics
iii. Sedatives/opiates
iv. Tranquilizers
v. Theophylline
vi. Beta-adrenergic agonists
vii. Nitrates
viii. Calcium channel blockers
2. Pharmacologic therapy
a. Antacids. Frequent use of antacids and lozenges (e.g., every 2 hours) is rec-
ommended. The most effective and commonly used antacids are those that
contain a combination of magnesium and aluminum hydroxides. For
patients with renal failure, only aluminum hydroxide-containing antacids
are recommended since magnesium may accumulate in the blood. Low-
sodium preparations (e.g., Riopan) are available for patients on severe
sodium restriction.
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134 Part V: Specific Complaints and Disorders

b. Drugs that decrease gastric acid output. Those most commonly used
drugs are histamine-2 (H2) blockers. For patients with intermittent, infre-
quent or mild symptoms of GER, H2 blockers may be prescribed. These
drugs are usually effective in controlling symptoms of mild to moderate
GER, but have not been shown to effectively heal erosive esophagitis.
H2-blockers do not suppress gastric secretions completely. They decrease
gastric acid secretion by binding to the histamine receptor on the parietal
cell in a competitive fashion. When their concentration decreases around
the parietal cell, histamine binds to the parietal cell receptor and acid secre-
tion is resumed. Thus, regular and frequent dosing is essential. H2 blockers
also have very limited acid suppressive ability at times of eating and the
gastric pH rarely rises above 2 to 3. Because GER occurs most commonly
during and after eating, acid and pepsin activity is not eliminated with
H2 blockers and their effectiveness is thus limited.
i. Cimetidine (Tagamet), 300 mg q.i.d. or 400 to 800 mg q12h a.c. and h.s.
ii. Ranitidine (Zantac), 150 to 300 mg q12h
iii. Famotidine (Pepcid), 20 to 40 mg at h.s.
iv. Nizatidine, 150 to 300 mg q12h
Note: Tagamet, Zantac, and Pepcid are also available at lower doses as
over-the-counter medications.
c. Proton-pump inhibitors. The final step of gastric acid secretion by the
parietal cell involves the extrusion of a proton or a hydrogen ion (H) into
the gastric lumen in exchange of a potassium ion (K), which enters the
parietal cell via the H K-ATPase or the “proton pump.” PPIs are a group
of drugs designed to inhibit acid secretion by forming a covalent bond
within the proton pump and, thus, inhibiting the exchange of (H) and
(K) ions permanently by that proton pump. These drugs are extremely
effective in inhibition of gastric acid secretion for 19 to 24 hours and allow
the gastric pH to rise above 4 or 5, thus, also eliminating the pepsin activ-
ity. PPIs have been shown to effectively heal erosive esophagitis, diminish
the formation of esophageal strictures, and control most symptoms and
signs of GERD. PPIs, when used continuously, prevent recurrence of ero-
sive esophagitis. As a group of drugs, they are safe and have minimal side
effects. In most instances, they are used as first line therapy for GERD.
Currently, there are six commercially available PPIs approved by the
U.S. Food and Drug Administration (FDA) for healing erosive GERD. These
are omeprazole (Prilosec), 20 to 40 mg p.o. (q.d. or b.i.d.); lansoprazole
(Prevacid), 15 to 30 mg p.o. (q.d. or b.i.d.); rabeprazole sodium (AcipHex),
20 mg orally (once daily); pantoprazole (Protonix), 40 mg p.o. (q.d.);
esomeprazole magnesium (Nexium), 20 to 40 mg p.o. (q.d.); and omepra-
zole sodium bicarbonate (Zegerid), 40 mg p.o. (q.d.). All PPIs are most
effective if taken 15 to 30 minutes before breakfast or dinner. Omeprazole,
lansoprazole, pantoprazole, and esomeprazole magnesium are excreted in the
urine. Rabeprazole sodium is mostly excreted in bile. No dose adjustments
are necessary in renal or hepatic insufficiency. Omeprazole, esomeprazole
magnesium, lansoprazole, and rabeprazole sodium are metabolized by the
p450 system in the liver and may have minor drug–drug interactions with
some drugs; however, these have not been shown to be clinically significant.
Pantoprazole has no known drug–drug interactions. Pantoprazole, esomepra-
zole, and lansoprazole are also available in intravenous (IV) formulation and
have been FDA-approved for in patients with GERD who are unable to
receive medications by the oral route.
Side effects of PPIs are rare and include minor headaches, diarrhea,
and nausea. PPIs have revolutionized the treatment of GERD and most of
its complications. These drugs have been noted to be safe and free of long-
term complications. Initial concerns about gastric bacterial overgrowth,
Vitamin B12 and iron malabsorption, and causation of gastric carcinoid
tumors have not been clinically observed. A retrospective observational
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Chapter 20: Gastroesophageal Reflux Disease 135

study suggests that patients taking PPIs for many years may have decreased
calcium absorption. Thus it may be prudent to encourage patients on pro-
longed PPI therapy to take calcium supplements.
d. Drugs that increase LES pressure and esophageal clearance
i. Metoclopramide hydrochloride, a dopamine antagonist, has been
shown to increase LES pressure and to improve esophageal and gastric
emptying. It counteracts the receptive relaxation of the gastric fundus
and increases duodenal and small-bowel motility. It is also a centrally
active antiemetic. This drug is especially helpful in patients with GERD
and abnormalities of gastric emptying. Since metoclopramide crosses
the blood–brain barrier, 10% of patients seem to experience psy-
chotropic side effects (e.g., somnolence, lassitude, restlessness, anxiety,
insomnia, and, rarely, extrapyramidal reactions). These side effects are
reversible with cessation of the drug. Elevated prolactin levels may
occur and cause galactorrhea. The usual dosage is 10 to 20 mg q.i.d.,
15 to 30 minutes a.c. and h.s.
ii. Other prokinetic drugs such as domperidone and cisapride do not
cross the blood–brain barrier and have only the peripheral effects of
metoclopramide. These drugs have excellent promotility qualities and
have been used successfully in the treatment of GERD.
However, cisapride, due to its drug–drug interactions with those
drugs that prolong the Q-T interval (on electrocardiogram) and the pos-
sibility of precipitating cardiac arrhythmias, has been removed from the
market in the United States by the manufacturer. Cisapride and dom-
peridone are available in Canada and other countries.
e. Drugs that enhance mucosal resistance. As the importance of mucosal
resistance is appreciated, drugs that potentiate cytoprotection and mucosal
resistance are being added to the medical armamentarium of acid-peptic
disease.
i. Sucralfate (Carafate), an aluminum sucrose polysulfate shown to be
effective in healing duodenal ulcers due to its cytoprotective action, has
not been shown to be highly effective in patients with esophagitis.
However, sucralfate suspension seems to give symptomatic and possibly
therapeutic benefit to patients with erosive esophagitis. Dose is 1 g 1–4
times daily.
ii. Prostaglandin analogs (e.g., misoprostol) have also been shown to be
cytoprotective and effective in the treatment of peptic ulcer disease, but
have not been found highly effective in the treatment of GERD.
f. The results of maintenance therapy with H2-receptor antagonists are dis-
appointing. Neither twice-daily nor single-dose-bedtime regimens of cimeti-
dine or ranitidine are significantly more effective than placebo in preventing
symptomatic or endoscopic evidence of relapse. However, maintenance ther-
apy with 20 mg of omeprazole daily sustains endoscopic healing in most
patients with severe, recalcitrant esophagitis. In some patients, the dosage
needs to be increased to 40 mg. Significant and persistent elevations in fast-
ing serum gastrin concentrations may occur in a minority of patients. It is
important to note that up to 90% of patients who healed with omeprazole
treatment had recurrence of their esophagitis within 6 months of stopping
treatment, indicating that some form of chronic treatment is needed. Similar
excellent results have also been achieved with the other PPIs (lansoprazole,
rabeprazole sodium, pantoprazole, and esomeprazole magnesium) at the
same doses used to heal erosive esophagitis.
B. Phase III, endoscopic interventional and/or surgical therapy, is reserved for
patients in whom intensive medical therapy has failed and those with complica-
tions such as a nonhealing or bleeding esophageal ulcer or a refractory stricture.
Surgery for Barrett’s esophagus is still controversial.
Endoscopic treatment of GERD has been attractive as an alternative to
surgery by providing a less invasive solution to GER refractory to medical therapy.
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136 Part V: Specific Complaints and Disorders

The initial procedures involved injection of collagen circumferentially at

the LES (Enteryx) which created a “tighter” LES and the Stretta procedure
which places minute areas of thermal injury in the muscle of the lower esophageal
sphincter and cardia using radio frequency waves. These procedures have shown
improvement in GERD symptoms, but have not shown a consistent reduction in
esophageal acid exposure or improved LES tone. Serious complications have been
reported and both of these procedures have been abandoned.
Endoscopic suturing devices, which place submucosal sutures in the gastric
cardia, and endoscopic plicators, which place transmural staples around the LES,
are still in evolution and offer promise. Both of these procedures decrease the luminal
size of the distal esophagus and gastric cardia to decrease GER and regurgitation.
The preferred antireflux operation is the Nissen fundoplication, in which
the LES is reinforced with a 360-degree gastric wrap for a distance of about 5 cm
around the lower esophagus, which is secured below the diaphragm. If a hiatal
hernia is present, it is reduced. An adequate esophageal lumen is secured with a
60-French, mercury-filled bougie placed in the esophageal lumen during the surgi-
cal procedure. Nissen fundoplication performed by a competent surgeon has been
shown to be successful with lasting effects. It should be considered in young
patients for long-term relief of GERD. This procedure is currently widely available
as a laparoscopic procedure (laparoscopic Nissen fundoplication) with much
lower morbidity and, in good hands with equivalent effectiveness to the open
Nissen fundoplication.

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21 DYSPHAGIA

I. ESOPHAGUS
A. Anatomy
1. The esophagus is a muscular tube measuring about 25 cm (40 cm from the
incisor teeth) extending from the pharynx at the cricoid cartilage to the cardia
of the stomach. It pierces the left crus of the diaphragm and has an intraab-
dominal portion of about 1.5 to 2.5 cm in length.
2. The esophageal mucosa consists of a nonkeratinizing squamous epithelium,
lamina propria extending into the basal layer as rete pegs, and muscularis
mucosa, which is sparse and thin in the upper portion but thicker near the gas-
troesophageal junction.
3. The submucosa contains mucous glands and an extensive lymphatic plexus in
a connective tissue network.
4. Between the submucosa and muscularis propria are the cell bodies of secondary
neurons forming the Auerbach’s plexus.
5. The muscularis propria, the main muscle layers of the esophagus, is composed
of inner circular and outer longitudinal coats. In the upper part, these are stri-
ated. There is a gradual change to smooth muscle in the middle. In the lower
third of the esophagus, both of these coats are entirely composed of smooth
muscle.
6. Between the muscle layers, the myenteric plexus contains the cell bodies of
other secondary neurons.
7. The esophagus does not have a serosal layer.
8. Lower esophageal sphincter. The distal 3 to 4 cm of the esophagus constitutes
a zone of increased resting pressure in an asymmetric fashion. This area, called
the lower esophageal sphincter (LES), behaves both physiologically and pharma-
cologically as a distinct entity from the esophageal smooth muscle immediately
adjacent to it. Basal LES pressure is normally 10 to 25 mmHg higher than intra-
gastric pressure and drops promptly (within 1–2 seconds) with swallowing. The
LES control remains poorly understood but is thought to involve the complex
interaction of neural, hormonal, and myogenic activities.
B. Physiology of esophageal function. The function of the esophagus is to transport
food and secretions from the mouth to the stomach. This coordinated process oper-
ates regardless of the force of gravity.
1. A swallow begins when a liquid or solid bolus is propelled to the back of the
mouth into the pharynx by the tongue. The upper esophageal sphincter (UES),
the cricopharyngeus, which is just below the pharynx, relaxes, allowing the
bolus to pass into the upper esophagus. In response to swallowing, an orderly,
progressive contraction of the esophageal body occurs (primary peristalsis),
propelling the bolus down the esophagus. When the esophagus is distended by
a bolus (i.e., with regurgitation), secondary peristaltic contractions are initi-
ated. The LES relaxes as the bolus reaches the lower esophagus, allowing pas-
sage of the food into the stomach.
2. The relaxation of the UES and peristalsis in the upper esophagus are ini-
tiated by the voluntary act of swallowing, controlled by the swallowing center
in the brainstem and the fifth, seventh, ninth, tenth, eleventh, and twelfth cranial
nerves. These nerves coordinate the movement of the bolus to the hypopharynx,

138
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Chapter 21: Dysphagia 139

closure of the epiglottis, relaxation of the UES, and contraction of the striated
muscle of the upper esophagus. The sequential nature of this function is due to
progressive activation of nerve fibers carried in the vagus nerve controlled
through a central mechanism.
3. The peristalsis in the smooth-muscle portion of the esophagus is regu-
lated by activation of neurons located in the myenteric plexus with cholinergic
neural transmission. The vagi innervate the upper esophagus in its striated mus-
cle portion only. If the vagi are cut below the level of mid esophagus, peristalsis
in the lower half of the esophagus and the function of the LES remain intact.

II. DYSPHAGIA
A. Definition
1. Dysphagia is difficulty in swallowing. Clinically, it includes the inability to ini-
tiate swallowing and/or the sensation that the swallowed solids or liquids stick
in the esophagus.
2. Odynophagia refers to pain with swallowing. In some disorders, odynophagia
may accompany dysphagia.
3. Globus hystericus describes the sensation of the presence of “a lump in the
throat” that is relieved momentarily by swallowing.
B. Preesophageal or oroesophageal dysphagia. Patients with this disorder have
problems with the initial steps of swallowing. They may have difficulty in pro-
pelling food to the hypopharynx. If the food passes normally to the hypopharynx,
the presence of pain, intra- or extraluminal mass lesion, or a neuromuscular disor-
der may interfere with the orderly sequence of pharyngeal contraction, closure of
the epiglottis, UES relaxation, and initiation of peristalsis by contraction of the
striated muscle in the upper esophagus.
1. Signs and symptoms. These patients usually cough and expel the ingested
food through their mouth and nose or aspirate when they attempt to swallow.
Their symptoms are worse with liquids than with solids. They may have a
“wet” voice quality, reduced cough, upper airway congestion, and aspiration
pneumonitis.
2. Causes
a. Central nervous system conditions. Cerebral vascular accidents (bulbar
or pseudobulbar palsy), multiple sclerosis, amyotrophic lateral sclerosis,
Wilson’s disease, Parkinson’s disease, Friedreich’s ataxia, tabes dorsalis, brain-
stem tumors, paraneoplastic disorders, reaction to drugs or toxins, other
congenital and degenerative disorders of the central nervous system.
b. Peripheral nervous system conditions. Poliomyelitis (bulbar), diphtheria,
rabies, botulism, diabetes mellitus, demyelinating diseases, Guillain-Barré
syndrome.
c. Disorders of the myoneural junction. Myasthenia gravis, Eaton-Lambert
syndrome.
d. Muscular disorders. Dermatomyositis, muscular dystrophies, myotonic
disorders, congenital myopathies, metabolic myopathies (thyrotoxicosis,
hypothyroidism, hyperthyroidism, steroid myopathy), collagen vascular dis-
eases, amyloidosis.
e. Toxins. Tetanus, botulism, tic paralysis, arsenic, lead, mercury poisoning.
f. Local structural lesions. Conditions involving the mouth, pharynx, and
hypopharynx.
i. Infection or inflammation. Abscess; tuberculosis; syphilis; viral, bacte-
rial, and fungal infections; Lyme disease; diphtheria; rabies.
ii. Space-occupying lesions. Neoplasms, congenital webs, Plummer-
Vinson syndrome.
iii. Extrinsic compression. Cervical spine spurs, lymphadenopathy, thy-
romegaly, Zenker’s diverticulum.
iv. Trauma. Surgical repair, foreign body ingestion, caustic injury.
g. Motility disorders of the upper esophageal sphincter. Hypertensive
UES, hypotensive UES with esophagopharyngeal regurgitation, abnormal
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140 Part V: Specific Complaints and Disorders

UES relaxation (incomplete relaxation: cricopharyngeal achalasia, prema-

ture closure, delayed relaxation).
C. Esophageal dysphagia describes difficulty with transport of food down the
esophagus once the bolus has been successfully transferred into the proximal
esophageal lumen. Any disorder, structural or neuromuscular, involving the body
of the esophagus, the LES, or the gastroesophageal junction may result in dyspha-
gia or the sensation of food being “stuck” behind the sternum. If the patient can
localize the symptom to some point along the sternum, a good correlation with the
anatomic site is possible. However, if the symptoms are felt at the sternal notch,
the anatomic site of the lesion cannot be predicted.
1. Structural disorders are usually caused by a discrete lesion such as a neo-
plasm, stricture, or extrinsic compression that interferes with the transport of
the swallowed bolus. Initially, dysphagia is noted with solid foods. However, as
the lumen narrows with enlarging lesions, passage of liquids also becomes
impaired.
a. Tumors (see also Chapter 23)
i. Squamous carcinoma accounts for approximately one third of all
esophageal cancers. Excessive alcohol intake and cigarette smoking seem
to increase the risk. Other predisposing factors include head and neck
cancer, Plummer-Vinson syndrome (anemia and esophageal web), tylosis,
achalasia, and lye stricture.
ii. Adenocarcinoma of the esophagus constitutes about two thirds of
esophageal cancers. It is thought to arise from extension of gastric cardia
carcinoma, from the esophageal glands or, more commonly, from the
columnar metaplasia of the esophagus (Barrett’s epithelium).
iii. Kaposi’s sarcoma, lymphoma, melanoma, and metastatic tumors from
the lungs, pancreas, breasts, and other structures may also involve the
esophagus.
iv. Benign tumors of the esophagus are rare and account for less than
10% of esophageal tumors. These tumors most commonly arise from
neuromesenchymal elements. Leiomyomas that arise from esophageal
smooth muscle are the most common. These intramural lesions are cov-
ered by normal squamous epithelium of the esophagus. They protrude
into the lumen, eventually causing narrowing of the passage. Other
lesions such as fibroadenomas, though rare, may become very long and
large and may cause obstruction.
b. Strictures
i. Peptic strictures. Most esophageal strictures are found in the distal or
mid esophagus and are the result of chronic inflammation caused by gas-
troesophageal reflux. Peptic strictures are usually benign, but those asso-
ciated with Barrett’s epithelium may be malignant.
ii. Burns caused by ingestion of corrosive substances (e.g., strong alkali and
acids) may result in esophageal strictures in single or multiple locations
of the esophagus.
iii. Some drugs in tablet form may lodge in a segment of the esophagus and
cause local inflammation, ulceration, and stricture.
iv. Foreign bodies (e.g., coins or button batteries) may be swallowed and
cause obstruction or injury of the esophagus.
c. Rings and webs are usually thin, circumferential mucosal shelves that pro-
trude into the esophageal lumen and cause intermittent dysphagia, especially
to solids. Webs occur in the upper esophagus and may be associated with
iron-deficiency anemia (Plummer-Vinson syndrome).
Rings (Schatzki) are most often found at the gastroesophageal junction.
Schatzki’s rings seem to be related to chronic gastroesophageal reflux. Most
of these contain only mucosal elements; however, thicker ones may also con-
tain a thickened muscle layer.
d. Eosinophilic esophagitis is an inflammatory condition of the esophagus
anatomically characterized by the presence of multiple concentric firm rings
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Chapter 21: Dysphagia 141

throughout the entire length of the esophagus. It is also referred to as corru-

gated esophagus, ringed esophagus, corrugated ringed esophagus, and
congenital esophageal stenosis occurring in children and young adults,
especially males.
i. Dysphagia is the primary presenting symptom with occasional food
impaction. Heartburn and GER is rare but may exist.
ii. Diagnosis: Barium swallow or UGI x-rays are usually too insensitive to
show the rings; however, with the use of fluoroscopy, double contrast
and a solid bolus, the corrugations may be demonstrated.
iii. Esophageal motility testing is normal or may show high amplitude
contractions.
On endoscopy, the esophageal lumen appears generally narrow and
the rings are clearly visible. There may be strictures. The esophageal
mucosal biopsies show intense eosinophilic infiltration. The degree of
eosinophilic infiltration may differ in patients however, the presences of
more than 20 eosinophils per each high power filed is used as a guide in
diagnosis. Eosinophilic infiltration, to a lesser degree, is also seen in other
GI disorders including GFRD, parasitic infections, fungal infections, reac-
tion to drugs, inflammatory bowel disease, scleroderma, Hodgkin’s disease,
and allergic vasculitis.
The etiology of eosinophilic esophagitis is thought to be due to a
sensitization after an exposure to food or airborne allergen followed by an
allergic reaction to subsequent exposures. However, the results of allergy
testing are inconsistent. The anatomical structure may be congenital
and/or inherited.
The treatment may involve esophageal dilation and elimination of
offending foods identified by skin testing. Best results are obtained with
the use of topical steroids used as an aerosol, four puffs twice daily applied
without a spacer. Patients should not eat or drink for 3 hours after each
treatment. The course of treatment is usually 6 weeks. The relief may last
4 to 6 months. Additional treatment may be needed intermittently.
e. Extrinsic compression. The esophageal lumen may be narrowed from
compression by an external lesion. These lesions include the following:
i. Mediastinal tumors, primary or metastatic.
ii. Vascular lesions, such as aberrant right subclavian artery (dysphagia
lusoria), a dilated aneurysmal aorta, or an enlarged cardiac chamber.
iii. Cervical osteoarthritis and bone spurs.
iv. Esophageal diverticula may cause dysphagia when they become large
and distended with food and secretions. They tend to occur in three main
parts of the esophagus: just above the UES (Zenker’s), at the middle
(traction), and near the diaphragm (epiphrenic). Zenker’s and epiphrenic
diverticula are thought to result from motor abnormalities of the esoph-
agus. Even though midesophageal diverticula have been attributed to
traction on the walls of the esophagus by external inflammatory and
fibrotic processes (e.g., tuberculosis or sarcoidosis), they also may result
from abnormal esophageal motility.
2. Gastroesophageal reflux (see Chapter 20). The reflux of the gastroduodenal
contents into the esophagus may cause dysphagia in some patients, especially if
severe inflammation, ulceration, or stricture develops. With resolution of the
inflammation and edema, dysphagia may abate. In some patients, gastro-
esophageal reflux (GER) may result in esophageal motility disorders, which
may contribute to dysphagia and chest pain.
3. Neuromuscular or motility disorders result in dysphagia to both liquids and
solids due to aberrant peristalsis. These disorders are present in about half the
patients who have dysphagia without an evident structural abnormality. In these
disorders, peristalsis is either absent, weak, too strong and sustained, or uncoor-
dinated. The LES function may also be abnormal. The resting LES pressure may
be too high or low and the sphincter may not relax completely on swallowing.
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142 Part V: Specific Complaints and Disorders

a. Primary motor disorders

i. Achalasia is a disorder of esophageal smooth-muscle function with three
diagnostic prerequisites. First, there is a complete absence of primary and
secondary peristalsis in the smooth muscle of the esophagus. Skeletal
muscle function is generally normal. Second, the LES does not relax com-
pletely with swallows. Third, the resting LES pressure is usually high.
The lack of peristalsis and the sustained high-pressure zone at the gas-
troesophageal junction results in retention of ingested material and oral
secretions in the esophagus with gradual loss of tone and progressive
dilatation of the body of the esophagus.
a) Cause. Achalasia is most likely the result of neuronal abnormalities
rather than a primary myopathy. Lesions have been found in the dorsal
vagal nucleus in the brainstem, in the vagal trunks, and in the myenteric
ganglia in the esophagus. Secondary achalasia may resemble primary
achalasia. It may result from tumor invasion of the LES region, con-
striction from malignant nodes, or paraneoplastic syndromes.
b) Signs and symptoms. Patients with achalasia consistently have dys-
phagia to both solids and liquids. Occasionally, early in the disease
and in patients with “vigorous achalasia,” chest pain may occur.
Regurgitation of esophageal contents often with tracheal aspiration is
a common complication of the disease.
c) Treatment of achalasia is designed to decrease the pressure in the
LES. This allows the aperistaltic esophagus to empty in the upright
position. LES myotomy may be accomplished surgically (open or
laparoscope) or by forceful dilatation with an inflatable, pneumatic
peroral balloon dilator or by intramucosal injection of Botulinum
toxin endoscopically. Medical management of achalasia is usually
unsuccessful. In some patients, calcium channel blockers may lower
the LES pressure and produce transient symptomatic improvement.
ii. Diffuse esophageal spasm (DES). This entity accounts for about 10%
to 15% of patients with esophageal motility disorders. Patients with this
disorder have high-amplitude, simultaneous contractions in the smooth-
muscle portion of the esophageal body. Skeletal muscle function is normal.
The “spastic” waves are usually initiated by swallows but may occur ran-
domly interspersed with normal-appearing peristalsis. The LES may have
normal or high pressure and may not completely relax with swallowing.
a) Signs and symptoms. In these patients, dysphagia is intermittent. It
occurs with both liquids and solids. Sometimes it is exacerbated with
hot or cold foods and may cause chest pain. In fact, the chest pain of
DES is often confused with angina pectoris. Thus, it is important in
these patients to exclude possible cardiac disease.
b) Treatment of DES is generally directed toward decreasing the fre-
quency and intensity of simultaneous contractions. Smooth muscle
relaxants, including nitrates (e.g., nitroglycerin, 0.4 mg sublingually
a.c. and p.r.n.); isosorbide dinitrate, 30 mg per os (p.o.) 30 minutes a.c.;
hydralazine, 25 to 50 mg p.o. three times daily; calcium channel block-
ers (e.g., nifedipine, 10–20 mg, four times daily); psychotropic drugs
(e.g., diazepam 1–5 mg p.o., four times daily; trazodone 50–100 mg
p.o., twice daily; doxepin, 50 mg p.o., h.s.); and anticholinergics
(e.g., dicyclomine 10–20 mg p.o., four times daily) have been tried with
variable results.
Because abnormal motility is not always documented in patients
with dysphagia secondary to dysmotility, provocation of symptoms
and manometric findings with drugs may be attempted. Edrophonium
is the best tolerated and most effective of currently available drugs.
Bougienage and pneumatic dilatation sometimes yield transient
symptom relief. In difficult cases, surgical myotomy may be tried. The
outcome is often variable, and successful relief of symptoms is rare.
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Chapter 21: Dysphagia 143

c) “Vigorous achalasia.” An overlap between DES and achalasia called

vigorous achalasia has been observed in some patients. In this condi-
tion, in addition to simultaneous, high-amplitude contractions in the
distal esophagus as in DES, the LES function is similar to that in acha-
lasia. The symptoms are usually chest pain and dysphagia. This over-
lap, as well as a transition from DES to achalasia in some patients,
suggests that these two disorders may be different manifestations of
the spectrum of esophageal smooth muscle dysfunction.
iii. Nutcracker esophagus or “super squeezer” is a motility disorder found
in approximately one half of the patients with chest pain of esophageal
origin and one tenth of the patients with dysphagia. These patients have
normal LES function and peristalsis; however, the contractile amplitude
is usually two to three times the normal value. Most of these patients
also have an abnormal prolongation of the peristaltic wave. A subgroup
of patients with contraction waves of normal amplitude but prolonged
duration also has been described.
The symptoms of patients with nutcracker esophagus are similar to
those associated with DES. Patients may have prolonged chest pain,
which may be nocturnal, and intermittent dysphagia. The nutcracker
esophagus may evolve into DES, suggesting that these disorders are
related. Treatment of nutcracker esophagus is similar to treatment of
DES (see section II.C.3.b).
iv. Nonspecific esophageal motor disorders (NEMD). Most patients
with symptoms of esophageal dysmotility cannot be classified neatly into
specific groups. The incidence of these disorders of the peristaltic wave
or LES function is at least five times that of achalasia and DES com-
bined. The patients may have an isolated abnormality of the LES
(increased pressure, incomplete relaxation, hypertensive LES) with or
without abnormal esophageal contractions (increased amplitude or dura-
tion, simultaneous contractions, nonpropagated waves).
a) Treatment. There is no reliable therapy for patients with nonspecific
esophageal motor disorders. Smooth-muscle relaxants have been tried
as in DES, again with variable results. Bougienage may give transient
relief in some patients.
b) Patients with diabetes mellitus may have abnormal esophageal
motility such as poor propagation of the peristaltic wave and diffuse
spasm, most likely due to visceral neuropathy.
b. Secondary motor disorders. Esophageal smooth-muscle dysfunction may
be associated with a number of systemic disorders.
i. Scleroderma. Approximately 80% of the patients with scleroderma,
particularly those who exhibit Raynaud’s phenomenon, have decreased
amplitude of peristalsis in the smooth-muscle portion of the esophagus
with decreased resting LES pressure. Initially, the disorder seems to be
neural; however, with progression of the disease, collagen deposition and
fibrosis of the smooth muscle are observed. These patients are a setup for
severe reflux esophagitis, which is frequently complicated by stricture
formation and Barrett’s esophagus.
ii. Other diseases. The abnormal esophageal motility associated with scle-
roderma has been reported in some patients with other collagen vascular
diseases and those with Raynaud’s phenomenon. Patients with
polymyositis and lupus also may exhibit esophageal smooth muscle
dysfunction.
iii. Chagas’ disease. An achalasialike disease has been seen as a secondary
disorder with Chagas’ disease (infection with Trypanosoma cruzi).
iv. Tumors of the mediastinum, lower esophagus, gastroesophageal junc-
tion, and gastric cardia, as well as lymphoma, pancreatic, lung, and bron-
chogenic carcinoma may also present as achalasia. Tumors may invade
the myenteric plexus or produce an obstruction at the gastroesophageal
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144 Part V: Specific Complaints and Disorders

junction; thus, aperistalsis may be secondary to neural invasion or a

response to LES obstruction.
v. Chronic idiopathic intestinal pseudoobstruction usually involves the
esophagus as well as all other parts of the gastrointestinal tract. The
esophageal abnormality includes aperistalsis and incomplete relaxation
of LES, producing a functional obstruction. Patients with this disease
usually have either congenital or acquired neuromuscular degeneration
of the entire gut, affecting the neural plexuses and the myenteric ganglia.
c. Reflux esophagitis and esophageal dysmotility (see also Chapter 20).
Patients with gastroesophageal reflux and reflux esophagitis have been shown
to have a number of abnormalities of smooth-muscle function. These include
a low resting LES pressure; abnormal, prolonged periods of relaxation of the
LES; and decreased esophageal clearance due to disorder of primary and sec-
ondary peristaltic waves. It is difficult to determine whether these defects are
a primary cause of reflux or a result of the associated esophagitis.

III. DIAGNOSTIC APPROACH

A. History. Differentiation of the major causes of dysphagia can be facilitated by elic-
iting the history on several critical points: consistency of the food causing symp-
toms, localization and duration of dysphagia, and presence of associated symptoms
such as odynophagia, heartburn, cough, and weight loss.
1. Consistency of foods causing dysphagia. As mentioned before, a motility
disorder usually causes dysphagia to both liquids and solids from the onset of
the symptoms, whereas a structural disorder causes dysphagia to solids first
and, if the lesion further compromises the esophageal lumen, progressively to
semisolids and liquids.
2. The duration and constancy of the symptoms are also diagnostically perti-
nent. Intermittent dysphagia for solid foods only is typical of lower esophageal
(Schatzki) ring. A patient with a long history of heartburn may notice its dis-
appearance when a stricture develops, which may cause dysphagia, especially
to solids. The patient with esophageal cancer typically has a more accelerated
course of progressive dysphagia over several months, usually accompanied by
weight loss and anorexia.
3. Other disorders. The possible presence of neurologic, muscular, connective
tissue, or other systemic disorders and the use of drugs that may affect striated
or smooth-muscle function of the esophagus should be determined.
B. The physical examination may be indirectly helpful in the diagnosis of dyspha-
gia related to another disease such as a central nervous system, muscular,
endocrine–metabolic, or connective tissue disorder. The presence of pharyngeal
inflammation, a mass in the neck, an enlarged thyroid, a deviated trachea, car-
diomegaly, or an epigastric mass may also be helpful in reaching the diagnosis.
C. Radiographic studies
1. The chest x-ray may be helpful indirectly in the diagnosis of the cause of dys-
phagia. In advanced achalasia with dilatation of the esophagus, patients may
have a widened mediastinal shadow with an air-fluid level made up of food and
secretions held up by the tight LES. Mediastinal masses or cardiomegaly with
chamber enlargement may also be evident on a chest x-ray.
2. Barium swallow, cineesophagogram, and upper gastrointestinal series are
usually the first specific diagnostic studies performed in the workup of dyspha-
gia. The patient is asked to swallow liquid barium or a piece of bread dipped in
barium. The movement of the bolus is then observed by the radiologist fluoro-
scopically and recorded on x-ray film or videotape (cineradiography). In this
way, the course of the bolus is followed from the mouth to the stomach.
This test gives visual information about the preesophageal swallowing
function, the nature of the peristaltic activity, and the presence of gastroe-
sophageal reflux as well as information about the anatomy of the esophagus
with respect to structural disorders, such as carcinoma, stricture, esophageal
web or ring, or presence of extrinsic compression.
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Chapter 21: Dysphagia 145

The barium study is less helpful in the diagnosis of motility disorders.

However, in achalasia one may see a dilated esophagus with a “parrot beak”
narrowing at the gastroesophageal junction. Tertiary or corkscrew contractions
may suggest the diagnosis of diffuse esophageal spasm; however, this may be a
normal finding, especially in elderly patients.
D. Upper gastrointestinal endoscopy. The direct visualization of the mucosa and
lumen of the esophagus, stomach, and proximal duodenum is possible with flexi-
ble endoscopes. Structural and inflammatory lesions may be directly examined,
and biopsies and cytologic specimens may be obtained. Intramural lesions such as
leiomyomas may also be seen. Biopsies of these lesions are not recommended, since
the scarred overlying mucosa may adhere to the movable tumor and prevent its
easy surgical enucleation. Submucosal tumors may be examined using endoscopic
ultrasonography (EUS).
E. Esophageal manometry is recommended when an esophageal motility disorder is
suspected. In this test, intraesophageal pressures and peristaltic activity are
recorded as a function of time with wet and dry swallows. This test yields infor-
mation about the lower and upper esophageal sphincter function and the nature of
the peristaltic wave.
The typical manometry tube consists of soft, flexible tubing that has three
recording sensors arranged linearly 5 cm apart from one another in a spiral fash-
ion at the distal end. The patient is asked to swallow the tube, which is then
advanced into the stomach. As the tube is gradually withdrawn, each sensor passes
through the LES, measuring its pressure. In the body of the esophagus, the peri-
staltic waves are recorded in a sequential manner as they progress down the esoph-
agus, first with the proximal sensor, next with the middle, and last with the distal
sensor. If peristalsis is progressive, this normal sequence is observed. If simultane-
ous, repetitive contractions are noted, their amplitude and duration will help in
establishing the type of motility disorder. When the middle or distal sensor lies
within the LES, the relationship between esophageal peristaltic contractions and
sphincter relaxation can be observed. Similarly, when the upper sensor lies in the
UES, the relationship between pharyngeal contractions and UES relaxation can be
recorded.
In patients with achalasia, a careful examination of the distal esophagus and
gastroesophageal junction is essential to rule out malignancy. Even benign appear-
ing strictures should be biopsied and brushed to look for malignant cells. EUS may
help in evaluation of strictures and give information on the extent of tissue involve-
ment with malignant infiltration.
Evaluation of the stomach and duodenum may be helpful in eliminating dis-
eases of these organs that may coexist or give symptoms that may be confused with
those of esophageal disorders.

IV. TREATMENT
A. Oropharyngeal dysphagia. The treatment of oropharyngeal dysphagia depends
on the specific cause.
1. Systemic disease (see section IV.B.1).
2. Neurologically impaired patients require special attention during feedings with
respect to dietary texture; body, head, and neck position; size and frequency of
food bolus administration; and aspiration precautions. Patients should sit fully
upright in bed or in a chair while eating. The bolus size should be small in sips
or bites. Foods with thicker textures (e.g., thick liquids and pudding textures)
are often better tolerated than clear liquids. Spicy, acidic foods and coffee, tea,
and alcohol should be avoided. After meals, patients should remain in the
upright position for an additional 1 to 3 hours to minimize the risk of aspira-
tion. The head of the bed should be elevated during resting and sleeping hours.
B. Esophageal dysphagia
1. Systemic disease. If the disorder is secondary to a systemic disease, the treat-
ment needs to be directed to the primary disease. Infections and inflammatory
lesions of the esophagus are discussed in Chapter 19.
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146 Part V: Specific Complaints and Disorders

2. Rings, webs, and strictures. Of the structural disorders, the treatment of

rings and webs is the most gratifying to both the patient and the physician.
Dilatation with a mercury-filled bougie usually relieves the symptoms.
Esophageal strictures may also be dilated under endoscopic guidance with bal-
loon dilators or savory dilators that allow progressively larger dilators to be
passed over a guidewire. (For further discussion, see section II.C.1.)
3. Motility disorders. Treatment of motility disorders is difficult, and variable
results are obtained (see section II.C.3).

Selected Readings
Adler DG, et al. Primary esophageal motility disorders. Mayo Clin Proc. 2001;76:195.
Fibbe C, et al. Esophageal motility in reflux disease before and after fundoplication:
A prospective, randomized, clinical and manometric study. Gastroenterology. 2001;121:5.
Fox M, et al. High-resolution manometry predicts the success of oesophageal bolus
transport and identifies clinically important abnormalities not detected by conventional
manometry. Neurogastroenterol Motil. 2004;16:533–542.
Jayaderan R, et al. Dysphagia in the elderly. Pract Gastroenterol. 2001;25:75.
Lee JI, et al. The effect of silderafil on esophageal motor function in health, subjects and
patients with nutcracker esophagus. Neurogastroenterol Motil. 2003;15:617–623.
Oelschlager BK. Surgical options for treatment of esophageal disorders. Gastroenterol
Hepatol. 2007;3(9):687–689.
Oh TL, et al. Dysphagia in inflammatory myopathy: clinical characteristics, treatment
strategies, and outcome in 62 patients. Mayo Clin Proc. 2007;82(4):441–447.
Rubenstein JH, et al. Dysphagia drives doctors to diagnose a disease: Pitfalls in interpreting
observational studies. Gastrointest Endosc. 2005;61:809–811.
Shay S, et al. Twenty-four-hour ambulatory simultaneous impedance and pH monitoring:
A multi-center report of normal values in 60 health volunteers. Am J Gastroenterol.
2004;99:1037–1043.
Straumann A, et al. Natural history of primary eosinophilic esophagitis: A follow-up of
30 adult patients for up to 11.5 years. Gastroenterology. 2003;125:1660–1669.
Tutuian R, et al. Clarification of the esophageal function defect in patients with manometric
ineffective esophageal motility: Studies using combined impedance-manometry. Clin
Gastroenterol Hepatol. 2004;2:230–236.
Varadarjullu S, et al. The yield and the predictors of esophageal pathology when upper
endoscopy is used for the initial evaluation of dysphagia. Gastrointest Endosc. 2005;
61:804–808.
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NONCARDIAC CHEST PAIN 22

T he term noncardiac chest pain generally means pain in the chest that mimics or
may be confused with cardiac chest pain. Often the pain is caused by a disorder of the
esophagus, stomach, or gallbladder. Diagnosis is particularly confusing in patients who
have both cardiac and noncardiac chest pain. Much of the diagnostic confusion arises from
the generous overlap in pain sensations entering the spinal cord from the heart, medi-
astinum, stomach, and other upper abdominal organs.

I. The differential diagnosis of noncardiac chest pain is outlined in Table 22-1. Although
this chapter deals mostly with esophageal causes of chest pain, one cannot neglect the
numerous other causes in evaluating patients with chest pain. Also, it seems an inherent
contradiction to say that cardiac chest pain should be a consideration in the differential
diagnosis of noncardiac chest pain; yet some patients who are referred because they
are thought to have noncardiac chest pain, but have not had an adequate cardiac eval-
uation, eventually are found to have cardiac disease or a combination of cardiac and
noncardiac chest pain.

II. DIAGNOSIS. Many patients with noncardiac chest pain already have had an evalua-
tion for cardiac disease. This evaluation may have consisted of an electrocardiogram
(ECG) only or may have been extensive, including stress testing and coronary arteri-
ography. In any event, the patient’s major concern usually is whether he or she has
heart disease. If the pain can be attributed to a noncardiac cause, the patient often
feels better, even though in some instances little can be done to relieve the pain.
Cardiac causes of chest pain must first be excluded. This cannot always be done
with absolute certainty, and in some patients a diagnosis of both cardiac and noncar-
diac chest pain is made. Furthermore, it appears that, in some of these patients,
noncardiac pain can stimulate cardiac chest pain.
A. Clinical presentation
1. The character of the pain may help differentiate cardiac from noncardiac
pain. Cardiac pain typically is aggravated by stress and exercise and radiates to
the neck, shoulder, and left arm. Chest wall and esophageal pain, however, also
sometimes appear to be aggravated by stress and exercise. The pain of gastroe-
sophageal reflux can radiate to the neck and jaw, but it rarely radiates down
the arm.
2. Accompanying symptoms and relation of the pain to other events can
help differentiate the cause. Dysphagia in association with the pain points to an
esophageal origin (see Chapter 21). If the dysphagia is for both liquids and
solids, an esophageal motility disorder is likely. Pain after eating can be cardiac,
but it is more likely to be of esophageal or perhaps gallbladder origin. Pressure
over the site of pain that aggravates the pain suggests a chest wall source such
as costochondritis or trauma, although chest wall tenderness has been described
in cardiac pain.
B. Diagnostic studies
1. Exclusion of cardiac disease
a. X-ray and ECG. All patients should be evaluated with a chest x-ray and
ECG. Some patients require exercise stress testing using standard ECG
monitoring or thallium scanning.

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148 Part V: Specific Complaints and Disorders

TABLE 22-1 Diagnostic Considerations in Noncardiac Chest Pain

I. Chest wall pain

A. Costochondritis
B. Trauma
II. Mediastinal pain
A. Inflammation
B. Tumor
III. Esophageal pain
A. Motility disorders
1. Achalasia (usually “vigorous” achalasia)
2. Diffuse esophageal spasm
3. “Nutcracker” esophagus
4. Nonspecific motor disorder
B. Mucosal disorders
1. Gastroesophageal reflux with or without gross injury
2. Viral or fungal infections
3. Acid or alkali ingestion
4. Cancer
IV. Gallbladder disease
V. Pancreatitis or pancreatic pseudocyst
VI. Peptic ulcer
VII. Cardiac chest pain (initial failure to diagnose)
A. Coronary artery disease
B. Pericarditis

b. Coronary arteriography, CT, or MRI. Not every patient with chest pain
requires coronary arteriography to exclude cardiac disease for practical clinical
purposes. Some patients clearly have a noncardiac problem, such as gastroe-
sophageal reflux or an esophageal motility disorder. In many patients, however,
coronary disease must be excluded by coronary arteriography, CT, or MRI.
2. Esophageal studies
a. Barium swallow radiography (see Chapter 9). X-ray films of the esopha-
gus usually are not of much help in evaluating chest pain that mimics cardiac
pain. However, obstructing lesions or severe esophagitis (reflux, monilial, or
herpetic) may be evident from the static films. Furthermore, fluoroscopy or
videotape of the swallowing function may suggest that a motility disorder is
present.
b. Endoscopy and esophageal mucosal biopsy. Endoscopy is indicated if
a structural abnormality is seen on the barium study. Biopsy of the
mucosa also may provide information that is not evident by radiography
or endoscopy. Endoscopic punch biopsies or suction biopsies of the
esophagus may show inflammation, thinning of the epithelium, hypertro-
phy of the basal regenerative layer, prolongation of the papillae of lamina
propria that project into the epithelium, or presence of eosinophils,
all of which have been correlated with gastroesophageal reflux (see
Chapter 20).
c. Esophageal motility studies (see Chapter 8).
i. Manometric examination of the esophagus may be crucial in the
diagnosis of an esophageal motility disorder. However, correlation
of manometric findings with clinical symptoms may be difficult. Because
symptoms and manometric abnormalities are usually intermittent, a nor-
mal motility tracing does not exclude a motility disorder. Manometric
abnormalities in the absence of symptoms are also difficult to interpret.
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Chapter 22: Noncardiac Chest Pain 149

It is only when chest pain occurs at the time a motor abnormality is

recorded that there is reasonable certainty that the patient’s chest pain is
caused by the motor disorder.
Several intravenous provocative agents have been used during
esophageal manometry to stimulate motor abnormalities and reproduce
pain. Ergonovine maleate is the most potent provocative agent, but it
also is dangerous; it has been associated with irreversible coronary
spasm in a few reported cases when used during coronary arteriography.
Currently, ergonovine maleate is regarded as unsafe for clinical use as an
esophageal provocative agent unless the patient can be monitored in a
cardiac catheterization laboratory. Other agents include pentagastrin,
bethanechol chloride, and edrophonium chloride (Tensilon). Of these,
edrophonium chloride intravenous (IV), 80 µg/kg, is the most successful
in producing a positive response, that is, reproduction of the clinical
chest pain in association with development of manometric abnormali-
ties. Edrophonium also appears to be safe.
ii. Esophageal motility disorders. As indicated in Table 22-1, several
esophageal motility disorders may be associated with chest pain.
a) Classic diffuse esophageal spasm (DES) causes substernal pain and
is characterized by high-amplitude, broad-based, simultaneous and
repetitive contractions. However, DES accounts for only a minority of
esophageal motility disturbances (Fig. 22-1).
b) Much more frequent are nonspecific esophageal motility disor-
ders (NEMD), which include a hypertensive lower esophageal sphinc-
ter (LES), in which the resting LES pressure exceeds 45 mmHg in the
presence of normal peristalsis in the body of the esophagus; decreased
or absent amplitude of esophageal peristalsis with normal LES pres-
sure and relaxation; and other abnormalities of peristaltic sequence,
such as abnormal waveforms, isolated simultaneous contractions, and
isolated spontaneous contractions.
c) The term nutcracker esophagus describes an esophagus in which
the peristaltic contractions squeeze too tightly. Peristalsis is propa-
gated normally, but the mean amplitude of contractions exceeds
120 mmHg (normal peristaltic contractions are usually in the range
of 50 to 100 mmHg), and contractions are often prolonged more
than 5.5 seconds.
d) Achalasia accounts for a small minority of esophageal motor disor-
ders associated with chest pain. Sometimes patients have so-called
vigorous achalasia. Their LES is hypercontracting and fails to relax
completely on swallowing, as in classic achalasia; instead of absence
of peristalsis, however, they have evidence of diffuse spasm or another
motility disorder in the body of the esophagus.
d. The Bernstein test, although rarely used in the clinical setting, has been a
time-honored study for determining whether or not a patient’s chest pain is
caused by acid irritation of the esophagus. A tube is positioned in the mid
esophagus and saline and 0.1N hydrogen chloride (HCl) are alternately
infused at 120 drops per minute in a sequence unknown to the patient. If
the patient experiences pain during acid infusion that is identical to the clin-
ical pain, it is presumed that the pain is a result of acid reflux. Measurement
of esophageal peristalsis during acid infusion can document a motility dis-
order that may be responsible for the chest pain. The reliability of the
Bernstein test is diminished by its dependence on the subjective interpreta-
tions of the patient and the physician.
e. Ambulatory pH monitoring (see Chapter 8) by documenting the frequency
and duration of gastroesophageal reflux, may provide evidence for the cor-
relation of chest pain with episodes of reflux.
In medical centers which specialize in esophageal motility disorders, the
24-hour pH monitoring may also be combined with esophageal impedance
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150 Part V: Specific Complaints and Disorders

Nutcracker
NEMD Esophagus
(25%–45%) (25%–45%)

DES
Achalasia (10%–15%)
(5%–10%)

Figure 22-1. Manometric diagnoses of esophageal motility disorders in patients with chest pain
of esophageal origin. NEMD, nonspecific esophageal motility disorder; DES, diffuse esophageal
spasm. (From data compiled from several reports. See Benjamin DS, Castell DO. Esophageal causes
of chest pain. In: Castell DO, Johnson LF, eds. Esophageal Function in Health and Disease. New York:
Elsevier; 1983.)

studies. There is a drop in impedance with each GER regardless of a change in

pH. Thus, impedance measurements allow the measurement and documenta-
tion of reflux episodes which may not be detected by pH monitoring as in alka-
line or neutral pH GER.
3. Other diagnostic studies. In most patients with noncardiac chest pain, it is
wise to look for gallstone disease by abdominal ultrasonography. Peptic disease
can be evaluated during the barium swallow radiographic study by extending
the examination to the stomach and duodenum. Similarly, endoscopy during
evaluation of esophageal disease should include examination of the stomach
and duodenum. In some patients, computed tomography (CT) scanning is
necessary to evaluate the pancreas and other abdominal organs.

III. TREATMENT
A. Esophageal motility disorders
1. With the exception of achalasia, all the esophageal motility disorders are
treated in roughly the same manner if they are associated with chest pain.
Specific foods or hot or cold beverages associated with symptoms should be
avoided. Agents to relax the esophageal smooth muscle have been used.
Sublingual nitroglycerin may be sufficient for intermittent symptoms, and long-
acting nitrates have been effective in some patients. The calcium channel block-
ing agents (nifedipine, diltiazem, verapamil) have received much attention, but
double-blind, placebo-controlled studies have not shown clear benefit.
2. Differentiation from angina pectoris. The perceptive reader already has dis-
cerned that the pharmacologic treatment of chest pain caused by an esophageal
motor disorder is similar to the treatment of angina pectoris. Thus, one may
ask whether it makes much difference to distinguish between the two. Although
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Chapter 22: Noncardiac Chest Pain 151

the treatment may be similar, the prognosis and the patient’s peace of mind cer-
tainly are different when the diagnosis is coronary artery disease.
3. Esophageal dilatation. One medical treatment of esophageal motor disorders
that does not apply to cardiac disease is esophageal dilatation. Simple passive
dilatation of the esophagus with a 30 French (F) to 40 F Maloney dilator has
been shown to provide temporary, sometimes long-standing, relief in some
patients.
4. Myotomy. An occasional patient with a well-documented motility disorder and
severe pain unresponsive to medical treatment may benefit from a long surgical
myotomy of the esophageal muscle coat.
5. Achalasia. The treatment of achalasia traditionally has been either forceful
dilatation or rupture of the hypercontracting LES with a balloon dilator or sur-
gical myotomy. Recently, long-acting nitrates and calcium channel blocking
agents have been successful in some patients.
B. Gastroesophageal reflux. The treatment of gastroesophageal reflux (GER) is
described in Chapter 20. A small minority of patients with GER also has an
esophageal motility disorder that is stimulated by GER. Treatment of the GER
treats the motility disorder in these patients.
C. Nonmotility esophageal disorders. The treatments of caustic ingestions, esophageal
infections, and esophageal cancer are reviewed in Chapters 16, 19, and 23, respectively.
D. Nonesophageal disorders. Identification of a nonesophageal disorder, such as
gallstones or peptic ulcer, in a patient complaining of chest pain does not neces-
sarily implicate that disorder as a cause of the chest pain. However, it is reasonable
to treat the disorder appropriately. If pain persists after successful treatment, addi-
tional esophageal or cardiac diagnostic studies may be indicated.

Selected Readings
Charbel S, et al. The role of esophageal pH monitoring in symptomatic patients on PPI
therapy. Am J Gastroenterol. 2005;1100:283–289.
Hobson AR, et al. Neurophysiologic assessment of esophageal sensory processing in
noncardiac chest pain. Gastroenterology. 2006;130:80–88.
Jones H, et al. Treatment of noncardiac chest pain; a controlled trial of hypastherapy. Gut.
2006;55:1403–1408.
Liuzzo JP, et al. Chest pain from gastroesophageal reflux disease in patients with coronary
artery disease. Cardiol Rev. 2005;13:167–173.
Rodriguez-Stanley S, et al. Effect of tegaserod on esophageal pain threshold, regurgitation,
and symptom relief in patients with functional heartburn and mechanical sensitivity.
Clin. Gastroenteral Hepatol. 2006;4:442–450.
Schey R, et al. Noncardiac chest pain: current treatment. Gastroenterol Hepatol.
2007;3:255–262.
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23 ESOPHAGEAL CANCER

I. EPIDEMIOLOGY. Esophageal cancer is the sixth leading cause of cancer death

worldwide. The incidence varies substantially in different countries. The highest rates
are seen in China, Singapore, Iran, South Africa, France, and Puerto Rico.
In the United States, the incidence of esophageal cancer for the year 2006 was
14,550 new cases and 13,770 deaths. It is the seventh leading cause of cancer death in
American men. In the last 25 years, there has been a significant increase in the inci-
dence of adenocarcinomas of the distal esophagus and gastroesophageal junction. Also,
in the last 30 years, the incidence of adenocarcinoma of the esophagus has increased
in men and the incidence of squamous carcinoma of the esophagus has declined.
The incidence of esophageal carcinoma increases with age. The median age of
onset is 69 years. Males are 2 to 4 times more likely to develop esophageal cancer
compared to females. Squamous cell carcinoma is more common in African Americans
and adenocarcinoma is more common among Caucasians. The incidence rates within
the United States are higher in the Northeast and urban areas.
Approximately 10% to 15% squamous cancers originate in the upper third,
35% to 40% in the middle third, and 40% to 50% in the distal third of the esopha-
gus. Adenocarcinomas arise predominately in the distal esophagus and are commonly
associated with Barrett’s esophagus.
Esophageal cancers may develop as second primary tumors in patients with other
primary tumors of the upper aerodigestive tract. Between 5% and 12% of patients
with esophageal cancer are found to have synchronous or metachronous aerodigestive
tract cancer.
Other less common tumors of the esophagus include lymphoma, carcinosar-
coma, pseudosarcoma, squamous adenocarcinoma, melanoma, mucoepidermoid carci-
noma, squamous cell papilloma, primary small cell carcinoma, verrucous carcinoma, and
malignant carcinoid tumor the esophagus. Local spread from the lung and thyroid and
metastasis from distant cancers may occur but are rare.

II. PREDISPOSING FACTORS. Chronic use of alcohol and smoking are associated with
esophageal carcinoma. This may be due to chronic irritation of the esophageal mucosa
with these agents. Other conditions with increased prevalence of esophageal carcinoma
are lye strictures, achalasia, previous exposure to ionizing radiation, head and neck
cancer, Plummer-Vinson syndrome, tylosis, celiac sprue, and Barrett’s epithelium.
Squamous cell carcinoma accounts for less than one half of esophageal carcino-
mas. Adenocarcinomas of the esophagus, which used to account for less than 10% of
esophageal cancers, now account for greater than two thirds of all esophageal malig-
nancies in the United States. Adenocarcinoma usually arises from metaplastic columnar
epithelium (Barrett’s epithelium) and rarely from esophageal glands. Adenocarcinoma
of the stomach may spread to the esophagus by extension.
Gastroesophageal reflux disease (GERD) is thought to be the major risk factor
for esophageal adenocarcinoma. Recurrent symptoms of GERD seem to increase the
risk of esophageal adenocarcinoma by eightfold. The annual incidence of cancer in
Barrett’s epithelium is approximately 0.8%. Anticholinergic calcium channel block-
ers, nitrates, and theophyllines, by decreasing the lower esophageal sphincter tone, are
thought to increase the risk of adenocarcinomas of the esophagus. In addition, obe-
sity, which increases intraabdominal pressure and GERD, is an added risk factor.

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Chapter 23: Esophageal Cancer 153

III. PROGNOSIS. The 5-year survival rate for all patients is approximately 16%. The
5-year survival even with the earliest stages of cancer is only 50% to 80% and with
lymph node involvement it drops to below 25%. With locally advanced esophageal
cancer the survival drops to 5% to 10% (with radiation or surgery alone) and with
chemoradiation and surgery, it may be 25% to 27%.
Esophageal cancers grow extensively locally and invade adjacent structures.
The tumor has the propensity to spread longitudinally via lymphatic channels within the
esophageal wall to mediastinal cervical and celiac lymph nodes. There may also
be hematogenous spread to lungs, liver, and other organs. Esophagobronchial or
esophagopleural fistulas may form and manifest as recurrent pneumonia or abscess.
Erosion into the aorta may result in exsanguination.

IV. CLINICAL FEATURES. Progressive dysphagia for less than a year, first with solids
then with semisolids and liquids, is the most common symptom. Substernal
pain, usually steady, radiating to the back may also be present and may suggest
periesophageal spread of the tumor. Most patients complain of anorexia and pro-
found weight loss. Patients may have iron-deficiency anemia from blood loss from
the lesion, but brisk bleeding is rare. Hoarseness may result from involvement of the
recurrent laryngeal nerve. If the lesion is obstructive, patients may aspirate
esophageal contents and may present with aspiration pneumonia and pleural
effusion. Horner’s syndrome, cervical adenopathy, hpeatoroegalys, boney pain, and
paraneoplastic syndromes including hypercalcemia, inappropriate ACTH, and
gonadotropins may be present.

V. DIAGNOSIS
A. A barium swallow is usually the first noninvasive test ordered to establish the
diagnosis of esophageal carcinoma. A double-contrast study may be helpful in
identifying small, plaquelike lesions. The usual finding is an irregular luminal nar-
rowing. There may be a ridge or shelf at the superior portion of the tumor.
However, the differentiation of the tumor from a benign peptic stricture can be
extremely difficult by radiography.
B. Endoscopy. Fiberoptic endoscopy allows direct localization and inspection of the
lesion. Retroflexion of the endoscope in the fundus of the stomach allows visual-
ization of lesions at the esophagogastric junction and cardia, which could not be
done by rigid scopes. Direct biopsies and brushings provide tissue for histologic
and cytologic examination.
C. Computed tomography (CT) is very helpful in determining the extent and spread
of extramucosal tumor.
D. Endoscopic ultrasonography (EUS). EUS, with its unique ability to define the
anatomy of the gut wall in detail, offers the most accurate method for evaluating
the depth of esophageal cancer invasion and detecting abnormal regional lymph
nodes. Because esophageal carcinoma originates in the mucosa and progressively
invades deeper layers of the esophageal wall, the TNM classification recommended
by the International Union Against Cancer and the American Joint Committee on
Cancer lends itself to accurate staging with EUS. T indicates depth of primary
tumor invasion, N indicates spread of cancer to regional lymph nodes, and M indi-
cates distant metastases.
E. Magnetic resonance imaging (MRI) is a technique in longitudinal and cross-
sectional body imaging. Currently, it offers no advantage over CT in detecting
infiltrating growth.
F. PET scan may improve the detection of stage IV disease.
G. Preoperative thoracoscopy and laparoscopy may help assess extent of local dis-
ease as well as the involvement of regional lymph nodes and celiac and perigastric
nodes.
H. Staging and prognosis. Pathologic stage is the most important factor in progno-
sis. Recurrence and survival are strongly related to depth of tumor invasion, metas-
tases to adjacent lymph nodes and distant organs. TNM system has been revised
and used in prognosis. T1-2, NOMO are potentially curable with surgery alone.
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154 Part V: Specific Complaints and Disorders

Tumor invasion into serosa (T3) or regional or distant lymph node metastases (T4)
are associated with significant reduction in survival.

VI. TREATMENT. The therapy for carcinoma of the esophagus is determined by the stage
of the disease. The mainstay of therapy has been surgery, with or without radiother-
apy and chemotherapy. Inoperable tumors have been treated by radiotherapy because
squamous carcinoma of the esophagus is relatively radiosensitive. Chemotherapy
alone has not been very successful. Treatment protocols combining chemotherapy and
radiation therapy before and after surgery offer somewhat better results than single-
modality therapy. Most successful chemotherapeutic agents are the combination of
cisplatin, 5-fluorouracil, paclitaxel, irinotecan hydrochloride, vinorelbine tartrate,
and gemcitabine hydrochloride preoperatively and as neoadjuvant chemotherapy.
A. Surgery. Total esophagectomy is the surgical procedure of choice. Patients with
lesions of the lower third that are less than 5 cm seem to do better. Because the
cure rate has been so dismally low with “curative” surgery, palliative resection has
been used to alleviate symptoms and allow patients to swallow.
The morbidity and mortality with a large thoracotomy are still very high in
these patients. The esophageal resection and esophagogastric anastomosis may be
done with a combined abdominal incision and a right thoracotomy. If the lesion is
low enough, an abdominal approach may suffice. For most lesions, it is preferred
to resect the involved portion of the esophagus with wide margins, bring the stom-
ach into the chest, and create an anastomosis with the remaining esophagus.
Colonic or jejunal segment interposition carries a high complication rate. For pur-
poses of palliation, the stomach may be anastomosed to the esophagus in a side-
to-side fashion to bypass the obstructed area.
B. Radiation therapy
1. Radiation therapy for squamous cell carcinoma of the esophagus has been
used for attempted cure with unsatisfactory results. It is used in protocols before
or after surgery and for palliation.
2. Presurgical radiation therapy alone has not been found to increase the cure
rate.
3. Adenocarcinomas are resistant to radiation therapy.
C. Other palliative measures
1. Mechanical dilatation. When surgery and radiation therapy are contraindi-
cated, or when these treatments have failed, mechanical dilatation of the
esophageal lumen may be attempted with Savary or balloon dilators under endo-
scopic guidance. Because the risk of esophageal perforation is high in these
patients, the dilatation should be done slowly and with great care.
2. Tube placement. If it becomes difficult to maintain a lumen at the area of the
tumor, a stent (plastic or metal) may be placed in the lumen endoscopically. These
tubes may also be used to close off, at least temporarily, a tracheoesophageal fis-
tula. These tubes may erode into the esophageal wall, causing ulceration, bleed-
ing, and perforation.
3. YAG-laser therapy has been found to be quite effective in palliation of patients
with advanced obstructing esophageal tumors. These masses may be “pared
down” by the laser to open the lumen. Lasers may also be useful in the treat-
ment of very early lesions. Additional controlled studies need to be done using
this technique.
4. Injection necrosis of fungating esophageal cancer can be accomplished with
intratumoral injection of absolute alcohol or ethylene glycol with endoscopic
visualization. In instances of luminal narrowing, malignant strictures may be
dilated first, and then injected concentrically to additionally “open up” the
lumen.
5. These palliative measures are usually repeated as needed with progressive,
repeated growth of the tumor.
D. Selection of therapy. Presently, the optimal therapy for esophageal cancer is
unclear. A strong case can be made for establishing comparable diagnostic staging
criteria and treating newly diagnosed patients according to well-designed, established
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Chapter 23: Esophageal Cancer 155

research protocols whenever possible. If the use of research protocols is not feasi-
ble, a reasonable approach is to use resectional surgery for “resectable” tumors in
the distal third of the esophagus (T1–3 N1) with pre- and neoadjuvant chemoradi-
ation therapy. For patients who are poor candidates for surgery or who have
obstructing tumors, one or more of the listed palliative measures may be used.
E. Prevention and surveillance. Patients with recurrent symptoms of GERD are rec-
ommended to have endoscopy and biopsies for the diagnosis of Barrett’s esophagus.
Endoscopic surveillance will allow the diagnosis of earlier stage tumors and allow
for improved survival. Patients should be advised to stop smoking and use alcohol
in moderation. Current recommendations for patients with Barrett’s esophagus are
still debated, but most centers offer biannual endoscopic surveillance and annually
if there is low-grade dysplasia. Patients with high-grade dysplasia are recommended
to substantiate the diagnosis by two different pathologists, and then consider under-
going esophagectomy or mucosal ablation with photodynamic therapy.

Selected Readings
Bowrey DJ, et al. Use of alarm symptoms to select dyspeptics for endoscopy causes patients
with curable esophagogastric cancer to be overlooked. Surg. Endosc. 2006;20:I725–8.
Dar M, et al. Can extent of high-grade dysplasia predict the presence of adenocarcinoma
at esophagectomy? Gut. 2003;52:486–489.
Fountoulakis A, et al. Effect of surveillance of Barrett’s esophagus on the clinical outcome
of oesophageal cancer. Br J Surg. 2004;91:997–1003.
Lagergren J, et al. Association between medications that relax the lower esophageal
sphincter and risk for esophageal adenocarcinoma. Ann Int Med. 2000;133:165.
Lagergren J, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal
adenocarcinoma. N Engl J Med. 1999;340:825–831.
Largi A, et al. EUS followed by EMR for staging of high grade dysplasia and early cancer
in Barrett’s esophagus. Gastrointest Endosc. 2005;62:16.
May A, et al. Accuracy of staging in early esophageal cancer using high resolution
endoscopy and high resolution endosonography: A comparative, prospective trial. Gut.
2004;53:634–640.
Papachritou GI, et al. Use of stents in benign and malignant esophageal disease. Rev.
Gastroenterol. Disord. 2007;7(2):75–88.
Pech O, et al. Long-term results of photodynamic therapy with 5-aminoevulinic acid for
superficial Barrett’s cancer and high-grade intraepithelial neoplasia. Gastrointest
Endosc. 2005;62:24–30.
Playford RJ. New British Society of Gastroenterology (BSG) guidelines for the diagnosis
and management of Barrett’s esophagus. Gut. 2006;55:442–443.
Portale G, et al. Comparison of the clinical and histological characteristics and survival of
the distal esophageal–gastroesophageal junction adenocarcinoma in patients with and
without Barrett’s mucosa. Arch Surg. 2005;140:570–575.
Ross WA, et al. Evolving role of self-expanding metal stents in the treatment of malignant
dysphagia and fistulas. Gastrointest Endosc. 2007;65:70–76.
Sharma P. Low-grade dysplasia in Barrett’s esophagus. Gastroenterology. 2004;127:
1233–1238.
Wang KK, et al. American Gastroenterological Association medical position statement: Role
of the gastroenterologist in the management of esophageal carcinoma. Gastroenterology.
2005;128:1468–1470.
Wong A, et al. Epidemiologic risk factors for Barrett’s esophagus and associated
adenocarcinoma. Clin Gastroenterol Hepatol. 2005;3:1–10.
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24 PEPTIC ULCER DISEASE

T he term peptic ulcer disease (PUD) refers to disorders of the upper gastrointestinal
tract caused by the action of acid and pepsin. These agents not only cause injury them-
selves, but also typically augment the injury initiated by other agents. The spectrum of
peptic ulcer disease is broad, including undetectable mucosal injury, erythema, erosions,
and frank ulceration. The correlation of severity of symptoms to objective evidence of dis-
ease is poor. Some patients with pain suggesting peptic ulcer disease have no diagnostic
evidence of mucosal injury, whereas some patients with large ulcers are asymptomatic.

I. PATHOGENESIS. Gastroduodenal mucosal injury results from an imbalance between

the factors that damage the mucosa and those that protect it (Fig. 24-1). Therefore,
injurious factors may predominate and cause injury not only when they are excessive,
but also when the protective mechanisms fail. Although we have learned much in
recent years about the mechanisms of injury and protection of the mucosa of the
upper gastrointestinal tract, we still have an imperfect understanding of why discrete
ulcers develop and why peptic disease develops in one person and not in another.
A. Injurious factors. The mucosa of the upper gastrointestinal tract is susceptible to
injury from a variety of agents and conditions. Endogenous agents include acid, pepsin,
bile acids, and other small-intestinal contents. Exogenous agents include ethanol,
aspirin, other nonsteroidal antiinflammatory drugs, and Helicobacter pylori infection.
Acid appears to be essential for benign peptic injury to occur. A pH of 1 to 2 max-
imizes the activity of pepsin. Furthermore, mucosal injury from aspirin, other non-
steroidal antiinflammatory agents, and bile acids is augmented in the presence of acid. On
the other hand, ethanol causes mucosal injury with or without acid. Corticosteroids,
smoking, and psychological and physiologic stress appear to predispose or to exacerbate
to mucosal injury in some people by mechanisms that are incompletely understood.
B. Protective factors. A number of mechanisms work together to protect the
mucosa from injury (Table 24-1).
1. Concepts
a. Gastric mucosal barrier. In the early 1960s, Horace Davenport identified
the so-called gastric mucosal barrier, which describes the ability of the gas-
tric mucosa to resist the back diffusion of hydrogen (H+) ions and thus to
contain a high concentration of hydrochloric acid within the gastric lumen.
When the barrier is broken by an injurious agent, such as aspirin, H+ dif-
fuses rapidly back into the mucosa, which results in mucosal injury.
b. Cytoprotection. More recently, the concept of cytoprotection has been
developed to explain further the ability of the mucosa to protect itself. The
term cytoprotection is somewhat of a misnomer in that it does not refer to
the protection of individual cells but rather to protection of the deeper layers
of the mucosa against injury. The classic experiments of Andre Robert illus-
trate the phenomenon of cytoprotection. When he introduced 100% ethanol
into the stomachs of rats, large hemorrhagic erosions developed. However,
when he first instilled 20% ethanol, a concentration by itself that did not
cause gross injury, and subsequently administered 100% ethanol, no hemor-
rhagic erosions developed. Clearly, some endogenous protective mechanism
had been elicited by the preliminary exposure to a low concentration

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Chapter 24: Peptic Ulcer Disease 157

Figure 24-1. Diagram of factors that promote mucosal injury (Offense) versus those that protect
the mucosa (Defense). On the offensive side, hydrochloric acid (H+) is essential for the action of
pepsin and many ulcerogenic factors. For example, aspirin, bile acids, and the nonsteroidal antiin-
flammatory drugs cause much more mucosal injury in an acid milieu. The roles of corticosteroids,
smoking, and stress are less clear, but these factors probably contribute to mucosal injury. Alcohol
can cause mucosal injury without the assistance of acid. The defense of the mucosa is a complex
phenomenon that involves the interaction of a number of protective mechanisms indicated in the
figure. (See Table 24-1 and text.)

of the injurious agent. This protective effect was abolished by pretreatment

with indomethacin at the time of instillation of 20% ethanol. Because
indomethacin is a potent inhibitor of prostaglandin synthesis, this observation
suggested that cytoprotection was mediated by endogenous prostaglandins.
In fact, application of exogenous prostaglandins has been shown to protect
the gastric mucosa. Prostaglandins do inhibit gastric acid secretion, but their
cytoprotective effects can be demonstrated at doses below those necessary to
inhibit acid.
2. Mediators of mucosal protection
a. Mucus is secreted by surface epithelial cells. It forms a gel that covers the
mucosal surface and physically protects the mucosa from abrasion. It also
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158 Part V: Specific Complaints and Disorders

TABLE 24-1 Gastroduodenal Mucosal Protective Factors

Concepts Mediators

Gastric mucosal barrier Mucus

Cytoprotection Surface bicarbonate
Hydrophobic layer
Mucosal blood flow
Alkaline tide
Epithelial renewal
Restitution
Prostaglandins
Epidermal growth factor

resists the passage of large molecules, such as pepsin; however, H+, other
small particles, and ethanol seem to have little difficulty in penetrating mucus
to reach the mucosal surface.
b. Bicarbonate is produced in small amounts by surface epithelial cells and
diffuses up from the mucosa to accumulate beneath the mucous layer, creat-
ing a thin (several micrometers) layer of alkalinity between the mucus and
the epithelial surface.
c. The hydrophobic layer of phospholipid that coats the luminal membrane
of surface epithelial cells is believed to help prevent the back diffusion of
hydrophilic agents such as hydrochloric acid.
d. Mucosal blood flow is important not only in maintaining oxygenation and
a supply of nutrients, but also as a means of disposing of absorbed acid and
noxious agents.
e. The alkaline tide refers to the mild alkalinization of the blood and mucosa
that result from the secretion of a molecule of bicarbonate (HCO3
) by the
parietal cell into the adjacent mucosa for every H+ ion that is secreted into
the gastric lumen. This slight alkalinity may contribute to the neutralization
of acid that diffuses back into the mucosa and may augment the effects of
mucosal blood flow.
f. Epithelial renewal, which involves the proliferation of new cells and sub-
sequent differentiation and migration to replace old cells, but which requires
several days, is necessary in the healing of deeper lesions, such as erosions
and ulcers.
g. Restitution refers to the phenomenon of rapid migration, within minutes, of
cells deep within the mucosa to cover a denuded surface epithelium. This process
probably accounts for the rapid healing of small areas of superficial injury.
h. Prostaglandins, particularly of the E and I series, are synthesized abun-
dantly in the mucosa of the stomach and duodenum. They are known to
stimulate secretion of both mucus and bicarbonate and to maintain mucosal
blood flow. Prostaglandins also may have beneficial protective effects
directly on epithelial cells.
i. Epidermal growth factor (EGF) is secreted in saliva and by the duodenal
mucosa and may exert topical protective effects on the gastroduodenal mucosa.
C. Relation of Helicobacter pylori to peptic disease. Since 1983, evidence has
accumulated to implicate a bacterium, H. pylori, in the pathogenesis of some forms
of peptic disease. The organism is found adherent to the gastric mucosal surface
and, when looked for, has been identified in more than 90% of patients with duo-
denal ulcer. Its presence has also been correlated with gastritis, gastric ulcer, and
gastric erosions and with chronic infection, gastric mucosal atrophy, intestinal
metaplasia, and in a minority of patients, gastric adenocarcinoma and MALT
lymphoma. Some patients with H. pylori are asymptomatic and may even have
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Chapter 24: Peptic Ulcer Disease 159

normal-appearing gastric mucosa by endoscopy, but identification of the organism

is associated with histologic gastritis in nearly 100% of patients.
1. The mechanisms by which H. pylori are involved in the pathogenesis of peptic
conditions are unclear. H. pylori produce ammonia and elaborate other toxins that
may directly damage the mucosa and initiate an inflammatory response. The organ-
ism can be treated by bismuth-containing compounds (e.g., bismuth subsalicylate
[Pepto-Bismol]), PPI, and some antibiotics, which appear to facilitate the treatment
of the associated peptic condition. For example, patients with H. pylori-associated
duodenal ulcer have a longer period of remission when they receive treatment for
both the ulcer and the organism than when they are treated for the ulcer alone.
2. Treatment. Several studies have shown that duodenal ulcers may be curable by
eradication of H. pylori with so-called triple therapy (e.g., bismuth subsalicylate
q.i.d., tetracycline (or ampicillin) 500 mg q.i.d., and metronidazole 250 mg
q.i.d. for 2 weeks, plus omeprazole (Prilosec) 20 mg b.i.d. until healing. Other
studies have shown eradication rates higher than 90% with omeprazole
(Prilosec) 40 mg b.i.d. or lansoprazole (Prevacid) 30 mg b.i.d. or Pantoprazole
40 mg q.d. or Esomeprazole 40 mg q.d., or Rabeprazole 20 mg b.i.d., plus
amoxicllin 1 g b.i.d. and clarithromycin (Biaxin) 500 mg b.i.d. for 7 to 14
days. In penicillin-allergic patients, metronidazole (Flagyl) 500 mg b.i.d. may
be used instead of Amoxicillin. H. pylori eradication clearly reduces peptic ulcer
recurrence rates and is recommended for all patients with peptic ulcer disease
who are infected with H. pylori.
D. Relation of aspirin and other nonsteroidal antiinflammatory drugs to peptic
disease. Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) cause
mucosal injury and ulceration throughout the entire gastrointestinal tract, especially
in the esophagus, stomach, and duodenum. The mechanisms of injury are multifac-
torial and include both direct mucosal injury and inhibition of prostaglandins that
are protective to the mucosa. The risk for mucosal damage related to aspirin and
NSAID ingestion is related to a previous history of peptic ulcer disease, high and
frequent doses of the drugs, and concomitant use of corticosteroids or use of more
than one NSAID. The mucosal injury may be diffuse, and ulcers may be multiple.
Patients may be asymptomatic or may have frank bleeding, anemia, or strictures.
There is some clinical evidence that the gastric infection, H. pylori, may contribute
to enhance mucosal damage from NSAIDs. Treatment is to discontinue the offend-
ing agents and, if necessary, begin histamine-2 (H2) blocker or PPI therapy. If NSAID
treatment must be continued, therapy with the synthetic prostaglandin E1 derivative,
misoprostol 100 to 200 µg q.i.d. or a proton-pump inhibitor (PPI) (e.g., omeprazole
20–40 mg daily) has been shown to heal the mucosal lesions. Prostaglandins are
produced in the gastric mucosa by the progressive enzymatic action of cycloxyger-
anase I and II (COX) on arachidonic acid released from membrane phospholipids.
NSAIDS inhibit COX I and COX II enzymes. Specific COX II inhibitors have been
developed to allow the selective inhibition of those prostaglandins that are proin-
flammatory (e.g., in the joints). COX II inhibitors (e.g., celecoxib [Celebrex])
inhibit prostaglandins that are effective in gastroduodenal mucosal protection to a
much lesser degree, and thus are thought to be safer to use in patients with history of
peptic ulcer disease.

II. COMPLICATIONS OF PEPTIC ULCER DISEASE

A. Bleeding / hemorrhage. It is estimated that PUD is responsible for greater than
50% of all cases of UGI tract hemorrhage. Ulcers may erode into blood vessels and
may result in life-threatening hemorrhage. If bleeding is slower or intermittent, iron-
deficiency anemia may result. Some patients may also present with occult GI bleeding.
1. Patients with brisk bleeding from PUD usually present with hematemesis,
melena, and/or with hematochezia with clots and hypotension.
2. Risk factors for bleeding from PUD include ingestion of aspirin, NSAIDS,
platelet inhibitory drugs, coagulopathy, older age, and the presence of H. pylori
infection.
3. Treatment of GI bleeding from PUD is discussed in Chapter 14.
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160 Part V: Specific Complaints and Disorders

B. Perforation. Duodenal or gastric ulcers may perforate into the peritoneal cavity. In
10% of patients, perforation is accompanied by hemorrhage. Initially, patients feel an
abrupt onset of intense abdominal pain which is then followed by hypotension and
shock as the peritoneal cavity is flooded by gastric juice and contents and peritonitis
develops. Mortality is imminent if appropriate therapy is not initiated immediately.
The risk of perforation is increased in patients with PUD who smoke, use
NSAIDs, and who are elderly. Use of crack cocaine has been associated with per-
forated ulcers in the younger patients, most likely as a result of cocaine-induced
vasoconstriction and ischemia of the gastric or duodenal wall.
Diagnosis is clinical; however, free air is noted within the abdominal cavity
on plain and upright x-rays of the abdomen in approximately 75% of patients. CT
scan offers confirmatory information. Endoscopy should be avoided. Patients
should receive intravenous broad spectrum antibiotics and immediate surgery is
recommended to close the perforation and irrigate the peritoneal cavity.
C. Penetration occurs when PUD burrows through the gut wall into an adjacent organ
(i.e., pancreas, liver, or colon). Occasionally fistulas may develop. Pancreatitis, hem-
orrhage, or peritonitis may develop. Diagnosis is usually by CT scan. Treatment should
be tailored to pathology and may include surgery.
D. Obstruction. PUD of the antrum, pyloric channel, and duodenum may result in
gastric outlet obstruction. Patients may present with early satiety, nausea, vomiting,
epigastric pain, and bloating. Dehydration and electrolyte abnormalities may occur.
Diagnosis may be made by plain x-rays, CT scan, and more definitely by UGI
endoscopy. The narrowed segment may be dilated endoscopically. Some cases
require surgery.

III. DIAGNOSIS
A. Clinical presentation
1. History. The classic symptoms of peptic ulcer disease—epigastric burning pain
on an empty stomach that is relieved by food or antacids—are familiar to most
physicians and laypeople. Sometimes the pain radiates to the back, suggesting
an ulcer of the posterior aspect of the duodenal bulb that may have penetrated
into the pancreas. However, many patients with peptic disease experience non-
specific abdominal discomfort, which broadens the differential diagnostic con-
siderations to include gastroesophageal reflux disease (GERD); gallbladder
disease; pancreatic disorders; cancer of the stomach, pancreas, or biliary system;
mesenteric vascular insufficiency; and irritable bowel syndrome. A minority of
patients has gastrointestinal bleeding, weight loss, or vomiting; the vomiting
may be caused by partial or complete gastric outlet obstruction.
Over the past three decades, the yearly incidence of discrete peptic ulcer
disease appears to have decreased, but peptic disease of other types, such as
gastritis and duodenitis, sometimes related to ingestion of aspirin, nonsteroidal
antiinflammatory drugs, corticosteroids, or ethanol have increased in incidence.
Thus, important historical information includes a record of drug and alcohol
use and a history of smoking, and previous diagnosis of peptic disease.
2. Physical examination. The physical examination of a patient with peptic dis-
ease may be normal. Some patients have upper abdominal tenderness and
guarding. Rigidity of the abdomen and absent bowel sounds suggests perfora-
tion. Stool should be tested for occult blood.
B. Diagnostic studies
1. Most patients with dyspepsia or uncomplicated peptic disease may initially
require no diagnostic study. It may be sufficient to begin empiric treatment H2
blockers or PPIs to control acid secretion. Patients also should be advised
regarding diet, smoking, and lifestyle, as described in section IV. If they do not
respond to treatment within a reasonable time, usually 2 to 4 weeks, endoscopy
should be considered, during which biopsies can be obtained to test for
H. pylori and, in the case of a gastric ulcer, to evaluate for a cancerous lesion.
2. Patients with potential complications. A minority of patients present initially
with signs or symptoms that should act as “red flags” to alert the physician
to the increased possibility of complications of peptic disease or cancer.
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Chapter 24: Peptic Ulcer Disease 161

These warnings are clinically significant weight loss, evidence of gastrointestinal

bleeding, repeated vomiting, and intractable abdominal pain. If one of these cir-
cumstances is present, prompt diagnostic evaluation rather than empiric therapy
is recommended. The diagnostic procedure preferred is upper gastrointestinal
(GI) endoscopy because of its superior diagnostic accuracy over upper GI series.
The upper GI series is often ambiguous or nondiagnostic and patients have to
undergo subsequent endoscopy to clarify the questions that remain. In general,
judicious use of endoscopy as the initial diagnostic study in selected patients
with peptic complaints probably is the most cost-effective approach.
3. Laboratory studies. Most patients with uncomplicated peptic disease require no
laboratory studies except for the determination of H. pylori status by serologic
testing. However, a complete blood count and serum electrolytes are indicated in
the evaluation of patients who have bleeding or vomiting. A serum amylase is
helpful in evaluating patients with persistent pain that radiates to the back. If
peptic disease is persistent or there is a strong family history of peptic disease, the
patient should be evaluated for a hypersecretory syndrome (see section III.C).
4. Serum gastrin levels may be elevated in conditions in which gastric acid secretion
is very low or absent or in conditions in which there is gastric acid hypersecretion
(Table 24-2). Because acid is the major inhibitory influence on antral gastrin release,
hypo- or achlorhydric conditions predispose to hypergastrinemia. However, in
these conditions there is no known adverse consequence of the hypergastrinemia
because the major end organ for gastrin, the parietal cell mass, is absent.
In hypersecretory conditions associated with hypergastrinemia, the source
of gastrin either is independent of normal physiologic control (e.g., Zollinger–
Ellison syndrome [ZES] and retained antrum syndrome), is an unusual phys-
iologic variant that results in too many G cells (antral G-cell hyperplasia), is a
consequence of antral stimulation (e.g., gastric outlet obstruction), is a result of
unopposed action of gastrin (e.g., hypersecretion after small-bowel resection),
or develops because of poor renal excretion of gastrin caused by renal disease.
Serum for gastrin determination should be drawn in the fasting state.
Because some patients with ZES may have intermittent secretion of gastrin,
repeated fasting serum gastrin determinations may be indicated.
5. The secretin stimulation test takes advantage of the peculiar response of gas-
trinomas to secretin. Normally, intravenous secretin inhibits the release of gas-
trin from antral G cells, and serum gastrin either falls or remains unchanged
after secretin injection. In patients with a gastrinoma, however, secretin stimu-
lates release of gastrin from the tumor, causing a prompt rise in serum gastrin.
To perform the test, give secretin-kai 2 U/kg of body weight by rapid intra-
venous push. Draw blood for serum gastrin 15 minutes and 1 minute before the
secretin injection, and at 2, 5, 10, 20, and 30 minutes after injection. In patients with
gastrinoma, the serum gastrin levels should rise rapidly within 5 to 10 minutes of
secretin administration. The increase usually is greater than 400 pg /mL. With other
causes of hypergastrinemia that are associated with hypersecretion of gastric acid,

TABLE 24-2 Hypergastrinemic Conditions

Hypergastrinemia without gastric acid Hypergastrinemia with gastric acid

hypersecretion hypersecretion

Pernicious anemia Zollinger–Ellison syndrome (gastrinoma)

Gastric atrophy Retained antrum syndrome
Antral G-cell hyperplasia
Gastric outlet obstruction
Partial small-bowel resection
Renal insufficiency
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162 Part V: Specific Complaints and Disorders

such as the retained antrum syndrome (observed occasionally after an antrectomy

and gastrojejunostomy), gastric outlet obstruction, small-bowel resection, and renal
insufficiency, the serum gastrin level should decline or remain unchanged.

IV. TREATMENT. If peptic disease is complicated by bleeding, obstruction, or perforation,

the usual initial treatment includes intravenous fluids and nothing by mouth, and
intravenous administration of H2 blockers or PPIs. For the patients with uncompli-
cated peptic ulcer disease, in addition to medical therapy, recommendations regarding
diet and lifestyle modifications are given.
A. Diet
1. Food. Several controlled trials have indicated that rigid dietary restrictions are of
little or no benefit in healing peptic ulcers that are not accompanied by bleeding,
obstruction, or perforation. Thus, patients are advised to eat what they want.
Because food intolerances are unique to each person, patients should be advised to
avoid foods that they know cause discomfort. Alcoholic beverages and coffee are
restricted because of their ability to irritate the mucosa and stimulate gastric acid.
Frequent small feedings are unnecessary. Although food does buffer acid, it also
stimulates acid secretion. Because there are very effective methods for controlling
acid secretion pharmacologically, there is no need to rely on intragastric food to
buffer acid. Thus, patients are advised to eat three nutritionally balanced meals a
day. For the same reason, milk, which in the past achieved almost medicinal sta-
tus, should be used in moderation. Although milk does dilute and buffer acid, the
calcium and peptides it contains are strong stimulants of acid secretion, which
may overwhelm any initial benefit of milk.
2. Drugs and lifestyle modifications. Patients are recommended to stop smok-
ing, decrease or eliminate drinking alcohol, and not use aspirin and other
NSAIDS (prescribed or over-the-counter). In special circumstances when
patients have to take these drugs for cardiovascular, neurologic, or rheumato-
logic reasons, concomitant use of PPIs are recommended.
B. Control of smoking. Cigarette smoking appears to be a risk factor for the devel-
opment, maintenance, and recurrence of peptic ulcer disease. Several epidemio-
logic observations support this relation. First, smokers are more likely than
nonsmokers to have peptic ulcers. Second, peptic ulcers in smokers are more diffi-
cult to heal; they may require longer periods of treatment, may require higher
doses of antiulcer medications, or may be refractory to healing. Finally, after heal-
ing has been accomplished in smokers, relapse occurs sooner and more frequently
than in nonsmokers. Clinical trials suggest that, if smokers with healed ulcers stop
smoking, the rate of ulcer recurrence approximates that of nonsmokers.
Smoking has a number of effects on the function of the upper gastrointestinal
tract that may be relevant to the pathogenesis of peptic disease, including the
following:
1. Increased gastric acid secretion.
2. Interference with the action of H2 antagonists.
3. Increased gastric emptying of liquids.
4. Increased duodenogastric reflux.
5. Inhibition of pancreatic bicarbonate secretion.
6. Diminished mucosal blood flow.
7. Inhibition of mucosal prostaglandin production.
The increased gastric emptying may present higher concentrations of acid
to the duodenum, whereas the inhibition of pancreatic bicarbonate secretion
interferes with the neutralization of acid within the duodenum. The adverse
effects on mucosal blood flow and prostaglandin synthesis would be expected
to decrease the mucosal resistance to injury.
All available evidence indicates that the adverse effects of smoking on gas-
tric emptying, duodenogastric reflux, pancreatic bicarbonate secretion, mucosal
blood flow, and mucosal prostaglandin production are related directly to the
act of smoking, and cessation of smoking is associated with recovery of these
functions within minutes to hours.
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Chapter 24: Peptic Ulcer Disease 163

C. Drug therapy
1. Agents that control acid
a. Antacids neutralize gastric acid within the lumen of the esophagus, stom-
ach, and duodenum. They have been used for many years and are effective in
relieving peptic symptoms.
i. Composition. The magnesium-containing antacids are more potent than
those that do not contain magnesium, but they tend to cause diarrhea.
Magnesium-free antacids tend to cause constipation. Sometimes the two
types are alternated to provide adequate acid control and regulate tolerable
bowel habits. Calcium-containing antacids offer the initial acid neutraliza-
tion and stimulate gastric acid secretion. Another consideration is the
sodium content of an antacid when prescribing for a patient who is on a
sodium-restricted diet.
ii. Dosage. Most patients take antacids for amelioration of symptoms only.
To treat peptic conditions with a full antacid regimen, about 30 mL
should be taken 1 and 3 hours after a meal and at bedtime. This regimen
requires a daily antacid intake of more than 200 mL, resulting in a
monthly cost in excess of $50. Because few patients are likely to adhere
to such a program and because of the expense, other medications,
described in the following sections, are preferred.
b. H2 antagonists. Histamine is a potent stimulant of gastric acid secretion. For
this reason, agents that block the histamine receptor on the parietal cell, so-
called H2 antagonists, are effective inhibitors of acid secretion. Interestingly,
the H2 antagonists inhibit not only histamine-stimulated acid secretion, but
also acid that is stimulated by the vagus nerve (acetylcholine) and by gastrin.
This phenomenon suggests an interrelation among these three receptors. The
commercially available H2 antagonists are cimetidine (Tagamet), ranitidine
(Zantac), famotidine (Pepcid), and nizatidine (Axid).
i. Dosage. Typical full therapeutic doses of these agents are cimetidine,
300 mg q.i.d. or 400 mg b.i.d.; ranitidine, 150 mg b.i.d.; famotidine,
20 mg b.i.d. or 40 mg once before bed; and nizatidine, 300 mg once
before bed. Alternate regimens also have been used, such as cimetidine,
800 mg at bedtime; and ranitidine, 300 mg at bedtime.
ii. Side effects. The H2 antagonists are remarkably safe, although side effects
have been reported. These reports include rare instances of leukopenia and
the occasional occurrence of elevated liver enzymes, skin rash, constipation,
and diarrhea. Long-term use of cimetidine has been associated with gyneco-
mastia. Ranitidine appears to offer some advantage over cimetidine in that
it appears to cause less feminization in men and fewer central nervous sys-
tem effects, and it has lesser affinity for the cytochrome-P450 system in the
liver than does cimetidine, resulting in fewer drug interactions. Both cimeti-
dine and ranitidine interfere with gastric mucosal alcohol dehydrogenase
and, if taken before ingestion of alcohol, may increase serum alcohol levels.
This effect on alcohol dehydrogenase does not occur with famotidine.
Famotidine appears to offer many of the advantages of ranitidine and is
slightly longer acting. Nizatidine has a similar profile to ranitidine.
c. Prostaglandins. Prostaglandins are attractive on theoretical grounds
because they affect both sides of the mucosal injury-protection balance. They
inhibit acid secretion and exert a cytoprotective effect on the mucosa.
However, the dose required to elicit the cytoprotective effect is much lower
than the acid-inhibitory dose. When prostaglandins are administered in the
lower, cytoprotective dose, there is little evidence that they have any clinical
benefit.
Prostaglandin analogs (e.g., misoprostol [Cytotec]) have been used to
treat peptic conditions in clinical trials and appear to be as effective as H2
antagonists in healing ulcers when administered in doses that inhibit acid
secretion. However, there is little evidence that synthetic prostaglandins are
clinically effective when given in the lower, purely cytoprotective doses that
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164 Part V: Specific Complaints and Disorders

have no effect on acid secretion. Whether the synthetic prostaglandins offer

any practical advantages over current therapy is debatable, although one
analog that is commercially available, misoprostol, appears to be useful in
the prevention and treatment of NSAID-induced gastric ulcers or erosions
(see section I.D). Side effects of prostaglandins are diarrhea and abdominal
cramping related to the stimulatory effects of prostaglandins on intestinal
smooth muscle and secretion. The contractile effect of prostaglandins on
uterine smooth muscle could lead to abortion in pregnant women. For this
reason, prostaglandins are not recommended for pregnant women or women
of childbearing age who are not using a method of contraception.
d. Proton-pump inhibitors (PPIs). Currently there are six commercially avail-
able PPIs in the United States: omeprazole (Prilosec) and esomeprazole
(Nexium), lansoprazole (Prevacid), rabeprazole (Protonix), and omepra-
zole sodium bicarbonate (Zegerid). PPIs inhibit gastric acid secretion
nearly completely by covalently bonding to the H+-K+–ATPase or the proton
pump in the luminal aspect of the cell membrane of the parietal cells. These
drugs have been shown to be superior to H2 antagonists in healing erosive
esophagitis and duodenal and gastric ulcers. Omeprazole was approved by
the Food and Drug Administration in 1989, lansoprazole in 1995, rabepra-
zole in 1999, pantoprazole in 2000, and esomeprazole sodium in 2001.
Pantoprazole, esomeprazole, and lansoprazole are also available in the intra-
venous formulation in the United States.
PPIs produce faster healing of duodenal ulcers than H2 antagonists,
typically healing ulcers in 2 weeks rather than 4 weeks. PPIs also heal ulcers
that were resistant to therapy with H2 antagonists. Similarly, PPIs heal gas-
tric ulcers faster than H2 antagonists and heal gastric ulcers that are resistant
to H2 antagonist therapy. Clinical studies have shown that PPIs heal gastric
and duodenal ulcers better than H2 antagonists in patients who continue to
take NSAIDs. Furthermore, PPIs provide better prophylaxis against NSAID
damage in the duodenum and stomach than H2 antagonists. All PPIs have
been shown to be highly effective as part of an anti–H. pylori regimen when
used along with clarithromycin and either amoxicillin or metronidazole.
PPIs are the drugs of choice for the treatment of patients with the ZES.
Extensive studies with omeprazole, lansoprazole, rabeprazole, pantoprazole,
and esomeprazole sodium confirmed their efficacy and long-term safety. Because
PPIs are safe, have minimal side effects, and heal peptic ulcers faster than H2
blockers, they are the drugs of choice in the treatment of peptic diseases.
2. Other drugs. Sucralfate (Carafate) is a substituted disaccharide related to
sucrose that appears to act, at least in part, by stimulating endogenous cyto-
protection. The drug disperses rapidly in gastric juice of any pH and adheres to
tissue protein. In addition to its cytoprotective effects, therefore, sucralfate may
temporarily cover ulcers and erosions to help protect them from gastric con-
tents, acid, and pepsin as they heal.
Sucralfate (1 g q.i.d.; or 2 g b.i.d.) is as effective as H2 antagonists in healing
peptic ulcers. It also has been used to treat gastritis associated with NSAIDs and
erosive esophagitis. The drug may cause constipation but has no serious side effects.
3. Perspective on drug therapy
a. Choice of drugs. A wide variety of antiulcer drugs are available to the prac-
titioner. There is little difference in efficacy among treatment regimens using
an antacid, an H2 antagonist, a prostaglandin, or sucralfate.
However, PPIs offer advantages in terms of acceleration of healing and
are preferred in the treatment of esophageal, gastric, and duodenal ulcers as
well as refractory peptic ulcer disease and gastric hypersecretory syndromes
(e.g., ZES). All of the drugs are remarkably safe, and the choice of a drug
regimen depends largely on patient or physician preference, cost, and ease of
administration. All patients with peptic ulcer disease should be tested for
H. pylori either by serologic testing, breath test, or by endoscopic biopsy
techniques and treated for the cure of H. pylori infection.
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Chapter 24: Peptic Ulcer Disease 165

b. Long-term treatment. Peptic ulcer disease in most patients is a chronic

relapsing condition. Numerous studies have shown that maintenance ther-
apy with a dose of medication that is lower than the dose used to treat acute
disease markedly reduces the risk of ulcer recurrence. For example, treat-
ment of patients who have a healed duodenal ulcer with either cimetidine
400 mg at bedtime, ranitidine 150 mg at bedtime, famotidine 20 mg at bed-
time, or sucralfate 1 g b.i.d. for 1 year reduces the ulcer recurrence rate to
about 25% compared to a 75% recurrence rate in placebo-treated patients.
This experience raises some issues. On one hand, one must consider the
costs and risks of the drugs over the long-term; on the other hand, one must
also consider the cost and morbidity of ulcer recurrence. In some patients,
because of frequent symptoms or complications such as recurrent ulcer bleed-
ing, it is clear that a long-term treatment program is indicated. Other patients
have symptoms at predictable times and benefit from therapy that is limited
to several weeks to months. Still other patients have such infrequent or mild
symptoms that short, intermittent courses of antiulcer drugs are sufficient.
In patients who have H. pylori infection and peptic ulceration, eradica-
tion of H. pylori has been shown to reduce the recurrence rate of duodenal
and gastric ulcers. In patients with recurrent ulcers, H. pylori eradication
may result in permanent cure. See Chapter 26.
c. Treatment of H. pylori can be accomplished by various regimens including
bismuth based or PPI regimens that include two antibiotics. Since effective
treatment requires patient compliance, the simpler regimens are preferred.
These oral regimens included a PPI b.i.d., clarithromycin 500 mg b.i.d., and
amoxicillin 1 g b.i.d. or metronidazole 500 mg b.i.d. for 7 to 14 days or
Pylera, a new combination tablet that contains bismuth, tetracyclene, and
metronidazole as perscribed at does of 3 tablets t.i.d. Plus a PPI b.i.d. In
resistant cases, Rifampin may be used as an additional antibiotic.
D. Surgery for the treatment of peptic disease has decreased drastically over the past
two decades, probably because of the increased effectiveness of medical treatment
and the decline in prevalence of peptic ulcer in westernized countries. Surgery may
be performed because of hemorrhage, obstruction, perforation, or intractability.
Intractability means that medical management has failed to relieve pain or heal an
ulcer that has caused obstruction or recurrent bleeding.
Most operations for peptic disease fall into the following categories:
1. Truncal vagotomy and pyloroplasty. In truncal vagotomy the vagi are cut as
they enter the abdomen adjacent to the esophagus. This not only deprives the
parietal cell mass of its vagal innervation, but also obliterates the vagal innerva-
tion to the muscle of the stomach, intestine, and gallbladder. A major conse-
quence is impairment in gastric emptying, which results in gastric stasis. To
counteract this effect, a gastric-emptying procedure, usually a pyloroplasty,
must be performed to allow adequate emptying of the stomach.
2. Highly selective vagotomy. Sometimes called a parietal cell vagotomy or
proximal gastric vagotomy, this operation selectively denervates the parietal
cell mass in the body and fundus while leaving intact the vagal innervation to
the antrum, thereby preserving antral motility and gastric emptying. This pro-
cedure obviates the need for a pyloroplasty.
The operation usually takes longer than a standard vagotomy and pyloro-
plasty because each neurovascular bundle that comes off the major branch of the
vagus along the lesser curve (the nerve of Latarjet) to supply the parietal cell mass
must be ligated and sectioned.
3. Billroth I and Billroth II. Billroth I operation is an antrectomy with reanasto-
mosis between the stomach remnant and the proximal duodenum; a Billroth II
procedure is an antrectomy with reanastomosis between the stomach remnant
and a loop of proximal jejunum. Both operations are usually coupled with a
truncal vagotomy. Thus, the cephalic (vagal) and gastric (gastrin) phases of acid
secretion are markedly attenuated. A Billroth procedure is more physiologic
because food traverses the same alimentary pathway as it did before surgery
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166 Part V: Specific Complaints and Disorders

except that the antrum has been removed. In a Billroth II procedure, the food
bypasses a large portion of the proximal intestine, resulting in suboptimal
stimulation of bile and pancreatic secretion and poor mixing of food with these
secretions (see Chapter 28). Whether a Billroth I or Billroth II is performed
depends largely on technical considerations at the time of surgery.
E. Treatment of hypersecretory states
1. Gastrinoma. Current management of gastrinoma, or ZES, includes treatment with
H2 antagonists or PPIs, such as omeprazole, often in high doses. For example, rani-
tidine 1,200 mg per day in divided doses is a typical regimen, but some patients may
require up to 6 g per day. Omeprazole 60 to 80 mg a day, or any other PPI, effec-
tively inhibits acid secretion in most patients who have ZES. Some evidence indicates
that highly selective vagotomy lessens the requirement for H2 antagonists in many of
these patients, but the use of PPI has decreased the need for this operation.
2. Antral G-cell hyperplasia. Patients with antral G-cell hyperplasia have
increased numbers of antral G cells, which results in excessive gastrin secretion.
Whether antral G-cell hyperplasia is a distinct entity or is merely the extreme
end of a range of quantitatively different G-cell populations remains conjec-
tural. The secretin test (see section III.B.5) does not result in a rise in serum gas-
trin, as it does in ZES. Most patients respond well to H2 antagonists. Because
antrectomy removes the source of gastrin in these patients, the operation should
be considered in patients with refractory illness.
3. Retained antrum syndrome. Retained antrum syndrome develops only in
patients who have had an antrectomy and gastrojejunostomy (Billroth II). At
the time of surgery, deformity of the antroduodenal area may make identifica-
tion of the demarcation between antral and duodenal mucosa difficult.
Inadvertently, a small portion of antral mucosa may remain behind and
become incorporated into the duodenal stump after the antrum has been
resected and the proximal duodenal stump has been oversewn. The G cells of
the retained antrum are bathed constantly in an alkaline milieu, which pro-
motes constant, uninhibited secretion of gastrin. Serum gastrin levels may rise
to the range of the ZES. However, the secretin tests (see section III.B.5) should
not produce a rise in serum gastrin as it does in ZES. Patients may respond to
H2 antagonists or omeprazole, but the definitive treatment is reoperation to
remove the small portion of retained antrum.

Selected Readings
Barrison AF, et al. Patterns of proton pump inhibitors in clinical practice. Am J Med. 2001;
111:469–473.
Chan FKL, et al. Celecoxib versus diclofenac and omeprazole in reducing the recurrent ulcer bleeding
in patients with arthritis. N Engl J Med. 2002;347:2104–2110.
Johnson JH. Endoscopic risk factors for bleeding peptic ulcers. Gastrointest Endosc. 2002;56:1–6.
Kahi CJ, et al. Endoscopic therapy versus medical therapy for bleeding peptic ulcers with adherent
clot—a meta analysis. Gastroenterology. 2005;129:855–863.
Law JYW, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment
of bleeding peptic ulcers. New Engl J Med. 2000;343:310–316.
Leontiadis G, et al. Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration
meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007; 82(3):286–296.
Leontiadis GI, et al. Systematic review and meta-analysis of proton pump inhibitor therapy in peptic
ulcer bleeding. BMJ. 2005;330:568–570.
Rostom A, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: A Cochrane Collaboration
systematic review. Clin. Gastroenterol Hepatol. 2007;7(5):818.
Sridhar S, et al. Hydrogen peroxide (H2O2), H. pylori, NSAIDS, and clot stability: Do they matter?
American College of Gastroenterology Annual Mtg P-37, 2005.
Talley NJ, et al. Practice Parameters Committee of the American College of Gastroenterology.
Guidelines for the management of dyspepsia. Am J Gastroenteral. 2005;I00:2324–37.
Zargar SA, et al. Pantoprazole infusion as adjuvant therapy to endoscopic treatment in patients
with peptic ulcer bleeding: prospective randomized controlled trial. J Gasteroenterol Hepatol. 2006;
21:716–721.
79466_CH25.qxd 1/2/08 12:19 PM Page 167

STRESS ULCER 25

S tress ulcer refers to an ulcer or, more often, multiple ulcers that develop during the
severe physiologic stress of serious illness.

I. The pathogenesis of stress ulcer is unclear but probably is related to a reduction in

mucosal blood flow or a breakdown in other normal mucosal defense mechanisms
(see Chapter 24) in conjunction with the injurious effects of acid and pepsin on the
gastroduodenal mucosa.
A. The ulcerations may be superficial and confined to the mucosa, in which case
they are more appropriately called erosions, or they may penetrate deeper into the
submucosa. The former may cause diffuse mucosal oozing of blood, whereas the
latter may erode into a submucosal vessel and produce frank hemorrhage.
B. Location. Stress ulcerations may develop anywhere within the stomach and prox-
imal duodenum but are more likely to occur in fundic mucosa, which lines the body
and fundus of the stomach. This is in contradistinction to the location of ordinary
peptic ulcers, which typically are found in the gastric antrum and the duodenum.
C. The clinical setting is usually one of severe and often multisystem illness. For
example, elderly patients in a surgical intensive care unit (ICU) with heart and lung
disease have a high postoperative prevalence of stress ulcers. Similarly, patients in a
medical ICU, particularly those who require respirators, are at high risk of develop-
ment of stress ulcers. Although not proved, it is possible that poor mucosal
oxygenation, differences in acid–base balance, and elevated circulating cortico-
steroids may contribute to the formation of these ulcers.

II. DIAGNOSIS. Upper gastrointestinal bleeding is the usual clinical manifestation of

stress ulceration. In the appropriate clinical setting, the onset of bleeding makes the
diagnosis likely. The diagnosis can be confirmed and the extent of involvement
documented by upper gastrointestinal endoscopy after the initial management of
gastrointestinal bleeding has been started (see Chapter 14).

III. Treatment of stress ulceration usually begins with prevention. Careful attention to
respiratory status, acid–base balance, and treatment of other illnesses helps prevent
the conditions under which stress ulcers occur.
Patients who develop stress ulcers typically do not secrete large quantities of gas-
tric acid; however, acid does appear to be involved in the pathogenesis of the lesions.
Thus, it is reasonable either to neutralize acid or to inhibit its secretion in patients at
high risk. In patients admitted to surgical ICUs, hourly antacid titration to keep the
intragastric pH above 4 has been shown to reduce markedly the frequency of acute
bleeding. Because gastric-acid suppression with PPIs is much more profound, allowing
the gastric pH to rise to 5 or 6, PPI infusion IV is more effective in the prevention of
stress ulcers and stress ulcer bleeding.
Not all patients in an ICU require acid suppressive prophylaxis. Patients who
should be considered for a prophylactic regimen include those who are on respirators
and have multisystem disorders and those with a history of peptic ulcer or upper gas-
trointestinal bleeding. Once bleeding has occurred, however, intravenous acid
suppressive therapy with a PPI to keep intragastric pH above 5 remains the most
appropriate therapy (see Chapter 14).

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168 Part V: Specific Complaints and Disorders

Selected Readings
Chak A, et al. Effectiveness of endoscopy in patients admitted to the intensive care unit
with upper G.I. hemorrhage. Gastrointest Endosc. 2001;53:6.
Dore MP, et al. Ulcers and gastritis. Endoscopy. 2004;36:42–47.
James YW, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic
treatment of bleeding peptic ulcers. N Engl J Med. 2000;343:310–316.
Klebl FH, et al. Therapy insight: prophylaxis of stress-induced gastrointestinal bleeding in
critically ill patients. Nat Clin Pract Gastroenterol Hepatol. 2007;4(10):562–570.
Martindale RG, et al. Contemporary strategies for the prevention of stress-related mucosal
bleeding. Am J Hosp Pract. 2005;62(suppl):S511–S517.
Wolfe MM, et al. Acid suppression: Optimizing therapy for gastroduodenal ulcer healing,
gastroesophageal reflux disease and stress-related erosive syndrome. Gastroenterology.
2000;118(suppl 2):S9.
79466_CH26.qxd 1/2/08 12:20 PM Page 169

HELICOBACTER PYLORI 26

I. EPIDEMIOLOGY. Helicobacter pylori (H. pylori or HP) is a microaerophilic, flagel-

lated, highly motile, gram-negative spiral bacteria that was first isolated from mucosal
biopsies of patients with chronic active gastritis by two Australian investigators, Warren
and Marshall, who subsequently received the Nobel Prize in 2005 for their discovery.
The organism was first named “Campylobacter pyloris,” then the name was changed
to Helicobacter pylori when it was shown genetically that it was not a member of the
Campylobacter genus. HP is one of the most common human infectious agents and is
causally linked with neutrophilic gastritis, chronic active gastritis, atrophic gastritis,
peptic ulcer disease, gastric intestinal metaplasia, gastric adenocarcinoma, gastric
mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric B-cell lymphoma.
HP infection occurs primarily during childhood and usually persists for life
unless the infection is adequately treated. The major risk factor for infection is the
socioeconomic status of the family during childhood. The prevalence of HP in the
United States has decreased in the white middle- and upper-class population 50 years
of age and younger, but the infection is still common among older persons (infected at
a younger age), the socially disadvantaged, and the immigrant populations.
HP has been found in water, stool, dental plaque, and saliva. There is strong
epidemiologic evidence for waterborne transmission in Peru and Colombia. Primary
mode of transmission is person to person, but oral, gastro-oral, and fecal spread is likely.

II. VIRULENCE FACTORS OF HP ARE NUMEROUS AND INCLUDE

A. Motility. HP with its spiral shape and unipolar flagella is able to move from the
gastric lumen with low pH to gastric mucosal surface where pH is neutral, as well
as to other parts of the gastric surface where its growth potential is optimal.
B. Adherence factors. HP binds to gastric-type epithelium. This tissue tropism and
binding prevents the organism from being easily shed during cell and mucus
turnover. HP has several adhesion proteins that bind to the gastric mucosal cell
receptors (which are genetically controlled) which increases successful HP infection
and spread.
C. Urease. HP produces urease, an enzyme which hydrolyzes urea to produce ammo-
nia (NH3) to protect itself from gastric acid. Ammonia neutralizes the acid
surrounding HP as well as provides an essential basis for the “CLO” test used for
testing mucosal biopsies for the presence or absence of HP.
D. Toxins. HP possesses and/or elaborates various toxins that cause tissue injury of
the gastric mucosa in infected individuals. These include lipopolysaccharide (endo-
toxin bound to HP), neutrophil activating protein (NAPA), vacuolating cytotoxin
(VacA), cytotoxin-associated antigen (CagA-A), and outer membrane inflamma-
tory protein (OipA). Not all strains of HP possess all these toxins. Those strains of
HP which possess CagA and OipA seem to be exceptionally virulent and are asso-
ciated with more severe disease activity, PUD, and cancer.

III. INFECTION. Acute infection has been demonstrated dramatically by Warren and
Marshall, who voluntarily ingested a culture of HP and developed acute HP disease.
It is not known how often infection with HP spontaneously clears. In most cases,
infection is lifelong. Most infected persons develop chronic active gastritis. Gastritis
may be confined mostly to the gastric antrum and/or involve the entire stomach. In

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170 Part V: Specific Complaints and Disorders

persons with predominately antral involvement, gastric acid secretion may be normal
or increased. In such persons, duodenal ulcer and esophagitis secondary to GER may
occur. In persons with diffuse HP infection of the entire stomach, gastric atrophy may
develop and acid secretion may diminish; in fact, these persons may develop hypo-
and achlordria and even vitamin B12 deficiency. In advanced cases, intestinal metapla-
sia and gastric adenocarcinoma may develop. Once patients develop severe atrophy,
intestinal HP metaplasia or gastric adenocarcinoma may not be present in these tis-
sues where there is no acid secretion.
Interestingly, in persons treated with proton pump inhibitors (PPIs) chronically,
there is usually a shift of HP infection from the antrum to the corpus and accelerated
atrophic changes. Thus some experts advise eradication of HP before long-term PPI
therapy is instituted in HP-infected individuals.
In some patients, HP infection arouses a robust induction of lymphocytic infil-
tration of gastric mucosa with lymphocytic follicle formation and in some cases MALT
lymphoma. These have been seen to regress after appropriate HP eradication therapy.
However, B-cell lymphomas that develop in association with HP infection may not
regress after HP eradication and may need oncologic intervention.

IV. DIAGNOSIS
A. Endoscopy and biopsy is the gold standard for the diagnosis of HP. Biopsies
should be obtained from all parts of the stomach since the colonization of HP is
spotty and is affected by the mode of infection, patients’ medications, and whether
patients are on acid-suppressive therapy. Histology not only confirms the presence
of HP, but also gives information on the presence or absence of gastritis, gastric
atrophy, intestinal metaplasia, MALT lymphoma, and cancer. Sensitivity ranges
from 90% to 95% and specificity 95% to 100%. False negative results occur in the
sections of recent GI bleeding, use of Bismuth-containing medications, antibiotics,
sucralfate, and acid-suppressive medications.
CLO test, PyloriTek test uses a biopsy in a medium containing urea which
undergoes color change if HP is present with urease activity.
HP may be cultured from gastric biopsies. This should be considered in
patients who have failed two courses of appropriate antibiotic treatment regimens
and are thought to have resistant HP.
B. Breath tests. Breath testing in patients infected with HP utilizes their ingesting
C14 (radioactive) or C13 containing urea, then blowing into a container to measure
the tagged CO2 released by HP degradation of urea (CONH3) by its urease which
releases CO2 and NH3. Sensitivity of breath testing ranges from 85% to 95% and
is operator-dependent. False negative results can occur in patients with history of
recent antibiotic, bismuth, sucralfate and antisecretionary therapy and in those
with advanced histologic changes such as atrophy and intestinal metaplasia.
C. Stool antigen test. A monoclonal and polyclonal antibody test is available to test
for HP antigen in stool samples. This has a similar sensitivity and specificity as
compared to breath tests. False negative tests are seen as in breath tests as well as
in patients with a history of recent GI bleeding.
Both the breath test and stool antigen test should not be done for at least
4 weeks after HP eradication therapy.
D. Serology. HP antibody may be detected in persons who have been infected with
HP. However, in many persons the IgG HP antibody persists in the plasma even
after proper eradication (at least for 18 months) and thus it is not a good measure
of current infection.
Salivary and urinary assay have similar sensitivity and specificity to serology.
E. When and whom to test. HP testing is recommended for patients who are to be
treated for the eradication of HP infection. In patients with history of PUD and
dyspepsia, if endoscopy is indicated, biopsies should be obtained from multiple
sites. In patients with gastric ulcer, biopsies should also be obtained from the ulcer
to check for cancer.
After eradication therapy, testing for presence of HP is not routinely
practiced. In patients with PUD-related GI hemorrhage or those with recurrent
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Chapter 26: Helicobacter Pylori 171

dyspeptic, symptoms may be tested for HP after at least 4 weeks have elapsed from
eradication, antibiotic, and acid antisecretory therapy. Stool antigen test, breath
test and, in indicated cases, endoscopy and biopsy may be used.

V. THERAPY. Combination therapy is required for successful HP eradication. The

current preferred therapy in the United States is twice daily PPI plus clarithromycin
500 mg b.i.d. and amoxicillin 1 g b.i.d. for 7 to 14 days.
Dual therapy with PPI and amoxicillin or clarithromycin is not recommended.
In patients with penicillin allergy, metronidazole 500 mg b.i.d. may be used.
In the United States there is documented resistance to metronidazole (25%),
clarithromycin (15%), and amoxicillin (1%).
Treatment failure may be attributed to patient noncompliance, smoking, concur-
rent use of sucralfate, and the presence of bacterial resistance to antibiotics.
Patients who fail the above therapy may be offered quadruple therapy recom-
mended by the European Helicobacter pylori Study Group. Quadruple therapy consists
of metronidazole 500 mg q.i.d., tetracycline 500 mg q.i.d., Bismuth subsalicylate
(Pepto-Bismol) tablets q.i.d., and a PPI b.i.d. for 2 weeks. To simplify this regimen, a
combination tablet (Pylera) is available. It contains Tetracyclene, metronidazole, and
bismuth salicate. The dose is 3 tablets t.i.d. plus twice daily PPI.
In patients who are allergic or wish another regimen, a 10-day course of
levofloxacin 500 mg q.d. or 250 mg b.i.d., amoxicillin 1g b.i.d. and a PPI b.i.d. or
rifabutin 300 mg q.d., amoxicillin 1 g b.i.d. and a PPI b.i.d. may be used. Rifabutin may
cause bone marrow suppression, leukopenia, hepatitis, uveitis, and a polyarthralgia-like
syndrome.

Selected Readings
Delchier JL. Gastric MALT lymphoma, a malignancy potentially curable by eradication of
Helicobacter pylori. Gastroenterol Clin Biol. 2003;27:453–458.
Duck WM, et al. Antimicrobial resistance incidence and risk factors among Helicobacter
pylori–infected persons, United States. Emerg Infect Dis. 2004;10:1088–1094.
Gisbert JP, et al. Helicobacter pylori “rescue” therapy after failure of two eradication
treatments. Helicobacter. 2005;10:363–372.
Gisbert JP, et al. Review article: C-urea breath test in the diagnosis of Helicobacter pylori
infection—a critical review. Aliment Pharmacol Ther. 2004;15:1001–1017.
Gisbert JP, et al. Stool antigen test for the diagnosis of Helicobacter pylori infection:
A systematic review. Helicobacter. 2004;9:347–368.
Janssen MJ, et al. Meta-analysis: The influence of pre-treatment with a proton pump inhibitor
on Helicobacter pylori eradication. Aliment Pharmacol Ther. 2005;21:341–345.
Jarbol D, et al. Proton pump inhibitor or testing for Helicobacter pylori as the first step for
patients presenting with dyspepsia? A cluster-randomized trial. Am J Gastroenterol.
2006;I0I:1200–8.
Laey C, et al. Helicobacter infection and gastric cancer. Gastroenterology. 2001;120:324.
Laine L, et al. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate,
metronidazole and tetracycline given with omeprazole versus omeprazole, amoxicillin, and
clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients:
A prospective, randomized, multicenter North American trial. Am J Gastroenterol. 2003;
98:562–567.
Ohata H, et al. Progression of chronic atrophic gastritis associated with Helicobacter
pylori infection increases risk of gastric cancer. Int J Cancer. 2004;109:138–143.
Qasim, A, et al. Rifabutin- and furazolidone-based Helicobacter pylori eradication
therapies after failure of standard first- and second-line eradication attempts in
dyspepsia patients. Aliment Pharmacol Ther. 2005;21:91–96.
Saad RJ, et al. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy
for persistent Helicobacter pylori infection: A meta-analysis. Am J Gastroenterol.
2006;101:488–496.
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172 Part V: Specific Complaints and Disorders

Sepulveda AR, et al. Role of Helicobacter pylori in gastric carcinogenesis. Gastroenterol

Clin North Am. 2002;31:517–535.
Suzuki T, et al. Smoking increases the treatment failure for Helicobacter pylori eradication.
Am J Med. 2006;119:217–224.
Vakil N. Helicobacter pylori treatment: A practical approach. Am J Gastroenterol. 2006;
101:497–499.
Vakil N. New guidelines for Helicobacter pylori: Applying these to your practice. Rev.
Gastroenterol Disorder. 2007;7(3):111–114.
79466_CH27.qxd 1/2/08 12:20 PM Page 173

GASTRIC NEOPLASMS 27

M ost neoplasms of the stomach are malignant, and most of those are adenocarci-
noma. A minority are lymphoma, leiomyosarcoma, and liposarcoma. Benign neoplasms
include adenomatous, hyperplastic, and hamartomatous polyps; leiomyomas; and lipomas.
Rarely, gastrinomas, carcinoids, vascular tumors, fibromas, and squamous cell carcinomas
occur in the stomach.
Adenocarcinoma of the stomach is the second most frequent cause of cancer death
worldwide. In East Asia, Latin America, and the former Soviet Union, the incidence is up
to eight times higher than in the United States and it remains high among immigrants from
those areas. Although screening programs in high-risk areas such as Japan may result in
the detection of early lesions, in lower risk areas such as the United States and Western
Europe, most cancers are relatively advanced by the time of diagnosis.

I. GASTRIC ADENOCARCINOMA
A. Pathogenesis
1. Pathology
a. Early gastric cancer (EGC) is gastric cancer that has not penetrated the
major muscle layer of the stomach wall. EGC can be divided into three types
based on macroscopic appearance (Fig. 27-1).

Figure 27-1. Classification of early gastric carcinoma according to the Japanese Endoscopy
Society. (From Green PHR, et al. Early gastric cancer. Gastroenterology. 81;247:1981. Reprinted with
permission.)

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174 Part V: Specific Complaints and Disorders

b. Advanced gastric cancer is gastric cancer that has penetrated the muscle
layer of the stomach. This condition also has been divided into three types:
i. Polypoid or intestinal
ii. Diffuse infiltrating or signet ring type
iii. Ulcerating
2. Risk factors (Table 27-1)
a. Some population groups appear to be at higher risk than others for devel-
opment of gastric adenocarcinoma. For example, the prevalence of gastric
cancer in Japan is about 10 times the prevalence in the United States.
Furthermore, in Japan approximately 30% of gastric cancers at the time of
diagnosis are EGC, whereas in the United States only 5% can be classified
as EGC. Japanese who move away from Japan to a low-risk area have a
similar risk to those who remain in Japan. However, second- and third-
generation Japanese children of these immigrants have a progressively lower
risk that approaches the local population.
b. Several dietary factors have been implicated. Increased consumption of salt
appears to be a consistent finding. Dietary nitrates also may be important.
Cigarette smoking increases risk. However, a diet rich in fresh fruits and
vegetables, daily aspirin use, and COX-II antagonist reduce the risk.
c. Conditions that predispose to achlorhydria, such as pernicious anemia and
atrophic gastritis, carry a higher than average risk of gastric cancer. Whether
this is because the reduced acid allows bacteria that have the capacity to
nitrosate dietary amines to carcinogenic nitrosamines to grow within the
stomach or because of other effects is not clear.
d. Partial gastrectomy 15 or more years in the past was thought to be asso-
ciated with a higher risk of development of adenocarcinoma within the gas-
tric remnant. Recent evidence indicates that this increased risk is lower than
originally anticipated. Virtually all these patients eventually have chronic
gastritis and become hypo- or achlorhydric, which, as indicated previously,
may increase the risk of development of cancer.
e. Helicobacter pylori infection has been associated with gastric adenocarci-
noma. The cancer is thought to arise from gastric intestinal metaplasia that
arises in patients who develop chronic atrophic gastritis with chronic infec-
tion with H. pylori. Especially those strains that are CagA
appear to be
more carcinogenic than CagA strains.
B. Diagnosis
1. Clinical presentation
a. EGC typically is asymptomatic and usually is discovered during endoscopy
performed for other complaints. When symptoms have been attributed to
EGC, they usually are vague, such as epigastric discomfort and nausea.

TABLE 27-1 Risk Factors for Adenocarcinoma of the Stomach

Chronic gastritis with Helicobacter pylori infection

National origin (e.g., high risk in Japan, Chile, Finland)
Diet (e.g., high salt consumption, nitrates, smoking)
Achlorhydria
Histologic changes (e.g., atrophic gastritis, intestinal metaplasia)
Gastric adenomatous polyps
Hypertrophic gastropathy (Ménétrièr’s disease)
Postgastrectomy
Male vs. female (1.5:1.0)
Blood group A
79466_CH27.qxd 1/2/08 12:20 PM Page 175

Chapter 27: Gastric Neoplasms 175

b. Most patients in North America present with symptoms of advanced gastric

cancer.
i. Symptoms are primarily abdominal pain and weight loss, which may be
accompanied by anorexia, weakness, gastrointestinal bleeding, and signs
of gastric obstruction, such as early satiety or vomiting.
ii. Physical examination. An epigastric mass, an enlarged liver due to
metastases, or ascites may be evident. An umbilical mass, known as a
Sister Joseph’s nodule, is unusual. Metastasis to the ovaries has been
called a Krukenberg’s tumor, although this eponym also has been applied
to colonic and other gastrointestinal tumors that metastasize to the
ovaries.
2. Diagnostic studies
a. Upper gastrointestinal x-ray series versus endoscopy. Traditionally, an
upper gastrointestinal (GI) x-ray series has been the first diagnostic study. If
the patient in fact has gastric cancer and not a benign peptic lesion, the upper
GI series may reveal a mass lesion, ulceration, irregularity of the mucosa,
lack of distensibility of the stomach, or no definite abnormality. Any of these
abnormal findings requires endoscopic confirmation and biopsy.
Furthermore, because patients with abdominal discomfort plus weight
loss, bleeding, or vomiting who have negative or inconclusive findings on
upper GI x-ray series still require endoscopy, the most cost-effective approach
to such patients may be to begin with endoscopy.
b. At endoscopy, the appearance of the lesion can be assessed, the lesion can be
biopsied and brushed for cytologic study, and the pH of the gastric contents
can be determined. In ulcerating lesions, six to eight biopsies of the ulcer edges
are necessary to provide a 95% chance of obtaining a positive result if the
lesion is indeed cancerous. An acid pH of the gastric aspirate indicates, of
course, that the stomach is capable of secreting acid. On the other hand, a
neutral pH at endoscopy does not necessarily indicate achlorhydria.
c. Endoscopic ultrasound is an excellent modality for staging of gastric can-
cers. The depth of invasion of the tumor can be easily determined, allowing
accurate diagnosis of EGC which may be treated by endoscopic mucosal
resection (EMR).
d. Serum carcinoembryonic antigen (CEA) levels are elevated in about one
third of patients with advanced gastric cancer but are not helpful in making
the diagnosis. As with colon cancer, serial CEA determinations may be use-
ful in the postoperative follow-up of patients to indicate recurrences or to
estimate metastatic tumor burden.
e. Hematocrit and hemoglobin levels may be normal but typically are
decreased in advanced gastric cancer due to bleeding and the extent of
chronic disease. If the patient has pernicious anemia (as a predisposing cause
of gastric cancer), the anemia may be macrocytic.
f. An elevated alkaline phosphatase level may indicate metastases to the
liver. An elevated 5-nucleotidase level confirms that the liver is the origin
of the abnormality in alkaline phosphatase.
g. Computed tomography (CT) of the abdomen should be performed to survey
for liver metastases, lymph node enlargement, and the extent of the primary
tumor. If endoscopic biopsy fails to make a histologic diagnosis, CT- or
ultrasound-guided needle aspiration of a mass lesion or a percutaneous liver
biopsy in patients with elevated alkaline phosphatase may provide diagnostic
tissue.
C. Treatment
1. The prognosis for gastric cancer is poor. The overall 5-year survival rate is
18.6%. Untreated, the median life expectancy in advanced disease with liver
metastases is 4–6 months and in patients with peritoneal carcinomatosis 4–6
weeks. However, if the tumor is confined to the mucosa and submucosa (EGC)
and there are no metastases or lymph node involvement, the 5-year survival
rate exceeds 90%. Unfortunately, most patients with gastric cancer in the
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176 Part V: Specific Complaints and Disorders

United States already have metastases or involvement of contiguous structures

or lymph nodes at the time of diagnosis.
2. Surgery currently is the only hope of cure. About 20% of patients are deemed
inoperable because of the extent of disease or high operative risk. Of the
remaining 80% who undergo surgery, about half undergo a curative resection,
and the other half are given palliative treatment for bleeding or obstruction.
However, only about 20% of patients who have had a curative resection sur-
vive 5 years. Results might be better with extensive lymph node dissection and
lymphadenectomy.
3. Chemotherapy and radiotherapy. Both chemotherapy and radiotherapy
alone for gastric cancer have been disappointing. If the patient’s condition is
operable, the initial resection of as much tumor mass as possible seems to
improve the efficacy of chemotherapy and radiotherapy. Adjuvant chemother-
apy using 5-fluororacil, mitomycin, doxorubicin, Cisplatin, and irinotecan
seems to improve survival. Adjuvant radiotherapy alone has no effect on long-
term survival. However, combined chemotherapy and radiation in the adjuvant
setting improves overall survival.
4. Other treatment measures. Patients with gastric cancer require careful atten-
tion to nutritional needs. Partial or complete gastric resection imposes addi-
tional nutritional consequences (see Chapter 28). These patients may require
supplemental vitamins, particularly vitamin B12, and minerals such as calcium
and iron.
5. Follow-up. Patients who have been operated on for cure should be examined
by the physician every several months for clinical and laboratory evidence of
recurrence. Weight loss, gastrointestinal bleeding, and obstruction—all the signs
of original disease—may signify recurrence. It is reasonable to check a complete
blood count, routine liver tests, and CEA level every 3 to 6 months for the first
1 to 2 years after surgery and every 6 to 12 months thereafter. Yearly upper GI
endoscopy to look for local recurrence also is appropriate during the first
5 years.

II. OTHER GASTRIC TUMORS

A. Malignant tumors. Other malignant tumors include lymphoma, leiomyosarcoma,
liposarcoma, and carcinoid. Of these, primary gastric lymphomas account for
most of the noncarcinomatous gastric malignancies. The stomach can also be
involved secondarily by disseminated lymphoma or by metastatic cancer from
other sites.
1. Clinical presentation and diagnosis. Patients with other gastric neoplasms
present clinically with abdominal pain, weight loss, anorexia, and vomiting,
signs and symptoms that are similar to those observed in patients with adeno-
carcinoma of the stomach. The methods of diagnosis are also similar.
2. Prognosis and treatment. Because lymphoma responds better than adenocar-
cinoma to radiation and chemotherapy, the prognosis is better. The 5-year sur-
vival rate of patients with gastric lymphoma is about 50%. If the lymphoma is
confined to the stomach, surgical treatment is indicated. If regional nodes or
distant sites are involved, radiotherapy or chemotherapy with or without
surgery may be indicated.
B. MALT lymphoma. Low-grade B-cell lymphomas of mucosa-associated lymphoid
tissue (MALT) are thought to arise within organized lymphoid tissue in the gastric
mucosa that is most frequently acquired in response to H. pylori infection. Long-
term remissions can be induced in the low-grade MALT lymphomas in 70% to
80% of cases by the successful eradication of the H. pylori infection. The lym-
phomas that are most likely to respond to the H. pylori eradication are those that
are located superficially within the gastric mucosa. Recurrences of low-grade
lymphoma are encountered in patients treated by H. pylori eradication, but
these appear to be infrequent and may be self-limiting and spontaneously regress
without surgery. Deeper and higher grade lesions need to be treated as B-cell
lymphomas.
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Chapter 27: Gastric Neoplasms 177

C. Polypoid lesions and benign tumors. The term polyp refers to any protrusion
into the lumen of a viscus and thus does not necessarily connote benign or malig-
nant histopathology. In common medical usage, however, the term polyp usually
refers to a lesion of epithelial origin.
1. Histologic types. Gastric polyps are adenomatous, hyperplastic, or hamar-
tomatous. Of these, only adenomatous polyps and carcinoids appear to have
malignant potential. Other benign lesions that may resemble gastric polyps
grossly are leiomyomas and lipomas. Small polyps normally seen in the gastric
corpus are usually fundic gland polyps that contain dilated gastric glands.
2. Diagnosis. Often, benign polypoid lesions are discovered incidentally during
upper GI x-ray series or endoscopy. The studies may have been performed for
complaints of nausea, abdominal pain, or weight loss, but whether the polyps
are responsible for those complaints is conjectural.
Regardless of how the polypoid lesion has been identified, endoscopy
should be performed to clarify the appearance of the lesion, to obtain biopsies,
and to survey for other lesions. If possible, adenomatous polyps should be
removed endoscopically. Polyps that cannot be removed should be biopsied and
brushed for cytologic study.
3. Treatment. The diagnosis of frank carcinoma, lymphoma, or other malignancy
leads to appropriate treatment of that condition. Removal of an adenomatous
polyp removes the risk of malignant degeneration. The diagnosis of a benign,
nonadenomatous polypoid lesion is reassuring in that the lesion is not cancer-
ous and will not become cancerous.

Selected Readings
Chan AO, et al. Synchronous gastric adenocarcinoma and mucosa-associated lymphoid
tissue lymphoma in association with Helicobacter infection: Comparing reported cases
between the East and the West. Am J Gastroenterol. 2001;96:1922–1924.
Chung DC, et al. A woman with a family history of gastric and breast cancer. N Eng J
Med. 2007;357:283–291.
Delchier JC. Gastric MALT lymphoma: A malignancy potentially curable by eradication of
Helicobacter pylori. Gastroenterol Clin Biol. 2003;27:453–458.
El-Serag HB, et al. Epidemiologic differences between adenocarcinoma of the oesophagus
and adenocarcinoma of the gastric cardia in the USA. Gut. 2002;50:368–372.
El-Zahabi N, et al. The value of EUS in predicting the response of gastric mucosa-
associated lymphoid tissue lymphoma to Helicobacter pylori eradication. Gastrointest
Endosc. 2007;65:89–96.
El-Zimaity HM, et al. Patterns of gastric atrophy in intestinal type gastric carcinoma.
Cancer. 2002;94:1428–1436.
Hwang JH, et al. A prospective study comparing endoscopy and EUS in the evaluation of
GI subepithelial masses. Gastrointest Endos. 2005;62:202–208.
Kurtz RC, et al. Gastric cardia cancer and dietary fiber. Gastroenterology. 2001;120:568.
Laey C, et al. Helicobacter pylori infection and gastric cancer. Gastroenterology. 2001;
20:324–330.
Lynch HT, et al. Gastric cancer: new genetic developments. J Surg Oncol. 2005;90:114–133.
MacDonald JS. Gastric cancer: New therapeutic options. N Engl J Med. 2006;355:76–77.
Meining A, et al. Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach:
A reality or merely a hypothesis? Best Pract Res Clin Gastroenterol. 2001;15:983–998.
Morita D, et al. Analysis of Sentinel Node involvement in gastric cancer. Clin Gastroenterol
Hepatol. 2007;5:1046–1052.
Noffsinger A, et al. Preinvasive neoplasia in the stomach: Diagnosis and treatment. Clin
Gastroenterol Heptatol. 2007;5:1018–1023.
Sakuramoto S, et al. Adjuvant chemotherapy for gastric cancer with S-1. N Eng J Med.
2007;357:1810–1820.
Usui S. Laparoscopy-assisted total gastroectomy for early gastric cancer: comparison with con-
ventional open toal gastrectomy. Surg Laparosc Endosc Percutan Tech. 2005;15:309–314.
Wagner AD, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst
Rev. 2005;2:CD004064.
TABLE 27.1
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28 POSTGASTRECTOMY DISORDERS

G astrectomy usually means removal of part of the stomach and anastomosis of the
gastric remnant with either the duodenum (Billroth I) or a loop of proximal jejunum
(Billroth II) (see Chapter 24). These operations typically are performed as surgical treatment
of peptic ulcer disease or cancer of the stomach. Rarely, the entire stomach is removed.
Removal of part or all of the stomach can be associated with a variety of conse-
quences and complications (Table 28-1). These may range in severity from a simple inabil-
ity to eat large meals, due to loss of the reservoir function of the stomach, to more serious
complications, such as severe dumping and profound nutritional sequelae.

I. DUMPING SYNDROME
A. Pathogenesis. The dumping syndrome develops as a result of the loss of pyloric
regulation of gastric emptying. Thus, strictly speaking, a portion of the stomach
does not necessarily have to be removed; a pyloroplasty alone can lead to the
dumping syndrome. After a pyloroplasty or an antrectomy, hyperosmolar food is
“dumped” rapidly into the proximal small intestine.
1. During the early phase of the dumping syndrome, the hyperosmolar small-
bowel contents draw water into the lumen, stimulate bowel motility, and release
vasoactive agents, such as serotonin, bradykinin, neurotensin, substance P, and
vasoactive intestinal peptide from the bowel wall. Patients experience abdomi-
nal cramps, diarrhea, sweating, tachycardia, palpitations, hypotension, and
light-headedness. These effects typically occur within 1 hour after eating.
2. In the late phase, because of the absorption of a large amount of glucose after
the meal, plasma insulin rises excessively and blood sugar may plummet.
Consequently, the patient may experience tachycardia, light-headedness, and
sweatiness 1 to 3 hours after a meal.
B. Diagnosis. The typical symptoms and signs in the setting of gastric surgery usu-
ally are sufficient to make the diagnosis of dumping syndrome. A blood sugar

TABLE 28-1 Complications of Gastric Surgery

I. Dumping syndrome
II. Recurrent ulcer
III. Nutritional and metabolic sequelae
A. Loss of weight
1. Poor food intake
2. Dumping syndrome
3. Malabsorption
B. Malabsorption, with or without weight loss
1. Malabsorption of iron, calcium, folate, vitamin B12
2. Malabsorption of fat, protein, carbohydrate
IV. Afferent loop syndrome
V. (?) Carcinoma in the gastric remnant

178
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Chapter 28: Postgastrectomy Disorders 179

determination several hours after a meal when symptoms are at their worst may be
helpful in confirming the late phase.
C. Treatment. Patients are advised to eat small meals six to eight times a day.
Carbohydrates are restricted to minimize glucose absorption. Medications to
reduce bowel motility, such as diphenoxylate or loperamide, may be helpful. In
rare instances, surgical revision with anastomosis of the gastric remnant to an
antiperistaltic segment of jejunum may be necessary.

II. RECURRENT ULCER

A. Pathogenesis. About 1% to 3% of patients who have undergone partial
gastrectomy for ulcer disease develop a recurrent ulcer. Recurrent ulcers nearly
always occur in small intestinal mucosa adjacent to the anastomosis (duodenal
mucosa in a Billroth I, jejunal mucosa in a Billroth II). The factors that contribute
to the development of a recurrent ulcer are similar to those that contributed to the
original ulcer disease (see Chapter 24). A recurrent ulcer after surgery raises the
question of the adequacy of the operation. Also, the possibility of an acid hyper-
secretory syndrome (e.g., gastrinoma or retained antrum) must be considered.
B. Diagnosis. Patients with recurrent ulcers usually experience abdominal pain that
may or may not be similar to their original ulcer pain. Typically, the pain is relieved
by food, although in some patients the pain is aggravated by eating. As in ordinary
ulcer disease, bleeding, obstruction, and perforation can occur. The diagnosis is
established by endoscopy. Because of the surgical deformity at the anastomosis, the
endoscopist must be especially attentive to examining the folds and crevices in the
vicinity of the anastomosis.
The documentation of a recurrent ulcer is an indication for at least a fasting
serum gastrin determination. Formal acid secretory testing (see Chapter 24) may
not be reliable because of the loss of acid through the widely patent anastomosis.
If the ratio of basal acid output to maximal acid output exceeds 60%, that is sug-
gestive of a gastrinoma or another acid hypersecretory syndrome, but a low ratio
does not exclude such a syndrome. If suspicion is high for a Zollinger–Ellison-like
syndrome, a secretin stimulation test should be performed (see Chapter 24).
C. Treatment. Conventional ulcer therapy (see Chapter 24) may be sufficient. Some
patients require chronic treatment with acid-suppressive drugs. Those in whom
such therapy fails may benefit from more extensive surgery. A demonstrated acid
hypersecretory condition may require more specific treatment (see Chapter 24).
III. NUTRITIONAL AND METABOLIC SEQUELAE
A. Pathogenesis
1. The weight loss that commonly occurs after gastric surgery is multifactorial.
First, the storage capacity of the postsurgical stomach is limited, thereby
restricting the amount of food that can be consumed at one meal. Second, if the
dumping syndrome is present, the patient may reduce food intake to avoid
unpleasant consequences. Thus, malabsorption may contribute to weight loss
due to failure to absorb adequate calories and nutrients.
2. The causes of malabsorption are numerous
a. The reduction in gastric acid contributes to the malabsorption of dietary
iron. If the patient has a gastrojejunal anastomosis (Billroth II), bypass of
the duodenum also results in poor absorption of iron, calcium, and folate.
Thus, iron- or folate-deficiency anemia or a manifestation of calcium defi-
ciency, such as osteoporosis, may develop.
b. Bypass of the duodenum also means that food-stimulated secretin and chole-
cystokinin release is diminished, resulting in delayed and attenuated bile
and pancreatic secretions. Furthermore, the digestive enzymes mix poorly
with the food as they “chase” it down the small intestine.
Rarely, bacterial overgrowth develops within the afferent loop after
Billroth II surgery, causing deconjugation of bile acids and contributing to
the fat malabsorption. The dumping syndrome, if present, adds to poor
mixing, even in patients with a gastroduodenal anastomosis (Billroth I).
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180 Part V: Specific Complaints and Disorders

c. Malabsorption of vitamin B12 may occur. Normally, intrinsic factor (IF) is

secreted by gastric parietal cells in excess of what is needed to complex with
dietary vitamin B12. An acid-reducing operation by itself is not sufficient to
compromise vitamin B12 absorption. However, most patients who have
undergone partial gastrectomy have chronic gastritis, presumably because of
reflux of small-intestinal contents, which can result in gastric atrophy and
loss of parietal cells over several years. Secretion of IF diminishes, and the
neurologic or hematologic consequences of pernicious anemia may develop.
B. Diagnosis. Many of the nutritional and metabolic manifestations of the postgas-
trectomy state are self-evident. Routine hematologic studies plus serum iron,
ferritin, and vitamin B12 levels help in determining the cause of anemia and in plan-
ning appropriate treatment. Because of normal homeostatic mechanisms, serum
calcium usually remains normal.
A quantitative stool fat determination may document the severity of malab-
sorption. However, even patients who do well after gastric surgery typically have
mild elevations in stool fat in the range of 5 to 10 g per day. An abnormal vita-
min B12 absorption test (Schilling test) without IF, which normalizes with added
IF, can document the lack of IF in patients with macrocytic or mixed anemia.
Endoscopic biopsy showing atrophic gastritis lacking parietal cells confirms the
diagnosis.
C. Treatment. The patient is advised to consume frequent small feedings to accom-
modate the small gastric remnant. Antidiarrheal agents may be helpful. If fat mal-
absorption is a prominent feature, a low-fat diet, perhaps supplemented with
medium-chain triglycerides (which do not require bile acids for absorption) should
be prescribed. In patients with fat malabsorption, an empiric trial of tetracycline,
250 mg four times daily for 7 to 10 days, is justified because documentation of
bacterial overgrowth in the afferent loop is difficult.

IV. AFFERENT LOOP SYNDROME

A. Pathogenesis. The afferent loop syndrome may occur in patients with a gastroje-
junostomy. This term does not refer to the blind loop syndrome. Occasionally this
is a point of some confusion. The blind loop syndrome, which means bacterial
overgrowth in a blind or stagnant loop of bowel or within a diverticulum with con-
sequent bile acid deconjugation and fat malabsorption, certainly can occur in the
afferent loop.
The afferent loop syndrome develops because of a stricture or kinking of the
afferent, or proximal, loop of a Billroth II anastomosis. This defect impairs the
egress of fluid from the duodenum. When the patient eats, biliary, pancreatic, and
duodenal secretions enter the duodenum. If these secretions cannot pass easily to
the gastrojejunal anastomosis, the afferent loop becomes distended, causing severe
epigastric pain. As the pressure within the loop increases, the obstruction is sud-
denly overcome, culminating in vomiting and prompt relief of pain.
B. Diagnosis. The clinical story of severe abdominal pain developing during or
shortly after eating and relieved promptly by vomiting in a patient with a Billroth II
anastomosis is highly suggestive. Documentation by objective testing is difficult.
HIDA scanning may help confirm the diagnosis if isotope is seen to fill and distend
the afferent loop during development of typical pain, without entry into the stom-
ach or distal jejunum. The patient should undergo endoscopy to look for an anas-
tomotic ulcer or a constriction within the afferent loop. However, kinking of the
loop is difficult to determine by endoscopy. Although an upper gastrointestinal
x-ray series usually is not helpful, it may suggest kinking of the loop and can indicate
the length of the afferent loop and its position in the abdomen.
The diagnosis of afferent loop syndrome is made after much deliberation in
patients who have symptoms consistent with the diagnosis and in whom another
cause for the symptoms cannot be found.
C. Treatment. Medical management of the afferent loop syndrome usually is unsat-
isfactory. Sometimes frequent small feedings prevent symptoms. If an anastomotic
ulcer is discovered, that can be treated. An occasional patient improves with the
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Chapter 28: Postgastrectomy Disorders 181

passage of time. The definitive treatment is surgical and consists of either relieving
adhesive bands or shortening the afferent loop and reforming the anastomosis.

V. CHRONIC GASTRITIS AND CARCINOMA IN THE GASTRIC REMNANT

A. Pathogenesis. In some studies, patients who have undergone partial gastrectomy
appear to be at increased risk to develop adenocarcinoma within the remnant
15 years or more after surgery. The first estimates of the prevalence of this
complication were about 5%, but subsequent evidence indicates that the risk may
be much lower. Postgastrectomy adenocarcinoma usually occurs in the gastric
mucosa at the anastomosis. The pathogenesis is thought to be related to the
chronic gastritis that invariably develops and is most severe at the anastomosis.
B. Diagnosis. In view of the evidence that the risk of adenocarcinoma arising in the
gastric remnant may be considerably less than originally estimated, routine sur-
veillance endoscopy in asymptomatic patients does not appear to be cost effective
and thus is not recommended. However, the physician should be attentive to
changes in symptoms or clinical status in postgastrectomy patients that may
indicate the development of neoplasia. These include the development of new or
different abdominal symptoms, anorexia, vomiting, weight loss, and gross or
occult gastrointestinal bleeding. The appropriate diagnostic study is endoscopy
with biopsy of the anastomosis.
C. The treatment of gastric cancer is discussed in Chapter 27, section I.C.

Selected Readings
Dulucq JL, et. al. A completely laparoscopic total and partial gastrectomy for benign and
malignant diseases: a single institute’s prospective analysis. 2005; 200:191–197.
Madura JA. Postgastrectomy problems: remedial operations and therapy. In: Camperon
JL, ed. Current surgical therapy. St. Louis:Mosby;2001:89–94.
Tersmette AC, et al. Long-term prognosis after partial gastrectomy for benign conditions:
survival and smoking-related death of 2633 Amsterdam postgastrectomy patients
followed up since surgery between 1931 and 1960. Gastroenterology. 1991;101:148.
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29 DIARRHEA

D iarrhea can be defined as an increase in the fluidity, frequency, and volume of daily
stool output. The daily stool weight is usually increased over the normal average of 200 g
due to an increase in the stool water above the normal content of 60% to 75%. There may
also be a change in the stool solids.

I. NORMAL INTESTINAL FLUID BALANCE. During fasting, the intestine contains very lit-
tle fluid. On a normal diet of three meals a day, about 9 L of fluid is delivered to the small
intestine. Oral intake accounts for 2,000 mL, and the remainder is secreted from various
parts of the gastrointestinal tract into the lumen (Table 29-1). Of this, 90% is absorbed in
the small intestine. One to two liters is presented to the colon, and approximately 90% is
absorbed. The colon has the capacity to absorb all of the fluid presented to it, but the pres-
ence of unabsorbed osmotically active solutes from the diet (e.g., some carbohydrates) and
from bacterial action prevents complete fluid absorption and desiccation of the fecal mate-
rial. This results in 100 to 200 mL of fluid in the stool. Thus, approximately 98% of the
fluid presented to the intestine each day is absorbed by the small and large intestines.
Feces on the average contain 100 mL of water, 40 mEq/L of sodium (Na+), 90 mEq/L
of potassium (K+), 16 mEq/L of chloride (Cl
), and 30 mEq/L of bicarbonate (HCO3
).
The remaining anions are organic and result from bacterial fermentation of unabsorbed
carbohydrates. The gastrointestinal tract does not have diluting mechanisms; thus, the
osmolality of the fecal fluid is never less than the osmolality of plasma. In fact, osmolality
of fecal fluid is usually greater than that of plasma due to continuing bacterial fermenta-
tion of unabsorbed carbohydrates into osmotically active particles after defecation.
Water transport across the intestinal epithelium is passive. It is secondary to
osmotic gradients generated by active transport of electrolytes such as Na+ and Cl
or
other solutes, such as sugars and amino acids. Intestinal ion absorption occurs mainly
across epithelial cells that reside at the tips of the villi. Crypt cells are involved in ion
secretion: Na+ is the major ion actively absorbed, and Cl
is the major ion secreted.
Na+ is actively absorbed throughout the intestinal tract empowered by the Na+
pump in the form of Na+-K
–ATPase located in the basolateral plasma membrane of
intestinal epithelial cells. Thus water is absorbed along with Na+.

TABLE 29-1 Normal Daily Intestinal Water Input

Source Volume (mL)

Oral 2,000
Secretions
Salivary 1,500
Gastric 2,500
Pancreatic 1,500
Biliary 500
Small intestinal 1,000
Total 9,000

182
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Chapter 29: Diarrhea 183

Active intraluminal secretion in the intestine is accomplished by active secretion of

Cl
. This process is also powered by Na+-K
–ATPase located in basolateral membranes
of the crypt cells. Cl
secretion is also followed by water secretion into the intestinal
lumen.
Any process that either impairs absorption of Na+ and water or causes Cl
and
water to be secreted into the intestinal lumen can result in diarrhea.

II. PATHOPHYSIOLOGY OF DIARRHEA. There are four major mechanisms of diarrhea.

A. Osmotic diarrhea, in which there is increased amounts of poorly absorbable,
osmotically active solutes in the gut lumen.
B. Secretory diarrhea, in which there is, increased Cl
and water secretion with or
without inhibition of normal active Na+ and water absorption.
C. Exudation of mucus, blood, and protein from sites of active inflammation into the
bowel lumen.
D. Abnormal intestinal motility, with increased or decreased contact between
luminal contents and mucosal surface.

III. OSMOTIC DIARRHEA

A. Causes. Osmotic diarrhea is caused by ingestion of a poorly absorbable solute,
usually a carbohydrate or a divalent ion (e.g., magnesium [Mg2+] or sulfate [SO24
])
(Table 29-2). The higher osmolality of the luminal contents causes water influx into
the intestinal lumen across the duodenal and jejunal epithelium to dilute the solute,
in an attempt to make the chyme isotonic. Due to the leakiness of this epithelium,
Na+ follows the influx of water from the plasma to the gut lumen due to the dif-
ference in the Na+ concentration gradient. This Na+ influx causes further influx of
water even after the osmolality of the luminal contents and plasma is identical. In
contrast, the epithelium of the ileum and colon has a low permeability to Na+ and
to the solute. It also has an efficient active ion transport mechanism that allows it
to reabsorb Na+ and water even against a steep electrochemical gradient. Thus,
water is absorbed as it traverses the ileum and colon, and the severity of the osmotic
diarrhea is reduced. This has been called “colon salvage.” Since the fluid volume
entering the colon still exceeds the ability of the colon to absorb, diarrhea results.
In lactase deficiency, lactose from the diet cannot be absorbed in the small
intestine, remains in the lumen, and reaches the colon, where it is broken down by
the endogenous bacteria into additional osmotically active solute particles, which
increase the osmotic load and cause diarrhea.
B. Clinically, osmotic diarrhea stops when the patient fasts. The stool osmolality
([Na+]+[K+])  2 (to account for anions) is less than the osmolality of the stool
fluid measured by freezing point depression. This osmotic anion gap accounts for
the presence of the poorly absorbable solutes in fecal fluid. Anion gaps greater

TABLE 29-2 Causes of Osmotic Diarrhea

I. Carbohydrate malabsorption
A. Disaccharidase deficiency in the small-intestinal mucosa
1. Primary (e.g., idiopathic lactase, sucrase–maltase deficiency)
2. Secondary (e.g., after infectious gastroenteritis and with mucosal inflammation)
B. Ingestion of mannitol, sorbitol (diet candy, soda, chewing gum)
C. Lactulose therapy
II. General malabsorption
A. Sprue (idiopathic gluten enteropathy, tropical)
B. Postradiation, postischemic enteritis
III. Ingestion of sodium sulfate (Glauber’s salt), sodium phosphate, magnesium sulfate
(Epsom salts), milk of magnesia, magnesium-containing antacids
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184 Part V: Specific Complaints and Disorders

than 50 are considered clinically significant. Determination of the stool pH may be

helpful in the diagnosis of osmotic diarrhea. Carbohydrates in stool yield an acid
pH; milk of magnesia, an alkaline pH; and poorly absorbable salts containing
Mg2+ or SO42
, a neutral pH.

IV. SECRETORY DIARRHEA

A. CAUSES. Diarrhea of 1 L or more per day results from secretion of fluid across
the intestinal mucosa. In most cases, a pathophysiologic event causes small intesti-
nal secretion by simultaneously stimulating active secretion and partial inhibition
of intestinal absorption. Often, the intestinal mucosa is intact and has normal his-
tologic findings. Some causes of secretory diarrhea are listed in Table 29-3.
B. Clinically, there are five features that characterize secretory diarrhea.
1. Stool volume is usually large (1 L per day).
2. Stools are watery in consistency.
3. Stools do not contain pus or blood.
4. Diarrhea typically continues while the patient fasts for 24 to 48 hours. However,
secretory diarrhea from fatty acid malabsorption or from laxative abuse will
stop when these agents are not ingested.
5. The osmolality of the stool is close to the osmolality of plasma, and there is no
anion gap.

TABLE 29-3 Causes of Secretory Diarrhea

Enterotoxins
Vibrio cholerae
Escherichia coli
Staphylococcus aureus
Bacillus cereus
Hormonal secretagogues
Vasoactive intestinal polypeptide (pancreatic cholera syndrome, secreting villous adenoma)
Calcitonin (medullary carcinoma of thyroid)
Serotonin (carcinoid)
Prostaglandins, prostanoids (intestinal lymphoma, inflammatory bowel disease)
Gastric hypersecretion
Zollinger–Ellison syndrome
Short-bowel syndrome
Systemic mastocytosis
Basophilic leukemia
Laxatives
Ricinoleic acid (castor oil)
Bisacodyl
Dioctyl sodium sulfosuccinate
Aloe
Senna
Danthron
Phenolphthalein
Bile salts
Terminal ileal disease/resection
Bile duct obstruction
Fatty acids
Pancreatic insufficiency
Small-intestine mucosal disease
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Chapter 29: Diarrhea 185

V. EXUDATIVE DIARRHEA. If the intestinal mucosa is inflamed and ulcerated, mucus,

blood, and pus leak into the lumen and are discharged as stool. This may also create
an increased osmotic load. If a large surface area of the bowel lumen is involved,
absorption of ions, solutes, and water will also be impaired, and patients may have
large-volume diarrhea. Inflammation may generate prostaglandins, which stimulate
secretion and may increase bowel motility, thus compounding the diarrhea. The sever-
ity of the diarrhea and the systemic signs and symptoms depends on the extent of
bowel involvement.
Inflammatory states may be
A. Idiopathic (e.g., Crohn’s disease, ulcerative colitis)
B. Infectious (e.g., from invasive organisms or cytotoxins: Shigella, Salmonella,
Campylobacter, Yersinia, tuberculosis, amebae, and Clostridium difficile)
C. Ischemic
D. Vasculitic
E. Due to radiation injury
F. Caused by abscess formation (e.g., diverticulitis, infected carcinoma)

VI. MOTILITY DISTURBANCES. Both reduced and increased motility of the intestine
may result in diarrhea.
A. Increased motility of the small intestine results in decreased contact time of
chyme with absorptive surfaces. Large amounts of fluid delivered to the colon may
overwhelm its absorptive capacity and result in diarrhea. The reduced contact time
in the small intestine may interfere with absorption of fatty acids and bile salts,
allowing them to reach the colon where they induce a secretory diarrhea. Diarrhea
associated with hyperthyroidism, carcinoid, and postgastrectomy dumping syn-
drome are examples.
B. Decreased motility of the small intestine may allow colonization of the small
intestine with colonic-type bacteria. The digestion and absorption of fats, carbo-
hydrates, and bile salts may be affected, resulting in osmotic or secretory diarrhea.
This mechanism is involved in the diarrhea seen with diabetes, hypothyroidism,
scleroderma, amyloidosis, and postvagotomy states.
C. Increased colonic motility with premature emptying of colonic contents is the
major cause of diarrhea in the irritable bowel syndrome.
D. Anal sphincter dysfunction caused by neuromuscular disease, inflammation,
scarring, and postsurgical states may result in fecal incontinence, which may be
interpreted by the patient as diarrhea.

VII. CLINICAL APPROACH. It is helpful to classify diarrhea into clinical categories, tak-
ing into consideration the duration, setting, and sexual preference of the patient.
Diarrhea of abrupt onset of less than 2 to 3 weeks’ duration is called acute diarrhea.
If the diarrheal illness lasts longer than 3 weeks, it is called chronic diarrhea. The
causes of acute and chronic diarrhea are listed in Tables 29-4 and 29-5. If diarrhea
occurs in the setting of antibiotic therapy or after a course of antibiotics, antibiotic-
associated diarrhea and pseudomembranous colitis due to C. difficile cytotoxin should
be considered.
A. Acute diarrhea. The most common cause of acute diarrhea is infection.
1. Food poisoning is produced by a preformed bacterial toxin that contaminates
the food. Bacterial replication in the host is not necessary for the development
of disease. The resultant illness usually has an acute onset and short duration
and occurs in small, well-defined epidemics, without evidence of secondary
spread.
2. Diarrhea resulting from multiplication of organisms in the intestine may be
divided into inflammatory–invasive versus noninflammatory–noninvasive cat-
egories, as seen in Table 29-4. Most of these types of diarrhea result from ingestion
of contaminated food or water after 1 to 2 days of incubation. Animal reservoirs
may exist for some common pathogens, including Salmonella, Campylobacter,
Yersinia, Giardia, Cryptosporidium, and Vibrio parahaemolyticus. Waterborne
disease in which the pathogens are spread from animals or water to humans is
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186 Part V: Specific Complaints and Disorders

TABLE 29-4 Causes of Acute Diarrhea

Causes Characteristics Organisms

Viral Infections
Small intestine Mucosal invasion absent Rotavirus (children, adults)
Noninflammatory
Watery diarrhea Norwalk virus
Fecal leukocyte absent Enteric adenovirus
Bacterial infections
Small intestine Mucosal invasion absent Vibrio cholerae
Noninflammatory Toxigenic Escherichia coli
Watery diarrhea
Fecal leukocytes absent
Colon Mucosal invasion present Salmonella
Inflammatory Shigella
Bloody diarrhea Campylobacter
Fecal leukocytes present Yersinia enterocolitica
Invasive E. coli
E. coli O157:H7
Staphylococcus aureu
(toxin)
Vibrio parahaemolyticus
(toxin)
Clostridium difficile (toxin)
Parasitic infections
Small intestine Mucosal invasion absent Giardia lamblia
Noninflammatory Cryptosporidium
Watery diarrhea
Fecal leukocytes absent
Colon Mucosal invasion present Entamoeba histolytica
Inflammatory
Bloody diarrhea
Fecal leukocytes present
Food poisoning
Small intestine Toxin induced Staphylococcus aureus
Mucosal invasion absent Bacillus cereus
Noninflammatory Clostridium perfringens
Watery diarrhea Clostridium botulinum
Drugs
Laxatives
Sorbitol
Antacids (Mg2+, Ca2+ salts)
Lactulose
Colchicine
Quinidine
Diuretics
Digitalis
Propranolol
Theophylline
Aspirin
Nonsteroidal antiinflammatory drugs
Chemotherapeutic agents
Antibiotics

(continued)
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Chapter 29: Diarrhea 187

TABLE 29-4 Causes of Acute Diarrhea (Continued)

Heavy metals (Hg, Pb)

Cholinergic agents
Miscellaneous
Fecal impaction
Diverticulitis
Ischemic bowel disease

TABLE 29-5 Causes of Chronic Diarrhea

Type Agent

Infection Giardia lamblia

Entamoeba histolytica
Tubercle bacillus
Clostridium difficile
Inflammation Ulcerative colitis
Microscopic colitis
Collagenous colitis
Crohn’s disease
Ischemic colitis/enteritis
Solitary rectal ulcer
Diverticulitis/abscess
Drugs Laxatives
Antibiotics
Antacids
Diuretics
Alcohol
Theophyllines
Nonsteroidal antiinflammatory drugs
Malabsorption Small-bowel mucosal disease
Disaccharidase deficiency
Pancreatic insufficiency
Ischemic/radiation enteritis
Short-bowel syndrome
Bacterial overgrowth
Endocrine Zollinger–Ellison syndrome
Hyperthyroidism
Carcinoid
Non--cell pancreatic tumor
Villous adenoma
Motility disorders Irritable bowel syndrome
Postvagotomy syndrome
Postgastric surgery dumping syndrome
Tumor/fecal impaction overflow diarrhea
Narcotic bowel
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188 Part V: Specific Complaints and Disorders

caused by Salmonella, Campylobacter, Shigella, Norwalk virus, Giardia, Vibrio

cholerae, toxigenic Escherichia coli, and E. coli: H7.
3. Diarrhea developing in individuals during or just after traveling is commonly
infectious. The most likely organisms are enterotoxigenic E. coli, Salmonella,
Giardia, and amebae.
4. Homosexual individuals are at a higher risk of exposure to infectious agents.
In this setting, it is important to consider amebiasis, giardiasis, shigellosis, rec-
tal syphilis, rectal gonorrhea, and lymphogranuloma venereum caused by
Chlamydia trachomatis and herpes simplex infections of the rectum and peri-
anal area. In patients with acquired immunodeficiency syndrome (AIDS), infec-
tious agents could include cytomegalovirus, Cryptosporidium, and Candida as
well as all of the organisms noted in homosexual persons and immunocompe-
tent individuals. (See Chapters 42 and 43.)
B. Chronic and recurrent diarrhea. Any diarrheal illness lasting longer than
3 weeks should be clinically investigated.
1. Infections. Most viral and bacterial diarrheas are self-limiting and abate
within 3 weeks. Diarrhea from Campylobacter and Yersinia may last a few
months but rarely becomes chronic. Bowel infections with tuberculosis, ame-
bae, and Giardia may become chronic.
2. Inflammatory bowel disease. Ulcerative colitis and Crohn’s disease may
result in diarrhea of varying severity, depending on the extent and degree of
bowel involvement. Diarrhea in Crohn’s disease of the small bowel may be
compounded by concomitant bile salt and fat malabsorption.
3. Malabsorption syndromes
a. Diseases of the small intestine may cause chronic diarrhea of varying
severity. The mechanism of the diarrhea is usually multifactorial and com-
plex. These diseases include:
i. Sprue (nontropical, tropical)
ii. Amyloidosis
iii. Whipple’s disease
iv. Lymphoma
v. Carcinoid
vi. Radiation enteritis
vii. Lymphangiectasia
viii. Bowel resection/bypass
b. Pancreatic insufficiency from chronic pancreatitis and cystic fibrosis may
cause severe fat malabsorption, resulting in chronic diarrhea.
c. Zollinger-Ellison syndrome resulting from a gastrin-secreting tumor causes
increased gastric acid output that overwhelms the absorptive capacity of the
proximal small intestine, neutralizes the bicarbonate, and inactivates the
pancreatic enzymes secreted into the duodenum. The resulting diarrhea is
complicated by malabsorption and bile salt—and fatty acid—stimulated
colonic secretion.
d. Postgastrectomy, enterostomy states may result in diarrhea due to
decreased mucosal–chyme exposure as well as poor mixing of digestive juices
with luminal contents, resulting in malabsorption.
e. Bacterial overgrowth of the small intestine may occur in patients with dia-
betes mellitus, scleroderma, amyloidosis, blind loop syndrome, and large
and multiple diverticula of the small bowel. Bacterial degradation of carbo-
hydrates, fatty acids, and bile salts results in diarrhea.
f. Disaccharidase deficiency. Lactase is deficient to a variable degree in
many adult populations, especially in blacks, Asians, southern Europeans,
and those of Jewish descent. Even small amounts of dairy products may
cause intermittent diarrhea in these individuals.
4. Endocrine disorders
a. Hyperthyroidism
b. Diabetes mellitus
c. Adrenal insufficiency
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Chapter 29: Diarrhea 189

d. Carcinoid
e. Medullary thyroid cancer
f. Hormone-secreting pancreatic tumors
g. Tumors secreting vasoactive intestinal polypeptide
h. Gastrinoma
5. Neoplasms. Villous adenoma, colon cancer with obstruction, and fecal
impaction may present with diarrhea.
6. Drugs and laxatives. Surreptitious use of laxatives and drugs, including those
listed in Table 29-4, should always be considered in the evaluation of chronic
diarrhea.
7. Irritable bowel syndrome is very common and may present with only chronic
intermittent diarrhea, constipation, or a combination of both. Most patients
also complain of abdominal cramps, gas, belching, and mucous stools.
8. Incontinence of stool. Anal sphincter dysfunction due to the presence of fis-
sures, fistulas, perianal inflammation, tears from childbirth, anal intercourse
or other trauma, diabetic neuropathy, or neuromuscular disease may result in
frequent stools, which may be interpreted by the patient as diarrhea.

VIII. DIAGNOSIS
A. History. The physician should find out from the patient an accurate description
of the nature of the diarrhea: the duration, frequency, consistency, volume, color,
and relation to meals. Also, it is important to determine the presence of any under-
lying illnesses or systemic symptoms and to establish the patient’s recent travel
history, use of medications or drugs, and sexual preferences.
1. The history can help determine whether the pathology is in the small or large
bowel. If the stools are large, watery, soupy, or greasy, possibly containing
undigested food particles, the disorder is most likely in the small intestine.
There may be accompanying periumbilical or right lower quadrant pain or
intermittent, crampy abdominal pain.
2. If the disease is in the descending colon or rectum, the patient usually passes
small quantities of stool or mucus frequently. The stools are usually mushy and
brown, and sometimes mixed with mucus and blood. There may be a sense of
urgency and tenesmus. If there is pain, it is usually achy and located in the
lower abdomen, pelvis, or sacral region. The passage of stool or gas may pro-
vide temporary relief of the pain.
3. Blood in the stool suggests inflammatory, vascular, infectious, or neoplastic dis-
ease. The presence of fecal leukocytes indicates mucosal inflammation.
4. Diarrhea that stops with fasting suggests osmotic diarrhea, except that
secretory diarrhea due to fatty acids and bile salt malabsorption may also stop
with fasting. Large-volume diarrhea that continues during fasting is most likely
secretory. Persistence of diarrhea at night suggests the presence of an organic
cause rather than irritable bowel syndrome. Fecal incontinence may be due to
anal disease or sphincter dysfunction.
5. Diet. The correlation of patients’ symptoms with ingestion of milk, other dairy
products, or sorbitol-containing artificially sweetened diet drinks, candy, and
chewing gum should also be noted.
B. Physical examination of the patient should focus on the general condition of the
patient, degree of hydration, presence of fever, and other systemic origins of tox-
icity. A variety of physical findings can be sought in a patient with chronic diar-
rhea and may give clues to the etiology of the diarrheal process. These include
goiter, skin rash, arthritis, peripheral neuropathy, postural hypotension, abdomi-
nal bruit, perianal abscess, fistula, and rectal mass or impaction.
C. Diagnostic tests. The initial laboratory evaluation of the patient should include
a complete blood count with differential, serum electrolytes, blood urea nitrogen,
and creatinine. A chemistry profile and urinalysis may also help to assess the sys-
temic involvement with the diarrheal state.
1. Examination of the stool is the most important diagnostic test in the evalua-
tion of a patient with acute or chronic diarrhea. A fresh sample of stool should
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190 Part V: Specific Complaints and Disorders

be examined for the presence of pus (white cells), blood, and bacterial and par-
asitic organisms. Best yield is obtained if the examination is repeated on three
fresh stool samples obtained on three separate days.
a. Presence of white blood cells. Wright or methylene blue stain of the
stool smeared on a glass slide will demonstrate the white cells if they are
present. The presence of fecal leukocytes suggests intestinal inflammation as
a result of a mucosal invasion with bacteria, parasite, or toxin (Table 29-4).
Inflammatory bowel disease and ischemic colitis may also result in white
blood cells in the stool.
b. The absence of fecal leukocytes suggests a noninflammatory noninvasive
process (e.g., viral infection, giardiasis, drug-related); however, it is never
diagnostic because a false-negative result may occur in inflammatory states.
c. Occult or gross blood in the stool suggests the presence of a colonic neo-
plasm, an acute ischemic process, radiation enteritis, amebiasis, or severe
mucosal inflammation.
d. Bacterial and parasitic organisms. Fresh stool samples must be examined
for the presence of ova and parasites. Organisms that colonize the upper
small intestine (Table 29-4) may not be found in stool samples and duodenal
or jejunal aspirates or biopsies or the string test may be required. Stool cul-
tures will help determine the bacterial pathogen in most cases. However,
special techniques may sometimes be necessary, such as for Yersinia,
Campylobacter, Neisseria gonorrhoeae, C. difficile, and E. coli: H7.
e. Fat and phenolphthalein. In the evaluation of chronic or recurrent diarrhea,
stool should also be examined for the presence of fat (qualitative and quanti-
tative) and phenolphthalein. Phenolphthalein is found in many laxative
preparations and gives a red color when alkali is added to the stool filtrate.
2. Sigmoidoscopy or colonoscopy or both should be performed without cleans-
ing enemas. Stool samples may be obtained with a suction catheter for micro-
scopic examination and cultures. Most patients with acute or traveler’s
diarrhea do not need proctosigmoidoscopic examination. Sigmoidoscopy is
especially helpful in the evaluation of:
a. Bloody diarrhea
b. Diarrhea of uncertain etiology
c. Inflammatory bowel disease, pseudomembranous colitis, pancreatic dis-
ease, or laxative abuse (melanosis coli)
3. Radiologic studies. Most causes of diarrhea become apparent after the pre-
ceding tests. However, in chronic or recurrent diarrhea, barium studies of the
large and small intestine may demonstrate the location and extent of the dis-
ease. It should be remembered that once barium is introduced into the bowel,
examination of the stool for ova and parasites and cultures may be fruitless for
several weeks because barium alters the gut ecology.
4. Other tests. In cases of chronic diarrhea, other specialized tests may be nec-
essary to assess for malabsorption, bacterial overgrowth, or abnormal hor-
monal states. These are discussed in appropriate chapters.

IX. TREATMENT. Acute diarrhea with fluid and electrolyte depletion is a major cause of
mortality, especially in children in developing countries of the world. Fluid repletion
by intravenous or oral routes can prevent death. Oral rehydration therapy can be
accomplished with a simply prepared oral rehydration solution. Physiologically, water
absorption follows the absorption of glucose-coupled sodium transport in the small
intestine, which remains intact even in the severest of diarrheal illnesses.
Oral rehydration solution can be prepared by adding 3.5 g of sodium chloride
(or three fourths of a teaspoon or 3.5 g of table salt), 2.5 g of sodium bicarbon-
ate (or 2.9 g of sodium citrate or 1 teaspoon of baking soda), 1.5 g of potassium chlo-
ride (or 1 cup of orange juice or 2 bananas), and 20 g of glucose (or 40 g of sucrose or
4 table spoons of sugar) to a liter (1.05 qt) of clean water. This makes a solution of approx-
imately 90 mmol of sodium, 20 mmol of potassium, 80 mmol of chloride, 30 mmol of
bicarbonate, and 111 mmol of glucose per liter. Not only is this solution lifesaving in
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Chapter 29: Diarrhea 191

severe diarrhea, but also it is less painful, safer, less costly, and superior to intravenous
fluids because the patient’s thirst protects against overhydration. It should therefore be
the preferred route of rehydration in conscious adult and pediatric patients in tertiary
and intensive care units. Furthermore, the output of stool can be reduced with food-
based oral rehydration therapy. With the additional sodium-coupled absorption of
neutral amino acids and glutamine (a key mucosal nutrient in the small bowel, analo-
gous to short-chain fatty acids in the colon), oral rehydration therapy can also be used
to speed recovery from small-bowel injury.
The composition of cereal-based oral rehydration solution is like that of
standard oral rehydration solution (3.5 g of sodium chloride, 2.5 g of sodium bicar-
bonate, and 1.5 g of potassium chloride), except that the 20 g of glucose is replaced
by 50 to 60 g of cereal flour (rice, maize, millet, wheat, or sorghum) or 200 g of
mashed, boiled potato; stirred into 1.1 L of water; and brought to a boil. Not only
can oral rehydration therapy (especially with cereal and continued feeding) reverse
the loss of fluid, but also it can prevent the fatal hypoglycemia seen with failure of
gluconeogenesis, a major cause of death in children with diarrhea in developing
areas. Furthermore, simple oral rehydration therapy can be started early in the home
and can prevent most complications of dehydration and malnutrition.
Attention should also be directed at reduction of the patient’s symptoms and dis-
comfort to reduce absenteeism from work or school as well as to improve the sense of
well-being of the patient. Available drugs can be divided into groups based on their
mechanisms of action: absorbents, antisecretory agents, opiate derivatives, anticholin-
ergic agents, and antimicrobial agents.
A. Absorbents (e.g., Kaopectate, aluminum hydroxide) do not influence the course
of the disease but help produce solid stools. This effect may allow the patient to
alter the timing of stooling and permit a more voluntary control of defecation.
B. Antisecretory agents. In most cases of diarrhea, regardless of etiology, invasive
or noninvasive, intestinal secretion contributes greatly to the stool volume.
Antisecretory drugs, including prostaglandin synthesis inhibitors, have been used
to diminish bowel secretion.
Bismuth subsalicylate (Pepto-Bismol) has been shown to block the secre-
tory effects of V. cholerae, enterotoxigenic E. coli, and Shigella as well as to prevent
intestinal infection by these agents if given prophylactically. The usual therapeutic
dosage of Pepto-Bismol is 30 mL every 30 minutes for eight doses. The prophylac-
tic dosage is 60 mL or two tablets q.i.d. for the duration of the prophylaxis (e.g.,
for travelers). Pepto-Bismol tablets are as effective as the liquid preparation.
C. Opiate derivatives are widely used in both acute and chronic diarrhea. By dimin-
ishing peristalsis, they delay gut transit of fluid and allow more time for fluid
absorption. They may be used in patients with moderate symptoms (3–5 stools per
day) but should not be used in patients with fever, systemic toxicity, or bloody
diarrhea. Their use should be discontinued in patients who have not shown
improvement or whose condition has worsened on therapy.
Opiate derivatives include paregoric (tincture of opium), diphenoxylate with
atropine (Lomotil), and loperamide (Imodium). Imodium has two advantages over
Lomotil in that it does not contain atropine and it has fewer central opiate effects.
D. Anticholinergic agents do not appear to be useful in the treatment of most diar-
rheal disorders. Some patients with irritable bowel syndrome may benefit from use
of dicyclomine hydrochloride (Bentyl).
E. Antimicrobial agents. When the diarrhea is severe and the patient has systemic
signs of toxicity, stool cultures should be performed to identify the pathogenic
organism. The most effective antimicrobial agent for the particular pathogen
should be used. In selected cases of severe diarrhea, if a laboratory is not available,
empiric antibiotics with activity against both Shigella and Campylobacter strains
may be administered (e.g., ciprofloxacin or trimethoprim/sulfamethoxazole or
erythromycin). Recently, rifaximin (Xifaxan), a nonabsorbable (gut specific)
antibiotic has become available for the treatment of traveler’s diarrhea. Table 29-6
lists common pathogens and recommended therapeutic agents. Table 29-7 summa-
rizes an approach to therapy of acute diarrhea.
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192 Part V: Specific Complaints and Disorders

TABLE 29-6 Antimicrobial Therapy of Infectious Diarrhea

Pathogen Clinical disease Therapy

Shigella Dysentery Trimethoprim/sulfamethoxazole

160/800 mg p.o. b.i.d.
for 5 d or tetracycline 500 mg
p.o. q.i.d. for 5 d or
ciprofloxacin 500 mg p.o.
b.i.d. for 5 d
Salmonella Enteric No antimicrobial therapy
Bacteremia Ampicillin or amoxicillin 1 g
p.o. t.i.d. or q.i.d. for 14 d
or chloramphenicol 1 g
p.o. or IV q8h for 14 d or
trimethoprim/sulfamethoxazole
160/800 mg p.o. b.i.d. for
10 d or a third-generation
cephalosporin or ciprofloxacin
500 mg p.o. b.i.d. for 5 d
Campylobacter Dysentery Erythromycin 250 mg p.o. q.i.d.
for 5–10 d or ciprofloxacin
500 mg p.o. b.i.d. for 5–7 d
Clostridium difficile Watery diarrhea; Cholestyramine 4 g p.o.
pseudomembranous colitis t.i.d. for 7 d or metronidazole
250 mg p.o. t.i.d. for 7 d
or vancomycin 125–500 mg
p.o. q.i.d. for 7 d rifaximin
200 mg p.o. b.i.d. for 3 d
Enterotoxigenic Watery diarrhea; Trimethoprim/sulfamethoxazole
Escherichia coli, bloody diarrhea 160/800 mg p.o. for
E. coli O157:H7, 5 d or ciprofloxacin 500 mg
and traveler’s diarrhea p.o. b.i.d. for 5 d or
ofloxacin 300 mg p.o. b.i.d.
for 5 d or norfloxacin 400 mg
p.o. b.i.d. for 5 d or
rifaximin (Xifaxan) 200 mg
p.o. t.i.d. for 3 day
Entamoeba histolytica Asymptomatic carrier; colitis Diloxanide furoate 500 mg
p.o. t.i.d. for 10 d plus
diiodohydroxyquin 650 mg
p.o. t.i.d. for 20 d or
metronidazole 750 mg p.o.
t.i.d. for 10 d
Giardia lamblia Watery diarrhea Quinacrine hydrochloride
100 mg p.o. t.i.d. for 7 d or
metronidazole 250 mg p.o.
t.i.d. for 7 d or furazolidone
100 mg q.i.d. or 7 d

p.o., by mouth; b.i.d., twice a day; q.i.d., four times a day; t.i.d., three times a day.
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Chapter 29: Diarrhea 193

TABLE 29-7 An Approach to Therapy of Acute Diarrhea

No. of diarrheal
Severity of illness stools/day Therapy

Mild 1–3 Fluids only

Moderate 3–5 Fluids, nonspecific therapy
(e.g., Pepto-Bismol, Lomotil, Imodium)
Severe ( fever) 6 Fluids, antimicrobial agent; if laboratory not
available, trimethoprim/sulfamethoxazole,
erythromycin, ciprofloxacin, or norfloxacin

Treatment of E. coli O157:H7 with a systemically absorbed antimicrobial

agent is controversial since there is some inconclusive data that suggests compli-
cations with hemolytic uremic syndrome may be higher with antimicrobial
therapy. However, in patients with severe diarrhea, antimicrobial therapy (e.g.,
ciprofloxacin hydrochloride 500 mg twice daily, by mouth) may be used with
caution.
F. Chemoprophylaxis of traveler’s diarrhea. Bismuth subsalicylate, doxycycline,
and trimethoprim/sulfamethoxazole, norfloxacin, and ciprofloxacin hydrochloride
have been shown to be effective in preventing most causes of traveler’s diarrhea.
Doxycycline resistance among enteric bacterial pathogens does occur in some
regions. Starting on the first day of travel, the dosage of each drug is as follows:
bismuth subsalicylate, 60 mL q.i.d.; doxycycline, 100 mg daily; trimethoprim/
sulfamethoxazole, 160/800 mg daily; ciprofloxacin hydrochloride, 500 mg daily;
norfloxacin, 400 mg daily. Aztreonam, 100 mg daily, has also been shown to be
effective. Each drug should be continued for 1 to 2 days after returning home. No
drug should be taken for more than 3 weeks.
Recently, rifaximin (Xifaxan), a nonabsorbable, gut specific antibiotic, has
been approved by the FDA for the treatment of traveler’s diarrhea at a dose of
200 mg one tablet t.i.d. for 3 days.
The use of antimicrobial chemoprophylaxis should be discouraged for most
travelers. Each drug has its side and adverse effects and will confer antimicro-
bial resistance to the gut flora of the individual. This may present a therapeutic
problem if another infection (e.g., a urinary tract infection) develops.
Antimicrobial chemoprophylaxis should be restricted to 2 to 5 days in persons
who are on a special “business” trip and who accept the risks of side and
adverse effects.
Rifaximin (Xifaxan) is an exception to the above statements. This gut-specific,
nonabsorbable antibiotic has been shown to be effective in preventing traveler’s
diarrhea if it is taken daily as prophylaxis during the travel period. It is recom-
mended for persons traveling to areas of the world with high risk of GI infections
with E. coli and other fecal pathogens, at a dose of 200 mg p.o. t.i.d.
G. Chronic or recurrent diarrhea. The therapy of chronic and recurrent diarrhea
should be based on the etiology and pathophysiology of the disease process.
Occasionally, when a diagnosis cannot be made, an empiric trial of diet restriction
(e.g., lactose, gluten, and long-chain fatty acids), pancreatic enzyme supplements
along with histamine-2 (H2) blockers, cholestyramine, clonidine, and antimicrobial
(e.g., metronidazole) therapy may be use. When all fails, the judicious use of
antidiarrheal opiate derivatives may result in symptom relief.
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194 Part V: Specific Complaints and Disorders

Selected Readings
Al Ghamdi MY, et al. Causation: Recurrent collagenous colitis following repeated use of
NSAIDs. Can J Gastroenterol. 2002;16:861–862.
Alaedini A, et al. Narrative review—celiac disease: Understanding a complex autoimmune
disorder. Ann Intern Med. 2005;142:289–298.
AUS, et al. Giardia intestinalis. Curr Opin Infect Dis. 2003;16:453–460.
Aziz B, et al. 25-year-old man with abdominal pain, nausea and fatigue. Mayo Clin Proc.
2007;82(3):359–362.
Bardhan PK, et al. Screening of patients with acute infectious diarrhoea: Evaluation of clinical
features, faecal microscopy, and faecal occult blood testing. Scand J Gastroenterol. 2000;
35:54–60.
Bengmark S, et al. Prebiotics and synbiotics in clinical medicine. Nutr Clin Pract. 2005;
20:244–261.
Butler T, et al. New developments in the understanding of cholera. Curr Gastroenterol
Rep. 2001;3:315.
Chermesh I, et al. Probiotics and the gastrointestinal tract: Where are we in 2005? World
Gastroenterol. 2006;12:853–857.
Erim TD, et al. Collagenous colitis associated with Clostridium difficile: A cause effect?
Dig Dis Sci. 2003;48:1374–1375.
Guarner F. Enteric flora in health and disease. Digestion. 2006;73(suppl 1):5–12.
Headstrom PD, et al. Chronic diarrhea. Clin Gastroenterol Hepatol. 2005;3:734–737.
Jaskiewicz K, et al. Microscopic colitis in routine colonoscopies. Dig Dis Sci. 2006;
51:241–244.
Lo W, et al. Changing presentation of adult celiac disease. Dig Dis Sci. 2003;4:395–398.
Nyhlin N, Bohr J, Eriksson S, Tysk C. Systematic review: microscopic colitis. Ailment
Pharmacol Ther. 2006;23:1525–1534.
Quigley EMM, et al. Small intestinal bacterial overgrowth: Roles of antibiotics, prebiotics
and probiotics. Gastroenterology. 2006;130:S78–S90.
Sanders JW, et al. Diarrhea in the returned traveler. Curr Gastroenterol Rep. 2001;3:304.
Saulsbury FT. Clinical update: Henoch-Schonlein purpura. Lancet. 2007;669:976–978.
Schiller JR. Chronic diarrhea. Gastroenterology. 2004;127:287–293.
Snelling AM. Effects of probiotics on the gastrointestinal tract. Curr Opin Infect Dis.
2005;18:420–426.
Thomas, PD, et al. Guidelines for the investigation of chronic diarrhea, 2nd. Edition. Gut.
2003;53(supp 1):v1–v15.
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79466_CH30.qxd 1/2/08 12:23 PM Page 195

VIRAL, BACTERIAL, AND PARASITIC

DISORDERS OF THE BOWEL 30

V arious microorganisms infect the gastrointestinal tract and cause gastroenteritis.

This chapter reviews pathogens that affect immunocompetent patients. A discussion of
opportunistic infections in immunocompromised patients is found in Chapter 43.

I. VIRAL GASTROENTERITIS. It is estimated that 30% to 40% of instances of infec-

tious diarrhea in the United States are caused by viruses; these infections far outnum-
ber the documented instances of bacterial and parasitic diarrhea.
Five major categories of viruses that cause gastroenteritis in humans have been
identified: rotavirus, enteric adenovirus, calcii virus, astrovirus, and Norwalk
and Norwalk-like viruses. The first four viruses cause diarrhea in infants and young
children but may also infect adults. Norwalk-group viruses, however, produce epi-
demics of gastroenteritis in adults and school-age children.
A. Rotavirus
1. Epidemiology. Human rotavirus is an RNA virus. It has been classified into three
genetically and antigenically distinct groups: A, B, and C. Groups A and C have
been associated with diarrheal epidemics around the world, and group B has
caused epidemics of diarrheal disease in adults in China. Rotavirus is the most
important cause of dehydrating diarrheal illness throughout the world, accounting
for 40% to 70% of all episodes requiring hospitalization of children under the age
of 2. In industrially developing countries, rotavirus causes approximately 125 mil-
lion cases of diarrhea annually, 18 million of the cases severe, with an estimated
death rate of 800,000 to 900,000 per year. Severe rotavirus infection is seen most
frequently in children 3 to 15 months of age. After age 3, the infections are usually
asymptomatic. The illness is rare in adults except among those in close contact
with infected children, in travelers, and in geriatric populations; it is also found in
epidemic form after exposure to contaminated water. The virus is shed in great
numbers in feces and is transmitted by the fecal–oral route. In North America and
northern Europe, the infection occurs seasonally, especially in the winter months.
In countries within 10 degrees of the equator, the infection occurs year-round.
2. Pathology and pathophysiology. Rotavirus infection spreads from the proxi-
mal small intestine to the ileum over 1 to 2 days. The virus infects the mature
enterocytes at the tips of intestinal villi and causes cell lysis resulting in
shortening of villi, hyperplasia of crypts, and round-celled lamina propria. It is
associated with decreased microvillous enzyme activity (e.g., sucrose, lactose),
net intestinal secretion, and increased gut mucosal permeability.
3. Clinical disease and complications. Rotavirus infection is frequently asymp-
tomatic. In symptomatic infection, the incubation period is 1 to 3 days, and the
illness lasts 5 to 7 days. The gastroenteritis is characterized by frequent vomit-
ing, fever, watery diarrhea, and dehydration. Necrotizing enterocolitis, Henoch-
Schönlein purpura, and hemolytic-uremic syndrome have been associated with
rotavirus infections.
4. Diagnosis. Fecal leukocytes may be present in 20% of patients. Viral antigens
may be demonstrated from stool specimens by a variety of assays such as the
Rotazyme test. The virus can also be visualized with electromicroscopy.
5. Treatment and prevention. Treatment of rotavirus infection is symptomatic
and supportive. Fluid and electrolyte replacement is essential. Oral rehydration

195
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196 Part V: Specific Complaints and Disorders

solutions (e.g., Rehydralylate, Pedialyte, and Rosol) are highly effective, even in
the presence of vomiting. Breastfeeding and transplacentally transmitted mater-
nal antibodies have been found to prevent rotavirus infections. Progress is being
made toward the development of a vaccine.
B. Enteric adenovirus
1. Epidemiology. Adenovirus serotypes 40 and 41 are enteric adenoviruses that
cause gastroenteritis without nasopharyngitis and keratoconjunctivitis. Infection
is transmitted from person to person. Enteric adenovirus is second to rotavirus
as the cause of pediatric viral gastroenteritis, especially in children under the age
of 2. Nosocomial outbreaks occur, but spread to adults is uncommon.
2. Clinical disease. Endemic enteric adenovirus gastroenteritis may occur year-
round without seasonal preference. The incubation period is 8 to 10 days. The
onset is with low-grade fever and watery diarrhea, followed by 1 to 2 days of
vomiting. Illness typically lasts 1 to 2 weeks but occasionally lasts longer.
3. Diagnosis. There are no fecal leukocytes in stool. Diagnosis may require
demonstration of the virus by electron-microscopy in stool samples, use of
nucleic acid hybridization, and radioimmunoassays using monoclonal antibod-
ies specific for adenovirus 40 and 41.
4. Treatment is supportive and symptomatic.
C. Norwalk virus and Norwalk-like viruses
1. Epidemiology. Norwalk virus is the prototype of the Norwalk-like group of
viruses that, unlike rotavirus and enteric adenoviruses, are small and round and
resemble the other small gastroenteritis viruses (e.g., calcii viruses, astroviruses,
and small featureless viruses). These viruses are refractory to in vitro cultivation
and purification. Norwalk virus possesses a single-stranded RNA, which has
been detected in diarrheal stools by immune electromicroscopy. The Norwalk
virus family causes approximately 40% of epidemics of gastroenteritis that
occurs in recreational camps; on cruise ships; in schools, colleges, nursing
homes, hospital wards, cafeterias, and community centers; and among sports
teams and families by the ingestion of contaminated foods such as salad and
cake frosting. Epidemics occur year-round, affecting older children and adults
but not infants and young children. Infection spreads rapidly by the fecal–oral
route, with an incubation period of 12 to 48 hours. In food-borne outbreaks,
infectious virus may be excreted in the feces for at least 48 hours after the
patients have recovered. Airborne transmission by means of droplets of vomit
or through the movement of contaminated laundry also occurs.
2. Histopathology. The infection affects the small intestine, sparing the stomach
and the colonic mucosa. There is blunting of villi and microvilli and cellular
infiltration in the lamina propria, especially in the jejunum. Malabsorption of
d-xylose, lactose, and fat occurs, but absorption returns to normal within 1 to
2 weeks after recovery. It is thought that gastric emptying is delayed, which
would explain the nausea and vomiting that accompanies the watery diarrhea.
3. Clinical disease. The onset is rapid with abdominal pain, low-grade fever,
vomiting, and diarrhea that usually last 48 to 72 hours.
4. Diagnosis. There are no fecal leukocytes. Specific diagnostic techniques are
restricted to a few research laboratories that use both a radioimmunoassay
(RIA) and an enzyme-linked immunosorbent assay (ELISA); the tests may be
used to measure Norwalk viral antigens in stool and antibody in serum.
5. Treatment is supportive.
D. Calcii virus
1. Epidemiology. Human calcii viruses are poorly understood agents that are
related to the Norwalk virus group. They affect mostly infants and young children
but may also infect adults in epidemics.
2. Clinical disease. The incubation period is 1 to 3 days. The clinical presenta-
tion resembles that of rotavirus or Norwalk viral gastroenteritis. The diarrhea
is accompanied by vomiting, abdominal pain, and low-grade fever.
3. Diagnosis. Calcii virus can be detected in stool by electron-microscopy and by
RIA from serum. Serum antibody may be protective against reinfection.
4. Treatment. The treatment is supportive.
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Chapter 30: Viral, Bacterial, and Parasitic Disorders of the Bowel 197

E. Astrovirus
1. Epidemiology. The virus can be cultivated in cell cultures. Astrovirus is a single-
stranded RNA virus with five human serotypes. It causes outbreaks of diarrhea in
children 1 to 7 years of age; in the elderly, especially in nursing homes; and rarely
in young adults, suggesting that adults may be protected by previously acquired
antibodies.
2. Clinical disease. The incubation period is 1 to 2 days. Watery diarrhea may be
accompanied by vomiting.
3. The diagnosis is by stool electron-microscopy and ELISA.
4. Treatment is supportive.
F. Other viruses associated with gastroenteritis. Several other groups of viruses
known to cause diarrhea in animals are associated with gastroenteritis in humans,
but their causative relation to disease is unclear. Coronaviruses are detected by
electron-microscopy in stools of persons living under poor sanitary conditions. It
has been associated with outbreaks in nurseries and with necrotizing enterocolitis
in newborns. Echoviruses and picornaviruses also have been implicated in diar-
rheal disease of the young. Enteroviruses have been shown in controlled epi-
demiologic studies not to be important causes of acute gastroenteritis.

II. BACTERIAL INFECTIONS OF THE BOWEL. Bacterial gastroenteritis may result from
the ingestion of a preformed bacterial toxin present in the food at the time of ingestion,
by the production of a toxin or toxins in vivo, or by invasion and infection of the
bowel mucosa by the bacterial pathogen. In this chapter, the most common bacterial
pathogens affecting immunocompetent hosts are discussed. Enteric bacterial infections
in HIV-infected and other immunocompromised patients are discussed in Chapter 44.
A. Toxigenic bacteria. In general, toxigenic bacteria produce watery diarrhea
without systemic illness. There may be low-grade fever in some patients. Some
microorganisms can produce other toxins in addition to an enterotoxin, for exam-
ple, neurotoxins that can cause extraintestinal manifestations. The stools contain
no blood or fecal leukocytes, which helps to distinguish these diseases from diar-
rheas caused by tissue-invasive organisms. Table 30-1 lists some of the common
causes of toxigenic diarrhea.
1. Staphylococcus aureus
a. Epidemiology. Staphylococcal food poisoning is the most frequent cause of
toxin-mediated vomiting and diarrhea encountered in clinical practice. All
coagulase-positive staphylococci can produce enterotoxins. Staphylococci
are introduced into food by the hands of food-handlers. The organisms mul-
tiply and produce the toxin if the food is kept at room temperature. The
foods most commonly implicated are coleslaw, potato salad, salad dressings,
milk products, and cream pastries. Food contaminated with staphylococci is
normal in odor, taste, and appearance.
b. Clinical disease. Staphylococcal food poisoning is manifested by an abrupt
onset of vomiting within 2 to 6 hours after ingestion of the contaminated
food. The diarrhea is usually explosive and may be accompanied by abdom-
inal pain. Fever is usually absent.

TABLE 30-1 Some Etiologic Agents for Toxigenic Diarrhea

Staphylococcus aureus Other toxigenic diarrheas

Bacillus cereus Scrombrotoxin poisoning
Vibrio cholerae Paralytic shellfish poisoning
Enterotoxigenic Escherichia coli Neurotoxic shellfish poisoning
Vibrio parahaemolyticus Ciguatoxin poisoning
Clostridium perfringens Tetrodotoxin poisoning
Clostridium botulinum
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198 Part V: Specific Complaints and Disorders

c. The diagnosis is usually suspected from the history. In most instances, the
organism can be cultured from the contaminated food.
d. Treatment. Gastroenteritis resolves with supportive care within 12 to
24 hours. Antimicrobial therapy is not indicated.
2. Bacillus cereus
a. Epidemiology. Bacillus cereus is a common gram-positive, spore-forming
organism found in soil. Contamination of food occurs before cooking.
Vegetative growth continues at temperatures of 30˚ to 50˚C, and spores can
survive extreme temperatures. The spores of the organism germinate and
produce toxins during the vegetative stage.
B. cereus is a frequent cause of food poisoning from many sources, but is
usually associated with contaminated rice or meat from Chinese restaurants.
b. Clinical disease. B. cereus intoxication manifests as two distinct clinical
syndromes. The “emesis syndrome” is caused by the thermostable toxin and
mimics staphylococcal food poisoning. Within 2 to 6 hours after ingestion of
the contaminated food, the patient has severe vomiting and abdominal pain
with or without diarrhea. There is no accompanying fever or systemic mani-
festations. Illness is self-limited and lasts 8 to 10 hours. The “diarrhea syn-
drome” is caused by the thermolabile enterotoxin and occurs after 8 to
16 hours of ingestion of the contaminated food. It is characterized by a foul-
smelling, profuse watery diarrhea, usually accompanied by nausea, abdomi-
nal pain, and tenesmus. Most of the symptoms resolve in 12 to 24 hours.
c. Diagnosis is made by history and stool cultures demonstrating the organism.
d. Treatment is supportive.
3. Vibrio cholerae
a. Epidemiology. V. cholerae is a mobile, gram-negative bacterium with a sin-
gle flagellum and is easily recognizable by a fecal Gram’s stain. It produces a
thermostable enterotoxin, which stimulates the adenylate cyclase in small-
intestinal crypt cells, especially in the jejunum, resulting in profuse secretory
diarrhea. V. cholerae is seen occasionally in the United States, especially along
the Gulf coast. Any fecally contaminated water or food has the potential to
cause cholera, but contaminated saltwater crabs and freshwater shrimp are
responsible for most instances seen in the United States.
b. Clinical disease. The incubation period is 1 to 3 days after ingestion.
Cholera is characterized by an abrupt onset of profuse, large-volume, watery
diarrhea. The stools are isotonic and do not contain blood or mucus. There
is usually no associated fever, abdominal pain, vomiting, or tenesmus.
Hypotension, shock, and death may result if volume depletion is not ade-
quately treated.
c. Diagnosis. Organisms may be demonstrated by dark-field microscopy of
the stool and by stool cultures.
d. Treatment. The mainstay of therapy is volume repletion intravenously or orally
with fluids that contain glucose and electrolytes. If dehydration is adequately
reversed, patients recover in 7 to 10 days without antimicrobial therapy. The
duration of the disease may be shortened to 2 to 3 days with oral tetracycline
500 mg q.i.d. or doxycycline 300 mg in a single dose. In resistant instances, alter-
native antimicrobials are furazolidone 100 mg q.i.d., erythromycin 250 mg q.i.d.,
or trimethoprim/sulfamethoxazole 160/800 mg b.i.d. for 3 days.
4. Enterotoxigenic Escherichia coli
a. Epidemiology. Enterotoxigenic E. coli (ETEC) can cause diarrhea by tissue
invasion or via its enterotoxin. The enterotoxin is thermolabile and produces
diarrhea by the same mechanism as the cholera enterotoxin. The organism is
transmitted from contaminated water and food by the fecal oral route. Even
though it may cause outbreaks in the United States, ETEC is the most
common traveler’s pathogen. A large inoculum is required for disease. The
incubation period is 1 to 3 days.
b. The clinical disease is similar to cholera. The watery diarrhea is profuse
and lasts 3 to 5 days. There may be accompanying mild abdominal pain.
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Chapter 30: Viral, Bacterial, and Parasitic Disorders of the Bowel 199

c. The diagnosis is by history and clinical observation. Serotyping of E. coli is

available only in research settings.
d. Treatment. Most patients require no antimicrobial therapy. Intravenous or
oral volume replacement with glucose–electrolyte solutions is usually ade-
quate. Severe instances may be treated with tetracycline, trimethoprim/
sulfamethoxazole, or ciprofloxacin.
5. Vibrio parahaemolyticus
a. Epidemiology. V. parahaemolyticus is a gram-negative bacillus that survives
in water with a high salt content. It is recognized as an important pathogen
in the Far East and more recently in the United States. It is most common in
the summer and least common in the winter months because the bacterial
populations in the ocean are temperature-dependent. It is associated with
acute diarrheal disease after the ingestion of contaminated raw or cooked
fish or shellfish. The organism produces a variety of toxins. The incubation
period is 12 to 48 hours after ingestion.
b. Clinical disease. The illness is characterized by explosive watery diarrhea.
Headaches, vomiting, and abdominal cramps are common. Low-grade fever and
chills occur in 25% of the patients. Bloody diarrhea may occur in some instances.
The stools are not as profuse as in V. cholerae, but hypotension and shock have
been seen. The illness is usually self-limiting and resolves within 1 to 7 days.
c. Diagnosis. The diagnosis is by stool culture on thiosulfate–citrate–bile
salt–sucrose agar.
d. Treatment is supportive with fluid repletion. Complicated instances may be
treated with oral tetracycline.
6. Clostridium perfringens
a. Epidemiology. Clostridium perfringens is a gram-positive, spore-forming
obligate anaerobe found in soil and in the gastrointestinal tract of humans
and animals. It produces 12 toxins. The thermolabile exotoxin is an impor-
tant cause of toxigenic diarrhea. The toxin is a structural component of the
spore’s coat and is formed during sporulation. Most of the toxin is synthe-
sized before ingestion. Additional toxin is produced in the gastrointestinal
tract after ingestion of contaminated beef, beef products, or poultry. The
pathogenesis of infection requires the food to be inadequately precooked
and then reheated before it is served. The toxin has its maximal activities in
the ileum. It inhibits glucose transport and activates adenylate cyclase of
small-intestinal crypt cells stimulating intestinal secretion. Outbreaks may
occur in institutions or after large gatherings.
b. Clinical disease. Watery diarrhea with severe, crampy abdominal pain usu-
ally occurs 8 to 24 hours after the ingestion of contaminated food. Vomiting,
fever, chills, and headaches are not seen. The stools are usually foul smelling.
The disorder is self-limited and resolves within 24 to 36 hours.
c. The diagnosis is by history.
d. Treatment is supportive.
7. Clostridium botulinum
a. Epidemiology. C. botulinum is a gram-positive, anaerobic, spore-forming
bacillus. Three exotoxin types, A, B, and E, have been associated with
C. botulinum intoxication. Types A and B are associated with improperly
prepared home-canned fruits and vegetables. Type E outbreaks are associated
with smoked freshwater fish and are most frequent in the Great Lakes region.
The contaminated foods may not appear, taste, or smell spoiled, thereby incit-
ing no suspicion of their contamination. The exotoxin is neurotoxic and ther-
molabile. It can be inactivated by boiling in water for 15 minutes.
b. Clinical disease. C. botulinum is responsible for one third of the deaths
from food-borne diseases. The intoxication results in acute cranial nerve
dysfunction, dysarthria, diplopia, blurred vision, dysphagia, and a symmet-
ric descending weakness without a sensory component. Dilated pupils occur
in 15% of patients. Respiratory muscle insufficiency may occur. The neuro-
logic disease may last for months and can result in death.
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200 Part V: Specific Complaints and Disorders

TABLE 30-2 Infectious Organisms That Result in Watery Diarrhea

Viruses
Rotavirus
Norwalk and related viruses
Adenovirus
Bacteria
Vibrio cholerae
Escherichia coli (enterotoxigenic)
All bacteria listed in Table 30-3
Protozoa
Giardia lamblia
Cryptosporidium

c. The diagnosis is made by history and culture or toxin assay from the con-
taminated food or the patient’s blood or stool. Electromyography may be
used to differentiate the disease from Guillain–Barré syndrome.
d. Therapy. When intoxication is suspected, therapy should be started imme-
diately with administration of the polyvalent antitoxin and penicillin.
Gastrointestinal lavage with orally administered solutions (e.g., GoLYTELY
or Colyte) may help eliminate the toxin from the gastrointestinal tract.
Guanidine hydrochloride may be used to reverse the motor weakness. Some
patients may require ventilatory support.
B. Bacteria causing “enteric” infection. The resulting diarrhea may be watery or
bloody. Although watery diarrhea is often associated with infections with viruses,
protozoa, and toxin-producing bacteria such as Vibrio cholerae and enterotoxi-
genic E. coli, invasive bacteria can also cause watery diarrhea (Table 30-2). The
diarrhea is usually greater than 1 L/day. Systemic symptoms such as fever,
headache, myalgia, and arthralgias are usually absent.
Bloody diarrhea, or dysentery, is usually accompanied by abdominal pain,
tenesmus, nausea, vomiting, and systemic symptoms such as fever and malaise.
Bacteria that result in bloody diarrhea are listed in Table 30-3. These enteric infec-
tions cannot be distinguished easily from one another clinically. Diagnosis must be
based on the identification of the infectious agent by appropriate cultures.
1. Campylobacter jejuni and Campylobacter fetus
a. Epidemiology. C. jejuni is the most common bacterial pathogen that causes
bloody diarrhea in the United States. It is implicated in infections in under-
developed countries also. The organism is a microaerophilic, gram-negative
curved rod transmitted to humans from contaminated pork, lamb, beef,

TABLE 30-3 Infectious Organisms That Result in Bloody Diarrhea

Campylobacter
Escherichia coli (enteropathogenic and invasive)
Shigella
Salmonella
Escherichia coli O157:H7
Yersinia
Vibrio parahaemolyticus
Clostridium difficile
Entamoeba histolytica
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Chapter 30: Viral, Bacterial, and Parasitic Disorders of the Bowel 201

milk and milk products, and water, and from exposure to infected house-
hold pets. The organism is destroyed by appropriate cooking, pasteuriza-
tion, and water purification. The incubation period is 1 to 7 days.
b. Histopathology. The bacterial endotoxin causes mucosal inflammation in the
small and large intestine that resembles the lesions seen in ulcerative colitis
and Crohn’s disease and those seen with Salmonella and Shigella infections.
The infection is usually more severe in the colon than in the small bowel.
c. Clinical disease
i. Enterocolitis. Bowel infections with C. jejuni and rarely C. fetus cause a
diarrheal illness resembling enteritis from Salmonella and Shigella.
Occasionally there is a prodrome of headache, myalgia, and malaise for
12 to 24 hours, followed by severe abdominal pain, high fever, and pro-
fuse watery and then bloody diarrhea. The diarrhea is usually self-limited
and in most instances resolves in 7 to 10 days; however, in one fifth of
the instances, the diarrhea has a protracted or a relapsing course.
ii. Systemic infection. C. fetus and rarely C. jejuni may cause a systemic
infection, especially in elderly, debilitated patients, and in those with
alcoholism, diabetes mellitus, and malignancies. Bacteremia may be tran-
sient or may lead to localized infection such as endocarditis, meningitis,
cholecystitis, and thrombophlebitis. There may or may not be clinically
evident enterocolitis.
d. Complications. Campylobacter infection may be complicated by Reiter’s
syndrome, mesenteric adenitis, terminal ileitis (resembling Crohn’s ileitis),
and rarely an enteric fever like illness.
e. Diagnosis is made by stool and blood cultures. Stool Gram’s stain may
show the organism with its characteristic “gull wings.” In dark-field/phase-
contrast microscopy, the organism shows “darting motility.” Fecal leuko-
cytes are present in 75% of instances.
f. Treatment. In mild cases, supportive therapy is given. In cases with bloody
diarrhea, erythromycin 250 mg p.o. q.i.d. for 5 to 7 days or ciprofloxacin
500 mg p.o. b.i.d. for 3 to 7 days is effective.
2. Salmonella
a. Epidemiology. The three primary species of Salmonella (Salmonella typhi,
Salmonella choleraesuis, and Salmonella enteritidis) may cause disease in
humans. S. enteritidis is a common cause of infectious diarrhea. There are
1,700 serotypes and variants of Salmonella, which are classified into 40
groups. Ninety percent of Salmonella organisms that are pathogenic for human
beings are in groups B, C, and D. The organism is transmitted from fecally
contaminated foods and water with fecal–oral contact. Poultry and poultry
products constitute the major reservoir for the bacteria. A large inoculum
(
105 organisms) is required to produce infection. Thus, the incidence is rela-
tively low despite the widespread contamination of commonly ingested foods.
b. Pathology. Salmonella elaborates an enterotoxin, which is responsible for
the watery diarrhea. The organism also adheres to the mucosal surface and
invades the epithelium, resulting in colitis and bloody diarrhea.
c. Clinical disease. Salmonella invades the mucosa of the small and large
intestine and produces an enterotoxin that causes a secretory diarrhea.
Watery diarrhea is more common, but bloody diarrhea may occur. Patients
complain of headache, malaise, nausea, vomiting, and abdominal pain
within 6 to 48 hours after ingesting the contaminated food. The disease is
usually self-limited and resolves in 7 days. Fever and bacteremia occur in
less than 10% of patients. Immunosuppression, malignancy, hemolytic
states, liver disease, achlorhydria, and chronic granulomatous disease of
children predispose patients to progressive salmonellosis with bacteremia,
with localized infection in joints, bones, meninges, and other sites. In 5% of
patients, the bacteria may localize in the reticuloendothelial system and may
cause an enteric fever (especially S. typhi). A carrier state also exists in some
patients, with bacteria carried in the gallbladder or in the urinary tract.
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202 Part V: Specific Complaints and Disorders

d. The diagnosis is made by history and stool and blood cultures. A fourfold
rise in serum O and H agglutinin titers 3 to 4 weeks after infection confirms
the diagnosis.
e. Treatment is supportive in most instances. Antimicrobial therapy is contraindi-
cated for most patients because it can increase the carrier state. However,
antimicrobial agents such as ampicillin, chloramphenicol, trimethoprim/sul-
famethoxazole, ciprofloxacin hydrochloride, or third-generation cephalosporins
can be used in young children or in patients who are susceptible to bacteremia
and prolonged salmonellosis (Table 30-4). Patients with bacteremia, enteric
fever, and metastatic infection should be treated with antimicrobial therapy.
Also, patients with underlying acquired immunodeficiency syndrome (AIDS),
hemolytic states, lymphoma, and leukemia, and neonates, the elderly and
chronic carriers should receive antimicrobials. Anticholinergic agents and opi-
ates should not be used because they can prolong the excretion of the bacteria.
3. Shigella
a. Epidemiology. There are four major groups: Shigella dysenteriae, Shigella
flexneri, Shigella boydii, and Shigella sonnei. S. dysenteriae causes the sever-
est form of dysentery. In the United States, 60% to 80% of instances of bacil-
lary dysentery are caused by S. sonnei with a seasonal preference for winter.
In tropical countries, S. flexneri dysentery is more common especially in the
late summer months. It is transmitted by the fecal–oral route. Human beings

TABLE 30-4 Treatment of Common Acute Enteric Infections

Organism Antimicrobial therapy

Campylobacter Erythromycin 250 mg p.o. q.i.d. for 5–10 d or ciprofloxacin

500 mg p.o. b.i.d. for 5 d
Shigella Trimethoprim/sulfamethoxazole DS p.o. b.i.d. for 5 d or
tetracycline 500 mg p.o. q.i.d. for 5 d or ciprofloxacin
500 mg p.o. b.i.d. for 5 d
Salmonella (severe disease) Ampicillin or amoxicillin 1 gm p.o. t.i.d. or q.i.d. for 14 d or chlor-
amphenicol 1 gm p.o. or IV q8h for 14 d or trimethoprim/
sulfamethoxazole DS p.o. b.i.d. for 10 d or a third-generation
cephalosporin or ciprofloxacin 500 mg p.o. b.i.d. for 5 d
Rifaximin 200 mg p.o. t.i.d.
Enterotoxigenic Escherichia Trimethoprim/sulfamethoxazole DS p.o. b.i.d. for 5 d or
coli, E. coli O157:H7, and ciprofloxacin 500 mg p.o. b.i.d. for 5 d or ofloxacin 300 mg
traveler’s diarrhea p.o. b.i.d. for 5 d or norfloxacin 400 mg p.o. b.i.d. for 5 d
Giardia lamblia Quinacrine hydrochloride 100 mg p.o. t.i.d. for 7 d or metron-
idazole 250 mg p.o. t.i.d. for 7 d or furazolidone 100 mg
q.i.d. for 7 d
Entamoeba histolytica Diloxanide furoate 500 mg p.o. t.i.d. for 10 d plus diiodohydroxy-
quin 650 mg p.o. t.i.d. for 20 d
Yersinia enterocolitica Trimethoprim/sulfamethoxazole DS p.o. b.i.d. for 7 d
or tetracycline 250–500 mg p.o. for 7 d
Vibrio cholerae Tetracycline 500 mg p.o. q.i.d. for 3 d or trimethoprim/
sulfamethoxazole DS p.o. b.i.d. for 3 d
Noncholera Vibrio Tetracycline 250 mg p.o. q.i.d. for 7 d
Clostridium difficile Cholestyramine 4 gm p.o. t.i.d. for 7 d or metronidazole
Mild disease 250 mg p.o. t.i.d. for 7 d
Severe disease Metronidazole 250 mg p.o. t.i.d. for 7 d or vancomycin
125–500 mg p.o. q.i.d. for 7 d

Trimethoprim/sulfamethoxazole DS, trimethoprim 160 mg/sulfamethoxazole 800 mg; p.o., by mouth;

q.i.d., four times a day; b.i.d., twice a day; t.i.d., three times a day.
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Chapter 30: Viral, Bacterial, and Parasitic Disorders of the Bowel 203

are the only natural host for this organism. Enteric infections with Shigella
are most commonly seen in children 6 months to 5 years old, although per-
sons of all ages can become infected. Clinical shigellosis is highly contagious
and can be caused by a very small inoculum: fewer than 200 organisms.
Food, water, and milk can be contaminated, which can result in epidemics.
Incidence of the disease increases in crowded, unsanitary conditions.
b. Pathophysiology. Shigella elaborates an enterotoxin that is responsible for
the watery diarrhea. The organism also adheres to the mucosal surface and
invades the epithelium, resulting in colitis and bloody diarrhea.
c. Clinical disease. The incubation period is 1 to 3 days. In most individuals,
the disease starts as lower abdominal pain and diarrhea. Fever is present in
less than half of the patients. In many patients, there is a biphasic illness that
begins as fever, abdominal pain, and watery diarrhea. In 3 to 5 days, rectal
burning, tenesmus, and small-volume bloody diarrhea characteristic of
severe colitis develop. Toxic megacolon and colonic perforation may recur.
Extraintestinal complications include conjunctivitis, seizures, meningismus,
Reiter’s syndrome, thrombocytopenia, and hemolytic uremic syndrome.
The course of shigellosis is variable. In children, it may resolve in 1 to
3 days and in most adults in 1 to 7 days. In severe instances, it may last
longer than 3 to 4 weeks with associated relapses. It may be confused with
idiopathic ulcerative colitis. A minority of patients become chronic carriers.
d. The diagnosis of shigellosis is made by identification of the gram-negative
bacillus in the stool. Sigmoidoscopic findings are identical to those of idio-
pathic inflammatory bowel disease.
e. Treatment. Patients should receive supportive therapy with antipyretics and
fluids. Antiperistaltic agents such as diphenoxylate hydrochloride (Lomotil)
or loperamide hydrochloride (Imodium) should be avoided. Antimicrobial
therapy decreases the duration of fever, diarrhea, and excretion of the organ-
isms in the stool. Trimethoprim/sulfamethoxazole, tetracycline, and ampi-
cillin (but not amoxicillin) are all effective; however, resistance has been
demonstrated. Ciprofloxacin and norfloxacin are also effective.
4. Escherichia coli. In addition to ETEC, other serotypes of E. coli also cause
diarrhea. These include enteroinvasive E. coli (EIEC), enteropathogenic E. coli
(EPEC), enterohemorrhagic E. coli (EHEC), diffuse adherence E. coli (DAEC),
and enteroaggregating E. coli (E AGGEC). All of these bacteria possess plasmid-
encoded virulence factors. They make specific interactions with the intestinal
mucosa by way of bacterially derived adhesions. Some produce enterotoxins
and cytotoxins. Transmission is fecal–oral.
a. Enteroinvasive E. coli
i. Epidemiology. EIEC is a traveler’s pathogen. Epidemics have been
described resulting from imported cheese. The organism also causes epi-
demics in young children, 1 to 4 years of age.
ii. Clinical disease. Similar to Shigella, EIEC invades and destroys the
colonic mucosal cells and causes, first, watery diarrhea followed by a
dysentery like syndrome. The incubation period is 1 to 3 days. The fever
and diarrhea last 1 to 2 days.
iii. Diagnosis. Fecal leukocytes are present. Serotyping and ELISA are avail-
able only in research settings.
iv. Treatment is supportive. Bismuth subsalicylate, by decreasing colonic
secretions, seems to decrease the diarrhea and other symptoms in all
infections with E. coli species. The antimicrobials used in shigellosis are
effective, as well as rifaximin 200 mg p.o. t.i.d.
b. Enteropathogenic E. coli
i. Epidemiology. EPEC is a major cause of diarrhea in both economically
developed and underdeveloped countries. It commonly causes outbreaks
in nurseries affecting children up to 12 months of age. It may also cause
sporadic diarrhea in adults. The bacteria adhere closely to the enterocyte
membrane via an adherence factor with destruction of microvilli.
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204 Part V: Specific Complaints and Disorders

ii. Clinical disease. Disease onset is with fever, vomiting, and watery diar-
rhea. Symptoms may continue for longer than 2 weeks and patients may
relapse.
iii. Diagnosis is by serotype analysis
iv. Treatment. Nonabsorbable antibiotics such as neomycin, colistin, and
polymyxin have been recommended. Ciprofloxacin hydrochloride, nor-
floxacin, and aztreonam are also effective and preferred.
c. Enterohemorrhagic E. coli
i. Epidemiology. EHEC or E. coli O157:07, and rarely E. coli O26:H11
have been detected in contaminated hamburger meat; outbreaks have
occurred in nursing homes, daycare centers, and schools.
ii. Pathogenesis and clinical disease. EHEC elaborates a Shigella-like
toxin (verotoxin 1) that is identical to the neuroenterocytotoxin of
S. dysenteriae and to verotoxin 2 and an adherence factor encoded by a
plasmid. Transmission is fecal–oral. Although the disease is more com-
mon in children, several outbreaks have occurred in adults from conta-
minated beef. The bloody diarrhea may be copious but may show no
fecal leukocytes. It usually lasts 7 to 10 days but may be complicated by
hemolytic uremia syndrome.
iii. Diagnosis. Stool cultures and serotyping sorbitol-negative E. coli iso-
lates may yield the organism.
iv. Treatment. Symptomatic treatment and ciprofloxacin or norfloxacin
may be used in severe illness. Supportive measures are recommended.
d. Diffuse adherence E. coli (DAEC) affects young children, especially in eco-
nomically underdeveloped countries. Diarrhea is usually watery, lasts less
than 2 weeks, and may become persistent.
e. Enteroaggregating E. coli (EAGGEC) has been recognized recently as a
pathogen especially affecting the ileum and the terminal ileum. The aggre-
gating bacteria gather around the villi and cause epithelial destruction. The
pathogenesis is transferred by a plasmoid via fimbriae. It causes persistent
diarrhea in children and is more common in economically underdeveloped
countries. The management of the diarrheal illness is similar to that of other
E. coli species strains.
5. Yersinia enterocolitica
a. Epidemiology. Y. enterocolitica can be found in stream and lake water and
has been isolated from many animals, including dogs, cats, chickens, cows,
and horses. It is transmitted to humans via contaminated food or water, or
from human or animal carriers. It most commonly affects children and
rarely causes disease in adults. It is found worldwide, especially in
Scandinavia and Europe, and may result in epidemics.
b. Pathogenesis and clinical disease. Yersinia causes a spectrum of diseases
ranging from gastroenteritis to invasive ileitis and colitis. The organism is
invasive and elaborates a heat-stable toxin. These properties allow its invasion
into and through the distal small-bowel mucosa and subsequent infection of
the mesenteric lymph nodes. The incubation period is 4 to 10 days. The dis-
ease normally lasts several weeks but can be prolonged for many months.
The manifestation of Yersinia infection is variable. In infants and
young children less than 5 years, it may be febrile gastroenteritis lasting 1
to 3 weeks. In older children, it may mimic acute terminal ileitis, mesenteric
adenitis, or ileocolitis. It may be confused with acute appendicitis. The
enterocolitis presents with bloody diarrhea, fever, and abdominal pain
accompanied by anorexia, nausea, and fatigue. The diarrhea usually lasts 1
to 3 weeks but may be protracted (
3 months). Polyarthritis, erythema
multiforme, and erythema nodosum occasionally develop 1 to 3 weeks after
the onset of diarrhea. Bacteremia is rare but may be seen in immunosup-
pressed patients and may result in hepatosplenic abscess, meningitis, and
infections of other organs. Metastatic foci may occur in joints, lungs, and
bones.
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Chapter 30: Viral, Bacterial, and Parasitic Disorders of the Bowel 205

c. Diagnosis can be made by stool and blood cultures using special media and
culture conditions. The laboratory should be notified. Serologic tests have
been useful in Europe and Canada. The serotypes found in the United States
do not give reliable serologic results.
d. Treatment in most instances is supportive. Antimicrobials such as tetracy-
cline, chloramphenicol, and trimethoprim/sulfamethoxazole may be used in
severe illness.
6. Aeromonas hydrophila
a. Epidemiology. A. hydrophila is a member of the Vibrionaceae family.
It is transmitted from contaminated food and water, especially in the
summer months.
b. Pathogenesis and clinical disease. Aeromonas produces several toxins.
The heat-labile enterotoxin and the cytotoxin are implicated in the intestinal
infection. The disease commonly follows ingestion of untreated water just
before the onset of symptoms and consists of fever, abdominal pain, watery
diarrhea, and vomiting lasting about 1 to 3 weeks in children and 6 weeks or
longer in adults. In 10% of instances, diarrhea is bloody and mucoid. Chronic
diarrhea and choleralike presentation have also been described. In immuno-
compromised patients and patients with hepatobiliary disease, bacteremia
may occur.
c. Diagnosis. Stool cultures are diagnostic. Fecal leukocytes may be present in
one third of instances.
d. Treatment is supportive in mild instances. In severe illness and with chronic
diarrhea, antibiotics may shorten the duration of the disease. Aeromonas is
resistant to beta-lactam antibiotics. Trimethoprim/sulfamethoxazole, tetra-
cycline, and chloramphenicol have been effective.
7. Plesiomonas shigelloides
a. Epidemiology. Plesiomonas is another member of the Vibrionaceae family
that causes sporadic diarrheal disease affecting travelers to Mexico, Central
America, and the Far East after ingestion of raw shellfish. It produces a
choleralike toxin but also has invasive potential.
b. Clinical disease. Diarrhea is usually watery, but in one third of the patients
it is bloody. Abdominal pain is usually severe. Vomiting and fever may be
present. Although the disease is usually over in 1 week, it may last longer
than 4 weeks.
c. Diagnosis is by stool culture. Fecal leukocytes may be present.
d. Treatment is supportive. The organism has the same microbial sensitivity as
Aeromonas.
8. Clostridium difficile
a. Epidemiology. C. difficile is a spore-forming obligate anaerobe. It is found
as “normal flora” in 3% of adults, 15% of hospitalized patients, and 70% of
infants in pediatric wards. It may cause disease in people of all ages, but it
most frequently affects elderly and debilitated patients. The transmission is
usually fecal–oral; however, it may be transmitted environmentally by spores
carried on fomites or on contaminated hands of health care workers. The dis-
ease usually follows antibiotic use with disruption of the normal colonic flora.
All antimicrobial agents with the exception of vancomycin and parenterally
administered aminoglycosides have been linked with C. difficile enterocolitis.
In most instances, the ingestion of the antimicrobial agent is within 6 weeks
of the onset of the diarrhea. Case reports of C. difficile disease in patients
who have not received antibiotics include patients with neutropenia or ure-
mia, those undergoing cancer chemotherapy, and homosexual males.
b. Pathogenesis and clinical disease. C. difficile produces two major tox-
ins. Toxin A is an enterotoxin, and toxin B is a cytotoxin used in commer-
cial latex agglutination testing for detection of the infection. Toxin A binds
to receptors on the colonic mucosal surface and causes severe inflammatory
changes. The toxigenic effect is catalyzed by previously present trauma or
injury to the mucosal cells. The severity of the disease varies from watery
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206 Part V: Specific Complaints and Disorders

diarrhea to severe pseudomembranous colitis with bloody diarrhea, fever,

and systemic toxicity.
c. Diagnosis is made by stool cultures or by the demonstration of the presence of
the associated cytopathic toxin produced by C. difficile in stool samples. Fecal
leukocytes may be absent in 50% of instances. Toxin assay may be negative in
10% to 20% of instances. Sigmoidoscopy, colonoscopy, and histologic exami-
nation of the mucosal biopsies support the diagnosis. Pseudomembranes, if
present, are most common in the rectum and distal colon. Occasionally, how-
ever, they are present only in the transverse colon or cecum.
d. Treatment. The strategies for treatment vary according to the severity of the
symptoms. Unnecessary antibiotics should be stopped. Corticosteroids and
antiperistaltic agents should be avoided because they may prolong C. difficile
carriage and exacerbate the diarrhea. Patients with colitis may be treated
with oral vancomycin 125 mg q.i.d. for 10 days or oral metronidazole
250 mg q.i.d. for 10 days. Cholestyramine may be used in mild disease to aid
in binding the elaborated toxins. Relapse after antimicrobial therapy occurs
in 20% of patients within 1 week after therapy. In such patients, the eradica-
tion of C. difficile may require vancomycin 250 to 500 mg q.i.d. for
1 month or pulsed doses of therapy for 5 days each time as long as necessary.
Combining rifampin 600 mg with vancomycin produces a synergistic effect.
Probiotics or bacterial therapeutic agents such as Lactobacillus or
Saccharomyces boulardii may add additional benefit. Over-the-counter yogurt
varities containing probiotics may be beneficial when ingested daily over
several weeks.

III. PARASITIC INFECTIONS OF THE BOWEL. Numerous parasites infect the human
bowel and cause disease. This chapter discusses only the most common parasitic
infections, namely, protozoan pathogens seen in the United States in normal, immuno-
competent people.
In recent years, there has been an increase in protozoan infections of the bowel
caused by increases in international travel to tropical and subtropical areas of the world,
in male homosexuality, and in AIDS. The protozoan infections seen in AIDS are dis-
cussed in Chapter 43. The antimicrobial therapy is summarized in Table 30-4 (page 204).
A. Giardia lamblia
1. Epidemiology. Giardia is a flagellated protozoan seen worldwide. It is trans-
mitted by the fecal–oral route from fecally contaminated water and food. It is
also a traveler’s pathogen and affects children and adults, especially people with
IgA deficiency, hypochlorhydria, and malnutrition.
2. Pathogenesis and clinical disease. After ingestion of the cysts, excystation
releases the organism in the upper small intestine. Giardia adheres to the brush
border membrane of the enterocytes. Histologically, it may cause a celiac
sprue-like lesion, resulting in lactose deficiency and malabsorption. Incubation
after ingestion of the organisms is 1 week. Most infections produce mild, self-
limiting enteritis with watery diarrhea, abdominal bloating, cramps, and flatu-
lence lasting 1 to 3 weeks. The stools may be bulky and foul smelling. In a
minority of the patients, the infection persists and results in a chronic or recur-
rent disease with weight loss and malabsorption.
3. Diagnosis is made by multiple stool examinations because the shedding of the
protozoan is episodic. In difficult illnesses, duodenal aspirates and touch prepa-
rations made by duodenal biopsy specimens can be used.
4. Treatment is with quinacrine hydrochloride (Atabrine), metronidazole (Flagyl),
or furazolidone (Furoxone). In recurrent illness, combination drug therapy may
be more efficacious.
B. Cryptosporidium
1. Epidemiology. Cryptosporidium is an important coccidian protozoan in veteri-
nary medicine. It is also a ubiquitous human pathogen affecting both immuno-
competent and immunosuppressed patients. There is a high rate of infection
among homosexual men, children in daycare facilities, and immigrants arriving
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Chapter 30: Viral, Bacterial, and Parasitic Disorders of the Bowel 207

from economically underdeveloped countries. It accounts for 1% to 4% of

instances of infectious diarrhea in the economically developed world. The
incidence of infection is greater in the summer and fall. The organism may be
transmitted by a variety of routes including fecal–oral, hand–to-mouth, and
person-to-person via contaminated food, water, and pets (especially cats).
2. Clinical disease. In normal hosts, profuse watery diarrhea, anorexia, and low-
grade fever occur approximately 5 days after ingestion of the oocysts. In most
instances, it is a self-limited disease lasting 5 to 20 days. In immunodeficient
hosts, it can be a chronic, relentless disease with watery diarrhea of up to 17 L
per day. The organism infects the jejunum most heavily but has been found in
the pharynx, esophagus, duodenum, ileum, pancreatic ducts, gallbladder, bile
ducts, appendix, colon, and rectum.
3. Diagnosis may be established by the demonstration of the oocysts in the stool
specimens or the organisms in biopsy specimens obtained at endoscopy.
Giemsa, acid-fast, and silver stains increase the diagnostic yield.
4. Treatment is supportive with fluid and electrolytes. Octreotide, the synthetic
somatostatin analog, may reduce the volume of watery diarrhea. Spiramycin
and puromycin have been used with limited efficacy.
C. Entamoeba histolytica
1. Epidemiology. E. histolytica is an endemic and travel-associated, tissue-invasive
protozoan transmitted via the fecal–oral route. It is common in institutionalized
patients and homosexual males. In the United States, the prevalence is about 5%.
2. Pathology. The infection starts with ingestion of the cysts. The excystation
occurs in the colon with the release of trophozoites, which invade the mucosa
and lead to mucosal inflammation and ulceration similar to that seen in idio-
pathic inflammatory bowel disease. The classic lesions of amebiasis are the
“flask-shaped ulcers” that may extend to the submucosa.
3. Clinical disease. The infection manifests in a spectrum of disease with varying
severity. In the mild form, patients have crampy abdominal pain, intermittent
diarrhea, and tenesmus. In the more severe form, there is bloody diarrhea with
abdominal pain, tenesmus, and fever.
Acute abdomen secondary to perforation or peritonitis may be seen. The
infection may encompass the entire colon but may be in the form of amebomas,
which are single or multiple annular inflammatory lesions more often seen in
the cecum or the ascending colon.
4. Diagnosis is made by the demonstration of the organism in the stool. In
mildly affected patients and in carriers, cysts are usually present in the stool.
Trophozoites may be demonstrated in stool or biopsy specimens obtained
from ulcer margins at sigmoidoscopy or colonoscopy. In amebic colitis, the
serology by indirect hemagglutination test is positive in greater than 90% of
patients.
5. Therapy is variable depending on the severity of the symptoms and disease.
Asymptomatic intestinal infection is treated with diiodohydroxyquin
(iodoquinol [Diquinol]) 650 mg t.i.d. for 20 days or diloxanide furoate
(Furamide) 500 mg t.i.d. for 10 days. Patients with moderate-to-severe intesti-
nal disease are treated with metronidazole (Flagyl) 750 mg t.i.d. for 10 days
plus diiodohydroxyquin 650 mg t.i.d. for 20 days. The alternative treatment is
paromomycin 25 to 35 mg/kg t.i.d. for 7 days plus diiodohydroxyquin 650 mg
t.i.d. for 20 days.

Selected Readings
Ali S, et al. Giardia intestinalis. Curr Opin Infect Dis. 2004;16:453–460.
Bardham PK, et al. Screening of patients with acute infectious diarrhea; evaluation of clinical
features, faecal microscopy and faecal occult blood testing. Scand J Gastroenterol.
2000;35:55–60.
Basnyat B, et al. Enteric (typhoid) fever in travelers. Clin Infect Dis. 2005;41:1467–1472.
Gahatsatos P, et al. Meta-analysis of outcome of cytomegalovirus colitis in immuno-
competent hosts. Dig Dis Sci. 2005;50:609–616.
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208 Part V: Specific Complaints and Disorders

Issa M, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin

Gastroenterol Hepatol. 2007 Mar;5:345–351.
Levwohl MV, et al. Giardiasis. Gastrointest Endosc. 2003;7:906–913.
Poutanen SM, et al. Clostridium difficile-associated diarrhea in adults. CMAJ. 2004;
171:51–58.
Reid G, et al. Selecting, testing and understanding probiotic microorganisms. FEMS
Immunol Med Microbiol. 2006;46:149–157.
Rossignol JF, Infectious diarrhea. Etiology, diagnosis and treatment. US Gastroenterol Rev.
2007;1:76–80.
Sanders JW, et al. Diarrhea in the returned traveler. Curr Gastroenterol Rep. 2001;3:315.
Stanley SL, Jr., Amoebiasis. Lancet. 2003;361:1025–1034.
Sunenshine RH, et al. Clostridium difficile-associated disease: new challenge from
established pathogen. Cleveland Cin J Med. 2006;73(2):187–197.
Surawicz CM. Treatment of recurrent ostridium difficile-associated disease. Nat Clin Pract
Gastroenterol Hepatol. 2004;1:32–38.
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MALABSORPTION 31

T he term malabsorption connotes the failure to absorb or digest normally one or more
dietary constituents. Patients with malabsorption often complain of diarrhea, and sometimes
the distinction between malabsorption and diarrhea of other causes (see Chapter 29) initially
is difficult. For example, patients with primary lactase deficiency fail to absorb a specific
dietary constituent, lactose, and a watery, osmotic diarrhea develops. However, most patients
with malabsorption present with a syndrome characterized by large, loose, foul-smelling
stools and loss of weight. On additional study, it is found that they cannot absorb fat and
often carbohydrate, protein, and other nutrients also. Table 31-1 indicates that a wide vari-
ety of disorders of the organs of digestion can cause malabsorption or maldigestion.

I. DIAGNOSTIC STUDIES. Before discussing the disorders that may cause malabsorp-
tion, it is useful to review several of the diagnostic studies that are available to aid in
evaluating patients with this condition. The number and order of diagnostic studies
used depends on the clinical signs and symptoms of the patient.
A. Blood tests. The hemoglobin and hematocrit levels may identify an anemia that
accompanies malabsorption. A low mean cell volume (MCV) may be found in iron
deficiency, whereas a high MCV may result from malabsorption of folate or

Disorders That May Cause Malabsorption or Maldigestion

TABLE 31-1
of One or More Dietary Constituents

Digestive disorder Examples

Pancreatic exocrine insufficiency Chronic pancreatitis

Pancreatic carcinoma
Bile acid insufficiency Small-bowel bacterial overgrowth
Crohn’s disease of the terminal ileum
Small-bowel disease
Mucosal disorders Celiac sprue
Collagenous sprue
Tropical sprue
Whipple’s disease
Radiation enteritis
Ischemic disease
Intestinal lymphoma
Regional enteritis
(Crohn’s disease)
Amyloidosis
Specific absorptive defects Primary lactase deficiency
Abetalipoproteinemia
Lymphatic disorders Intestinal lymphangiectasia
Mixed defects in absorption Zollinger-Ellison syndrome
Postgastrectomy disorders

209
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210 Part V: Specific Complaints and Disorders

Figure 31-1. Plain x-ray film of the abdomen in a patient with extensive calcification of the pan-
creas (arrows) and pancreatic insufficiency.

vitamin B12. Serum levels of liver enzymes, protein, amylase, calcium, folate, and
vitamin B12 may be abnormal and should be ordered.
B. Radiographic studies
1. Plain films or computed tomography scan of the abdomen may show
calcification within the pancreas, which indicates chronic pancreatic insufficiency
(Fig. 31-1).
2. A barium examination of the upper gastrointestinal tract, including the small
bowel, usually is one of the first diagnostic studies in the evaluation of malab-
sorption syndrome. Often the findings are nonspecific. The bowel may be dilated
and the barium diluted because of increased intraluminal fluid. A more specific
finding is thickening of the intestinal folds caused by an infiltrative process, such
as lymphoma, Whipple’s disease, or amyloidosis. The narrowed, irregular termi-
nal ileum in Crohn’s disease is virtually diagnostic (Fig. 31-2), although lym-
phoma and other infiltrative disorders also must be considered. Diverticula,
fistulas, and surgical alterations in bowel anatomy also may be evident.
C. Fecal fat determination. Malabsorption of fat (steatorrhea) is common to most
malabsorptive conditions (Table 31-2). Patients should ingest at least 80 g of fat
per day to obtain reliable interpretation of qualitative or quantitative fat determi-
nation. Mineral oil and oil-containing cathartics should be avoided.
1. Qualitative screening test. The Sudan stain for fecal fat is easy to perform
and reasonably sensitive and specific when interpreted by an experienced per-
son. A small amount of fresh stool is mixed thoroughly with normal saline or
water on a glass slide. A drop of glacial acetic acid is added, and the slide is
heated to hydrolyze the fatty acids from the triglycerides in the stool. The Sudan
stain is then added. Increased stool fat is indicated by abnormally large or
increased numbers (
100/40  field) of fat droplets.
2. The quantitative determination of stool fat is more accurate than qualitative
screening, but the collection of stool often is disagreeable to patients, family, and
nursing personnel. The stool is collected over 72 hours in a large sealed container,
which can be enclosed in a plastic bag and refrigerated to contain unpleasant
odors. Most normal people excrete up to 6 g of fat per 24 hours on a diet that
contains 80 to 100 g of fat. Stool fat in excess of 6 g per 24 hours can result from a
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Chapter 31: Malabsorption 211

Figure 31-2. Small-bowel x-ray series in a patient with Crohn’s disease. Note the narrowed, irreg-
ular contour of the terminal ileum and cecum (arrow). (From Eastwood GL. Core Textbook of
Gastroenterology. Philadelphia: Lippincott Williams & Wilkins; 1984:102. Reprinted with permission.)

disorder of fat digestion at any stage, including pancreatic insufficiency (decreased

lipase), bile acid insufficiency, mucosal disease, or lymphatic obstruction.
D. Pancreatic function tests
1. Collection of pancreatic secretions from the duodenum. The volume of pan-
creatic secretion and the content of bicarbonate and enzymes can be measured by
collecting pancreatic secretions from the duodenum after stimulation of the pan-
creas with secretin or with a test meal. Pancreatic insufficiency or carcinoma of the
head of the pancreas, which partially obstructs the pancreatic duct, may be detected
by this means. For example, bicarbonate concentrations less than 90 mmol/L sug-
gest pancreatic insufficiency. However, pancreatic secretory tests are performed so
infrequently in most gastrointestinal laboratories that the results may be unreliable.
2. The bentiromide test is a test of pancreatic exocrine function that does not
require duodenal intubation. The chemical name of bentiromide is N-benzoyl-L-
tyrosyl-P-aminobenzoic acid. The test is performed by administering a single oral
dose of 500 mg of bentiromide after an overnight fast and the urine is then col-
lected for 6 hours. The pancreatic enzyme chymotrypsin cleaves the molecule
within the lumen of the small intestine, releasing paraaminobenzoic acid (PABA).
The PABA is absorbed and excreted in the urine. Less than 60% excretion of
PABA suggests pancreatic insufficiency, although mucosal disorders, renal dis-
ease, severe liver disease, and diabetes also can cause low PABA excretion.
3. Radiographic studies. Although computed tomography of the abdomen
(see Chapter 9) and endoscopic retrograde cholangiopancreatography (ERCP) (see
Chapter 5) do not measure pancreatic function directly, abnormalities such as
212
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1/2/08

TABLE 31-2 Expected Diagnostic Findings According to Cause of Malabsorption

Diagnostic Test

Small-bowel Xylose tolerance Schilling Small-bowel

12:24 PM

Disorder x-ray Fecal fat test test biopsy

Pancreatic Abnormal Severe Normal May be Normal

exocrine steatorrhea abnormal
insufficiency
Page 212

Bile acid Normala Mild-to-moderate Normala Normala Normala

insufficiency steatorrhea
Small-bowel Abnormal Mild-to-severe Abnormal Usually Abnormal
mucosal steatorrhea normalb
disease
Lymphatic May be Mild steatorrhea Normal Normal Abnormal
disease abnormal

aMay be abnormal in bacterial overgrowth.

bAbnormal if terminal lieum is involved.
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Chapter 31: Malabsorption 213

dilated or strictured ducts, calcification, and pancreatic masses can imply pan-
creatic disease.
E. Bile acid breath test. Conjugated bile acids that are secreted into the duode-
num are resorbed with about 95% efficiency in the terminal ileum. If radio-
labeled [14C]-glycocholate is given orally to a healthy person, about 5% of it
enters the colon and undergoes bacterial deconjugation. The carbon dioxide
(14CO2) derived from the glycine is absorbed and excreted by the lungs and can
be measured in expired air. Bacterial overgrowth in the small intestine promotes
earlier bacterial deconjugation of the [14C]-glycocholate, and consequently, a
larger amount of 14CO2 is measured in the breath. Similarly, disease or resection
of the terminal ileum allows more bile acids to pass into the colon and undergo
bacterial deconjugation, resulting in an increase in expired carbon dioxide.
F. Xylose tolerance test. D-Xylose is a five-carbon sugar that remains intact when it
is absorbed across intestinal mucosa. Consequently, measurement of xylose absorp-
tion can be used as a screening test for diffuse disease of the small-intestinal mucosa.
The patient drinks 25 g of xylose dissolved in 500 mL of water, and the urine is col-
lected for the next 5 hours. A healthy person absorbs enough xylose to excrete more
than 5 g of xylose. Because low xylose excretion can result from inadequate hydra-
tion, the patient is encouraged to drink an additional 1,000 mL of water during the
5 hours of urine collection. In addition to mucosal disease, a low urinary xylose
excretion can result from small-bowel bacterial overgrowth, decreased circulatory
volume, massive ascites, and renal disease. To avoid the problem of urine collection
in patients with renal disease or who are unable to collect the urine accurately, a
blood xylose level at 2 hours after ingestion of the xylose can be determined. The
normal 2-hour blood xylose level is above 40 mg/dL.
G. Lactose absorption tests. The lactose tolerance test is an indirect measurement
of the activity of intestinal lactase, a brush border enzyme that hydrolyzes lactose
to glucose and galactose. To perform the lactose tolerance test, a fasting blood glu-
cose level is drawn, and the patient swallows 50 g of lactose mixed in 500 mL of
water. The blood glucose level is determined 15, 30, 60, and 90 minutes after
ingestion of lactose. If the patient is lactase deficient, the blood glucose level fails
to rise more than 20 mg/dL above the fasting level (Fig. 31-3).

20 mg/dL above fasting value

(mg/dL)

Figure 31-3. Serial blood glucose levels during a lactose tolerance test in a patient with primary
lactase deficiency. The blood glucose failed to rise more than 20 mg/dL above the fasting value.
(From Eastwood GL. Core Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins;
1984:113. Reprinted with permission.)
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214 Part V: Specific Complaints and Disorders

Lactose absorption also can be assessed by measuring breath hydrogen (H2)

after oral administration of 25 g of lactose. If lactose absorption in the small bowel
is impaired, an abnormally large amount of lactose reaches the colon, where bac-
teria ferment it, forming excessive amounts of H2. The H2 is absorbed and excreted
by the lungs.
H. Vitamin B12 absorption (Schilling) test. The standard Schilling test measures
the 24-hour urinary excretion of orally administered cobalt-labeled vitamin B12
and has been used to diagnose conditions in which intrinsic factor (IF) may be
absent, such as pernicious anemia or gastric atrophy. When IF is given with vita-
min B12, the test becomes a measure of terminal ileal or pancreatic function,
because dietary vitamin B12 is bound in the stomach to an endogenous protein
called R protein. Pancreatic enzymes degrade the R protein in the proximal small
bowel and lower its affinity for vitamin B12, resulting in the rapid transfer of B12
to IF. The IF-B12 complex continues to the terminal ileum, where it binds to spe-
cific receptors on the surface of the epithelial cells. Thus lack of sufficient pan-
creatic enzymes or of terminal ileal mucosa may result in abnormal vitamin B12
excretion. Normally, more than 10% of the labeled dose is excreted within 24
hours. Other conditions that predispose to a low urinary excretion include poor
hydration, decreased circulatory volume, renal disease, small-bowel bacterial
overgrowth, and infestation with the tapeworm Diphyllobothrium latum.
1. Small-bowel biopsy. The specific diagnosis of several mucosal diseases can be
made by small-bowel biopsy, and the diagnosis of other disorders can be
inferred on the basis of nonspecific findings (see Chapter 5).
Photomicrographs of normal human small-intestinal mucosa and of the
mucosa from a patient with celiac sprue are shown in Figs. 31-4 and 31-5,
respectively.

Figure 31-4. Photomicrograph of a normal human small-intestinal mucosal biopsy taken from the
distal duodenum. The villi are tall and straight and the villus-to-crypt ratio is about 5:1. (From
Eastwood GL. Core Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins;
1984:105. Reprinted with permission.)
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Chapter 31: Malabsorption 215

Figure 31-5. Photomicrograph of a mucosal biopsy from the distal duodenum in a patient with
celiac sprue. The villi are severely blunted, the crypts are elongated, the surface epithelial cells are
flattened, and the lamina propria contains a dense inflammatory cell infiltration.

II. PANCREATIC EXOCRINE INSUFFICIENCY

A. Pathogenesis. Pancreatic insufficiency usually is the result of chronic inflammatory
disease of the pancreas. Most often, this is caused by alcohol abuse, but it may result
from traumatic pancreatitis, familial pancreatitis, or chronic hypercalcemic pancre-
atitis. Rarely, pancreatic carcinoma presents as pancreatic insufficiency before jaun-
dice and pain develop. Because pancreatic enzymes are necessary for the digestion of
fat, protein, and carbohydrate, pancreatic insufficiency leads to panmalabsorption.
B. The diagnosis of pancreatic insufficiency is suspected on clinical grounds in a per-
son with chronic relapsing pancreatitis. Abdominal pain may or may not be a fea-
ture, but loss of weight is common. Calcification evident on abdominal plain x-ray
films is a sure sign of pancreatic exocrine insufficiency, although insufficiency cer-
tainly can exist in the absence of calcification.
Table 31-2 outlines the expected findings of several diagnostic studies that
may be applied to the evaluation of patients with malabsorption. Not all of the
studies listed are necessarily performed in patients with suspected pancreatic insuf-
ficiency. The small-bowel x-ray series in pancreatic insufficiency may be abnormal
in a nonspecific manner; that is, the barium may be diluted and segmented because
of the increased intraluminal contents. Because pancreatic lipase is essential for fat
digestion, the 24-hour quantitative fecal fat determination is elevated, sometimes in
the range of 30 to 40 g.
The xylose tolerance test and small-bowel biopsy usually are not performed
in patients with pancreatic insufficiency. If performed, they are normal. If the
Schilling test is performed, it may indicate mild malabsorption of vitamin B12
because of the role the pancreas plays in facilitating vitamin B12 absorption (see
section I.H). The bentiromide test is usually abnormal in patients with moderate-
to-severe pancreatic insufficiency.
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216 Part V: Specific Complaints and Disorders

C. Treatment. Pancreatic enzyme preparations can be given orally to augment or

replace endogenous enzymes. Because these tablets are inactivated rapidly by gas-
tric acid, two to three tablets must be taken before, during, and after each meal.
Supplemental acid-suppressive medications may prolong the activity of these
preparations. Specially designed sustained-release pancreatic enzyme preparations,
which are unaffected by gastric acid, are also available. A low-fat diet may be use-
ful in the control of severe steatorrhea. Some patients require supplemental cal-
cium, vitamin D, and other fat-soluble vitamins.

III. BILE ACID INSUFFICIENCY

A. Pathogenesis. Insufficient bile acids can result from a disorder at any step in the
enterohepatic circulation of bile acids. In severe intrinsic liver disease, the liver may
not produce enough bile acids; in partial biliary obstruction, the bile acids do not
reach the intestinal lumen in sufficient concentration; in bacterial overgrowth of the
small intestine, bile acids are deconjugated before they can participate in fat absorp-
tion; and in disorders of the terminal ileum, bile acids are not reabsorbed ade-
quately to maintain the bile acid pool. Because bile acids facilitate the absorption of
dietary fat by the formation of intraluminal micelles, a deficiency in bile acids
results in malabsorption of fat. Absorption of protein and carbohydrate is normal.
B. Diagnosis. The upper gastrointestinal and small-bowel x-ray series usually are
normal in bile acid insufficiency, unless the results suggest a lesion that obstructs
the common bile duct; small-bowel stasis or diverticula, which may allow bacter-
ial overgrowth; or terminal ileal disease.
Because bile acids facilitate but are not necessary for fat absorption, steator-
rhea usually does not exceed 20 g per 24 hours. The bile acid breath test is abnor-
mal if bacterial overgrowth or terminal ileal disease is present. A normal xylose
tolerance test and a normal small-bowel biopsy are expected unless there is bacte-
rial overgrowth. Bacterial overgrowth and disease of the terminal ileum also may
cause abnormal results on the Schilling test.
C. The treatment of bile acid insufficiency varies with the cause. Improvement in the
liver disease or relief of the biliary obstruction may be adequate.
1. Small-bowel bacterial overgrowth. Patients who have small-bowel bacterial
overgrowth may respond to the administration of metronidazole or tetracycline
or another broad-spectrum antibiotic or rifaximin (Xifaxan) 400 mg p.o. t.i.d.
for 10 days more. If bile acid deficiency is not correctable, a reduction in dietary
long-chain triglycerides is indicated. Medium-chain triglycerides, which do not
require bile acids for absorption, can be used to supplement dietary fat.
Additional fat-soluble vitamins may be indicated.
2. Terminal ileal disorders. Patients who have disorders of the terminal ileum
may have malabsorption of vitamin B12 and of bile acids. An abnormal
Schilling test in these patients indicates that they should receive monthly injec-
tions of vitamin B12. When disease of the terminal ileum impairs bile acid
absorption, the bile acids pass into the colon, where unconjugated dihydroxy
bile acids inhibit the absorption of water and electrolytes. Thus, these patients
may have both steatorrhea as a result of bile acid deficiency and watery diar-
rhea from the effects of bile acids on the colon. More extensive disease or
resection of the terminal ileum predisposes to greater reductions in the bile
acid pool, and steatorrhea predominates. In patients with lesser involvement,
watery diarrhea is prominent, and steatorrhea may not be clinically evident.
Cholestyramine, which binds bile acids, may be taken orally to treat the
watery diarrhea in patients who have less extensive disease or small resections.
The dosage ranges from one-half packet (2 g) once or twice a day to several
packets a day with meals. Because bound bile acids do not participate in fat
absorption, the steatorrhea may actually worsen. In patients with little involve-
ment of the terminal ileum, however, the net effect may be an improvement in
the diarrhea. In patients with more extensive involvement in whom steatorrhea
is aggravated by cholestyramine, supplemental medium-chain triglycerides may
be necessary. Nearly all patients benefit from restriction of long-chain triglyc-
erides (i.e., ordinary dietary fat).
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Chapter 31: Malabsorption 217

If Crohn’s disease is responsible for the terminal ileal dysfunction, treat-

ment with mesalamines, sulfasalazine, immune modulating drugs, or steroids
may be necessary (see Chapter 37).

IV. SMALL-BOWEL DISEASE

A. Mucosal disorders
1. Pathogenesis. A number of disorders of varying etiology affect the mucosa of
the small intestine (see Chapter 5, section IV.C.3). Because all ingested foodstuffs
are assimilated across the small-bowel mucosa, disorders that affect the mucosa
have the potential for causing malabsorption of fat, protein, carbohydrate, vita-
mins, and minerals. Whether malabsorption is clinically significant depends on
the site and extent of involvement. For example, in celiac sprue (gluten-sensitive
enteropathy), the lesion begins first in the proximal intestine and extends distally.
Because iron, calcium, and folate are absorbed preferentially in the proximal
small bowel, these nutrients may not be absorbed normally in patients with celiac
sprue. On the other hand, because Crohn’s disease most often affects the distal
ileum, which is the site of vitamin B12 and bile acid absorption, patients with
Crohn’s disease may have vitamin B12 and bile acid deficiency.
2. Diagnosis
a. The small-bowel x-ray series usually is abnormal in small-bowel mucosal
disease. It may be nonspecifically abnormal, showing dilatation of the bowel
and dilution of the barium, such as in celiac sprue. In contrast, infiltrative
disorders, such as Whipple’s disease, lymphoma, or amyloidosis, cause thick-
ening of the mucosal folds. Irregular mucosal contour and narrowed loops
may suggest Crohn’s disease.
b. Small-bowel biopsy. When small-bowel mucosal disease is suspected, the
question often is when to perform the small-bowel biopsy. Some physicians
proceed directly to biopsy in the clinical setting of apparent panmalabsorp-
tion and an abnormal small-bowel x-ray series without clinical suspicion of
pancreatic disease. Others first order a xylose tolerance test to confirm
mucosal disease and obtain a 72-hour stool fat collection to quantitate the
steatorrhea. A Schilling test usually is not performed. The small-bowel biopsy
may or may not be diagnostic (see Chapter 5, section IV).
i. Celiac sprue (CS) (celiac disease/gluten-sensitive enteropathy) is a
chronic disorder. Classical presentation is with malabsorption, diarrhea,
bloating, flatulence and weight loss. However, it can also present with ane-
mia, chronic fatigue, fibromyalgia, short stature, infertility, seizures, osteope-
nia, and osteoporosis. It may coexist with autoimmune and connective tissue
disorders (see Table 31-3). Patients with dermatitis herpetiformis (DH) often
have the intestinal pathology; however, not all patients with CS have DH.
Celiac sprue is most prevalent in non-Hispanic Caucasians, espe-
cially in persons of western European and Irish descent. The prevalence
may be as high as 1:125 to 1:300 in the Western world. There is a 70%
concordance rate in identical twins and a prevalence of 10% in first-
degree relatives. HLA studies indicate that most celiacs possess DR3-DQ2
or DR5/7-DQ2 and some celiacs have DR-4-DQ8.
Patients with celiac sprue have inappropriate mucosal T-cell response to
ingested gluten or prolamines from dietary grains resulting in intestinal
mucosal injury. The putative prolamines include gliadin in wheat, secalin in
rye, and hordein in barley. Avenin in oats does not induce immunoreactivity.
It is thought that prolamines such as gliadin form an immunogenic
complex with tissue transglutaminase (tTG). This gliadia-tTG complex
forms the substrate for antigliadin antiendomysial and anti-tTG antibodies.
The resulting T-cell response mediates small intestinal mucosal damage.
Diagnosis is confirmed with combination of clinical, serologic and
histopathologic findings. IgA and IgG antigliadin antibodies (AGA) are
sensitive but nonspecific. Endomysial IgA antibody (EMA) and IgA tTG
have 95% sensitivity and specificity, especially in classic cases of CS. Both
have lower sensitivity in patients with lesser degrees of villous atrophy.
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218 Part V: Specific Complaints and Disorders

TABLE 31-3 Conditions Associated with Celiac Disease

Disorder Examples

Anemia
Iron deficiency Primary biliary cirrhosis
Folate deficiency Primary sclerosing cholangitis
Vitamin B12 deficiency
Prolonged prothrombin time
Osteopenic bone disease Autoimmune cholangitis
Short stature
Idiopathic hepatits
and cirrhosis
Infertility
Neuropsychiatric disorders
Peripheral neuropathy Lymphocytic gastritis
Ataxia Lymphocytic colitis
Seizures
Cognitive deficits
Hyperactivity-attention deficit disorder
IgA deficiency Non-Hodgkin’s lymphoma
IgA nephrolpathy Intestinal T-cell lymphoma
Intestinal adenocarcinoma
Type I diabetes mellitus
Oropharyngeal and esophageal squamous
cell carcinoma
Autoimmune thyroid disease
Autoimmune adrenal disease
Sjögren’s syndrome
Systemic lupus erythematosis
Rheumatoid arthritis

To ascertain the diagnosis of celiac sprue, small-bowel biopsy is rec-

ommended since the mucosal involvement may be patchy. At least six dis-
tal duodenal sites should be biopsied during endoscopy. Biopsies should
not be obtained from the duodenal bulb or the immediate post-bulbar
duodenum since the presence of submucosal mucous glands in these areas
may influence epithelial and mucosal histology. Diagnostic features
include villous blunting; deepening of crypts; and increased intraepithelial
lymphocytes (IEL), monocytes, and plasma cells.
Serologic tests should not replace small-intestinal biopsy findings for
making the diagnosis of celiac sprue. However, if small-intestinal biopsies
are unavailable, the presence of high titer EMA or IgA tTG is most sug-
gestive of CS. Because IgA deficiency is common in patients with celiac
sprue, IgA levels should be determined. In patients with IgA deficiency,
IgG tTG may have value in diagnosing celiac sprue.
ii. Other mucosal disorders. The mucosal lesion of Whipple’s disease is
characterized by blunted villi that are distended by dense accumulations
of periodic acid—Schiff (PAS)—positive macrophages. These PAS-positive
macrophages contain the etiologic agent of Whipple’s disease:
Tropheryma Whippelii, a gram-positive actinomycete. T. Whippelii has
also been isolated from pleural fluid, vitrous sample, and peripheral blood
mononuclear cells by polymerase chain reaction.
Whipple’s disease is a systemic disorder that usually presents
with weight loss, cough, fever, diarrhea, hypotension, abdominal swelling,
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Chapter 31: Malabsorption 219

anemia, and mental status changes. PAS-positive macrophages may be

found in the small bowel, pericardium, endocardium, synovia, lymph
nodes, lung, brain, meninges, uvea, retina, and optic nerves. The disease
in some instances may present as a sarcoidlike syndrome and involve the
mediastinal nodes.
Other small-bowel mucosal disorders include abetalipoproteine-
mia, which is identified by villous epithelial cells that contain large fat
vacuoles. The absence of plasma cells suggests agammaglobulinemia.
Other disorders may or may not be evident on mucosal biopsy (see
Chapter 5, section IV.C.3).
3. Treatment. A discussion of the clinical management of all the small-bowel
mucosal disorders is beyond the scope of this book. The reader is referred to
standard textbooks of medicine and gastroenterology.
a. Celiac sprue. The treatment of celiac sprue is primarily the rigorous restric-
tion of all dietary gluten. The patient must avoid all wheat, barley, and rye.
Rice, corn, soy, and the flours of these grains are acceptable. Sprue patients
must also avoid many commercially prepared foods, such as some brands of
ice cream, some desserts, and meats that contain wheat fillers. Even some
vitamin and drug preparations are enclosed in capsules that contain small
amounts of gluten, which may be sufficient to produce mucosal injury in
some patients. Adjunctive treatment of sprue may include vitamin, calcium,
and iron supplements.
b. Whipple’s disease. Patients with Whipple’s disease should receive procaine
penicillin G, 1.2 million units per day intramuscular (IM) injection or intra-
venously, plus streptomycin 1 g per day IM for 2 weeks, followed by
trimethoprim/sulfamethoxazole double-strength twice daily for 1 year.
c. The mucosal lesion in other disorders, such as intestinal lymphoma, para-
sitic infestations, and Crohn’s disease, responds to treatment directed at the
underlying disease. If clinically significant steatorrhea persists, restriction of
dietary fat is indicated. Supplemental vitamins and minerals may be necessary.
B. Specific absorptive defects
1. Lactase deficiency
a. Pathogenesis. Primary lactase deficiency is an example of a defect in a spe-
cific brush border enzyme, lactase, which causes the malabsorption of the
disaccharide lactose. Infants and young children in all populations and most
white adults of North America and Europe normally have sufficient lactase
to hydrolyze milk lactose to its constituents, glucose and galactose.
However, most of the adult populations of the world, including blacks,
Asians, South and Central Americans, and Inuits, are typically “lactase-
deficient.” On a worldwide scale, therefore, whether the presence or lack of
lactase is normal or abnormal depends on the population under consideration.
b. Diagnosis. People with lactase deficiency typically experience abdominal
cramps and watery diarrhea within minutes after ingesting milk. These
symptoms develop because the unhydrolyzed lactose is not absorbed and
remains within the intestinal lumen, where it acts as an osmotic cathartic.
As the lactose passes into the lower bowel, bacterial action converts it
to lactic acid and carbon dioxide, which contribute to the catharsis and
cramping. The clinical history of abdominal cramps and diarrhea after milk
ingestion usually is sufficient evidence of lactase deficiency. If the diagnosis is
uncertain, however, a lactose tolerance test can be performed (see section I.G).
c. Treatment consists of restricting milk and milk products. Some milk is
available commercially in which the lactose has been hydrolyzed.
2. Abetalipoproteinemia
a. Pathogenesis. Because lipoproteins are necessary for the formation of the
apoprotein that combines with triglycerides, cholesterol, and phospholipids
within the intestinal absorptive cells to form chylomicrons, the lack of beta-
lipoproteins results in an accumulation of fat within the enterocyte and con-
sequent fat malabsorption.
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220 Part V: Specific Complaints and Disorders

b. Diagnosis. Stool fat is increased, but the small-bowel x-ray series and the
xylose tolerance test are normal. Serum cholesterol and triglycerides are low,
and beta-lipoproteins are absent. A small-bowel biopsy is diagnostic, show-
ing villous epithelial cells distended with fat, but the appearance is otherwise
normal.
c. Treatment. There is no specific treatment of the underlying disease. The fat
malabsorption improves with restriction of dietary long-chain triglycerides
and substitution of medium-chain triglycerides, which do not require chy-
lomicron formation but rather are absorbed directly from the villous epithe-
lial cells into the blood. Fat-soluble vitamins also are indicated.

V. LYMPHATIC DISORDERS
A. Pathogenesis. Obstruction of lymphatic drainage from the gut causes dilatation of
the lymphatics (lymphangiectasia) and loss of fat and protein in the stool. In some
patients, the disorder appears to be congenital or idiopathic. In others, there is an
association with Whipple’s disease, congestive heart failure, right-heart valvular dis-
ease, or frankly obstructive lesions, such as abdominal lymphoma, retroperitoneal
fibrosis, retractile mesenteritis, mesenteric tuberculosis, and metastatic cancer.
B. Diagnosis. Patients commonly seek treatment for weight loss, diarrhea, and
edema caused by the decrease in plasma proteins. Some patients have chylous
ascites. Barium examination of the small intestine may be normal, may have an
appearance of nonspecific malabsorption, or may indicate a nodular mucosal pat-
tern caused by distended or infiltrated villi. Steatorrhea usually is mild. The xylose
tolerance test should be normal unless the underlying disease (e.g., lymphoma) has
infiltrated the mucosa. Small-bowel biopsy should confirm the diagnosis by iden-
tifying dilated lymphatics within the cores of the villi.
C. Treatment. In addition to undergoing treatment of any associated disorder that
may be responsible for the lymphatic obstruction, patients with lymphatic disease
should receive medium-chain triglycerides, limit their intake of long-chain triglyc-
erides, and take supplemental fat-soluble vitamins.

VI. MIXED DEFECTS IN ABSORPTION

A. Gastric acid hypersecretory states
1. Pathogenesis. Malabsorption may accompany the Zollinger-Ellison syndrome
and other gastric acid hypersecretory conditions. The large amounts of acid that
reach the duodenum and proximal small intestine may have several adverse
effects. First, there may be villous blunting and mucosal inflammation. These
conditions may impair absorption in the proximal bowel. Second, the mucosal
lesion may predispose to the inadequate release of cholecystokinin and secretin
with consequent poor stimulation of gallbladder contraction and pancreatic
secretion. Third, the acid environment in the duodenum also inactivates pancre-
atic enzymes and may precipitate glycine-conjugated bile acids, additionally
impairing the digestion of fat, protein, and carbohydrate. Finally, in hypergas-
trinemic conditions, gastrin itself may inhibit absorption of water and electrolytes
in the small bowel, which contributes to the diarrhea that occurs in some patients.
2. Diagnosis and treatment. The upper gastrointestinal and small-bowel x-ray
series may show peptic ulcerations in the stomach, duodenum, or proximal
small intestine and may have a nonspecific malabsorption pattern. Other tests
of malabsorption may or may not be abnormal, depending on the severity of
the disease. The diagnosis and treatment of the Zollinger-Ellison syndrome and
other hypersecretory conditions are discussed in Chapter 24.
B. Postgastrectomy disorders. The multiple causes of malabsorption and maldiges-
tion in patients after gastric surgery, and their diagnosis and treatment, are
discussed in Chapter 28.

Selected Readings
Buchman AL, et al. AGA technical review on short bowel syndrome and intestinal
transplantation. Gastroenterology. 2003;124:1111–1134.
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Chapter 31: Malabsorption 221

Catassi C, et al. Association of celiac disease and intestinal lymphomas and other cancers.
Gastroenterology. 2005;128:S79–S86.
Chitkara DK, et al. Gastrointestinal complications of cystic fibrosis. Clin Perspect
Gastroenterol. July/August 2000:201.
Cureton P, The gluten-free diet: can your patient afford it? Pract Gastroenterol. 2007;
xxxi(4):75–84.
Desai AA, et al. Bacterial overgrowth syndrome. Curr Treatment Options Infect Dis.
2003;5:189–196.
Dewar DH, et al. Clinical features and diagnosis of celiac disease. Gastroenterology.
2005;128:S19–S24.
Ginsburg PM, et al. Malabsorption testing: A review. Curr Gastroenterol Rep. 2000;2:370.
Graham DY, et al. Visible small intestinal mucosal injury in chronic NSAID users. Clin
Gastroenterol Hepatol. 2005;3:55–59.
Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterology. 2005;128:
S10–S18.
Kupper C. Dietary guidelines and implementation for celiac disease. Gastroenterology.
2005;128:S121–S127.
Leung WK, et al. Small bowel enteropathy associated with chronic low-dose aspirin
therapy. Lancet. 2007;369:614.
Rostom A, et al. The diagnostic accuracy of serologic tests for celiac disease: A systemic
review. Gastroenterology. 2005;128:S38–S46.
Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: A guide for the
primary care physician. Arch Intern Med. 1999;159:1289.
Southerland JC, et al. Osteopenia and osteoporosis in gastrointestinal diseases: Diagnosis
and treatment. Curr Gastroenterol Rep. 2001;3:399.
Sundaram A, et al. Nutritional management of the short bowel syndrome in adults. J Clin
Gastroenterol. 2003;34:207–210.
Swartz MN. Whipple’s disease—past, present, and future. N Engl J Med. 2000;342:647.
TABLE 31.1
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32 SMALL-INTESTINAL NEOPLASMS
AND CARCINOID TUMORS

N eoplasms of the small intestine, either benign or malignant (Table 32-1), are unusual
but not rare, comprising less than 5% of all gastrointestinal tumors. Because they are
uncommon and relatively inaccessible to standard diagnostic studies, the diagnosis of
small-bowel tumors is sometimes delayed.

I. DIAGNOSIS
A. Clinical presentation. Small-intestinal (SI) tumors usually occur in people over
age 50. The presenting signs and symptoms are similar whether the tumors are
benign or malignant. Small-bowel obstruction, either partial or complete, mani-
fested by abdominal pain or vomiting or both, is a frequent presentation. Chronic
partial obstruction may predispose to stasis and bacterial overgrowth, leading to
bile acid deconjugation and malabsorption (see Chapter 31). Bleeding from the
tumor or ulceration in association with the tumor also is common. Perforation of
the bowel is rare. If a duodenal tumor is located in the vicinity of the ampulla of
Vater, obstruction of the common bile duct may develop, resulting in biliary stasis
and jaundice. Weight loss commonly accompanies malignant tumors.
The physical examination usually is nondiagnostic. Signs of small-bowel
obstruction may be evident, such as a distended, tympanic abdomen and high-
pitched bowel sounds. Occasionally malignant small-bowel tumors can be pal-
pated. Stool may be positive for occult blood.
B. Laboratory and other diagnostic studies
1. Blood studies. Anemia may develop because of blood loss or malabsorption.
Hypoalbuminemia can result from malabsorption, extensive metastatic liver
disease, or chronic illness. Evaluation of serum alkaline phosphatase or biliru-
bin levels may indicate biliary obstruction or metastatic liver disease.
2. An upright plain x-ray film of the abdomen may show air-fluid levels in
patients with small-bowel obstruction. If the obstruction is acute and does not
resolve with nasogastric suction and intravenous fluids, surgery may be
required without additional diagnostic testing.
3. Barium-contrast x-ray studies. The patient who has a small-bowel tumor with-
out frank obstruction but perhaps with colicky pain or bleeding typically undergoes

TABLE 32-1 Neoplasms of the Small Intestine

Malignant Benign

Adenocarcinoma Adenoma
Lymphoma Leiomyoma
Leiomyosarcoma Lipoma
Carcinoid Hamartoma
Metastatic tumors Neurogenic tumors
Melanoma Endometrioma
Kaposi’s sarcoma Inflammatory polyp

222
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Chapter 32: Small-Intestinal Neoplasms and Carcinoid Tumors 223

Figure 32-1. Small-bowel x-ray series showing a polypoid filling defect in the proximal small
intestine (arrow). At surgical resection, the lesion was found to be a histiocytic lymphoma.

barium-contrast x-ray studies. The small-bowel series may show a polypoid lesion
(Fig. 32-1) or the typical “napkin ring” deformity of adenocarcinoma encircling the
bowel. Often the routine upper gastrointestinal x-ray series with small-bowel fol-
low-through is nondiagnostic because the lesion is obscured by the large amount of
barium in the small intestine. In these instances, a small-bowel enema, or entero-
clysis, may delineate the lesion. This procedure is performed by passing a small tube
into the proximal duodenum and instilling a small amount of barium with air. This
provides excellent air–barium contrast of the small intestine and enhances the diag-
nostic capability. For example, a diffuse nodular appearance of the mucosa on
barium-contrast study may suggest lymphoma.
4. Endoscopy and biopsy. If a lesion is within the duodenum, endoscopic exam-
ination and biopsy are indicated.
5. Capsule endoscopy may be used to directly visualize SI tumors. There is risk
of the capsule being retained if the tumor is large.
6. Ultrasound and computed tomography scan. In patients with biliary obstruc-
tion, abdominal ultrasound may help define the lesion and identify dilated bile
ducts. These patients also should undergo endoscopic retrograde cholangiopan-
creatography (ERCP) or percutaneous transhepatic cholangiography (PTC).
Computed tomography (CT) scanning of the abdomen is useful in delineating
mass lesions and surveying for metastatic disease to the liver, lymph nodes, and
mesentery.
7. Selective arteriography of the celiac axis and superior mesenteric artery may
be helpful to the surgeon in planning appropriate surgery.

II. TREATMENT
A. Surgery. The treatment of most small-bowel tumors, benign or malignant, is surgi-
cal. Even malignant tumors that have metastasized may require surgical palliation
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224 Part V: Specific Complaints and Disorders

for obstruction or bleeding. In patients with small-intestinal lymphoma, surgery

may be required to make the diagnosis. The role of surgery in treating lymphoma
depends on the extent of involvement and on local institutional protocols, which
may include surgical resection in addition to radiotherapy and chemotherapy.
B. Radiation therapy and chemotherapy of other malignant small-bowel tumors
have been largely ineffective.
C. Nutritional therapy. Patients who have undergone partial resection of the small
intestine for a small-bowel tumor typically lose only a small portion of the bowel
and thus do not suffer nutritionally as a consequence of the surgery. However,
nutrition may be a clinical issue if the patient has extensive metastatic disease, the
duodenum has been bypassed, or the terminal ileum has been resected. Bypass of
the proximal small intestine leads to malabsorption of iron, calcium, and folate
and to ineffective stimulation of pancreatic and biliary secretions. Terminal ileal
resection may result in vitamin B12 and bile acid malabsorption, the latter leading
to fat and fat-soluble vitamin malabsorption.

III. CARCINOID TUMORS. In the United States, the incidence of carcinoid tumors is
approximately 8 per 100,000. Since most cases are asymptomatic and follow an indo-
lent course, the true incidence may be higher.
Carcinoid tumors are most commonly found in the appendix, ileum, rectum,
stomach, and lungs.
Carcinoid tumors are commonly classified according to their derivation from the
embryonic gut: foregut (bronchial and gastric), midgut (small intestine [SI] and
appendiceal), and hindgut (rectal). The clinical presentation and management of these
tumors varies according to their site of origin.
Of the foregut carcinoids, gastric carcinoids are usually asymptomatic and are
found incidentally; however, patients with bronchial carcinoids may present with cough,
hemoptysis, postobstructive pneumonia, Cushing’s syndrome, or carcinoid syndrome.
Midgut carcinoids, especially small-intestinal carcinoids, may cause inter-
mittent SI obstruction or mesenteric ischemia. Appendiceal carcinoids are usually
found incidentally. If there are metastases, carcinoid syndrome may occur.
Hindgut or rectal carcinoids are usually found incidentally, but may cause consti-
pation and rectal bleeding. Carcinoid syndrome is rarely seen even if there are metastases.
A. Bronchial carcinoid tumors comprise about 2% of primary lung tumors. They
usually present in the fifth decade of life and are rarely associated with carcinoid
syndrome; however, they have been associated with ectopic ACTH secretion result-
ing in Cushing’s syndrome. One third of patients, especially smokers, may present
with atypical carcinoids which are much more aggressive and usually metastasize
to the mediastinal lymph nodes. Surgery may be indicated.
B. Gastric carcinoid tumors make up less than 1% of gastric neoplasms. They are
classified into three distinct groups:
1. Type I: Associated with chronic atrophic gastritis
2. Type II: Associated with the Zollinger-Ellison syndrome and ectopic gastric
secretion
3. Type III: Sporadic gastric carcinoids
Both type I and type II gastric carcinoids are associated with
achlorhydria and hypergastrinemia, which is thought to result in hyperplasia
of the enterochromaffin cells in the stomach, leading to small, multiple carci-
noid tumors. These tumors generally follow an indolent course and are rarely
invasive. The small tumors may be resected endoscopically. Larger or recur-
rent tumors may require more extensive surgery. In patients with atrophic
gastritis, antrectomy has been used to eliminate the source of the gastrin pro-
duction to achieve tumor regression. In patients with Zollinger-Ellison syn-
drome, the use of somatostatin analogs has resulted in tumor regression.
Between 15% and 25% of gastric carcinoids are sporadic and develop
in the absence of hypergastrinemia. These are usually solitary and greater than
1 cm in size. They are frequently invasive, metastatic, and tend to pursue an
aggressive clinical course. Sporadic gastric carcinoids have been associated with
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Chapter 32: Small-Intestinal Neoplasms and Carcinoid Tumors 225

an atypical carcinoid syndrome which is primarily manifested by flushing

through and thought to be mediated by histamine. Most of these tumors are
treated with total gastrectomy.
C. Small-intestinal carcinoid tumors make up one third of all SI tumors and gener-
ally present in the sixth or seventh decade of life with abdominal pain and/or
small-bowel obstruction (SBO). Between 5% and 7% may present with carcinoid
syndrome and have liver metastases. These tumors are usually multicentric and
grow into the SI wall. Detection is often difficult with SI barium x-rays or CT scan;
however, their detection may be increased by the use of capsule endoscopy. Most
SI carcinoid tumors are found in the distal ileum. The tumor size is an unreliable
predictor of metastatic disease, since metastases have been reported from tumors
smaller than 0.5 cm. Mesenteric fibrosis and mesenteric ischemia are often present
with SI carcinoids. These tumors are also frequently associated with “buckling” or
tethering of the SI due to extensive mesenteric involvement. Surgical resection of
the SI primary tumor along with the mesenteric metastases leads to significant
reduction in tumor-related obstruction and pain, and is therefore recommended
even in patients with known metastatic disease.
D. Appendiceal carcinoid tumors are thought to arise from the subepithelial neu-
roendocrine cells and are more commonly diagnosed in younger patients, mostly
during appendectomy. About 95% of appendiceal carcinoid tumors are smaller than
2 cm in diameter at the time of diagnosis and rarely associated with metastases.
Tumors greater than 2 cm in diameter often have nodal or distant metastases. For
this reason, simple appendectomy is the treatment of choice for smaller tumors;
however, complete right colectomy is recommended for tumors larger than 2 cm. In
elderly patients or patients with other comorbid conditions, simple appendectomy
may be tried.
E. Rectal carcinoid tumors comprise only 1% to 2% of all rectal tumors and are usu-
ally found in the sixth decade of life. Fifty percent are asymptomatic and are usually
found at colonoscopy. When symptoms occur, patients complain of rectal pain, con-
stipation, and bleeding.
Rectal carcinoids of less than 1 cm in size are rarely metastatic and are suc-
cessfully treated with local excision. The management of tumors larger than 1–2 cm
is controversial. Endoscopic ultrasound is useful in examining extent of rectal wall
invasion and those without invasion of the muscularis propria, local resection may
suffice. Tumors larger than 2 cm, or those with invasion of the muscularis propria,
may require low anterior resection or abdominoperineal resection.
F. Metastatic carcinoid tumors
1. Diagnosis. Patients in whom metastases are suspected should be evaluated
with abdominal CT scan to rule out liver metastases. Liver chemistry tests
may be normal and are unreliable. Since carcinoid liver metastases are often
hypervascular and may become isodense relative to the liver and may be missed
with the administration of intravenous (IV) contrast, CT scan should be per-
formed both with and without IV contrast administration.
Somatostatin receptor scintography with IV administration of radio-
labeled octreotide also provides a useful imaging modality for the detection of
metastatic disease. Over 90% of neuroendocrine carcinoid tumors contain
high concentrations of somatostatin receptors. The uptake of radiolabeled
octreotide is also predictive of a clinical response to therapy with somatostatin
analogs.
Twenty-four-hour urinary serotonin metabolite 5-hydroxyndoleacetic
acid (HIAA) levels are elevated in about 75% of patients with metastatic car-
cinoid tumors of the midgut and not useful in patients with foregut (gastric and
bronchial) and hindgut (rectal) carcinoid tumors.
Chromogranin A (CGA) is a protein contained in the neurosecretory
vesicles of neuroendocrine tumor cells. CGA concentrations in the blood are
a more sensitive marker than urinary 5-HIAA levels in patients with carci-
noid tumors. CGA levels greater than 5,000 mg/mL are associated with poor
prognosis.
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226 Part V: Specific Complaints and Disorders

2. Treatment
a. Surgical resection of the involved liver segment(s), when possible, may
provide long-term symptomatic relief and prolonged survival times.
b. Liver transplantation may be offered to patients with liver-isolated
metastatic disease; however, the role of OLT in such patients is unclear.
c. Hepatic artery embolization may be used as a palliative procedure in
patients with liver metastases who are not candidates for surgical resection.
However, the duration of response may be brief, ranging from 4 to 24
months. Side effects may include renal failure, hepatic necrosis, and sepsis.
d. Radiofrequency ablation and cryoablation (either alone or in tandem
with surgical resection) may be offered as less invasive procedure; however,
efficacy, especially in patients with extensive hepatic metastases, has not
been well studied.
e. Systemic therapy
i. Somatostatin analogs (i.e., octreotide) at a dose of 150
g t.i.d.
improves the symptoms of carcinoid syndrome in nearly 90% of patients.
Long-acting octreotide at a dose of 20 mg intramuscularly may be
administered once monthly with gradual increase in dose as needed to
control symptoms. Patients may also use additional short-acting
octreotide for breakthrough symptoms. Lanreotide (another somato-
statin analog) has similar clinical efficacy. These drugs are well tolerated
by patients; however, possible side effects include injection-site reactions,
stearrhea, and hyperglycemia.
ii. Interferon-
(IFN) may be used alone or in combination with somato-
statin analogs. The addition of IFN- therapy to somatostatin analogs
has been reported to be effective in controlling symptoms in patients
with carcinoid syndrome who may be resistant to somatostatin analogs
alone. The combination of these drugs may also significantly slow the
rate of tumor progression in the majority of patients. Side effects of IFN-
therapy include bone marrow suppression (especially myelosuppression),
autoimmune thyroid disease, fatigue, and depression.
iii. Chemotherapy. Streptozocin combined with fluorouracil (5-FU),
cyclophosphamide, or doxorubicin have been used in patients with
metastatic carcinoid disease with poor results. Even though there may be
slight survival benefit with streptozocin and 5-FU, the renal toxicity,
myelosuppression, nausea, vomiting, and fatigue limits the use of these
drugs as first-line therapy.
iv. Newer agents in the treatment of metastatic carcinoid include radiola-
beled somatostatin analog drugs, inhibiting binding of proangiogenic
growth factor (vascular endothelial growth factor, or VEGF) to its
receptor (vascular endolethial growth factor receptor, or VEGFR)
with blocking antibodies such as bevacizumab (Avastin) and sunitinib
(Sutent).

Selected Readings
Eamonn MM, et al. Small intestinal transplantation. Curr Gastroenterol Rep. 2001;3:408.
Gill SS, et al. Small intestinal neoplasms. J Clin Gastroenterol. 2001;33:267–282.
O’Neil BH. Management of carcinoid tumors and the carcinoid syndrome. Clin Perspect
Gastroenterol. 2001;4:279..1
79466_CH33.qxd 1/2/08 12:30 PM Page 227

IRRITABLE BOWEL SYNDROME 33

T he irritable bowel syndrome (IBS) is the most common of all digestive disorders,
affecting nearly everyone at one time or another and accounting for up to 50% of patients
referred to a gastroenterology practice. Although characterized as a disorder of bowel
motility, in many patients it usually is an exaggeration of normal physiologic responses and
possibly heightened perception of pain.
Numerous terms have been used to describe the syndrome (Table 33-1). Irritable
bowel syndrome seems to be the most appropriate. Terms that include the words colon
or colitis are inaccurate because the condition is not limited to the colon, and inflamma-
tion is not a feature. Furthermore, use of the term colitis leads to confusion with ulcerative
colitis and conveys an inaccurate impression to the patient.
In many patients IBS may be characterized as diarrhea predominant (IBS-D),
constipation predominant (IBS-C), and for some patients, an alternation of diarrhea
with constipation (alternators).

I. PATHOGENESIS. The causes and pathogenesis of IBS remain obscure. Nevertheless,

clinical and laboratory evidence indicate that it most likely is a disorder of bowel
motility and increased sensory perception of pain. Constipation and abdominal
cramps are prominent complaints of many patients with IBS-C. These symptoms
could be explained on the basis of hypertonic segmental contractions, which would
slow transit by increasing the resistance to passage of feces. On the other hand, it is
possible that patients with diarrhea (IBS-D) have a hypomotile bowel, which would
decrease resistance to passage of feces, or that they simply have an increase in peri-
staltic contractions.
A. Myoelectric activity of the colon is composed of slow waves and spike poten-
tials superimposed on the slow waves. In healthy individuals, slow-wave fre-
quency ranges from 6 to 10 cycles per minute, although rates of 3 cycles per
minute occur some of the time. The superimposed spike potentials take the form
of short spike bursts and long spike bursts. The short spike bursts are less than
5 seconds and occur at the same time as the slow waves, resulting in muscular
contractions of the same frequency as the slow waves. On the other hand, long
spike bursts last from 15 seconds to several minutes and produce sustained con-
tractions. Abnormalities in colonic myoelectric activity have been described in
patients with IBS, but the findings have been inconsistent and, thus far, of no prac-
tical clinical use.
B. Intestinal motor activity. In patients with IBS the increase in colonic motor
activity that normally occurs after eating is blunted but continues longer than in

TABLE 33-1 Synonyms for Irritable Bowel Syndrome

Irritable colon syndrome Splenic flexure syndrome

Spastic bowel syndrome Functional bowel disease
Spastic colitis Psychophysiologic bowel disease
Mucous colitis Nervous bowel

227
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228 Part V: Specific Complaints and Disorders

asymptomatic individuals and may even become stronger. Emotional stress also
induces colonic motor activity, both in healthy individuals and in patients with
IBS, but it is possible that symptoms are perceived to a greater degree in patients
with IBS. Balloon distention of the rectosigmoid colon in patients with IBS causes
spastic contractions of greater amplitude than in asymptomatic subjects.
Furthermore, there is evidence that patients with IBS who complain of gaseous
distention and abdominal cramps cannot tolerate quantities of small-bowel intra-
luminal gas that are easily tolerated by healthy individuals (see Chapter 34).

II. DIAGNOSIS
A. Clinical presentation
1. Symptoms. Patients with IBS typically complain of crampy abdominal pain,
diarrhea, or constipation. In some patients, chronic constipation is punctuated
by brief episodes of diarrhea. A minority of patients have only diarrhea.
Symptoms usually have been present for months to years, and it is common for
patients with IBS to have consulted several physicians about their complaints
and to have undergone one or more gastrointestinal evaluations.
2. Timing of symptoms. The patient may be able to correlate symptoms with
emotional stress, but often such a relation is not evident or becomes apparent
only after careful questioning as the physician becomes acquainted with the
patient. If abdominal cramps are a feature, they often are relieved temporarily
by defecation. Bowel movements may be clustered in the morning or may occur
throughout the day, but rarely is the patient awakened at night. Stools may be
accompanied by an excessive amount of mucus, but blood is not present unless
there is incidental bleeding from hemorrhoids.
3. The differential diagnosis is broad, including most disorders that cause diar-
rhea and constipation (see Chapters 28, 29, 30, and 35). However, there are several
features that suggest the diagnosis of IBS (Table 33-2). Several organic disorders
may mimic IBS and, in fact, may be unrecognized for years in patients who
mistakenly have been diagnosed as having IBS. Patients with lactose intoler-
ance typically have postprandial diarrhea associated with crampy pain (see
Chapter 31). They are healthy in all other respects. A careful history and a trial
of a lactose-free diet usually are sufficient to make a diagnosis. Celiac sprue,
Crohn’s disease, and endometriosis also can masquerade as IBS because of the
vagueness of the symptoms in many patients. A clinical history of postprandial
abdominal pain suggests the possibility of gallbladder, pancreatic, or peptic
disease. Because IBS may affect the entire digestive tract, belching and symp-
toms of gastroesophageal reflux and dyspepsia are common in patients with IBS.
Anorexia, weight loss, fever, rectal bleeding, and nocturnal diarrhea
all suggest a cause other than IBS for the patient’s symptoms. The physician

TABLE 33-2 Features Suggestive of Irritable Bowel Syndrome

Characteristic Uncharacteristic

Constipation or diarrhea or both Anorexia

Crampy abdominal pain Weight loss
Mucus in stools Rectal bleeding
Symptoms related to stress Fever
Weight stable or increasing Nocturnal diarrhea
Appearance of health Recent onset of symptoms
Chronic symptoms
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Chapter 33: Irritable Bowel Syndrome 229

Clinical and Laboratory Evaluation of Patients

TABLE 33-3
with Suspected Irritable Bowel Syndrome

All patients Selected patients

Stool for occult blood Ultrasound of gallbladder

If diarrhea, stool for leukocytes, ova, Abdominal and pelvic CT scan
parasites, bacterial pathogens Serum amylase level
Lactose tolerance test
UGI endoscopy, colonoscopy and mucosal
biopsy of small bowel and colon

CT, computed tomography; UGI, upper gastrointestinal.

should remember, however, that other gastrointestinal disorders can develop

in patients with IBS, thus one should be alert to a change in the patient’s
complaints.
4. Physical examination. Patients generally appear healthy, although they may
be somewhat tense or anxious. If abdominal pain is a prominent symptom, vol-
untary guarding may be evident, and sometimes a tender, firm sigmoid colon is
palpable. A thorough physical examination, including a rectal examination, is
important in the evaluation for a non-IBS disorder.
B. Diagnostic studies. Because the diagnosis of IBS is largely one of exclusion, a
number of clinical and laboratory studies should be performed to rule out other
treatable disorders (Table 33-3). The extent of the evaluation depends on the age
of the patient, nature of the patient’s symptoms, and the adequacy of previous
evaluations.
Again, it is important to note that patients with IBS are not immune to the
development of other gastrointestinal disorders. Thus, the length of time that has
elapsed since the last evaluation and the character of the current symptoms affect
the decision of whether to proceed again with further diagnostic studies.
1. Routine tests such as a complete blood count, an erythrocyte sedimentation
rate, and a stool test for occult blood are appropriate for all patients. If the
patient complains of diarrhea, the stool should be examined for leukocytes,
ova, parasites, and bacterial pathogens.
2. Whether additional diagnostic studies are indicated is a matter of judgment.
If the postprandial pain is predominantly in the upper abdomen, ultrasonogra-
phy of the gallbladder may be indicated to rule out gallstones. Postprandial
pain also raises the possibility of pancreatic disease. If the clinical context is
suggestive of a pancreatic disorder, a serum amylase level and perhaps a com-
puted tomography (CT) scan of the abdomen are indicated. A lactose toler-
ance test may be necessary to confirm lactase deficiency in some patients. If
there is blood in the stool, colonoscopy and an upper-GI endoscopy may be
indicated. Lymphocytic and collagenous colitis can be diagnosed only by
colonic mucosal biopsies. Small-bowel biopsy may be indicated to rule out
small-intestinal mucosal disease (e.g., celiac sprue, Whipple’s disease, Crohn’s
disease, and others). Because Crohn’s disease can be confused with IBS, an
upper gastrointestinal series with a small-bowel follow-through should be per-
formed in patients with persistent abdominal pain, particularly if they have had
some weight loss. In selected patients, capsule endoscopy may be helpful.

III. TREATMENT (TABLE 33-4)

A. Emotional support. Making the diagnosis of IBS is sufficient in some patients to
alleviate anxiety about their symptoms. In particular, patients who suffer from
cancer phobia are relieved to learn that they are cancer-free. However, most
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230 Part V: Specific Complaints and Disorders

TABLE 33-4 Treatment of Irritable Bowel Syndrome

All patients Anticholinergics–antispasmodics

Reassurance and emotional support (e.g., dicyclomine hydrochloride
Stress reduction [Bentyl], 10–20 mg b.i.d.–q.i.d.)
Judicious use of tricyclic Patients with diarrhea
antidepressants and serotonin Antidiarrheal agents (e.g.,
reuptake inhibitors diphenoxylate hydrochloride
Patients with abdominal pain and [Lomotil], 2.5–5.0 mg, or loperamide
constipation hydrochloride [Imodium], 2 mg q6h
Increase dietary fiber p.r.n.)
Stool softeners (e.g., Colace) Increase dietary fiber
Laxatives (e.g., lactulose, MiraLax, Tricyclic antidepressants
and Senokot)

b.i.d., twice a day; q.i.d., four times a day; p.r.n., as needed.

patients with IBS experience no relief merely from reassurance. Many have carried
the diagnosis of IBS for years and continue to experience distressful symptoms
despite supportive reassurance and diet and drug therapy. Although these patients
often understand that they have a “nervous bowel,” that understanding does little
to alleviate symptoms, and they continue to seek treatment. Stress reduction pro-
grams may be helpful.
B. Diet and fiber therapy. The commonsense approach to diet therapy is the most
appropriate. There is no need for bland or highly restrictive diets in the treatment
of IBS. Patients should avoid foods that they find cause symptoms. If lactose-
containing foods produce cramps and diarrhea, these should be eliminated from
the diet.
The role of fiber in the treatment of IBS has been controversial. However,
clinical experience suggests that a high-fiber diet and/or fiber supplements provide
symptomatic relief in some patients. Patients with crampy abdominal pain and
constipation seem most likely to benefit, although sometimes patients with watery
diarrhea also experience a firming of their stools after the fiber content of the diet
has been increased. However, fiber supplements may result in increased gas and
bloating due to bacterial fiber.
C. Drug therapy
1. Antispasmodics. Unfortunately, drug therapy of IBS often is empiric. Patients
with diarrhea and abdominal pain may benefit from a so-called antispasmodic.
These drugs are anticholinergic in their mode of action, but whether they actually
relieve spasm is conjectural. A reasonable choice is dicyclomine hydrochloride,
10 to 20 mg three to four times daily because it is less likely than others to
cause unpleasant nongastrointestinal anticholinergic side effects. Regardless of
what preparation is used, patients should be cautioned about the possibility of
the development of dry mouth, blurred vision, and urinary retention.
2. Laxatives should be used judiciously in the treatment of the IBS with constipa-
tion (IBS-C). However, many patients with constipation become dependent on
the long-term use of laxatives and may need to be withdrawn from these agents.
3. Tegaserod (Zelnorm), a partial 5-HT4 agonist, has clinical efficacy in the treat-
ment of IBS-C in female patients up to age 65. It facilitates the secretion of
serotonin within the intestinal wall and thus enhances peristalsis through the
GI tract. It is contraindicated in patients with cardiovascular risk factors.
(Zelnorm has been removed from the U.S. market by the manufacturer for fur-
ther evaluation of its safety in long-term use.)
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Chapter 33: Irritable Bowel Syndrome 231

4. Lubiprostone (Amitiza) is indicated in the treatment of chronic constipation in

both male and female adults of all ages. It increases small- and large-intestinal
stool transit by increasing the stool fluid content and volume. Its mode of action
is stimulation of chloride channels of the intestinal mucosal and facilitation of
chloride and water secretion into the small-intestinal lumen. Since excess water
and eletrolytes are reabsorbed in the colon it does not result in systemic elec-
trolyte or water imbalance.
5. Diphenoxylate hydrochloride (Lomotil) and loperamidehydrochloride
(Imodium). The diarrhea of IBS often responds to low doses of diphenoxylate
or loperamide hydrochloride (see Table 33-4). These drugs are synthetic opioids
with low potential for abuse. They control diarrhea by reducing gastrointesti-
nal motility and by inhibiting watery secretion. Loperamide hydrochloride
(Imodium) may be preferred for long-term use because of its longer duration of
action. Also, it does not cross the blood–brain barrier and thus is less likely to
cause addiction.
6. Tranquilizers and antidepressants may be useful in selected patients for the
short-term management of situational anxiety and depression. Low-dose tricyclic
antidepressants such as amitriptyline hydrochloride (Elavil) or desipramine
hydrochloride (Norpramin) may be helpful in some patients with diarrhea-
predominant IBS. Serotonin uptake inhibitors (SSRIs) such as fluoxetine
hydrochloride (Prozac), sertraline hydrochloride (Zoloft), and paroxetine (Paxil)
may help some patients with IBS. Cymbalta, a newer psychotropic agent, may
also be useful.

Selected Readings
Cash BD, et al. Fresh perspectives in chronic constipation and other functional bowel
disorders. Rev. Gastroenterol Disord. 2007;7(3):116–133.
Hammer J, et al. Disturbed bowel habits in patients with non-ulcer dyspepsia. Ailment
Pharmacol Ther. 2006;24:405–I0.
Henningsen P, et al. Management of functional somatic syndromes. Lancet. 2007;369:
946–955.
Johanson JF, et al. A dose-ranging, double-blind, placebo-controlled study of lubiprostone
in subjects with irritable bowel syndrome and constipation (c-IBS). Gastroenterology.
2006;130(4 suppl 2):A-131.
Longstreth GF, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491.
Marshall JK, et al. Post-infectious irritable bowel syndrome (IBS) after the Walkerton
outbreak of waterborne gastroenteritis (GE). Gastroenterology. 2006;130(4 suppl 2):
A-T1160.
Pimentel M, et al. A 10 day course of rifaximin, a nonabsorbable antibiotic, produces a
durable improvement in all symptoms of irritable bowel syndrome: A double-blind,
randomized controlled study. Gastroenterology. 2006;130(4 suppl 2):A-134.
Quigley EMM. The use of probiotics in functional bowel disease. Gastroenterol Clin
North Am. 2005;34:533–545.
Saier MH Jr, et al. Priobiotics and prebiotics in human health. J Mol Microbiol Biotechnol.
2005;10:22–25.
Sander DS, et al. Association of adult coeliac disease with irritable bowel syndrome:
A case-controlled study in patients fulfilling ROME II criteria referred to secondary
care. Lancet. 2001;358:1504–1508.
Spiller R. Clinical update: irritable bowel syndrome. Lancet. 2007;369:1586–1588.
Tack J, et al. A randomized controlled trial assessing the efficacy and safety or repeated
tegaserod therapy in women with irritable bowel syndrome with constipation. Gut.
2005;54(12):1707–1713.
Tack J, et al. Functional gastroduodenal disorders. Gastroenterology. 2006;I30:I466–79.
79466_CH34.qxd 1/2/08 12:31 PM Page 232

34 INTESTINAL GAS AND BLOATING

G as occurs normally within the gastrointestinal tract, yet many patients complain of
excessive gas. The complaint of gas has no uniform connotation. Some patients mean that
they belch too much, others experience abdominal discomfort and attribute it to gas,
whereas still others regard the amount of flatus passed as being excessive.

I. COMPOSITION AND SOURCES OF INTESTINAL GAS

A. Composition. Nitrogen, oxygen, carbon dioxide, hydrogen, and methane make
up more than 99% of the volume of intestinal gas. Their proportions vary widely
in healthy people (Table 34-1). These five gases are odorless; the characteristic
odor of flatus is conferred by a combination of trace gases that together constitute
no more than 1% of the total volume of intestinal gas. The odoriferous trace gases
include ammonia, hydrogen sulfide, volatile amino acids, and short-chain fatty
acids.
B. Sources. All people swallow air in variable amounts. Swallowed air is the major
source of nitrogen and oxygen (Fig. 34-1). Nitrogen and oxygen also diffuse from
the blood into the intestinal lumen. Oxygen is largely consumed by intestinal aer-
obic bacteria.
Large amounts of carbon dioxide are generated by neutralization of gastric
acid, fatty acids, and amino acids within the upper gastrointestinal tract.
Carbonated drinks also provide an exogenous source of carbon dioxide. Most car-
bon dioxide within the upper gastrointestinal tract is absorbed and excreted by the
lungs. Carbon dioxide in flatus is derived largely from the action of bacteria on
intestinal substrates. Bacterial action on intestinal substrates also produces hydro-
gen and, in about one third of adults, methane.

TABLE 34-1 Composition and Sources of Intestinal Gas

Gas Amount (%) Sources

Nitrogen 25–80 Swallowed air, diffusion from blood

Oxygen 0.1–2.5 Swallowed air, diffusion from blood
Carbon dioxide 4.5–30.0 Neutralization of gastric acid, fatty
acids, and amino acids by bicarbonate
Ingestion of carbonated beverages
Bacterial action on intestinal substrates
Hydrogen 0.5–50.0 Bacterial action on intestinal substrates
Methane 0–25 Bacterial action on intestinal substrates
Trace gases (ammonia,
1 Bacterial and digestive action on
hydrogen sulfide, intestinal substrates
volatile amino acids,
short-chain fatty acids)

232
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Chapter 34: Intestinal Gas and Bloating 233

Figure 34-1. Diagram of the gastrointestinal tract, indicating the sources and composition of
intestinal gas. (From Eastwood GL. Core Textbook of Gastroenterology. Philadelphia: Lippincott
Williams & Wilkins; 1984:188. Reprinted with permission.)

II. PATHOGENESIS. Patients with gaseous symptoms may complain of belching, abdom-
inal pain and bloating, or of excessive flatus. The pathogenesis of each condition is
different. Also, there is considerable overlap in the patients who complain of gas and
bloating and those with irritable bowel syndrome (see Chapter 33).
A. Belching is caused by the eructation of swallowed air. If the normal volume of
swallowed air cannot be passed into the proximal small bowel because of a motil-
ity disorder, gastroparesis or gastric outlet obstruction, or due to an incompetent
lower esophageal sphincter (LES), belching may develop. Thus, patients with gas-
troesophageal reflux disease (GERD), gastric carcinoma, peptic ulcer disease, or
uremia may complain of belching.
Patients with gallbladder disease often belch for unknown reasons.
Sometimes belching is a nervous habit, and the swallowed air may not even reach
the stomach before eructation takes place. Rarely, belching of feculent-smelling gas
indicates chronic gastric stasis or a gastrocolic fistula.
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234 Part V: Specific Complaints and Disorders

B. Abdominal pain and bloating are often attributed to an excess of gas. In some
instances, failure to adequately digest a component of food (e.g., lactase defi-
ciency) with consequent bacterial degradation and gas production is responsible
for the abdominal pain and bloating. In other patients, the cause of symptoms is
unclear. When patients with abdominal pain and bloating who did not have spe-
cific food intolerance were compared to healthy people, they did not differ with
respect to volume or content of intestinal gas, either under fasting conditions or
after a meal. However, patients with gaseous complaints seem to have more reflux
of gas from the duodenum into the stomach and experience painful symptoms
after infusion of gas into the proximal small bowel in volumes that are well toler-
ated by healthy people. Thus, patients who complain of bloating and abdominal
gas may be suffering from a defect in gut motility and a decreased threshold to
pain rather than from too much gas. As indicated previously, some of these patients
may suffer from irritable bowel syndrome.
C. Excessive flatulence may result from a disorder of intestinal motility but usually
is a consequence of increased amounts of gas produced by the action of bacteria
on dietary substrates. Lactase deficiency is a good example, although the list of
dietary substrates that could be implicated is virtually endless. Bacterial degrada-
tion of undigested carbohydrates and simple sugars also cause gas and bloating.

III. DIAGNOSIS
A. Belching. A careful history may identify nervous air swallowing or ingestion of
excessive quantities of carbonated beverages. An abdominal ultrasound examina-
tion to evaluate the gallbladder and either an upper gastrointestinal (GI) x-ray series
or endoscopy to evaluate the proximal gastrointestinal tract may be indicated.
B. Abdominal pain and bloating. Patients who complain of abdominal pain and
bloating present a different diagnostic problem. Some have intolerance for a
specific dietary component, such as lactose. Other organic diseases must be con-
sidered, such as celiac sprue, regional enteritis, recurrent partial small-bowel
obstruction, or even giardiasis. The evaluation of such patients usually includes
ultrasound of the abdomen, Esophagogastroduodenoscopy (EGD), biopsy,
upper GI and small-bowel x-ray series, and, if stools are loose, stool examina-
tion for ova, parasites, and bacterial pathogens and possibly colonoscopy and
biopsy.
C. Excessive flatus. Complaints of excessive flatus should be evaluated by a search
for a specific food or group of foods that may be causing symptoms.

IV. TREATMENT. Unless a specific diagnosis such as gallstones, peptic ulcer, or lactase
deficiency is made, the treatment of patients who complain of gas is often unreward-
ing. Patients with nervous air swallowing may improve simply by becoming aware of
their air swallowing. Elimination of milk, legumes, cabbage, and similar foods, and
white-sugar- and flour-containing foods may be effective in patients who complain of
abdominal pain, gas, bloating, or flatus. Extensive elimination diets are helpful in
occasional patients who have the perseverance to eliminate one dietary constituent at
a time each week for several weeks.
In patients who do not have a demonstrable, treatable disorder or in whom a spe-
cific food has not been implicated, so-called antispasmodic agents, such as dicyclomine
hydrochloride, or bulking agents sometimes are useful. However, bulking agents,
because they contain nondigestible substrates, have the potential for increasing
flatus. Some patients have responded to stress-reduction techniques or psychological
counseling.

Selected Readings
Camilleri M. Treating irritable bowel syndrome: Overview, perspective and future
therapies. Br J Pharmacol. 2004;141:1237–1248.
Comilleri M. Diabetic gastroparesis. New Engl J Med. 2007;356:820–829.
Floch MH. Use of diet and probiotic therapy in the irritable bowel syndrome: Analysis of
the literature. J Clin Gastroenterol. 2005;39(4 suppl 3):S243–S246.
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Chapter 34: Intestinal Gas and Bloating 235

Levitt MD, et al. The relation of passage of gas and abdominal bloating to colonic gas
production. Ann Intern Med. 1996;124:422.
Levitt MD, et al. Evaluation of an extremely flatulent patient, case report and proposed
diagnostic and therapeutic approach. Am J Gastroenterol. 1998;93:2276.
Pimentel M, et al. Eradication of small intestinal bacterial overgrowth reduces symptoms
of irritable bowel syndrome. Am J Gastroenterol. 2000;95(12):3503–3506.
Poredenoord AJ, et al. Physiologic and pathologic belching. Clin Gastroenterol Hepatol.
2007;5(7):772–775.
Reddymason S, et al. New methodology in assessing gastric emptyizing and gastrointestinal
transit. US Gastroenterol Rev. 2007;1:19–22.
Reid G. Porbiotics in gastrointestinal management—what’s new. US Gastroenterol Rev.
2007;1:66–75.
Serra J, et al. Intestinal gas dynamics and tolerance in humans. Gastroenterology. 1998;
115:542.
Spiller R. Clinical update: irritable bowel syndrome. Lancet. 2007;369:1586–1588.
Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology. 2003;124:1662–1671.
Suarez FL, et al. An understanding of excessive intestinal gas. Curr Gastroenterol Rep.
2000;2:413.
Suarez FL, et al. Intestinal gas. Clin Perspect Gastroenterol. July/August 2000:209.
79466_CH35.qxd 1/2/08 12:32 PM Page 236

35 DIVERTICULAR DISEASE

T he term diverticular disease generally refers to diverticulosis of the colon and its
complications. However, diverticula can occur throughout the gastrointestinal tract. In the
esophagus, diverticula may be associated with dysphagia (see Chapter 21). Diverticula of
the stomach usually are asymptomatic. In the small intestine, they can predispose to bac-
terial overgrowth and malabsorption (see Chapter 31). In this chapter, we confine the dis-
cussion to diverticula of the colon.
Colonic diverticulosis is exceedingly common in westernized countries. The preva-
lence of diverticula increases with age: About 30% of the general population at age 60 and
about 80% at age 80 have colonic diverticula. Although 90% of people with diverticula
remain asymptomatic, because of the high prevalence of the condition, symptomatic diver-
ticular disease occurs frequently.

I. DEFINITIONS. Several of the terms used to describe colonic diverticula and their com-
plications have caused confusion or have been misused. Thus, it is important to review
some terminology (Table 35-1).
A single outpocketing from the bowel wall is called a diverticulum. Because
diverticulum is a Latin neuter word, it ends in um, and its plural form ends in a. Thus
several outpocketings are referred to as diverticula, not diverticuli or diverticulae.
The presence of a diverticulum or diverticula is called diverticulosis. Diverticu-
losis does not imply a pathologic condition or set of symptoms. Diverticulitis means
inflammation in one or more diverticula. Sometimes the diagnosis of diverticulitis is
assumed on the basis of clinical symptoms (see section IV.A.1) that may overlap with
the symptoms of irritable bowel syndrome (see Chapter 33) and gaseousness (see
Chapter 34). In the absence of firm evidence for diverticulitis, perhaps a more general
term should be used, such as diverticular disease or symptomatic diverticulosis.

II. PATHOGENESIS. True diverticula, that is, those in which the walls contain all layers
of the bowel, are found occasionally in the colon. However, the most prevalent colonic
diverticula are pseudodiverticula. These are herniations of mucosa and submucosa
through the muscularis propria at the sites of penetration of the nutrient arteries. The
development of diverticula seems to be related to increased pressure within the lumen
of the bowel, which over time causes the herniations. Most diverticula occur in the
sigmoid and descending colons, although they also may be found more proximally.
Epidemiologically, the prevalence of colonic diverticulosis is related to age and
diet. The condition is much more frequent in populations in which dietary fiber has
been replaced by refined carbohydrates.

TABLE 35-1 Terminology of Diverticulosis

Diverticulum—singular
Diverticula—plural
Diverticulosis—the presence of one or more diverticula
Diverticulitis—inflammation in one or more diverticula
Diverticular disease—any complication of diverticulosis

236
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Chapter 35: Diverticular Disease 237

III. SYMPTOMATIC DIVERTICULOSIS

A. Diagnosis
1. Clinical presentation. Most people with colonic diverticula are asymptomatic.
However, some patients complain of chronic or intermittent left lower abdom-
inal pain. Typically, these patients also report infrequent bowel movements or
constipation. Flatulence and dyspepsia may accompany the lower abdominal
pain. In many patients, symptoms of irritable bowel syndrome and of divertic-
ular disease are indistinguishable.
The physical examination may reveal tenderness and a firm, feces-filled
sigmoid colon in the left lower abdomen. By rectal examination, the stool may
be firm, and tests for occult blood are usually negative.
2. Diagnostic studies. It is a matter of clinical judgment whether patients with
mild symptoms of diverticular disease require diagnostic studies if they are oth-
erwise healthy. However, patients who consult a physician for a particular com-
plaint usually are concerned enough that additional investigation is warranted.
Certainly, diagnostic studies are indicated if the patient is anorectic or has lost
weight or if there is blood in the stool.
A complete blood count and urinalysis are appropriate initial laboratory
studies. These should be followed by CT scan of abdomen and pelvis, sigmoi-
doscopy, and barium enema x-ray or colonoscopic examination (Fig. 35-1). In
many patients with symptomatic diverticulosis, the evaluation is similar to that
for irritable bowel syndrome (see Chapter 33).

Figure 35-1. Barium enema x-ray examination showing extensive diverticulosis throughout the
colon. Note the numerous barium-filled pockets protruding outside the bowel lumen. The distortion
of the normal mucosal architecture by diverticulosis sometimes makes it difficult to exclude carci-
noma or polyp by barium enema examination.
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238 Part V: Specific Complaints and Disorders

3. The differential diagnosis includes the irritable bowel syndrome, frank diver-
ticulitis (see section IV), carcinoma of the colon, Crohn’s disease or proctocol-
itis, urologic disorders, and gynecologic disorders.
B. Treatment. In many respects, the treatment of uncomplicated symptomatic diver-
ticulosis resembles the treatment of irritable bowel syndrome (see Chapter 33).
A high-fiber diet has been shown to alleviate the discomfort of diverticular disease.
Fiber also can be added in the form of unprocessed bran and other hydrophilic
bulk laxatives, such as Metamucil. Antispasmodic–anticholinergic drugs, such as
dicyclomine hydrochloride, may be useful in the treatment of crampy abdominal
pain. In constipated patients, lubiprostone (Amitiza) may be preferred to induce
softer stools. Cathartic laxatives should be avoided.

IV. DIVERTICULITIS
A. Diagnosis
1. Clinical presentation. The point at which symptomatic diverticulosis
becomes diverticulitis may be difficult to determine in some patients. Fully
developed diverticulitis is characterized by acute lower abdominal pain,
fever, and tachycardia. The lower abdomen is tender to palpation, and there
may be rebound tenderness. The patient may present with an acute abdomen
(see Chapter 13); more typically, symptoms evolve over several hours or
days. A mass in the lower abdomen may connote an abscess or inflammatory
phlegmon. Bowel sounds may be active if partial or complete obstruction
has occurred, or they may be hypoactive or absent if peritonitis has devel-
oped. A rectal examination may help localize the abscess or inflammatory
mass.
In some patients with chronic diverticulitis, chronic inflammatory changes
may develop that resemble inflammatory bowel disease (IBD) or Crohn’s disease.
2. Diagnostic studies
a. Blood studies. The white blood cell count typically is elevated in acute diver-
ticulitis, with a predominance of immature forms (left shift) in the differential
count. Hemoglobin and hematocrit levels may reflect hemoconcentration.
b. A urinalysis may show white blood cells and red blood cells. An unusual
complication of diverticulitis is a colonic–urinary bladder (colovesical) fis-
tula; in this condition, the urine contains large numbers of white blood cells
and bacteria and possibly feces. Patients with colovesical fistulas frequently
complain of pneumaturia.
c. Plain abdominal x-ray films, both supine and upright, should be obtained.
Air-fluid levels suggest ileus or obstruction. Free air in the abdomen, indi-
cating a perforated diverticulum, may be evident on lateral decubitus
abdominal films or under the diaphragm on the upright chest x-ray film.
d. Computed tomography (CT) scan and/or ultrasound of the abdomen and
pelvis are helpful in identifying the inflammatory mass or an abscess cavity
and by demonstrating other conditions in the differential diagnosis, such as
an ovarian cyst.
e. Sigmoidoscopy, colonoscopy, and barium enema x-ray examinations.
Sigmoidoscopy or colonoscopy may be performed cautiously if perforation
is not suspected. However, it is best to delay these tests until symptoms have
subsided. The radiologic diagnosis of diverticulitis by barium enema
requires evidence of perforation of a colonic diverticulum by demonstrating
either a fistulous tract or an abscess cavity. Although these findings are
unequivocal, they are not necessary to make the clinical diagnosis of diver-
ticulitis. Acute lower abdominal pain in association with fever and an ele-
vated white blood cell count in a person with demonstrated diverticula are
sufficient.
3. The differential diagnosis includes inflammatory bowel disease, infectious
C. difficile or ischemic colitis, carcinoma of the colon, other causes of bowel
obstruction, gynecologic disorders (e.g., ruptured ovarian cyst), and urologic
disorders (e.g., renal colic).
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Chapter 35: Diverticular Disease 239

B. Treatment
1. General. Patients with severe acute diverticulitis are best treated by allowing
nothing by mouth and administering intravenous fluids and electrolytes.
Intravenous broad-spectrum antibiotics, such as the combination of ampicillin,
gentamicin, and ciprofloxacin hydrochloride or second- or third-generation
cephalosporin and metronidazole, are indicated and should be continued for 10
to 14 days. If an abscess is identified by ultrasonography or CT scan, percuta-
neous drainage under ultrasound or CT guidance should be considered.
Patients whose symptoms are less severe may be treated with oral antibiotics
(e.g., ciprofloxacin hydrochloride 500 mg p.o. b.i.d. or Levaquin 500 mg q.d.
and metronidazole 250–500 mg p.o. t.i.d. for 10–14 days).
2. Surgery. Few would argue that generalized peritonitis, with or without evi-
dence of free perforation, should be treated surgically. Unresolved obstruction
and colovesical fistula also are indications for surgical treatment. Because most
patients with uncomplicated diverticulitis recover with medical treatment and
do not have recurrences of acute disease, surgery is not recommended routinely.
However, failure to improve after several days of medical treatment or recur-
rence after successful treatment are indications for surgery in a patient whose
operative risk is reasonable.
A one-stage procedure with resection and primary anastomosis is ideal. If
active infection is evident, a primary resection with a proximal colostomy, fol-
lowed several months later by reanastomosis, may be indicated. Alternatively,
the surgeon may elect to perform a proximal diverting colostomy as the pri-
mary operation, allowing the infection and inflammation to resolve, before
proceeding at a later date with the resection and anastomosis.

V. Diverticular bleeding is one of the most common causes of lower gastrointestinal

bleeding in older people. The clinical dictum is that diverticular bleeding and acute
diverticulitis rarely coexist. However, it is likely that some degree of peridiverticular
inflammation is present in patients who bleed from diverticula. (See Chapter 14 for a
discussion of the diagnosis and treatment of diverticular bleeding.)

Selected Readings
Anaya DA, et al. Risk of emergency colectomy and colostomy in patients with diverticular disease. Arch
Surg. 2005;140:681–685.
Chapman JR, et al. Diverticulitis: a progressive disease? Do multiple recurrences predict less favorable
outcomes? Ann Surg. 2006;243:876–883.
Constantinide VA, et al. Primary resection with anastomosis is Hartman’s procedure in nonelectric surgery
for acute colonic diverticulitis: a systematic review. Dis Colon Rectum. 2006;49:966–981.
Jacobs DO. Diverticulitis. N Eng J Med. 2007;357:2057–2066.
Jensen DM, et al. Urgent colonoscopy for diagnosis and treatment of severe diverticular hemorrhage.
N Engl J Med. 2000;342:78.
Korzenik JR. Case closed? Diverticulitis: epidemiology and fiber. J Clin Gastroenterol. 2006;40:
Suppl 3:S112–S116.
Kumar RR, et al. Factors affecting the successful management of intraabdominal abcesses with antibiotics
and the need for percutaneous drainage. Dis Colon Rectum. 2006;49:183–189.
Mueller MH, et al. Long-term outcome of conservative treatment in patients with divrticulitis of the
sigmoid colon. Eur J Gastroenterol Hepatol. 2005;17:649–654.
Parra-Blanco A. Colonic diverticular disease: pathophysiology and clinical picture. Digestion. 2006;
73(suppl)1:47–57.
Rafferty J, et al. Buie and the Standards Committee of the American Society of Colon and Rectal
Surgeons. Practice parameters for sigmoid diverticulitis. Dis. Colon Rectum. 2006;49:939–944.
Ramirez FC, et al. Successful endoscopic hemostasis of bleeding colonic diverticula with epinephrine
injections. Gastrointest Endosc. 1996;43:167.
Salzman H, et al. Diveticular disease: diagnosis and treatment. Am Fam Physician. 2005;72:1229–1234.
Stollman N, et al. Diverticular disease of the colon. Lancet. 2004;363:631–639.
Zaidi E, et al. CT and clinical features of acute diverticultis in an urban U.S. population: rising frequency
in young, obese adults. AJR Am J Roentgenol. 2006;187:689–694.
79466_CH36.qxd 1/2/08 12:33 PM Page 240

36 CONSTIPATION AND FECAL IMPACTION

C onstipation, like diarrhea, is difficult to define with precision due to the wide vari-
ation in normal bowel habits. However, because 95% of people have at least three bowel
movements per week, for practical purposes constipation can be defined as a condition in
which fewer than three stools per week are passed. In addition, patients may experience
difficulty in passing stools, may use manual maneuvers (i.e., digital disimpaction, pressing
on the perineum and/or lower abdomen), and may complain of hard and lumpy stools.
The economic costs of constipation are impressive. In the United States, more than
$250 million is spent annually on laxatives. Additional costs of unknown magnitude are
incurred in the evaluation of patients for underlying disorders that may predispose to
constipation.

I. ETIOLOGY AND DIFFERENTIAL DIAGNOSIS. Constipation is a symptom, not a dis-

ease. It may develop as a functional condition, in which case it appears to be related
to changes in bowel motility or pelvic floor dysfunction; or it may be a secondary con-
dition, such as symptomatic diverticular disease or irritable bowel syndrome; or it
may result from a specific abnormality or disorder, such as an obstructing cancer of
the colon or hypothyroidism or other causes as listed in Table 36-1.
A. Diet. Functional or idiopathic constipation occurs with somewhat greater fre-
quency in women and increases in prevalence with age in both sexes. It appears to
be influenced by the composition of the diet, particularly the fiber and fluid con-
tent. Normal daily stool weight in the United States ranges from 100 to 200 g, and
the stool is composed of about 80% water. Increasing the dietary fiber and fluid
intake increases the stool weight, primarily because of retained water, and increases
the stool frequency.
Recent evidence also indicates that several grams of dietary carbohydrates
and polysaccharides found in fruits and vegetables normally pass undigested to the
colon, where they are metabolized by bacteria to osmotically active particles and
cathartic agents. Thus, a diet low in fruits and vegetables may contribute to
constipation.
B. Lack of exercise also is associated with constipation. It’s difficult to determine
whether this is the major predisposing factor to constipation of bedridden patients
and elderly people and if their poor dietary intake of fiber, carbohydrates, and fluids
is an additional important factor.
C. Colonic obstruction. Some patients with an obstructing lesion, such as a sigmoid
carcinoma or a fecal impaction, may have diarrhea (overflow diarrhea), character-
ized by the frequent passage of small amounts of loose or liquid stool. This is
because the stool water proximal to the obstruction is poorly absorbed and seeps
around the obstruction. The physician must be attentive in recognizing this condi-
tion in such patients to avoid inappropriate treatment with antidiarrheal medica-
tions, which would only worsen the underlying disorder.

II. DIAGNOSIS
A. Clinical presentation
1. History. To paraphrase a common saying, “One man’s constipation is another
man’s diarrhea.” Thus it is important that the physician determine what the
patient means by constipation. How frequently are stools passed? What is their

240
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Chapter 36: Constipation and Fecal Impaction 241

TABLE 36-1 Differential Diagnosis of Constipation

“Functional” constipation
Conditions in which constipation is part of the symptom complex
Irritable bowel syndrome
Symptomatic diverticular disease
Disorders of bowel muscle function (e.g., pseudoobstruction, myotonic dystrophy,
systemic sclerosis)
Disorders that can cause constipation
Endocrine–metabolic conditions (e.g., diabetes, hypokalemia, hypothyroidism,
hypercalcemia, pregnancy)
Bowel obstruction (e.g., neoplasm, benign stricture, ischemic colitis, surgical stenosis)
Disorders causing painful passage of stool (e.g., proctitis, anal fissure)
Neurogenic disorders (e.g., Hirschsprung’s disease [aganglionosis], autonomic neuropathy,
multiple sclerosis, Parkinson’s disease)
Drugs (e.g., calcium channel blockers, nitrates, anticholinergics, antidepressants, opiates)

consistency? Is the condition acute or chronic? Are there associated signs or

symptoms, such as weight loss, abdominal pain, or blood in the stool?
Constipation of long duration accompanied by crampy abdominal pain
without weight loss or systemic symptoms suggests functional or idiopathic
constipation, irritable bowel syndrome, or symptomatic diverticular disease.
On the other hand, constipation of recent onset, blood in the stool, or change
in the stool caliber suggests another causative disorder, such as carcinoma of
the lower bowel. A history of calcium channel blocker, anticholinergic, or opi-
ate drug intake should be sought as a possible explanation for constipation.
2. The physical examination may give a clue to systemic disease, such as
hypothyroidism or a neurologic disorder. An abdominal mass may indicate an
obstructing lesion or merely firm stool in the colon. The character of the stool
itself and the tone of the anal sphincter as well as the possible presence of anal
fissures, painful hemorrhoids, and rectal prolapse can also be determined by
rectal examination.
B. Diagnostic studies. Most patients who have constipation that is severe enough
to cause them to consult a physician require some diagnostic evaluation beyond
the history, physical examination, and stool testing for occult blood. The extent of
the evaluation varies according to the individual circumstances, but in general, a
minimal evaluation of constipation may include serum electrolytes, thyroid func-
tion studies, blood glucose, serum calcium, and a colonoscopic examination if
indicated.
Anorectal manometry (see Chapter 8, section III) is helpful in making the
diagnosis of the rare disorder Hirschsprung’s disease (aganglionosis of the dis-
tal colon or rectum). The normal relaxation of the internal anal sphincter is absent
in Hirschsprung’s disease when the rectum is distended by stool or a balloon.
However, some patients with long-standing constipation in whom the rectal vault
remains chronically distended may also have an abnormal rectoanal reflex. The
barium enema in Hirschsprung’s disease characteristically shows a narrow rectum,
corresponding to the aganglionic segment. For best results, the barium enema
should be performed in an unprepared bowel, that is, with stool in the distal colon.
Rectal biopsies are of value only if they show the presence of ganglia, thus ruling
out Hirschsprung’s disease. Sampling error and failure to obtain deep enough tis-
sue may yield inadequate specimens. The absence of ganglia does not necessarily
imply Hirschsprung’s disease, however. If the diagnosis remains in question, a full-
thickness surgical biopsy of the rectal wall may be necessary.
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242 Part V: Specific Complaints and Disorders

III. Treatment of constipation involves addressing a number of issues, including lifestyle,

diet, and medications. If a specific cause of constipation is identified, therapy of course
includes treatment of the cause.
A. Lifestyle. Some patients literally do not take time to have a bowel movement.
Their busy schedules require frequent cortical inhibition of the urge to defecate.
Although it may be difficult to put in practice, simply recognizing the urge to defe-
cate and acting on it may be the first step for many patients in achieving normal
bowel habits. A program of mild exercise (e.g., walking) for sedentary patients
may also be helpful.
B. Diet. The average daily intake of crude fiber in the United States is about 4 g. This
is roughly one fifth of the daily intake of the native populations of some areas in
Africa, who typically have four or five bulky stools per day. Because fiber is
hydrophilic, increasing the fiber intake should produce large stools that require
more frequent passage.
Dietary fiber can be increased by eating fruits, vegetables, potato skins, and
bran-containing foods. Some patients find it easier to consume fiber in the form of
raw, unprocessed bran, 1 to 2 tablespoons per day, or a commercial product such
as Metamucil. Bran or commercial fiber supplements should be mixed in water or
juice before ingestion. Increasing total daily intake of water to 1 to 2 L augments
the laxative effects of dietary fiber.
C. Laxatives. Most patients with chronic constipation have had ample experience
with laxatives. Sometimes a vicious cycle develops: Constipation is relieved by lax-
atives or cathartics; because the bowel has been evacuated, the patient has no urge
to pass stool for several days and becomes concerned; the patient perceives consti-
pation again and resumes intake of laxatives.
The chronic use of laxatives is to be avoided, although from time to time a
laxative may be necessary to relieve constipation.
1. Mineral oil. Virtually any patient with functional constipation responds to
mineral oil, provided enough is given. The initial dosage is 1 tablespoon a day,
preferably taken in the morning while the patient is upright for several hours
after taking it. If that amount is ineffective, the dosage can be increased by
1 tablespoon each day until constipation is relieved, up to a maximum of
4 tablespoons. Mineral oil should be avoided in patients who might aspirate it
since lupoid pneumonia may occur. Also, it should not be taken chronically
because of its interference with the absorption of fat-soluble vitamins.
2. Lactulose. If a patient has a genuine need for frequent laxation, a reasonable
alternative to the traditional laxatives and cathartics is lactulose. Lactulose is a
disaccharide that is not absorbed but is metabolized by colonic bacteria to
osmotically active particles. It also acidifies the stool by the production of lac-
tic acid. The usual dosage is 1 to 2 tablespoons one to four times daily.
Lactulose may also be given in powder form. (See Chapter 17 for discussion of
the use of lactulose in the treatment of hepatic encephalopathy.)
3. Polyethylene glycol (PEG) laxative, MiraLax, or GlycoLax may be used daily
to lubricate the stool and relieve constipation. The usual dose is one to four
glasses each day. This agent is indicated only for short-term use.
4. Tegaserod (Zelnorm) is a partial 5-HT4 agonist that increases gastrointestinal
motility by facilitating the release of serotonin in the Auerbach’s plexus. It has
been shown to increase spontaneous bowel movements when taken 6 mg twice
daily. It is indicated in adults up to age 65 and is not recommended for patients
who may have intraabdominal adhesions, gallbladder disease or cardiovascular
risk factors. However, it has been removed from the market in the U.S.
5. Lubiprostone (Amitiza) is novel agent approved by the FDA for the treatment
of chronic idiopathic constipation in adults, regardless of age and gender. It
works intraluminally by enhancing chloride ion and water secretion into
the intestinal lumen by stimulating the chloride-2 channels found in crypts in
the apical membrane of intestine (especially in the small intestine [SI]). The
increased stool water increases stool volume and intestinal transit. The excess
water and electrolytes are reabsorbed in the proximal colon. This mechanism
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Chapter 36: Constipation and Fecal Impaction 243

of action results in soft stools and predictable bowel function. In the studies,
there were no electrolyte or fluid imbalances or drug–drug interactions.
Recommended dose is 24
g p.o. b.i.d. Clinical studies show that it is also
effective in the treatment of IBS-C.

IV. FECAL IMPACTION. Impaction of a firm, immovable mass of stool is found most
often in the rectum but may occur within the sigmoid or descending colon. Fecal
impaction typically develops in elderly, inactive patients, but the differential diagnosis
is the same as for ordinary constipation, ranging from functional constipation to
hypotonic bowel disorders to distal bowel obstruction (Table 36-1).
Regardless of the underlying cause, the treatment consists of several
approaches. First, the impaction may be broken manually during digital rectal exam-
ination. If that attempt is not completely successful, the mass can be softened and
evacuated by warm water or saline lavage through a sigmoidoscope or rectal tube.
Sometimes glycerine suppositories or mineral oil enemas are useful. Oral mineral oil
may be administered if there is no risk of aspiration. Occasionally dilatation of the
anus under general anesthesia is used to gain access to the fecal impaction. Rarely,
surgical removal of the impaction is necessary.

Selected Readings
Brandt LJ, et al. Systematic review on the management of chronic constipation in North
America. Am J Gastroenterol. 2005;100:S5–S22.
Camilleri M, et al. Effect of a selective chloride activator, lubiprostone, on gastrointestinal
transit, gastric sensory and motor functions in healthy volunteers. Am J Physiol
Gastrointest Liver Physiol. 2006;290:G942–G947.
Cash BD, et al. Fresh perspectives in chronic constipation and other functional bowel
disorders. Rev. Gastroenterol Disord. 2007;7(3):116–133.
Chiaroni G, et al. Biofeedback is superior to laxatives for normal transit constipation due
to pelvic floor dyssynergia. Gastroenterology. 2006;130:675–664.
Dukas L, et al. Association between physical activity, fiber intake, and other lifestyle variable
and constipation in a study of women. Am J Gastroenterol. 2003;98:1790–1796.
Ehrenpreis E. Constipation, colonic inertia and colonic marker studies. Pract Gastroenterol.
2001;24:18.
Fernandez-Banares F. Nutritional care of the patient with constipation. Best Pract Res Clin
Gastroenterol. 2006;20:575–587.
Kamm MA, et al. Tegaserod for the treatment of chronic constipation: A randomized,
double-blind placebo-controlled multinational study. Am J Gastroenterol. 2005;100:
362–372.
Kamm, MA. Clinical case: Chronic constipation. Gastroenterology. 2006;131:233–239.
Lembo A, et al. Chronic constipation. N Engl J Med. 2003;349:1360–1368.
Muller-Lissner SA, et al. Myths and misconceptions about chronic constipation. Am J
Gastroenterol. 2005;100:232–242.
Rao SS. Constipation: Evaluation and treatment. Gastroenterol Clin North Am. 2003;32:
659–683.
Talley NJ. Definition, epidemiology, and impact of chronic constipation. Rev Gastroenterol
Disord. 2004;4(suppl 2):S3–S10.
Ueno R, et al. Evaluation of safety and efficacy in a twelve-month study of lubiprostone for
the treatment of chronic idiopathic constipation. Am J Gastroenterol. 2006;101:S491.
Abstract 1269.
Wald A. Chronic constipation: advances in management. Neurogastroenterol Motil. 2007;
19:4–10.
79466_CH37.qxd 1/2/08 12:35 PM Page 244

37 INFLAMMATORY BOWEL DISEASE

I nflammatory bowel disease (IBD) refers to the idiopathic inflammatory bowel dis-
orders, ulcerative colitis, Crohn’s disease, and microscopic or lymphocytic and collagenous
colitis. Clearly, a number of other conditions also are associated with inflammation, includ-
ing bacterial and parasitic infections, ischemic bowel disease, and radiation colitis.
Nevertheless, until the causes of ulcerative colitis and Crohn’s disease are identified, the
term inflammatory bowel disease serves a useful purpose in distinguishing these conditions
from other bowel disorders.
IBD has a prevalence of 0.3% to 0.5% in the adult U.S. population with a slight
female preponderance. It is most commonly seen in young patients between the ages of
15 and 25; however, there is second peak in the incidence of IBD at 40 to 60 years.
Approximately 15% of patients with IBD have close relatives who also have IBD.

I. DISTINGUISHING FEATURES OF ULCERATIVE COLITIS (UC) VERSUS CROHN’S

DISEASE (Table 37-1). Ulcerative colitis is an inflammatory disorder of the mucosa
of the rectum and colon. The rectum is virtually always involved, and if any portion
of the remaining colon is involved, it is in a contiguous manner extending proximally
from the rectum. On the other hand, Crohn’s disease typically affects all layers of the
bowel wall and may do so usually in a patchy distribution throughout the entire gas-
trointestinal (GI) tract. Crohn’s disease may involve any part of the GI tract from the
mouth to the anus, most frequently involves the terminal ileum. Approximately one
third of cases involve the small bowel only, one third involve the colon only, and one
third involve both the colon and the small bowel. The rectum may be spared. Crohn’s
disease in the elderly usually involves only the colon. Crohn’s disease of the esopha-
gus, stomach, and duodenum is rare, but may present alone or in combination with
involvement of the other segments of the GI tract.
Patients with Crohn’s disease may have predominantly inflammatory, obstructive,
or perianal disease. Chronic inflammation leads to fibrosis and strictures. Fistulas may
connect the diseased bowel with another bowel loop (enteroenteric), the bladder
(enterovesical), vagina, or skin (enterocutaneous). The presentation of Crohn’s disease

Distinguishing Features of Ulcerative Colitis

TABLE 37-1
versus Crohn’s Disease

Ulcerative colitis Crohn’s disease

Pain crampy, lower abdominal, relieved by Pain constant, often in right lower quadrant,
bowel movement not relieved by bowel movement
Bloody stool Stool usually not grossly bloody
No abdominal mass Abdominal mass, often in right lower quadrant
Affects only colon May affect small and large bowel, occasionally
esophagus and stomach
Mucosal disease (granulomas are Transmural disease (granulomas found in a
not a feature) minority of patients)
Continuous from rectum May be discontinuous (skip areas)

244
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Chapter 37: Inflammatory Bowel Disease 245

Extraintestinal Manifestations of Inflammatory

TABLE 37-2
Bowel Disease

Common to both ulcerative colitis

and Crohn’s disease
Conditions related
Area Condition to Crohn’s disease

Joints Peripheral arthritis Gallstones

Sacroiliitis Renal oxylate stones
Ankylosing spondylitis Vitamin B12 deficiency
Skin Erythema nodosum Malabsorption
Pyoderma gangrenosum Anemia
Eyes Conjunctivitis Obstructive hydronephrosis
Iritis
Episcleritis
Liver Fatty infiltration
Chronic active hepatitis
Pericholangitis
Sclerosing cholangitis
Bile duct carcinoma
Kidneys Pyelonephritis
Renal stones
General Amyloidosis
Anemia

varies with the site and degree of involvement. It may be gradual in onset or may pre-
sent with recurrent episodes of abdominal pain, diarrhea, and/or low-grade fever.
Physical examination may reveal a right lower quadrant mass or tenderness, anal fis-
sures, perianal abscess, or fistulas. Some 10% to 15% of patients with either ulcerative
colitis or Crohn’s disease have extraintestinal manifestations of the disease (Table 37-2).
In most patients, the two disorders can be distinguished on clinical, radiologic,
and pathologic grounds. However, in about 20% of patients with IBD affecting the
colon, it is impossible to make a definitive diagnosis (indeterminate colitis).

II. ETIOLOGY. Because the causes of IBD are not known, the pathophysiology of the
disorders is incompletely understood. An immunologic mechanism in the pathogenesis
is assumed, but the inciting causes are incompletely understood. The intestinal flora,
various cytokines including tumor necrosis factor (TNF) and some of the interleukins,
and other factors are thought to play a role in the ongoing inflammatory process.
Hereditary factors appear to play a role; patients with ulcerative colitis or
Crohn’s disease have a 10% to 15% chance of having a first- or second-degree rela-
tive who also has one or the other type of IBD.

III. DIFFERENTIAL DIAGNOSIS. A variety of conditions can cause intestinal inflamma-

tion and present with signs and symptoms similar to those of ulcerative colitis or
Crohn’s disease. These conditions are summarized in Table 37-3.
The bacterial and parasitic colitides must be considered in all patients with
new-onset bloody diarrhea and rectal or colonic mucosal inflammation; also, some
infections are associated with exacerbations of known idiopathic IBD. Thus, stool
examinations for ova and parasites, bacterial pathogens, and Clostridium difficile
toxin is indicated. Eosinophilic colitis–enteritis is a variation of IBD of unknown eti-
ology. It may represent an allergic reaction of the mucosa to allergen.
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246 Part V: Specific Complaints and Disorders

TABLE 37-3 Differential Diagnosis of Inflammatory Bowel Disease

Bacterial colitis Behçet’s colitis

Campylobacter Sexually transmitted colitis
Shigella Gonococcus
Salmonella Chlamydia
Escherichia coli (invasive) Herpes
Clostridium difficile–associated colitis Trauma
Parasitic colitis Crohn’s disease look-alikes
Amebiasis Lymphoma
Schistosomiasis Yersinia
Ischemic colitis Tuberculosis
Radiation colitis

Ischemic colitis, which may occur in patients with cardiac arrhythmias or

cardiovascular disease, or individuals taking estrogen, birth control pills, or estrogen
agonists (SERMs), can be confused with IBD, particularly Crohn’s disease, because of
its segmental distribution and tendency to produce strictures.
Radiation bowel injury may involve any portion of the GI tract but typically affects
the rectum or sigmoid colon in patients who have received pelvic irradiation. Acute radi-
ation injury occurs during or shortly after the radiation treatment, but chronic radiation
colitis, which is a form of ischemic bowel disease, may occur months to years later.
Because lymphoma, Yersinia enterocolitis, and tuberculosis often involve the dis-
tal small intestine and the cecum, they may be confused with Crohn’s disease. The diag-
nosis of lymphoma may be made by biopsy of enlarged lymph glands or other involved
organs. Sometimes laparotomy is necessary. Y. enterocolitis can be diagnosed by stool
cultures or serologic tests. Enteric tuberculosis is rare in the United States but should be
suspected in patients from areas of the world in which the disease is endemic.

IV. CLINICAL PRESENTATION

A. History
1. Signs and symptoms. Patients with ulcerative colitis typically complain of
bloody stool. If the inflammation is confined to the rectum, stools may be
formed. Patients may even present with constipation. More extensive involve-
ment of the colon is associated with bloody diarrhea caused by the diminution
in absorption of water, electrolytes, and oxidation by the affected mucosa.
Crampy lower abdominal pain is temporarily relieved by bowel movements.
Patients with Crohn’s disease usually have a history of additional chronic
signs and symptoms, such as fatigue, weight loss, and persistent abdominal pain,
often in the right lower quadrant. Blood in the stool occurs if there is colonic
involvement. Stools are often formed but may be loose if there is extensive involve-
ment of the colon or if there is disease of the terminal ileum. The latter causes diar-
rhea because of the malabsorption of bile salts and the consequent inhibition of
water and electrolyte absorption in the colon. Bile acid malabsorption also may
reduce the bile acid pool, which leads not only to fat malabsorption but also to
supersaturation of cholesterol in bile in the gallbladder and risk of development of
cholesterol gallstones. The fat malabsorption also predisposes to oxalate renal
stones. The inflammatory nature of Crohn’s disease can be responsible for several
complications outside the bowel, including hydronephrosis due to ureteral
obstruction and pneumaturia secondary to an enterovesical fistula.
2. Onset and course of symptoms. Both Crohn’s disease and ulcerative colitis
typically begin in childhood or early adulthood, although ulcerative colitis may
develop in patients of any age; a second peak in incidence of Crohn’s disease
occurs in the elderly, in whom the illness can be confused with ischemic bowel
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Chapter 37: Inflammatory Bowel Disease 247

disease. Most patients with ulcerative colitis experience intermittent exacerba-

tions with nearly complete remissions between attacks.
In ulcerative colitis, about 5% to 10% of patients have one attack without
subsequent symptoms for decades. A similar number have continuous symptoms,
and some have a fulminating course requiring total proctocolectomy. Patients
with Crohn’s disease generally have recurrent symptoms of varying frequency.
3. Growth retardation and failure to develop sexual maturity are common in
children and adolescents with ulcerative colitis or Crohn’s disease. In fact, these
complications may be the primary reason for the patient to consult a physician.
Growth failure is rarely caused by endocrine abnormalities but rather is a con-
sequence of reduced caloric and nutritional intake or utilization. Treatment of
the ulcerative colitis or Crohn’s disease, with attention to good nutrition, usu-
ally results in reestablishment of normal growth and development.
B. Physical examination. Patients with IBD often are thin and undernourished.
Pallor due to anemia of blood loss or chronic disease may be evident. Tachycardia
may result from dehydration and diminished blood volume, and a low-grade fever
may be present. Mild-to-moderate abdominal tenderness is characteristic of ulcer-
ative colitis. A tender mass in the right lower quadrant is typical of Crohn’s disease.
The rectal examination in patients with ulcerative colitis reveals bloody stool or
frank blood, whereas in Crohn’s disease, perianal scarring or fistulas may be iden-
tified. Abdominal distention, rebound tenderness, absence of bowel sounds, and
high fever suggest toxic megacolon or abscess (see section VII.A). Extraintestinal
manifestations of IBD may be evident (Table 37-2).

V. DIAGNOSTIC STUDIES. IBD is diagnosed based on integration of clinical, endo-

scopic, histopathologic, radiologic, and other imaging data.
A. Laboratory studies. A complete blood count (CBC), urinalysis, and serum chem-
istry tests are appropriate during the initial evaluation of a patient with suspected IBD.
Serologic examination of blood for specific antibodies, such as ANCA, is rec-
ommended. Several different serologic markers for IBD have been identified,
including perinuclear antineutrophil cytoplasmic antibodies (pANCA), antibodies
to Saccharomyces cerevisiae (ASCA), pancreatic antibodies (PAB), antibodies to
the outer membrane Porin C of Escherichia coli (anti-Omp C), antibodies to a
DNA sequence from Pseudomonas Fluorescens (anti-12) and anti-C B 1 flagellin.
These antibodies are not sufficiently sensitive to be used to screen for IBD in
the general population. However, they may be helpful for predicting the phenotype
of IBD. The finding of ASCA
/pANCA predicted Crohn’s disease in 80% to
95%, the finding of pANCA
/ASCA predicted ulcerative colitis in about 90%
of patients tested. Several studies suggest that Crohn’s disease patients with more
positive serologies and higher titers are more likely to have complications such as
strictures, fistulae, perforations, and requirement for surgery.
Several commercial laboratories offer “panels” of the serologic markers using
computerized recognition patterns to distinguish subtypes of IBD (CD vs. UC).
B. Examination of the stool. Stool from patients suspected of having ulcerative col-
itis should be examined for leukocytes and ova and parasites, cultured for bacter-
ial pathogens including Escherichia coli O157:47, Campylobacter jejuni, and
Yersinia enterocolitica and tested for C. difficile toxin titer.
1. Fecal leukocytes are common to most inflammatory conditions of the colon
but are not common in irritable bowel syndrome or noncolonic diarrhea.
2. Examination for ova and parasites may establish the diagnosis of amebiasis,
although the sensitivity of stool examination for amebae is lower than 40%.
The serum indirect hemagglutination and gel diffusion precipitant tests are
more than 90% sensitive for amebic infection. It is particularly important to
obtain several fresh stool samples for examination of ova and parasites before
barium-contrast studies are performed because the presence of barium in the GI
tract can obscure ova and parasites for a week or more.
3. Bacterial pathogens may be identified by stool culture. Of particular interest is
Campylobacter jejuni ileocolitis, which may present with acute, colicky lower
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248 Part V: Specific Complaints and Disorders

abdominal pain, fever, bloody diarrhea with mucus, and many of the endoscopic,
radiologic, and histologic features of ulcerative colitis. The disease typically sub-
sides within several days but may run a protracted course, in which case treat-
ment with erythromycin or ciprofluxin may provide relief of symptoms.
Another pathogen that may complicate the diagnosis of ulcerative colitis is
C. difficile, the bacterial agent that has been implicated in antibiotic-associated
pseudomembranous colitis. C. difficile may be relevant to ulcerative colitis in two
ways. First, antibiotic-associated colitis may be confused with ulcerative colitis.
Second, C. difficile may be responsible for exacerbations of preexisting ulcerative
colitis. When chronic ulcerative colitis is in remission, the demonstration of C. dif-
ficile toxin in the stool is probably related to recent treatment with sulfasalazine
or antibiotics. Colonic infection with enteroinvasive E. coli, especially E. coli
O157:H7, may resemble ulcerative colitis and present with similar findings.
C. Flexible sigmoidoscopy or colonoscopy is indicated in the evaluation of rectal
bleeding of any cause. The normal rectal and colonic mucosa appears pink and
glistening. When the bowel is distended by insufflated air, the submucosal vessels
can be seen. Normally, there is no bleeding when the mucosa is stroked with a cot-
ton swab or touched gently with the tip of the sigmoidoscope.
In ulcerative colitis, the mucosal surface becomes irregular and granular. The
mucosa is friable, meaning that it bleeds easily when touched. With more severe
inflammation, bleeding may be spontaneous. These findings are nonspecific and
may be seen in most of the conditions listed in Table 37-3. In some patients with
chronic ulcerative colitis, pseudopolyps develop. The rectal mucosa is normal in
patients who have Crohn’s disease without rectal involvement. If the disease does
affect the rectum, the appearance may be similar to that of ulcerative colitis or may
include aphthous, deep or linear ulcerations and fissures.
D. Mucosal biopsy. Sigmoidoscopic or colonoscopic mucosal biopsies in patients
with IBD generally are safe; however, they should not be performed if toxic
megacolon is suspected. In ulcerative colitis, the histopathology of the rectal
mucosa may show a range of abnormal findings. These include infiltration of the
mucosa with inflammatory cells, flattening of the surface epithelial cells, a
decrease in goblet cells, thinning of the mucosa, branching of crypts, and crypt
abscesses (Fig. 37-1). All of these findings, including crypt abscesses, are non-
specific and may be seen in other colitides, including Crohn’s disease, bacterial
colitis, and amebiasis. Because endoscopic biopsies include mucosa and a vari-
able proportion of submucosa, the transmural nature of Crohn’s disease cannot
be appreciated. However, substantial submucosal inflammation or fissuring of
the mucosa may suggest Crohn’s disease. The finding of noncaseating granulo-
mas also strongly favors a diagnosis of Crohn’s disease (Fig. 37-2), but granulo-
mas are identified infrequently in mucosal biopsies from patients with established
Crohn’s disease and may accompany other conditions, such as tuberculosis and
lymphogranuloma venereum. The identification of amebic trophozoites by
biopsy confirms that diagnosis. Large numbers of mucosal eosinophils are typi-
cal of eosinophilic colitis.
E. Radiography
1. The plain film of the abdomen usually is normal in patients with mild-to-
moderate IBD. Air in the colon may provide sufficient contrast to indicate loss
of haustral markings and shortening of the bowel in ulcerative colitis or nar-
rowing of the bowel lumen in Crohn’s disease.
In severe colitis of any cause, the transverse colon may become dilated
(Fig. 37-3). When this finding is accompanied by fever, elevated white cell
count, and abdominal tenderness, toxic megacolon is likely (see section VII.A).
The plain film of the abdomen should be repeated once or twice a day in
patients with toxic megacolon to follow the course of colonic dilatation.
2. Computed tomography (CT) of the abdomen and pelvis may be very informa-
tive in patients presenting with chronic or recurrent abdominal pain and suspicion
of IBD. Abdominal masses and abscesses, fistulas, and, most commonly, inflam-
matory thickening of the involved bowel wall may facilitate the diagnosis of IBD.
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Chapter 37: Inflammatory Bowel Disease 249

Figure 37-1. Photomicrograph of a rectal biopsy from a patient with ulcerative colitis.
Inflammatory cells predominate in the lamina propria. The surface epithelial cells are flattened, and
the number of goblet cells appears to be decreased. A crypt abscess is evident (arrow).

Figure 37-2. Photomicrograph of the mucosa and submucosa within a resected portion of termi-
nal ileum from a patient with Crohn’s disease. A fissure extends through the mucosa to the submu-
cosa. At the base of the fissure is a granuloma. (From Eastwood GL. Core Textbook of Gastroenterology.
Philadelphia: Lippincott Williams & Wilkins; 1984:137. Reprinted with permission.)
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250 Part V: Specific Complaints and Disorders

Figure 37-3. Plain abdominal x-ray film of a patient with toxic megacolon showing dilatation of the
transverse colon.

3. CT enterography and colography are much more sensitive than UGI, SBFT,
and barium enema and should be preferred when available.
4. Barium enema should not be performed in patients who are acutely ill with
colitis because of the possibility that the preparation for barium enema or the
procedure itself may precipitate toxic megacolon. Even in patients with mild-to-
moderate colitis, vigorous cathartic preparation for barium enema should be
avoided. Rather, oral PEG electrolyte solutions are preferable to prepare
patients for barium enema or colonoscopy.
Some patients with early ulcerative colitis have normal findings on bar-
ium enema examination. Double-contrast studies, however, usually reveal a
diffuse granular appearance of the mucosa. Loss of haustration, ulcerations,
pseudopolyps, and shortening of the bowel are later developments (Fig. 37-4).
Sometimes an area of narrowing requires differentiating between a benign
stricture and carcinoma. Reflux of barium into the terminal ileum may show
dilatation and mild mucosal irregularity for several centimeters, the so-
called backwash ileitis associated with ulcerative colitis.
The diagnosis of Crohn’s disease can be inferred on the basis of several
radiologic findings (Fig. 37-5; see also Fig. 31-2). Narrowing of the bowel
from fibrosis or edema and formation of fistulas reflect the transmural
nature of the disease. Involvement of the terminal ileum and presence of
skip areas in either the large or the small bowel strongly favor a diagnosis
of Crohn’s disease rather than ulcerative colitis. Finally, mucosal changes of
deep ulcers and linear fissures are characteristic of Crohn’s disease.
5. An upper GI and small-bowel series may be of diagnostic help in the evalu-
ation of Crohn’s disease. It is important to remember that, in the radiologic
evaluation of a patient with chronic or recurrent abdominal pain, a routine
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Chapter 37: Inflammatory Bowel Disease 251

Figure 37-4. Barium enema x-ray examination showing ulcerative colitis involving the entire colon
from rectum to cecum. The mucosal pattern is irregular, the haustral markings are absent from the
left colon, and several pseudopolyps are evident (arrows). (From Eastwood GL. Core Textbook of
Gastroenterology. Philadelphia: Lippincott Williams & Wilkins; 1984:132. Reprinted with permission.)

upper GI series is not sufficient. It should be accompanied by a small-bowel

series to evaluate the small intestine for Crohn’s disease, tumors, and strictures.
The typical findings of Crohn’s disease in UGI and SBFT include stricture for-
mation and fistulous tracts.
As indicated previously, Crohn’s disease can affect any portion of the
digestive tract. However, about 75% of patients with Crohn’s disease have, at
a minimum, involvement of the terminal ileum. In about 5%, Crohn’s disease
involves the duodenum. Sometimes these patients clinically resemble patients
with peptic ulcer disease. Although they may improve with a peptic ulcer reg-
imen, symptoms typically recur. Nodularity and narrowing of the proximal
duodenum and sometimes involvement of the adjacent antrum are evident by
barium-contrast studies. The diagnosis is confirmed by endoscopy and biopsy.
F. Colonoscopy and upper GI endoscopy. Colonoscopy with intubation of the ter-
minal ileum is useful in diagnosis of IBD. Periodic colonoscopy also is recommended
for screening patients who have IBD for longer than 7 years for cancer and precan-
cerous changes (see section VII.C). Although the diagnosis of Crohn’s disease often
is made on the basis of clinical and radiologic findings, colonoscopy is useful in
obtaining biopsy material from the proximal colon and the terminal ileum to help
confirm the diagnosis. As with barium enema examination, colonoscopy may pre-
cipitate toxic megacolon in patients with severe colitis, thus should be performed
when clinically indicated. The preceding comments regarding preparation for bar-
ium enema apply also to colonoscopy.
Upper GI endoscopy may be useful in differentiating Crohn’s disease of the
duodenum from peptic ulcer disease.
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252 Part V: Specific Complaints and Disorders

Figure 37-5. Barium enema x-ray examination of a patient with Crohn’s disease showing a stric-
ture in the sigmoid colon. Several years before, the patient had undergone resection of the terminal
ileum and right colon with an ileum–transverse colon anastomosis. (From Eastwood GL. Core
Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins; 1984:143. Reprinted with
permission.)

G. Pill-cam imaging has become a newer useful tool in the diagnosis of small-
intestinal Crohn’s disease. The pill may become lodged in narrow structures and
may require surgical removal. Nonspecific superficial ulcers may signify Crohn’s
ulcers, or may have resulted from use of aspirin or nonsteroidal anti-inflammatory
drugs. Thus, clinical judgement is needed to make the appropriate diagnosis.

VI. TREATMENT
A. Diet and nutrition. Patients with mild symptomatic IBD usually are able to take
food orally. The diet should be nutritious. Traditionally, fiber has been restricted
during periods of active symptoms. Some patients cannot tolerate milk, which may
or may not be related to lactase deficiency. Patients with Crohn’s disease who have
terminal ileal involvement and steatorrhea may require supplemental fat-soluble
vitamins, medium-chain triglycerides, and parenteral vitamin B12. Replacement
iron may be indicated in patients who are iron-deficient. Patients in remission do
not require any restriction of fiber or other dietary constituent except as dictated
by his or her own experience.
In severe IBD, an elemental oral diet or nothing by mouth with total parenteral
nutrition (TPN) has been recommended when patients are hospitalized. The use of
TPN to treat fistulas of Crohn’s disease is controversial. Administration of TPN over
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Chapter 37: Inflammatory Bowel Disease 253

TABLE 37-4 Sulfasalazine and 5-ASA (Mesalamine) Preparations

Drug name Formulation Dosage

Azulfidine 500-mg tablets 1–2 tablets global p.o. q.i.d (1–4 g/d)
Dipentum 500-mg tablets 2 capsules p.o. b.i.d. (1 g/d)
Asacol 400-mg tablets 2–4 tablets p.o. t.i.d (2.4–4.8 g/d)
Pentasa 250-mg capsules 4 capsules p.o. t.i.d. (3–4 g/d)
Colazal 750-mg capsules 3 capsules p.o. t.i.d. (1,250 mg/d)
Rowasa enema 4 g-unit dose/60-mL 1–2 daily (preferably at bedtime)
enema
Canasa suppositories 500-mg rectal 1–2 times daily
suppositories

ASA, aminosalicylic acid; p.o., orally; q.i.d., four times daily; t.i.d., three times daily.

several weeks has been associated with the closure of a high proportion of fistulas.
However, the fistulas commonly recur after reinstitution of oral feedings.
B. Drugs. Because the etiology of IBD is incompletely understood, drug treatment is
aimed at alleviating and reducing inflammation.
1. Sulfasalazine and aminosalicylates (mesalamines) (Table 37-4).
Sulfasalazine (Azulfidine) historically has been the most commonly used drug
in the treatment of colitis. It has been show to be efficacious in the treatment of
UC and Crohn’s disease when the colon is involved. The drug consists of sul-
fapyridine linked to 5-aminosalicylic acid (5-ASA or mesalamine) via an azo
bond. Intestinal bacteria break the azo bond and release the two components.
The sulfapyridine moiety is systemically absorbed and excreted in the urine and
the 5-ASA moiety, the active component, stays in the intestinal lumen in con-
tact with the mucosa and eventually is excreted in the feces.
a. Side effects. Abdominal discomfort is common and is attributed to the
effects of the salicylate portion of the drug on the upper GI tract. This prob-
lem is minimized by ingestion of the sulfasalazine after eating. Patients also
may become folate-deficient because of competition between folate and sul-
fasalazine for absorption. Other side effects, such as skin eruptions and bone
marrow suppression, are less common and are attributed to the sulfa portion.
b. Dosage. The initial daily dose is low (1 g) to minimize GI side effects. A
therapeutic dose of 3 to 4 g per day is appropriate. A CBC and liver chem-
istry tests should be obtained before starting therapy, every 1 to 3 months
initially, and every 6 to 12 months during long-term treatment.
c. Maintenance treatment with sulfasalazine has been shown to reduce the
frequency of exacerbations of ulcerative colitis. The usual maintenance
dosage is 2 to 3 g per day in divided doses, although an occasional patient
may benefit from 1 g per day (i.e., 500 mg twice daily).
2. Other 5-ASA (mesalamine) preparations. Because the serious side effects of
sulfasalazine are related to the sulfa portion, there has been much interest in
developing similar drugs that retain the salicylate portion but replace the sul-
fapyridine. Several oral 5-ASA preparations are available (Table 37-4).
Olsalazine (Dipentum), which consists of two 5-ASA molecules joined
by an azo bond such as sulfasalazine, requires bacterial degradation in the
colon. It is as effective against active UC and in maintaining remission. High
incidence of diarrhea as a side effect of Dipentum limits its use in most patients.
Asacol is a controlled-release tablet form of 5-ASA, which is encapsu-
lated by an acrylic resin that dissolves at a pH higher than 6.0. It has been
shown to be effective in both active and remitted UC and Crohn’s disease,
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254 Part V: Specific Complaints and Disorders

especially when the ileum is involved. The usual dose is 2.4–4.8 mg daily in two
or three divided doses.
Pentasa is a controlled-release formulation of 5-ASA that is encapsulated
in ethylcellulose microgranules. It is effective in active and remitted UC and in
active Crohn’s disease regardless of disease location. Pentasa appears to help in
maintaining remission in both small-bowel and colonic Crohn’s disease. The
recommended dose is 1 g q.i.d.
Balsalazide disodium (Colazal) is a 5-ASA preparation containing an
azo bond. The active 5-ASA moiety is released in the colon by cleavage of the
azo bond by colonic bacteria. It is primarily effective in treating IBD involving
the entire colon, as well as left-sided colitis and proctitis. The recommended
dose is 750 mg three tablets t.i.d. one a day.
Once daily dosing with mesalamine (Liallda) has recently been made avail-
able. The tablets contain a novel matrix which protects the mesalamine from
degredation until it reaches the colon, then allows its gradual release through the
entire length of the colon. The recommended dose is 1–2 g 2–4 tablets daily. The
topical 5-ASA preparations include Rowasa enema and Canasa rectal supposito-
ries. These are effective in active and remitted distal UC and ulcerative proctitis.
The 5-ASA preparations are also recommended for patient with Crohn’s dis-
ease to prevent postoperative recurrence of Crohn’s disease, especially in patients
with colitis and to some extent in patients with small-bowel involvement. The
5-ASA preparations and sulfasalazine are safe to use in pregnant women.
3. Corticosteroids. Historically, corticosteroids have been used in patients with
severe UC or Crohn’s disease to induce a remission. Intravenous (IV) steroids (i.e.,
hydrocortisone 100 mg IV q6h or methylprednisolone 10–30 mg IV q6–8h) are
usually used in such patients. When patients can take oral medications, pred-
nisone at doses of 40 to 60 mg per day is usually given. If symptoms improve, the
drug is tapered and withdrawn over a period of several weeks to months. Steroids
are not recommended for maintenance therapy of UC or Crohn’s disease, because
steroids do not prevent relapse of Crohn’s disease or UC and they have major side
effects. However, many patients become steroid dependent and experience recur-
rence of symptoms when the dose of prednisone is reduced to less than 15 mg per
day. One strategy is to use 6-mercapopurine (6-MP), or azathioprine (Imuran)
for steroid-dependent patients to help taper them off steroids. Biologic agents
such as Remicade and Humira may be used instead of corticosteroids.
Several corticosteroid enema preparations are available for the treat-
ment of proctitis and distal colitis. These are usually administered once or
twice a day.
Budesonide (Entecort) is an orally administered corticosteroid that is
released in the ileum and right colon at a pH of about 5.5. It has low systemic
effects due to less than 20% absorption into the systemic circulation and a very
efficient first-pass metabolism in the liver. It is effective in treating Crohn’s dis-
ease involving the ileum and right colon, as well as microscopic (lymphocytic)
colitis. The dose is 9 mg daily in active disease. It is usually tapered from 6 to
3 mg daily after 2 to 6 months. It is helpful in inducing remission. The drug is
then stopped. Due to its low systemic bioavailability, it has minimal side effects
of glucocorticoid steroids. However, bone mineral density may diminish during
therapy. Patients receiving glucocorticoid therapy should be offered supplemen-
tal calcium and vitamin D.
4. Antibiotics. Most patients with mild-to-moderate IBD are successfully main-
tained on therapy with either sulfasalazine or 5-ASA and occasionally may
require systemic or topical steroid therapy to treat disease relapses. However,
about 20% to 25% of patients with UC and one third of patients with Crohn’s
disease require additional therapy for refractory disease, steroid dependency,
and fistulas. Bacteria is known to play an important role in the pathogenesis of
Crohn’s disease and it may play a role in UC. In Crohn’s diseases, the indica-
tions for the use of antibiotics include perianal disease, localized peritonitis due
to microperforation, bacterial overgrowth secondary to a chronic stricture, and
as an adjunct to drainage therapy for abscesses and fistulas. Antibiotics should
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Chapter 37: Inflammatory Bowel Disease 255

be considered in patients not responding to 5-ASA preparations prior to

initiating of corticosteroid therapy. The antibiotics most commonly used in IBD
include metronidazole, ciprofloxacin, Levaquin, and Xifaxan.
a. Metronidazole (Flagyl) has been shown to be effective in patients with
Crohn’s disease of the colon or combined small-bowel and large-bowel
disease as well as patients with perirectal Crohn’s disease and fistulas. Some
patients with UC or indeterminate colitis also respond successfully to metron-
idazole. The usual dosage is 250 to 500 mg three times daily. In patients with
Crohn’s disease, metronidazole therapy has been shown to decrease the sever-
ity of early recurrence and clinical recurrence rate at 1 year.
Major limitations regarding the use of metronidazole include its side
effects (peripheral neuropathy, stomatitis, nausea, and headache). Alcohol
should be avoided due to its potential Antabuse-like side effects. Its use dur-
ing pregnancy is controversial due to its potential teratogenic effects.
b. Ciprofloxacin hydrochloride (500 mg twice daily) has been successfully
used in patients with Crohn’s disease with colonic involvement as well as in
patients with perirectal and fistulizing Crohn’s disease. The data for the use
of ciprofloxacin hydrochloride in patients with UC are controversial; how-
ever, there is anecdotal evidence that the drug may be effective in some
patients with UC.
c. Metronidazole plus ciprofloxacin hydrochloride in combination has been
used in the treatment of active, refractory Crohn’s disease. In a comparison
trial with steroids, the remission rate was similar. This combination may also
be used in UC.
5. Immunomodulators
a. Azathioprine (Imuran, AZA) at 2 to 2.5 mg/kg/d or its active metabolite,
6-MP (1 to 1.5 mg/kg/d), is effective and safe. Indications include refractory
Crohn’s disease, steroid-dependent Crohn’s disease, fistulizing Crohn’s disease,
Crohn’s disease remission maintenance, refractory UC, steroid-dependent UC,
UC remission maintenance, and prevention of postoperative Crohn’s disease
recurrence. Maximum clinical response takes 2 to 3 months. Monthly or
bimonthly CBC is recommended to monitor and prevent neutropenia. Data are
available for their long-term safety when used longer than 5 years and, based
on renal transplant experience, these drugs seem to be safe for use during preg-
nancy. AZA is metabolized to 6-Thioguanine (6-T6) which is the active
metabolite. The blood level of T6 may be monitored to ensure proper dosing
of AZA. Thiopurine methyltransference (TPMT) plays a key role in the
metabolism of AZA. One in 300 persons are homozygous for a recessive muta-
tion and produce exceedingly high levels of 6-T6 and develop profound leu-
copenia. TPMT genotype/phenotype should be determined in patients prior
to initiation of AZA therapy. Allopurinol (a xanthine oxidase inhibitor) com-
petes with AZA for xanthine oxidase and increases levels of AZA metabolites.
The dose of AZA should be decreased in patients also taking Allopurinol.
b. Methotrexate (1.5–7.5 mg per week by mouth [p.o.] or 25 mg per week
intramuscularly [IM]) has been effective in the treatment of refractory and
steroid-dependent Crohn’s disease but not in UC. Its effect on long-term
remission with maintenance therapy is not clear. Clinical response is rapid
(2–8 weeks). Liver biopsy may be helpful prior to starting therapy in patients
with liver chemistry abnormalities to monitor adverse effects. Monthly mon-
itoring for bone marrow and hepatic toxicity is required. If cytopenias occur,
methotrexate should be withheld for 2 to 3 weeks and then restarted at
a lower dose. In all patients, liver biopsy should be performed after every
1,500 mg of methotrexate administered. A minority of patients develops
pulmonary fibrosis.
c. Cyclosporin (Neoral/Sandimmune) (4 mg/kg per day IV; therapeutic
range 250–350 mg/mL) has been used successfully in severe steroid refrac-
tory UC as a bridge therapy to either long-term immunomodulatory therapy
(i.e., with Imuran or 6-MP) or definitive colectomy (e.g., in pregnant or
young patients in whom immediate surgery is not optimal.) However, while
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256 Part V: Specific Complaints and Disorders

the short-term response rates are impressive, over half of these patients must
undergo colectomy during 6 months of follow-up. In patients with Crohn’s
disease, cyclosporin has not been consistently effective.
Oral cyclosporin at low doses (5 mg/kg per day) is not efficacious in
IBD. Higher doses (8–10 mg/kg per day) of cyclosporin may be more effec-
tive; however, the side effect profile (hypertension, and nephro- and bone
marrow toxicities) limits its usefulness. Cyclosporin should not be used for
the maintenance of remission for UC or Crohn’s disease.
Clinical response in patients who respond to cyclosporin therapy is rapid
(within 2 weeks). The total duration of therapy should not exceed 4 to 6
months. Monitoring of nephrotoxicity is required. The dose should be adjusted
downward whenever the baseline serum creatinine level increases by 30%.
d. Infliximab (Remicade) is a chimeric monoclonal antibody to human tumor
necrosis factor-2 (TNF-2), a proinflammatory cytokine that plays an important
role in the pathogenesis of Crohn’s disease. Controlled trials have demon-
strated high efficacy for infliximab in moderate to severely active Crohn’s dis-
ease, in fistulizing Crohn’s disease, and in severe UC with sufficient evidence
for its safety. Clinical response is rapid (within 1–2 weeks) and the duration of
response ranges from 8 to 12 weeks per infusion. Infliximab has probably
supplanted the role of cyclosporin and corticosteroids in Crohn’s disease.
Infliximab is administered IV (5 mg/kg) over 2 hours. Infusions for active or
fistulizing Crohn’s disease are given as three doses at 0, 2, and 6 weeks for a
starting dose. Infusion reactions may be minimized by pretreatment with an
antihistamine and a steroid preparation. To minimize symptomatic disease
recurrence, the IV infusions are repeated at 8-week intervals.
Toxicities observed for infliximab therapy include formation of human
antichimeric antibodies (HACA), autoantibodies and a serum sickness–like
delayed hypersensitivity reaction in some patients 2 to 4 years after initial
treatment. There may be activation of dormant tuberculosis (TB). Patients
should be tested for TB prior to initiation of therapy with infliximab. The risk
of development of lymphoma in treated patients seems to be slightly increased.
e. Adalimumab (Humira) (Human antitumor necrosis factor [TNF] mono-
clonal antibody) has been approved by the FDA for the treatment of rheuma-
toid arthritis and Crohn’s disease. It has also been shown to be effective in
the treatment of Crohn’s disease unresponsive to conventional therapies and
also to a percentage of patients who have not responded to Remicade or
who have lost their response to Remicade. The advantage of adalimumab
over Remicade is that it has less immunogenicity and that it is administered
subcutaneously (sc) 40 mg every 2 weeks after a starting dose of 80 mg sc.
The dose may be increased to weekly in refractory patients.
f. Certolizumab pegol (Cimzia) is a humanized TNF alpha Fab monoclonal
antibody fragment linked to polyethylene glycol (PEG). It is waiting for FDA
approval for the treatment of moderate to severe Crohn’s disease. This bio-
logic drug is administered subcutaneously at weeks 0, 4, and 8 weeks, then
once monthly at the same dose (400 mg). It has been shown to be effective
in inducing response and remission in adult patients with active Crohn’s dis-
ease unresponsive to conventional therapy as well as other biologic agents.
g. Thalidomide has shown anti-TNF activity in a subset of patients with
Crohn’s disease; however, due to its highly teratogenic potential, it is not
suitable for routine use.
h. Nicotine given in enema form has shown some benefit in patients with dis-
tal UC but due to its side effect profile, it is not widely used.
6. Prebiotics and probiotics. It is believed that luminal bacterial flora influ-
ences the development and/or progression of IBD.
Prebiotics are nutrients utilized by specific microorganisms and support the
growth of these organisms that interact with the host to improve the host barrier
function and impact the innate immune response. Prebiotics include carbohy-
drates resistant to digestion (i.e., inulin, lactulose, and other oligosaccharides).
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Chapter 37: Inflammatory Bowel Disease 257

Probiotics are live microorganisms that are important for the develop-
ment of a healthy innate immune system. Commonly used probiotics include
Lactobacillus, Bifidobacterium, and other organisms including yeast such as
Saccharomyces and combination VSL#3.
The data whether pre- and probiotics are helpful in IBD are controver-
sial. However, probiotics have been shown to be effective in the treatment of
pouchitis.
7. Antidiarrheal medications. If diarrhea does not improve with the previously
described medical therapy in patients with mild-to-moderate IBD, treatment
with an antidiarrheal drug may be helpful. Codeine is most effective, although
loperamide (Imodium) or diphenoxylate (Lomotil) may be preferred because
of their lower addictive potential. These and other opiate derivatives should
not be used in patients with severe IBD because of the possibility of inducing
toxic megacolon.
Nonsteroidal antiinflammatory drugs (NSAIDs) should not be used in
patients with IBD. The role of cyclooxygeranase (Cox)-2 NSAIDs in pain con-
trol for IBD is not clear.
8. Bile acid-binding resins and medium-chain triglycerides. Because many
patients with Crohn’s disease have involvement of the terminal ileum with con-
sequent bile acid malabsorption, diarrhea, and steatorrhea, treatment with a
bile acid-binding resin such as cholestyramine or with medium-chain triglyc-
eride supplements may be indicated (see Chapter 30) in addition to other
antidiarrheal drugs.
In summary, patients with mild and moderate IBD are usually started
on a 5-ASA, and clinical response is determined within 2 to 4 weeks. If patients
continue to be symptomatic, an AZA is added to the treatment. Patients who
achieve remission are followed at 1 to 3 months clinically. Those who do not
reach remission are then offered pulse steroid therapy or a biologic agent.
C. Psychotherapy. Formal psychotherapy appears to be of little benefit in the pri-
mary treatment of IBD. However, emotional support of the patient by the physi-
cian, family, clergy, and other concerned people is important. Psychotherapy may
be indicated in some patients to help them cope with living with a chronic disease.
D. Surgery
1. Ulcerative colitis. The standard noncontroversial indications for surgery in
ulcerative colitis include toxic megacolons perforation, abscess, uncontrollable
hemorrhage, unrelieved obstruction, fulminating disease, carcinoma, and high-
grade dysplasia on colonic biopsies. Usually a total proctocolectomy is per-
formed. Historically, this operation has been accompanied by a permanent
ileostomy. Currently rectal sphincter-saving operations are the norm. In this
operation, the rectal mucosa is removed, but the muscular wall of the rectum is
left intact. The terminal ileum is anastomosed to the anus, usually with the for-
mation of a reservoir pouch. If the operation is performed in an acutely ill
patient with severe colitis, it is usually carried out in two steps: the colectomy
first and the reanastomosis several months later.
Despite increased surgical experience and patient appeal, problems with the
ileal pouch–anal anastomosis remain. Technical failure occurs in approximately
5% to 8% of patients within the first 5 to 10 years. Pouchitis occurs acutely in
40% to 50% of patients. Most of these patients respond to a course of antibiotic
therapy with metronidazole or ciprofloxacin hydrochloride, or both. Xifaxan has
also been shown to be effective in some patients. Approximately 5% to 8% will
develop chronic pouchitis and require maintenance suppressive therapy or possi-
ble pouch takedown and formation of a permanent ileostomy. There are reports
of the development of neoplasia in the pouch after a number of years.
2. Crohn’s disease. Surgery in Crohn’s disease is indicated for perforation,
abscess, obstruction, unresponsiveness to treatment, intractable disease, and
some fistulas. Because removing a segment of diseased bowel does not “cure”
the patient of Crohn’s disease as proctocolectomy cures a patient with ulcera-
tive colitis, the dictum is to remove as little bowel as is necessary to correct the
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258 Part V: Specific Complaints and Disorders

problem. Patients with a single, short segment of Crohn’s disease respond the
best to surgery. The rectal sphincter-saving operation is not an option in
Crohn’s patients because of the possibility that anorectal Crohn’s disease may
develop later. Stricturoplasty may be a surgical option in some patients with
stricturing Crohn’s disease.
a. The recurrence rate after surgery of Crohn’s disease is high: 30% after
5 years, 50% after 10 years, and 70% after 15 years. Whether this is because
of some deleterious effect of surgery on the bowel or merely represents the
natural history of patients with severe Crohn’s disease is difficult to deter-
mine. In any event, the aim of surgery is to remove grossly diseased bowel
and preserve as much normal-appearing bowel as possible. If the terminal
ileum has been removed, the patient should undergo a Schilling test 3 to 6
months after surgery to survey for vitamin B12 malabsorption. Most patients
will require monthly vitamin B12 injections.
b. Fistulas often respond to medical treatment, and even those that persist do
not always require surgery. However, enterocutaneous fistulas that are
poorly tolerated by the patient and all enterovesical fistulas may require sur-
gical correction. Also, fistulas between loops of bowel should be corrected
surgically if clinically significant malabsorption occurs.

VII. SPECIAL ISSUES

A. Toxic megacolon and severe IBD. Toxic megacolon is a condition in which the
colon becomes atonic and dilated because of transmural inflammation. It is char-
acteristically associated with severe ulcerative colitis, but it may complicate any
severe inflammatory condition of the bowel, including Crohn’s disease, bacterial
colitis, amebiasis, pseudomembranous colitis, and ischemic colitis. Patients with
toxic megacolon are seriously ill. They typically have fever, elevated white blood
cell count, bloody diarrhea, and sepsis. Some patients with severe ulcerative colitis
do not have toxic megacolon but require similar intensive treatment.
1. Pathogenesis. In most instances of colitis, the inflammatory process is con-
fined to the mucosa and submucosa. Toxic megacolon develops as a result of
the extension of the inflammatory process to the muscularis propria and serosa,
causing atony and leading to perforation and peritonitis. Several factors appear
to predispose to the development of toxic megacolon. These include dosage
reduction of medications for IBD; enteric infections; cessation of smoking in
patients with UC; hypokalemia; and the administration of NSAIDs, narcotics,
anticholinergics, and other agents that diminish bowel motility. Bowel stasis
may facilitate extension of the inflammatory process to the deeper layers of the
colonic wall with subsequent penetration of bacteria. Barium enema and
colonoscopy also have been implicated as causative factors in some patients
with toxic megacolon, perhaps for similar pathogenic reasons.
2. Diagnostic features at the onset of the disease are worsening of the diarrhea
(more than six stools per day), hematochezia, fever, abdominal tenderness, and
abdominal distention. As the disease progresses, the stool frequency may dimin-
ish as the colon becomes atonic and dilated.
On physical examination the patient appears severely ill. Signs of sys-
temic toxicity include fever, tachycardia, and change in mental status. The
abdomen is diffusely tender with diminished-to-absent bowel sounds, and there
may be signs of peritoneal inflammation. The rectal examination typically
reveals bloody stool.
3. Diagnostic studies
a. Laboratory studies. The CBC may reveal anemia and leukocytosis, often with
a left shift. Blood sugar; blood urea nitrogen (BUN); serum electrolytes, albu-
min, and creatinine; urinalysis; and arterial blood gases should be obtained.
Plain chest x-ray films and an electrocardiogram also should be ordered. A CT
scan of the abdomen and pelvis will be helpful to exclude perforation, abscess
formation, and masses.
b. Stool studies. Stool samples should be examined for ova and parasites,
cultured, and tested for C. difficile toxin.
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Chapter 37: Inflammatory Bowel Disease 259

c. Abdominal plain x-ray films. Measurement of the diameter of the trans-

verse colon on supine films of the abdomen taken every 12 to 24 hours is
useful in assessing the status of the illness (see Fig. 37-3). A diameter greater
than 6 cm is regarded as abnormal. Perforation is a common complication
of toxic megacolon. Thus, upright or lateral decubitus films also should be
taken to rule out free air in the abdomen. Because air in the bowel seeks the
most superior location, lateral decubitus films may show dilatation of the
ascending or descending colon rather than of the transverse colon.
d. CT scan of the abdomen and pelvis is more sensitive in the detection of
intraabdominal free air and abscesses.
e. Sigmoidoscopy. Physicians often wonder whether sigmoidoscopy should be
performed in patients with severe colitis or toxic megacolon because of con-
cerns about perforation and worsening of the bowel distention by insufflated
air. Limited sigmoidoscopy, by an experienced endoscopist using either a rigid
or a flexible instrument, is both safe and indicated in such patients. The exam-
ination should be limited to the rectum or distal sigmoid colon. The severity
of the mucosal injury can be assessed, and other conditions in the differential
diagnosis, such as Crohn’s disease, ischemic colitis, and pseudomembranous
colitis, may be eliminated.
f. Colonoscopy and barium enema are contraindicated in severe colitis or
toxic megacolon. One or both of these studies may be indicated later, after
recovery has occurred, to document the extent of the colitis and to survey for
development of complications, such as stricture, pseudopolyps, dysplasia,
and cancer.
4. Management
a. General medical management. Patients should receive nothing by mouth
and IV fluids. Opiates and anticholinergic agents should be stopped.
Nasogastric suction is indicated. Careful attention should be paid to correcting
electrolyte imbalances. Anemic patients may require blood transfusions. The
clinical status is assessed frequently by physical examination, determination of
vital signs, and abdominal flat and decubitus x-ray films every 12 to 24 hours.
b. Antibiotics. Patients should be treated with a broad-spectrum antibiotic
regimen including anaerobic coverage after cultures of stool, blood, and
urine have been obtained.
c. Corticosteroids. High-dose IV corticosteroids should be administered;
for example, hydrocortisone (100 mg q6h) or methylprednisolone
(10–15 mg q6–8h).
d. Cyclosporin has been shown to be effective in the management of severe and
fulminant colitis at doses of 4 mg/kg per day given IV. The role of cyclosporin
in toxic megacolon is controversial, but has been used successfully in some
cases. Patients who have responded to the IV regimen should then receive
oral cyclosporin twice a day at double the IV dose (4 mg/kg twice daily) to
maintain trough levels between 200 and 400 kg/mL and azathioprine or
6-MP therapy should also be started. The azathioprine or 6-MP is continued,
but the cyclosporin and corticosteroids are tapered over the next 3 months.
e. Fufliximab (Remicode) has been used successfully in patients with severe IBD
and may be a safer alternative to intravenous Cyclosporin. The dosing is as in 4d.
f. Surgery. Patients with severe colitis or toxic megacolon should be evalu-
ated by a surgeon early during the course of the illness. Indications for
surgery are perforation, unremitting colonic hemorrhage, and failure of the
clinical status to improve despite intensive therapy with IV corticosteroids as
described above or in combination with cyclosporin. In most centers, the
patients are treated initially with broad-spectrum antibiotics and IV corti-
costeroids. Patients who fail to improve on this regimen within the first 3 to
7 days should be offered surgery or IV cyclosporin. Cyclosporin therapy
does not increase the risk of postsurgical morbidity.
If surgery is indicated, subtotal colectomy and ileostomy with forma-
tion of a Hartmann’s pouch is considered the conservative procedure of
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260 Part V: Specific Complaints and Disorders

choice in patients with systemic toxicity. Restorative proctocolectomy and

ileal pouch–anal anastomosis is possible for patients with severe colitis with-
out systemic toxicity.
f. Subsequent medical management. Patients who improve on medical
treatment without surgery should be treated with parenteral nutrition. When
they are able to take oral fluids, the steroid therapy can be changed to the
equivalent of 40 to 60 mg prednisone daily.
B. Management of pregnant patients with IBD. Statistically, a woman with quies-
cent IBD runs roughly the same risk of having an exacerbation during 9 months of
pregnancy as during any other 9 months of her life. In some women, however, the
disease appears to be exacerbated by pregnancy, and in others it is improved. Some
women experience their first attack of colitis during pregnancy or within a few
weeks of delivery. If colectomy is necessary for the treatment of severe colitis early
in pregnancy, therapeutic abortion also may be necessary.
1. Congenital abnormalities and premature births occur no more frequently in
women with IBD than in the general population. Women with active disease
during pregnancy are often treated with sulfasalazine or other 5-ASA com-
pounds, antibiotics, or steroids, which appear to have no deleterious effects on
the fetus. Metronidazole should not be prescribed for pregnant women. Women
who become pregnant while on 6-MP or azathioprine and who continue to take
it during pregnancy have not been shown to experience deleterious effects on
the pregnancy or on the fetus.
a. What advice should you give a woman with IBD who is contemplating
becoming pregnant? Encourage her to become pregnant during a period of
remission. Reassure her that exacerbations of the disease most likely can be
treated effectively with medications. Inform her that most likely she will do
well but that there is a small chance severe symptoms will develop. If blood
loss or malabsorption is evident, supplemental iron and vitamins should be
administered.
C. Cancer surveillance in IBD
1. Chronic ulcerative colitis and Crohn’s disease predisposes to adenocarci-
noma of the colon. The cancers tend to be multifocal, and infiltrating. The risk
of cancer is directly related to the extent of colonic involvement and to the
duration of the disease. Data from large referral centers originally indicated
that the risk of cancer development in patients with pancolitis begins after
about 7 to 10 years of disease and that the incidence of cancer thereafter is
about 20% per decade. More recent data suggest that the risk may be some-
what lower but still represent a clinical threat. The current recommendation for
cancer surveillance in patients with ulcerative colitis and Crohn’s disease is to
perform colonoscopy yearly after 7 to 10 years of disease in patients with pan
colitis and after 10 to 15 years of disease in patients with colitis only in the
descending colon. During colonoscopy, multiple biopsies are taken from cecum
to rectum. The colonoscopist should biopsy any grossly suspicious lesions.
Otherwise, biopsies should be obtained from noninflamed, flat mucosa because
inflammation can be associated with dysplasia and thus affect the pathologic
findings. Pathologists are encouraged to interpret the biopsies according to
published criteria. Each biopsy should be interpreted as normal, indeterminate,
or dysplastic. Dysplastic biopsies are to be read as either low-grade dysplasia or
high-grade dysplasia. Patients with biopsies showing indeterminate or low-
grade dysplasia should undergo colonoscopy again in 1 to 6 months. The
response to an interpretation of high-grade dysplasia has been debated, but
many experts believe that the diagnosis is grounds for recommending total
colectomy.
2. Microscopic (lymphocytic and collagenous) colitis is diagnosed in patients
presenting with watery chronic diarrhea by histologic examination of the colonic
biopsies, especially obtained from the right colon. The visual appearance of the
mucosa during colonoscopy is usually normal. However, on histologic examina-
tion of the mucosa, if there is increased lymphocytic infiltrate in the lamina propria
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Chapter 37: Inflammatory Bowel Disease 261

with preserved crypts, the colitis is called lymphocytic colitis. However, if there
is a collagen band thicker than 10 mm below the epithelium, the condition is
called collagenous colitis. The etiology of microscopic colitis is not known.
Treatment is usually initiated with a 4- to 8-week trial of bismuth subsal-
icylate two tablets three to four times a day. If symptoms do not abate, a 5-ASA
compound and/or budesonide may be used to achieve remission. Antibiotics
such as ciprofloxacin 500 mg b.i.d. or metronidazole 250–500 mg t.i.d. or
Xifaxan 200 mg one or two tablets t.i.d. may be used for 1 to 3 months. In
some cases, corticosteroids and immunomodulators may be necessary to induce
remission.

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VASCULAR DISEASE OF THE BOWEL 38

V ascular disorders of the gastrointestinal (GI) tract typically present as abdominal

pain or bleeding, or both. Several of the disorders that cause bleeding, such as ischemic col-
itis, angiodysplastic lesions, and vascular–enteric fistulas, are mentioned in Chapters 14
and 44, but are discussed more thoroughly here.

I. MESENTERIC VASCULAR INSUFFICIENCY. The clinical spectrum of mesenteric

vascular insufficiency is broad, ranging from transient postprandial “abdominal
angina” to severe abdominal pain caused by acute occlusion of a mesenteric vessel.
Some patients with mild symptomatic vascular insufficiency are otherwise well,
whereas acute occlusion of a mesenteric artery can be catastrophic. Occlusion of a
mesenteric vessel by a thrombus or an embolus is dramatic, and the pathogenesis is
easy to understand. However, nonocclusive mesenteric vascular disease also is recog-
nized and may affect a larger number of patients than the occlusive type does. The lat-
ter includes transient ischemia due to inadequate perfusion under some circumstances,
such as the high demand for mesenteric blood flow after eating, resulting in “intestinal
angina,” or the reduction in blood flow during an episode of heart failure or a cardiac
arrhythmia, resulting in bleeding and abdominal pain. Vascular disorders of the bowel
are more common in older people, and as the elderly population increases, these dis-
orders are becoming more prevalent.
A. Intestinal circulation. The stomach and intestines are supplied by three unpaired
arteries: the celiac axis, the superior mesenteric artery, and the inferior mesenteric
artery. The gut receives nearly 30% of the resting cardiac output through these
three splanchnic arteries. Small vessels, called arteriae rectae, derive from the
terminal branches of the intestinal arcade in the small intestine and from the mar-
ginal artery in the colon and penetrate the muscle layer of the gut to form a rich
submucosal plexus. In the small intestine, arterioles arise from the submucosal
plexus to supply each villus. A central arteriole runs the length of each villus and
branches at the tip to form a capillary network, which is drained by venules that
parallel the central arteriole. Oxygen diffuses directly from the arterial to the
venous side along the villus, thus creating a countercurrent mechanism that dimin-
ishes the oxygen concentration at the tip of the villus. This shunt is accentuated by
low-flow states. It also may explain why small-intestinal ischemia is first mani-
fested by destruction of the villous tips and consequently by breakdown of the
barrier to bacteria, which predisposes the mucosa to bacterial invasion. In the
colon, arterioles and venules also lie in close approximation, creating a similar
predisposition to ischemia at the mucosal surface.
B. Occlusive vascular disease
1. Pathophysiology. Occlusion of the celiac axis, superior mesenteric artery, or
inferior mesenteric artery, or their branches, can result from thrombosis or
embolus, resulting in acute intestinal ischemia. A dissecting aortic aneurysm
also can occlude one or more mesenteric vessels. If collateral circulation is
inadequate, the bowel becomes ischemic and the patient experiences severe
abdominal pain. The most common cause of arterial thrombosis is ordinary
atherosclerotic vascular disease. Emboli may accompany acute myocardial
infarction, ventricular aneurysm, atrial fibrillation, valvular heart disease, or
bacterial endocarditis.

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264 Part V: Specific Complaints and Disorders

2. Clinical presentation. Occlusion of a splanchnic artery by thrombosis or

embolus causes acute abdominal pain. Initially, the pain may be colicky, but as
transmural infarction and peritonitis develop, the pain becomes constant and
more severe. Tachycardia, hypotension, fever, elevated white cell count, and
bleeding ensue. A careful examination should be done to evaluate for abdominal
aortic aneurysm, abdominal bruits, and changes in peripheral pulses.
3. Differential diagnosis. The differential diagnosis includes most causes of
abdominal pain, including dissecting aortic aneurysm, bowel obstruction, per-
foration of a viscus, acute cholecystitis, appendicitis, diverticulitis, peptic ulcer
disease, pancreatitis, and pancreatic carcinoma. Patients with a dissecting aor-
tic aneurysm may have severe abdominal pain radiating to the back. During the
dissection, occlusion of the mesenteric vessels also may occur. Bowel obstruc-
tion and perforation of a viscus are acute events that may be confused with
mesenteric vascular thrombosis or embolus. Inflammatory conditions, such as
cholecystitis, appendicitis, and diverticulitis, often have localizing signs but
may be difficult to distinguish from ischemic bowel disease that is accompanied
by fever and elevated white blood cell counts. The signs and symptoms of pep-
tic ulcer disease, pancreatitis, and pancreatic cancer usually are less acute than
those of mesenteric vascular disease.
4. Diagnostic studies. Patients in whom acute ischemic bowel disease is sus-
pected should have a complete blood count and differential white cell count
and levels of serum amylase and electrolytes. The white cell count and amylase
level may be increased in intestinal ischemia, but the latter usually is not ele-
vated more than five times above normal level. Higher levels of serum amylase
are more typical of acute pancreatitis. A urinalysis also should be performed. A
metabolic acidosis may develop as ischemia worsens.
Plain films of the abdomen may show distended loops of bowel with air-
fluid levels. Bowel loops may be separated by edema and blood within the
bowel wall. Barium-contrast studies are not indicated during the initial evalua-
tion and treatment of patients with acute ischemic bowel disease. The diagno-
sis is confirmed by angiography, although in some instances, when the clinical
course is rapid and perforation is suspected, immediate surgery is indicated.
5. Treatment. The initial treatment of thrombotic or embolic infarction of the bowel
consists of nasogastric suction, intravenous fluid and electrolyte replacement,
blood transfusions as indicated, broad-spectrum antibiotics, and, if necessary,
vasopressors. Definitive treatment is surgical resection of the infarcted bowel.
C. Nonocclusive vascular disease
1. Abdominal angina
a. Pathophysiology. Abdominal angina is an uncommon but distinct condi-
tion that, if diagnosed correctly, usually can be corrected, providing the
patient with remarkable relief of pain. Patients typically have arterioscle-
rotic disease involving at least two of the three major visceral arteries
(celiac axis, superior mesenteric artery, and inferior mesenteric artery).
Arteriosclerotic disease of the heart and other blood vessels usually coexists,
sometimes complicated by diabetes mellitus. The pain, which occurs several
minutes after eating, is caused by mesenteric ischemia. The postprandial
blood flow simply is not sufficient to meet the increased energy demands of
the intestine during digestion.
b. Clinical presentation. Postprandial mid-abdominal pain, usually severe and
incapacitating, is the hallmark. The pain continues for minutes to hours.
Patients are reluctant to eat; consequently, losses of 10 to 30 lb (4.5–13.5 kg)
are common. This clinical picture is remarkably similar to that of pancreatic
cancer, from which abdominal angina must be differentiated. A mild-
to-moderate malabsorption also may contribute to the weight loss.
Sometimes patients experience nausea, vomiting, and diarrhea. A minority of
patients have intestinal infarction after weeks to months of ischemic symptoms.
On physical examination, the signs of weight loss are evident. An
abdominal bruit may be heard but is not diagnostic.
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Chapter 38: Vascular Disease of the Bowel 265

c. Diagnostic studies and differential diagnosis. The clinical presentation

of abdominal pain and weight loss is nonspecific and raises the possibility of
cancer and other disorders of the stomach, small intestine, colon, gallblad-
der, and pancreas. Thus patients who ultimately are diagnosed as having
abdominal angina usually undergo upper GI and small-bowel x-ray series,
barium enema, ultrasound of the gallbladder, and abdominal computed
tomography (CT) scan.
The diagnosis of abdominal angina depends on a high degree of clinical
suspicion coupled with absence of evidence for other common causes of pain
and weight loss and an abdominal arteriogram that shows complete or nearly
complete occlusion of at least two of the three major splanchnic arteries.
d. Treatment. Arterial bypass surgery or surgical endarterectomy has been the
treatment of choice. Percutaneous endarterectomy under fluoroscopic guid-
ance may be an alternative in some patients. Rarely, in patients whose
operative risk is prohibitive, treatment with an elemental diet or chronic
intravenous alimentation may be attempted.
2. Ischemic colitis
a. Pathophysiology. Mucosal ischemia in patients with nonocclusive vascular
disease of the bowel is thought to result from transient low flow through an
inadequate vascular system. Affected patients typically are elderly or have a
cardiovascular condition, such as congestive heart failure or an arrhythmia,
which predisposes them to a transient reduction in bowel perfusion. The
condition may involve any portion of the small or large intestine but usually
affects the descending colon, most commonly in the region of the splenic
flexure or the sigmoid colon. These areas are the so-called watersheds
between the distributions of the superior mesenteric artery and the inferior
mesenteric artery in the first instance and between the inferior mesenteric
artery and the internal iliac artery in the second.
Ischemic colitis may occur in up to 10% of patients in the postopera-
tive period after aortic aneurysm repair because of interruption of inferior
mesenteric artery blood flow in the absence of adequate collateral circula-
tion. It has also been reported in patients using birth control pills, estrogen
supplement therapy, raloxifene (Evista), and pseudoephedrine.
b. Clinical presentation. Patients with ischemic colitis characteristically
report an abrupt onset of lower abdominal pain and bloody stool. The phys-
ical examination is variable. Low-grade fever may be present. Typically the
abdomen is soft, and there is less tenderness than would be expected from
the degree of abdominal discomfort. In most patients, the course is self-limited,
with spontaneous recovery. However, a minority of patients may initially or
eventually have peritoneal signs and absent bowel sounds, indicating bowel
infarction and peritonitis, and require surgical treatment.
c. Diagnostic studies and differential diagnosis. Most causes of abdominal
pain and rectal bleeding, in particular ulcerative colitis, Crohn’s disease,
infectious colitis, and diverticular bleeding, are included in the differential
diagnosis. Abdominal plain films may show the typical “thumbprints” in the
affected area of bowel (Fig. 38-1). These are nodular protrusions into the
bowel lumen caused by accumulations of submucosal edema and blood. A
cautious sigmoidoscopic examination may identify a range of findings,
including nonspecific colitis, ulcerations, and soft bluish nodules, which are the
counterparts of the radiologic thumbprints. If the patient remains stable for
24 to 48 hours, colonoscopy or a single-contrast barium enema can reveal
the affected bowel by confirming the thumbprint appearance (Fig. 38-2). In
most patients, angiography is of little value. However, angiography may be
useful to the surgeon for identifying the vascular anatomy if surgical treat-
ment becomes necessary.
d. Treatment. Initial treatment consists of nothing by mouth and intravenous
fluids. The patient should be examined several times a day for the develop-
ment of peritoneal signs. Congestive heart failure and cardiac arrhythmias
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266 Part V: Specific Complaints and Disorders

Figure 38-1. Plain x-ray film of the abdomen in an elderly patient with nonocclusive ischemic
colitis. Air within the bowel provides a natural contrast medium. The characteristic “thumbprint”
indentations are evident in the upper descending colon (arrows).

Figure 38-2. Barium enema x-ray film of the region of the splenic flexure in a patient with nonoc-
clusive ischemic colitis. The “thumbprint” pattern is present in the descending colon (arrows).
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Chapter 38: Vascular Disease of the Bowel 267

should be treated appropriately. Antibiotics generally are not indicated

unless fever persists and peritoneal signs develop. In patients with peritoneal
signs, surgical resection of the ischemic segment is indicated, with either pri-
mary anastomosis or temporary colostomy. As mentioned previously, most
patients with nonocclusive bowel ischemia recover with medical treatment.
Some experts recommend a follow-up barium enema examination about
2 months later to determine whether an ischemic stricture has developed.

II. ANGIODYSPLASIA
A. Pathophysiology. Angiodysplasias are ecstatic, vascular lesions within the submu-
cosa consisting of arterial, venous, and capillary elements. They may be found
throughout the GI tract but occur most frequently in the cecum and ascending
colon. Angiodysplasias are clinically important because they are a cause of acute
and chronic GI bleeding, particularly in elderly patients.
Most angiodysplasias are thought to develop as a consequence of normal
aging. Aortic stenosis occurs in up to 15% of patients with bleeding angiodys-
plasias, but pathogenic association is uncertain. In some patients, angiodysplastic
lesions may occur throughout the GI tract as part of the hereditary disorder known
as Osler-Weber-Rendu disease. In this disease, telangiectatic lesions also are found
on the skin, in the nail beds, and in the mucosa of the mouth and nasopharynx.
B. Clinical presentation. Angiodysplasias cause no symptoms until they bleed. In
patients who ultimately are diagnosed as having bled from an angiodysplasia,
therefore, the only common history is that of GI bleeding. The usual presentation
is one of acute lower GI bleeding. Often a cause of bleeding is not found or the
bleeding is attributed to another common, coexisting disorder, such as peptic dis-
ease or diverticulosis. Patients may experience several bleeding episodes, some-
times over a period of months, before the correct diagnosis is made.
C. Diagnostic studies. The two methods of diagnosing angiodysplasias are colonoscopy
and angiography.
1. Colonoscopy. An angiodysplastic lesion appears as a submucosal red blush
resembling a spider angioma of the skin. To optimize the chance of visualizing
the lesion by colonoscopy, however, the bowel must be free of blood and debris,
which may not be possible during acute bleeding.
2. Angiography. The lesions may be identified angiographically by the following
findings:
a. An early-filling vein
b. A vascular tuft of dilated vessels
c. A slowly emptying vein
D. Treatment. The traditional treatment of a bleeding angiodysplasia has been to
resect the segment of bowel that contains the lesion, usually the ascending colon.
Up to 30% of patients so treated bleed again, either from a new angiodysplastic
lesion or from a lesion that was not resected. An alternative to surgical resection is
colonoscopic electrocoagulation if the lesions can be identified by colonoscopy.

III. VASCULAR–ENTERIC FISTULAS

A. Pathophysiology. An unusual cause of GI bleeding is a fistula between a vascular
structure and the GI tract. Most commonly, the fistula develops between an aortic
graft and the third portion of the duodenum months to years after an aortic
aneurysm repair. Fistulas also may develop between an unresected aneurysm and
the bowel. Less common sites are the sigmoid colon, the cecum, and the esopha-
gus. Fistulas between aneurysms of the aorta or smaller vessels and virtually every
portion of the GI tract have been reported.
B. Clinical presentation. Patients with vascular–enteric fistulas typically have mas-
sive hematemesis or hematochezia. A history of an aneurysm or aneurysm repair
raises the likelihood. A “herald bleed” is characteristic: Most patients with
vascular–enteric fistulas stop bleeding after the initial dramatic hemorrhage, only
to rebleed within hours or days.
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268 Part V: Specific Complaints and Disorders

C. Diagnostic studies and treatment. Upper GI endoscopy is useful chiefly in

excluding another bleeding lesion but usually does not identify the fistula.
Angiography rarely identifies the fistula. Barium studies are not recommended due
to the risk of severe bleeding but also are not likely to identify the fistula. CT of
the abdomen may show a leaking aneurysm or fistula and therefore is helpful in
making the decision to operate. A high index of suspicion for a vascular–enteric
fistula in a patient with an aortic aneurysm or a history of an aneurysmectomy is
worth more than diagnostic studies because immediate surgery usually is indicated
after nondiagnostic upper GI endoscopy is performed.

Selected Readings
Bismar MM, Sinicrope FA. Radiation enteritis. Curr Gastroenterol Rep. 2002;4:361–365.
Brandt IJ, et al. AGA technical review on intestinal ischemia. Gastroenterology. 2000;
118:195.
Chang L, et al. Incidence of ischemic colitis and serious complications of constipation
among patients using alosetron: Systematic review of clinical trials and post-marketing
surveillance data. Am J Gastroenterol. 2006;101:1069–1079.
Deana DG, et al. Reversible ischemic colitis in young women. Association with oral
contraceptive use. Am J Surg Pathol. 1995;19:454.
Dowd J, et al. Ischemic colitis associated with pseudoephedrine: Four cases. Am J
Gastroenterol. 1999;943:2430.
Flobert C, et al. Right colonic involvement is associated with severe forms of ischemic
colitis and occurs frequently in patients with chronic renal failure requiring
hemodialysis. Am J Gastroenterol. 2000;95:195.
Nehme OS, et al. New developments in colonic ischemia. Curr Gastroenterol Rep. 2001;3:416.
Noyer CM, et al. Colon ischemia: Unusual aspects. Clin Perspect Gastroenterol.
November/December 2000:315.
Schuller JG, et al. Cecal necrosis: Infrequent variant of ischemic colitis: Report of five
cases. Dis Colon Rectum. 2000;43:708.
Shrestha S, et al. Henoch Schonlein purpura with nephritis in adults: adverse prognostic
indicators in a UK population. QJM. 2006;99:253–265.
Uzoigwe CE, et al. A surgical solution for vasculitis? Lancet. 2007;369:1054.
79466_CH39.qxd 1/2/08 12:38 PM Page 269

COLONIC POLYPS AND

COLORECTAL CANCER 39

C olorectal cancer (CRC) is the second leading cause of cancer mortality in the United
States. In men, CRC is second in prevalence only to lung cancer, and in women, it is third
behind breast and lung cancer. More than 95% of the cancers are thought to have their ori-
gin in adenomatous polyps. In the United States, the prevalence of CRC is 30 to 40 per
100,000 and it increases with age.

I. COLONIC POLYPS
A. Pathogenesis. The term polyp refers to any protrusion into the lumen of the gas-
trointestinal (GI) tract. A sessile polyp is a raised protuberance with a broad
base. A pedunculated polyp is attached to the bowel wall by a stalk that is nar-
rower than the body of the polyp. Submucosal polyps are lipomas, leiyomyomas,
hemangiomas, fibromas, lymphoid tissue, endometriomas, melanomas, or metasta-
tic lesions. Most submucosal polyps are benign; however, many patients with
carcinoid metastatic lesions, melanomas, lymphomas, and Kaposi’s sarcomas have
malignant polyp formation in the colon.
Polyps may be benign or malignant. In the colon, polyps can be described
as adenomatous, hamartomatous, hyperplastic, or inflammatory, according to
their histopathologic appearance. Hyperplastic and inflammatory polyps are
usually benign, but are also at risk for carcinoma. Adenomatous polyps can be
classified as tubular, villous, or tubulovillous, depending on whether their his-
tologic appearance is primarily glandular, villous, or mixed, respectively.
Although most adenomatous polyps are benign, some may contain carcinoma
and others may degenerate later to carcinoma. The risk of a polyp containing
carcinoma increases directly with the size of the polyp (Table 39-1). Cancer is
more likely to occur in villous adenomas than the other types, and benign ade-
nomatous polyps may coexist with adenocarcinoma elsewhere in the bowel. In
short, a colon that has a tendency to produce polyps also is at higher risk of the
development of cancer.
B. Clinical presentation. Because colonic polyps are so common—some estimates of
prevalence are as high as 50% in people over age 50—they are an important risk
factor in the development of CRC in the general population.
Most patients with polyps are asymptomatic. In those instances, the polyps
remain undiscovered or are diagnosed during surveillance examination. Sometimes
polyps cause occult or gross bleeding. Occasionally patients complain of abdominal

TABLE 39-1 Relation of Polyp Size to Risk of Cancer in the Polyp

Polyp size Risk of cancer (%)

1 cm 0–2
1–2 cm 10–20
2 cm 30–50

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270 Part V: Specific Complaints and Disorders

Figure 39-1. Air-contrast barium enema showing a sigmoid polyp on a long stalk (arrows).

discomfort, which may be caused by tugging on the polyp by peristaltic contrac-

tions. If the polyp is large, frank obstruction can occur. Rarely, polyps may cause
intussusception of the small or large intestine.
C. Diagnostic and screening. Studies for colonic polyps and CRC include colonoscopy,
virtual colonoscopy, CT colography, sigmoidoscopy, and air contrast barium enema x-
ray examination (Fig. 39-1). Often the barium enema has been ordered for symptoms
that have no relation to the polyp. If the possibility of a polyp is raised by barium
enema findings, complete colonoscopy should be performed. Similarly, identification
of a polyp by sigmoidoscopy is justification for colonoscopy because the chance that
there is a synchronous polyp in the colon above the reach of the sigmoidoscope exceeds
20%. For discussion of cancer surveillance, see section V.
D. Treatment
1. Polypectomy. Nearly all polyps can be removed during colonoscopy.
Polypectomy is performed by encircling the polyp with a wire snare through
which an electrocauterizing current is passed. Sessile polyps may be removed in
a piecemeal fashion. Injection of saline to the base of sessile lesion before snar-
ing may give better visualization of the polyp and help its complete removal. If
a polyp is too large to be removed, it should be adequately biopsied.
2. Careful histologic examination of resected polyps is essential for formulat-
ing appropriate recommendations for the patient. Nonadenomatous polyps are
thought to have little or no malignant potential, and removal of those polyps is
sufficient treatment. On the other hand, adenomatous polyps not only predis-
pose to the subsequent development of cancer but also may contain cancer at
the time of removal. Thus, it is important that all polyps, particularly those
larger than 1 cm in diameter, be examined carefully for adenocarcinoma.
3. Adenocarcinoma may be present in adenomatous polyps in one of four ways
(Fig. 39-2, Table 39-2).
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Chapter 39: Colonic Polyps and Colorectal Cancer 271

Figure 39-2. Stages of involvement of adenomatous polyps with cancer.

TABLE 39-2 Diagnosis and Treatment of Cancerous Adenomatous Polyps

Extent of involvement
of polyp by cancer Implication Recommendations

Cancer involves only the The cancer has been Surgery not indicated;
mucosa without penetration cured by polypectomy. repeat colonoscopy in 1 y.
of muscularis mucosae
(carcinoma in situ).
Cancer (moderately or well The cancer probably Surgery not indicated
differentiated) has penetrated has been cured. because the surgical risk
the muscularis mucosae but outweighs the risk of
does not involve blood vessels residual cancer; repeat
or lymphatics in the stalk. colonoscopy in 1 y.
Cancer has penetrated the Residual cancer may Segmental resection of
muscularis mucosae and be present in the colon is indicated if
involves blood vessels or the colon. the patient is a good
lymphatics, or the cancer is operative risk. If residual
poorly differentiated, whether cancer is found in the
or not it involves blood patient at surgery, repeat
vessels or lymphatics. colonoscopy in 3–6 mo; if
no residual cancer, repeat
colonoscopy in 6–12 mo.
Cancer involves the resectional Cancer remains Segmental resection of
margin of the polyp stalk. in the bowel. the colon is indicated if
the patient is an operative
candidate. Repeat
colonoscopy in 3–6 mo.

a. The cancerous change involves only the mucosa and does not penetrate
the muscularis mucosa into the stalk of the polyp. This condition is
sometimes called carcinoma in situ or high-grade dysplasia. Colonoscopic
resection of the polyp in this instance is regarded as curative. No surgical
treatment is indicated. The patient should be scheduled to return in 1 year for
follow-up colonoscopy.
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272 Part V: Specific Complaints and Disorders

b. The cancer penetrates the muscularis mucosae of the polyp into the
stalk but does not involve blood vessels or lymphatics within the resected
portion of the stalk, and the cancer is moderately to well differentiated.
Although a small number of patients with this finding has cancerous
involvement of the bowel or local lymph nodes, the mortality (
2%) and
morbidity of surgery to resect the portion of the colon that contained the
polyp exceeds the risk of residual cancer. Thus, additional surgery for these
patients is not recommended. Repeated colonoscopy should be scheduled
for 1 year later.
c. The cancer not only penetrates the muscularis mucosae of the polyp but
also has invaded blood vessels or lymphatics within the stalk. In these
patients, cancer also is likely to be present in the bowel or local lymph nodes.
Also in this category are patients with poorly differentiated cancers that do
not involve blood vessels or lymphatics. If operative risk is not prohibitive,
these patients should undergo resection of the segment of colon that con-
tained the polyp. Repeated colonoscopy to examine the anastomosis for
recurrent tumor should be scheduled for 3 to 6 months if residual cancer is
found at surgery. If no residual cancer is found, colonoscopy should be
scheduled for 6 to 12 months.
d. The cancer involves the resectional margin of the polyp, indicating that
residual cancer remains in the patient. If the patient is an operative candi-
date, segmental resection of the colon is indicated. These patients should
undergo follow-up colonoscopy in 3 to 6 months to check for residual tumor
at the anastomosis and for other polyps.

II. Polyposis syndromes differ in their clinical manifestations, pathology, patterns

of inheritance, and predisposition to carcinoma (Table 39-3).
A. Familial adenomatous polyposis (FAP) and Gardner’s syndrome. These condi-
tions probably are related and expressions of the same genetic syndrome: one that
is inherited in an autosomal dominant pattern. The prevalence in the United States
is 3 per 100,000 persons. Affected individuals with FAP have hundreds of col-
orectal polyps in the first three decades of life. Polyps may also occur in the stom-
ach and small intestine. The risk of polyp occurrence in the duodenum is 3% to
5%. Two percent of patients may have pancreatic, thyroid cancer, and hepato-
blastoma. If the colon is not resected, virtually 100% of the patients eventually
develop cancer. Gardner’s syndrome is distinguished from FAP by the presence of
osteomas, fibromas, and other features (Table 39-3) in addition to the intestinal
polyps. Yearly colonoscopy should begin at age 10 in asymptomatic individuals
carrying the gene for FAP. Total proctocolectomy with an ileostomy or an anal
sphincter–saving procedure is indicated if the diagnosis of FAP is made. Genetic
testing is available for family members.
B. Turcot’s syndrome. In this rare disease, colonic polyposis is associated with brain
tumors. Both recessive and dominant patterns of genetic transmission have been
described. Screening and treatment of affected individuals are the same as for FAP.
C. In Peutz-Jeghers syndrome, intussusception, obstruction, or infarction of
the polyps may develop with consequent abdominal pain and bleeding. For these
reasons, surgery may be indicated. Because the risk of cancer is less than 3%, pro-
phylactic surgery is not indicated.
D. The other polyposis syndromes are not associated with an increased risk of can-
cer, although relatives of patients with juvenile polyps may have cancers of the
stomach, small intestine, colon, or pancreas. However, patients with these syn-
dromes may have complications of the polyps, such as bleeding and obstruction; if
conservative treatment fails, they require surgery.

III. COLON CANCER

A. Pathogenesis. As mentioned, CRC is the second and third most prevalent cancer
in men and women, respectively, in the United States. The lifetime risk of a person
in the general population for development of CRC is about 6%. A number of risk
factors have been implicated (Table 39-4).
 TABLE 39-3 Polyposis Syndromes
79466_CH39.qxd

Histology of Location of Associated Cancer

Syndrome polyps polyps abnormalities predisposition

Familial polyposis Adenomas Colon primarily; Osteomas Yes

1/2/08

also stomach of mandible

and small bowel
Gardner’s syndrome Adenomas Colon primarily; Osteomas of Yes
also stomach mandible, skull, long bones;
and small subcutaneous fibromas,
12:38 PM

bowel lipomas, epidermoid cysts,

exostoses, mesenteric
fibromatosis, supernumerary
teeth; thyroid and adrenal
carcinoma
Page 273

Turcot’s syndrome Adenomas Colon Brain tumors Yes

Peutz–Jeghers Hamartomas Small bowel Pigmented plaques of buccal Yes (low risk,
3%)
syndrome primarily; also mucosa, hands, feet, perianal
stomach and skin; bladder and nasal polyps
colon
Juvenile Hamartomas, Colon primarily; Rare
polyposis adenomas also stomach and
small bowel
Neurofibromatosis Neurofibromas Stomach and Neurofibromas No
(von Reckling- small bowel of skin
hausen’s disease)
Cronkhite–Canada Inflammatory Small bowel Alopecia, No
syndrome primarily; also hyperpigmentation,
stomach and colon dystrophic nails

273
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274 Part V: Specific Complaints and Disorders

TABLE 39-4 Conditions That Predispose to Colon Cancer

Advancing age
Family history of colorectal or polyps
High-fat, low-fiber diet
Bowel disorders
Inflammatory bowel disease (ulcerative colitis, Crohn’s disease)
Adenomatous polyps
Some polyposis syndromes (see Table 39-3)
Familial colon cancer syndrome
Genital tract cancer in women

First, merely growing older increases the risk. Over age 40, the annual inci-
dence of colon cancer begins to accelerate, doubling every decade. Second,
dietary factors, such as a high-fat, low-fiber diet, may increase the risk of devel-
oping CRC. Third, bowel conditions such as ulcerative colitis, Crohn’s disease,
adenomatous polyps, and some of the polyposis syndromes (see sections I and II)
predispose to colon cancer. Finally, there seems to be a hereditary predisposi-
tion to the development of CRC. The probability of CRC developing in a person
who has a first-degree relative with CRC is more than 15%, compared to a 6%
risk in the general population. For hereditary nonpolyposis colon cancer syn-
drome (HNPCC) (see section IV), a high risk of development of colon cancer is
inherited in an autosomal dominant manner. These patients may have coexisting
adenomatous polyps and may also have melanoma or cancer of the uterus or
ovaries. Patients with breast cancer may also have increased risk of developing
colon cancer.
CRC may develop in any part of the colon. Approximately 45% of CRC
is seen in the rectosigmoid and 25% in the ascending colon and cecum. Genetic
examination of the tumors shows mutations in K-ras, APC, VCC, and P53
genes.
B. Clinical presentation
1. History. The most common presenting sign is lower GI bleeding, and the most
common symptom is change in bowel habit. Unfortunately, these are both late
manifestations of the disease. Bleeding may be gross or occult. Occult bleeding
typically is detected on routine rectal examination or stool screening tests. A
change in bowel habit may be manifested as a decrease in the caliber of the
stool if the lesion is distal and constricts the bowel lumen. Patients may com-
plain of constipation. Sometimes diarrhea develops around a partially obstruct-
ing lesion. Mass lesions of the ascending colon, because of the larger diameter
of the ascending colon, may grow to a considerable size before symptoms
develop. Other possible consequences include anemia, weight loss, anorexia,
malaise, abdominal mass, and enterovesical or enterocutaneous fistula. Rarely,
the patient may seek treatment initially for symptoms of metastatic disease,
such as jaundice or bone pain.
2. Physical examination may reveal the effects of weight loss, muscle wasting, or
anemia. A mass may be evident in the abdomen or by rectal examination. Stool
may be positive for gross or occult blood.
C. Diagnostic studies
1. A complete blood count should be obtained to evaluate for anemia. Serum
iron studies confirm iron deficiency. An elevated serum alkaline phosphatase
level, if confirmed to originate in the liver either by fractionation or by the find-
ing of an elevated 5-nucleotidase, suggests liver metastases. Sometimes an
isolated elevation of serum lactic dehydrogenase or G-glutamyltranspeptidase
is the only indicator of liver involvement. Hyperbilirubinemia in conjunction
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Chapter 39: Colonic Polyps and Colorectal Cancer 275

with an elevated alkaline phosphatase level suggests either extensive liver

metastases or obstruction of the external bile ducts by metastatic lymph nodes.
Carcinoembryonic antigen (CEA) may be elevated but is not helpful in mak-
ing a diagnosis. Its role is largely confined to the follow-up period after primary
treatment of the cancer to monitor for recurrence or metastatic spread.
2. Historically, a barium enema, preceded by flexible sigmoidoscopy, has been used
as the first specific diagnostic study. An irregular filling defect or an encircling
“apple core” lesion on the barium enema is highly suggestive of adenocarcinoma.
3. Colonoscopy is the gold standard in the evaluation of the colon for the pres-
ence of colon polyps or cancer. Polyps amenable for colonoscopic polypectomy
are removed and those that are too large or too sessile to remove are biopsied
for histopathologic evaluation.
4. Virtual colonoscopy or CT colography of the colon may be used for screen-
ing of the colon for the presence of polyps and cancer; however, it is not yet
widely available. If a polyp is seen or suspected, a colonoscopy needs to be per-
formed to confirm its presence and for its removal.
5. An attempt should be made to identify metastatic disease. A computed
tomography (CT) scan of the chest, abdomen, and pelvis with intravenous
contrast should be obtained. For some patients, MRI of the liver may be
obtained to assess the number and size of the liver metastases.
D. Differential diagnosis. If a patient has weight loss, blood in the stool, and a mass
in the colon, the overwhelming likelihood is adenocarcinoma of the colon. Other
considerations include other malignant tumors such as leiomyosarcoma and lym-
phoma. Sometimes an inflammatory mass caused by diverticulitis or amebiasis
mimics colon cancer.
Histopathologically, the differentiation between a large, benign polyp and
colon cancer is not difficult.
E. Treatment and prognosis. Both treatment and prognosis depend largely on how
extensively the cancer involves the colon, contiguous structures, and distant sites.
The modified Dukes’ classification is in common usage to stage colorectal carci-
noma and determine prognosis (Table 39-5).
1. Treatment for Dukes’ A, B, and C lesions is surgical unless operative risk is
prohibitive. Rectal cancers usually require an abdominoperineal resection.
Preoperative chemo radiation therapy of rectal cancers seems to improve surgi-
cal and overall outcome. More proximal colon cancers are treated by wide
resection of the involved segment. Regional lymph nodes also are removed.
Patients with stage D cancers may require palliative resection to control bleed-
ing or to treat or prevent obstruction. Preoperative irradiation, sometimes in
conjunction with chemotherapy, has been reported to shift the Dukes’ staging
to less extensive disease and improve surgical results.
Chemotherapy and radiotherapy in patients with inoperable cancer
have been marginally effective. Radiotherapy of bony metastases may relieve
bone pain. Adjuvant chemotherapy of metastatic colon cancer involves the
administration of 5-fluorouracil, leucovorin, and irinotecan or a combination
of oxiplatin and raltitrexed, Avastin and bevacizumab show promise of sur-
vival benefit.
2. Prognosis. The 5-year survival rate is directly related to the extent of tissue
invasion, as indicated by the Dukes’ classification (Table 39-5). In addition,
prognosis and recurrence are adversely affected when tumors are poorly differ-
entiated. Liver metastases may be resected to increase survival.

IV. FAMILIAL COLON CANCER SYNDROME. Hereditary nonpolyposis colorectal cancer

(HNPCC) syndrome is a condition that is transmitted in an autosomal dominant fash-
ion with a high degree of penetrance for the development of colorectal carcinoma.
Two types are recognized. In type 1, cancers are confined predominantly to the colon.
In type 2, cancers occur not only in the colon but also in the female genital tract,
breast, brain, small bowel, pancreas, lymph system, and bone marrow. The diagnosis
is suspected when CRC occurs in a young person with a family history of CRC.
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276 Part V: Specific Complaints and Disorders

TABLE 39-5 Modified Dukes’ Classification to Stage Colorectal Cancer

Dukes’ Five-year survival (%)

category Definition after treatment

A Cancer limited to mucosa or submucosa 90

B1 Cancer penetrates into but not through 80
the muscularis propria
B2 Cancer penetrates through the 70
muscularis propria or the serosa
C1 Same as B1 plus lymph node metastases 50
C2 Same as B2 plus lymph node metastases 50
D Distant metastases
30

Surveillance of family members in kindreds that may be affected should begin

when members are age 10 with genetic testing. Fecal occult blood should be tested
yearly. Total colonoscopy should be performed every 3 years beginning at age 20.
Because of the high prevalence of cancers in the proximal colon, flexible sigmoi-
doscopy is not sufficient. Women with type 2 HNPCC syndrome should undergo
yearly pelvic examinations. If colon cancer is detected, total or subtotal colectomy is
indicated.

V. RECOMMENDATIONS FOR CANCER SURVEILLANCE AND FOLLOW-UP OF

POLYPS AND CANCER
A. Rationale for CRC screening
The overall 5-year survival rate for patients in the United States is approximately
60%. This correlates almost directly with the stage of diagnosis. Early detection of
CRC can improve outcome significantly. The 5-year survival rate for patients with
stage I to II disease is 80% to 90%, whereas it is 60% for those with stage III dis-
ease and less than 10% for stage IV disease. Studies have shown decreased
mortality for CRC when screening is performed and the improved survival is asso-
ciated with a shift to earlier stages at diagnosis.
The relatively long duration of adenoma-to-cancer sequence provides a period
of predisease time during which early detection may be effective. Most sporadic
CRCs arise from adenomatous polyps and the progression from normal mucosa
through polyp formation and subsequent development of cancer is a process that
occurs over a 5- to 15-year period. Consideration of this time frame is important
when deciding what intervals are optimal for repeated screening.
B. Tests available for cancer screening
1. Digital rectal examination. Most physicians are able to examine the rectum
digitally to a depth of 7 to 9 cm. This should detect about 5% to 10% of polyps.
An infiltrating cancer feels hard and irregular, whereas a benign polyp is more
likely to be soft and pliable.
2. Test for occult blood in the stool. Because bleeding is the most common
sign of CRC, testing for occult blood in the stool is valuable in cancer sur-
veillance. Currently available guaiac-impregnated cards have low false-nega-
tive and false-positive rates when used properly. Patients should adhere to a
special diet (Table 39-6) for 48 hours before the stool is tested for occult
blood. The diet eliminates foods and agents that are likely to give a false-neg-
ative or false-positive result but includes “roughage,” which is believed to
stimulate bleeding from existing bowel lesions. The most reliable method of
testing for occult blood is to obtain two smears per day from different parts
of the stool for 3 days. A report by Mandel and associates indicates that
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Chapter 39: Colonic Polyps and Colorectal Cancer 277

TABLE 39-6 Diet for Fecal Occult Blood Testing

Avoid Include in diet

Red meat Chicken

Aspirin and nonsteroidal drugs Tuna fish
Peroxidase-containing foods Raw or cooked vegetables
(e.g., turnips, horseradish) Fruit
Vitamin C, citrus juices Bran cereal
(false-positive) Peanuts
Iron-containing drugs Popcorn
(false-positive)

annual fecal occult blood testing decreased the 13-year cumulative mortality
from CRC by 33%.
3. Colonoscopy, sigmoidoscopy, barium enema x-ray, CT colographic exam-
ination. See Chapters 5 and 9.
C. In the general population. See Figure 39-3.
D. In patients with colonic polyps. See Figure 39-4.
E. For people with a family history of CRC. People who have a parent, a sibling,
or a second-degree relative with colorectal carcinoma are at higher risk of devel-
opment of CRC, albeit much less than those who have familial colon cancer
syndrome. Such people also are at higher risk of the development of CRC and
polyps. People who have one first-degree relative with CRC should undergo CRC
screening (preferably with colonoscopy) starting at age 40, or 10 years before the
age of the onset in the affected relative. For people with two affected first-degree
relatives, or one first-degree relative and one or more second-degree relatives, ini-
tial colonoscopy at age 40 may be justified, followed by routine yearly stool occult
blood testing and periodic colonoscopy every 3 to 5 years.
F. For postoperative colonoscopic follow-up of patients with resected CRC.
Patients who have had a colorectal carcinoma are at greater risk of the develop-
ment of another colorectal carcinoma. Patients who have had resection of the
colon for cancer should undergo colonoscopy 12 months after surgery to look for
recurrence at the anastomosis and elsewhere in the colon. Subsequent colono-
scopic examinations should be every 2 to 3 years.
G. Chemoprevention of prevention of CRC. Compliance to screening programs for
CRC remains poor and alternative approaches are being sought. Chemoprevention
of CRC involves the long-term use of a variety of oral agents to prevent the devel-
opment of adenomatous polyps and their subsequent progression to CRC.
Molecular analyses of adenomas and CRCs have led to a genetic model of colon
carcinogenesis in which the development of cancer results from the accumulation of
a number of genetic alterations. By interfering with these molecular events, chemo-
prevention could inhibit or reverse the development of adenomas or the progression
from adenoma to cancer. Recent observations suggest that patients taking inhibitors
such as celecoxib, aspirin, NSAIDs, cyclooxygenerase-2 (COX-2), supplemental
folate, calcium, and estrogen, as seen in postmenopausal women taking hormone
replacement therapy, experience a chemopreventive benefit. Other potential
chemopreventive agents as ursodiol, eflornithine, and oltipraz are undergoing eval-
uation in clinical studies.
Chemoprevention should not replace periodic fecal occult blood tests and
endoscopic screening as well as modification in known risk factors of CRC such as
reduction in the intake of red meat, appropriate exercise, smoking cessation, and
weight control.
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278 Part V: Specific Complaints and Disorders

Figure 39-3. Recommendations for cancer surveillance in the general population.

Figure 39-4. Recommendations for cancer surveillance in patients with colonic polyps.
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Chapter 39: Colonic Polyps and Colorectal Cancer 279

Selected Readings
Anderson JC, et al. Prevalence of colorectal neoplasia in smokers. Am J Gastroenterol.
2003;98:2777–2783.
Barclay RL, et al. Colonoscopic withdrawal times and adenoma detection during screening
colonoscopy. N Engl J Med. 2006;355:2533–2541.
Chan AT, et al. Aspirin and the risk of colorectal cancer in relation to the expression of
COX-2. N Engl J Med. 2007 May 24;356:2131–2134.
Cho E, et al. Alcohol intake and colorectal cancer: A pooled analysis of 8 cohort studies.
Ann Intern Med. 2004;140:603–612.
Cole BF, et al. Folic acid for the prevention of colorectal adenomas: A randomized clinical
trial. JAMA. 2007 June 6;297:2351–2359.
Coluca G, et al. Phase III randomized trial of FOLFIRI versus FOLFAX 4 in the treatment
of advanced colorectal cancer. J Clin Oncol. 2005;23(22):4866–4875.
DeJong A, et al. Decrease in mortality in Lynch syndrome families because of surveillance.
Gastroenterology. 2006;130:665–671.
Dove-Edwin I, et al. Prevention of colorectal cancer by colonoscopic surveillance in
individuals with a family history of colorectal cancer: A 16 year prospective follow-up.
BMJ. 2005;331:1047–1052.
Eng C, et al. Impact of quality of life of adding cetuximab to irontecan in patients who have
failed prior oxaliplatin-based therapy:the EPIC trial. J Clin Oncol. 2007;25:suppl:18s.
Giardiello FM, et al. AGA technical review on hereditary colorectal cancer and genetic
testing. Gastroenterology. 2001;121:198.
Goldberg RM, et al. A randomized controlled trial of fluoro acid plus leukovour, Irinotecan
and oxiplatin combinations in patients with previously untreated metastatic colorectal
cancer. J Clin Oncol. 2004;22(1):23–30.
Hur C, et al. The management of small polyps found by virtual colonoscopy: results of a
decision analysis. Clin Gastroenterol Hepatol. 2007;5:237–244.
Kapiteijn E, et al. Preoperative radiotherapy combined with total mesorectal excision for
resectable rectal cancer. N Engl J Med. 2001;345:638.
King JE, et al. Care of patients and their families with familial adenomatous polyposis.
Mayo Clin Proc. 2000;75:57.
Latreille MW, et al. Colonoscopy screening for detection of advanced neoplasia. N Engl
J Med. 2007;356:632–634.
Lierbeman DA, et al. Risk factors for advanced colonic neoplasia and hyperplastic polyps
in asymptomatic individuals. JAMA. 2003;290:2959–2967.
Offit K, et al. Reducing the risk of gynecologic cancer in the Lynch syndrome. N Engl
J Med. 2006;354:292–294.
Pickhardt P, et al. Computed tomographic virtual colonoscopy to screen for colorectal
neoplasia in asymptomatic adults. N Engl J Med. 2003;349:2191–2200.
Poston GJ, et al. Onco Surge: A strategy for improving resectability with curative intent in
metastatic colorectal cancer. J Clin Oncol. 2005;23(9):2038–2048.
Ratto C, et al. Combined modality therapy in locally advanced primary rectal cancer. Dis
Colon Rectum. 2003;46:59–67.
Rex DK, et al. ACG colorectal cancer prevention action plan: update on CT-colonography.
Am J Gastroenterol. 2006;I0I:1410–1403.
Rex DK, et al. Guidelines for colonoscopy surveillance after cancer resection: A consensus
update by the American Cancer Society and the U.S. Muti-Society Task Force on
Colorectal Cancer. Gastroenterology. 2006;130:1865–1871.
Rex DK, Maximizing detection of adenomas and cancers during colonoscopy. Am J
Gastroenterol. 2006;101:2866–2877.
Tonkef DJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med.
2007;357:2040–2048.
Ulrich DM and Potter JD. Folate and cancer—Timing is everything. JAMA. 2007 Jun 6;
297:2408–2409.
Winawer S, et al. Colorectal cancer screening and surveillance: Clinical guidelines and
rationale-update based on new evidence. Gastroenterology. 2003;124:544–560.
Winawer SJ, et al. Guidelines for colonoscopy surveillance after polypectomy: A consensus
update by the U.S. Multi-Society Task Force on Colorectal Cancer and the American
Cancer Society. Gastroenterology. 2006;130:1872–1885.L
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40 OSTOMY CARE

T he word ostium means “opening.” Thus the words ileostomy and colostomy refer
to openings into the ileum and colon, respectively, which are the subjects of this chapter.
Other ostomies include gastrostomies and jejunostomies, which usually are formed for the
purpose of alimentation, and ileal loop urostomies, which are formed to replace the urinary
bladder.
An ileostomy is usually the end result of a total proctocolectomy. A colostomy may
be formed after a partial colon resection, typically for cancer, diverticulitis, or ischemic
disease.

I. FORMATION OF OSTOMIES. Most ileostomies and colostomies are formed by bring-

ing the bowel out through an incision in the abdominal wall and suturing the mucosa
to the skin. Some are “double-barrel,” meaning that the bowel leads both to and away
from the opening. Two important modifications of ileostomies are available.
A. The Kock pouch, or continent ileostomy, is a pouch fashioned from ileum just
proximal to the ostomy and functions as a reservoir for stool. The stoma is
formed in the shape of a nipple, which is cannulated for drainage several times a
day. Most patients with Kock pouches remain continent and do not require an
ostomy bag.
B. Ileorectal pull-through. The second modification is not actually an ileostomy but
rather a form of anorectal anastomosis, called an ileorectal pull-through. The
entire colon is removed except for the distal rectum. The distal rectum is stripped
of mucosa, and the ileum is connected to the anus within the muscular sheath of
the rectum, which includes the anal sphincter. To improve continence, a pouch can
be formed from the distal ileum.

II. CONSEQUENCES AND COMPLICATIONS OF OSTOMIES. Because the colon

absorbs water and electrolytes in sufficient amounts to form a firm stool, patients
with ileostomies can be expected to lose water and electrolytes more than healthy
people do. The normal daily stool of a person whose bowel is intact weighs 100 to
200 g and contains 80% to 85% water. A normally functioning ileostomy discharges
500 to 1,000 g of stool per day, containing 90% to 95% water. Furthermore, whereas
healthy people can reduce stool sodium losses to 1 to 2 mEq per day by conserving
sodium in the colon, patients with ileostomies have obligatory daily sodium losses of
30 mEq or more.
If the terminal ileum has been removed in addition to the colon, bile salt and
vitamin B12 malabsorption may occur (see Chapter 31). The loss of bile salts may
predispose to steatorrhea, which worsens the diarrhea.
Complications of ileostomies and colostomies include irritation of the skin sur-
rounding the ostomy, obstruction of the ostomy, recurrence of inflammatory bowel
disease at or proximal to the stoma, and mechanical difficulties with the stoma appli-
ances. Patients also may have psychological and social problems related to the ostomy.

III. MANAGEMENT OF THE PATIENT WITH AN OSTOMY

A. Preoperative considerations. Ileostomies and colostomies are performed under
elective conditions in most instances. Thus, there should be adequate time to dis-
cuss the intended surgery with the patient, explain the necessity for the ostomy,

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Chapter 40: Ostomy Care 281

explore the patient’s concerns about it, review possible consequences and compli-
cations, and reassure the patient that after full recovery from surgery most patients
are able to conduct normal lives, including participation in normal physical, sex-
ual, and social activities. The physician, surgeon, and ostomy nurse all play impor-
tant roles in the preoperative preparation of the patient. Patients almost always
benefit from talking with another person who has an ostomy. Such people may be
well known to the physician or the ostomy nurse or they may be contacted through
the local Ostomy Association, which is listed in the telephone book of most
medium-to-large communities. The United Ostomy Association (36 Executive
Park, Suite 120, Irvine, CA 92714; telephone 1-800-826-0826) is a source for
informational material.
B. Skin care. The skin surrounding an ostomy is at risk for injury. Patients with an
ileostomy are likely to have more skin irritation than patients with a colostomy
because ileostomy stool is liquid and contains digestive enzymes. Tape and ill-
fitting appliances can also contribute to skin excoriation.
Nondetergent soap and water are the most appropriate peristomal skin-
cleansing agents. A variety of skin-conditioning agents and seals for appliances are
available. However, an improperly fitting appliance will negate the best skin care.
C. Fluids, salt, and diet
1. Fluids and salt. Because patients with ileostomies may lose up to a liter of
water and 30 mEq of sodium in the stool per day, they are encouraged to drink
2 to 3 L of water per day and not to restrict salt. Mild-to-moderate diarrhea
may be treated by increasing fluid and sodium intake and by adding bicarbon-
ate of soda and orange juice to provide potassium. More severe diarrhea may
require intravenous fluids and electrolytes. Patients with colostomies generally
do not have problems with excessive loss of fluid and electrolytes because suf-
ficient colon remains to maintain water- and electrolyte-conserving function.
2. Diet. Patients should be encouraged to eat a normal diet, with some modifica-
tion. Gas-producing foods may cause discomfort and embarrassment. Fresh
fruits may promote loose stools. Most patients discover through trial and error
the diet to which they are best suited.
3. Vitamin and mineral supplements. Some patients require vitamin and min-
eral supplements, particularly patients who have steatorrhea or vitamin B12
malabsorption.
D. Odors. Disagreeable odors from the ostomy bag can be distressful. The odors are
due to gases that are derived from the action of bacteria on intestinal substrates
(see Chapter 34). The problem is treated by emptying the bag frequently, avoiding
gas-forming foods, and adding a deodorant to the bag, such as chlorine tablets or
sodium benzoate.
E. Ostomy dysfunction. Partial obstruction of the ostomy, usually an ileostomy,
may result from recurrent disease, impaction of nondigestible material, or kinking
of a loop of bowel just proximal to the stoma. Patients experience abdominal
cramping pain and increased ostomy effluent.
1. Diagnosis. Gentle examination of the stoma with the small finger is indicated.
This may be followed by endoscopic examination, perhaps with a pediatric
sigmoidoscope or fiberoptic gastroscope. Retrograde barium-contrast radio-
logic studies through the stoma also may be helpful.
2. Treatment is dictated by the diagnosis. Recurrent inflammatory bowel disease
may respond to a course of treatment. Some patients require surgical revision
of the stoma.

Selected Readings
Bradley M, et al. Essential elements of ostomy care. Am J Nurs. 1997;97:38.
Catanzaro J, et al. High-tech wound and ostomy care in the home setting. Crit Care Nurs
Clin North Am. 1998;10:327.
Erwin-Toth P. The effect of ostomy surgery between the ages of 6 and 12 years on psychosocial
development during childhood, adolescence and young adulthood. J Wound Ostomy
Continence Nurs. 1999;26:77.
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282 Part V: Specific Complaints and Disorders

Evans JP, et al. Revising the troublesome stoma: Combined abdominal wall recountering
and revision of stomas. Dis Colon Rectum. 2003;46:122–126.
Mitchel JV. A clinical pathway for ostomy care in the home: Process and development.
J Wound Ostomy Continence Nurs. 1998;25:200.
Turnbull GB, et al. Ostomy care: Foundation for teaching and practice. Ostomy Wound
Manage. 1999;45(suppl 1A):23.
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HEMORRHOIDS AND OTHER

ANORECTAL DISORDERS 41

N early everyone has experienced anorectal discomfort. Our low-fiber diet, which
results in small, hard stools; our lifestyle, which restricts the opportunities for defecation;
and our erect posture, which promotes engorgement of the hemorrhoidal plexus all com-
bine to make anorectal problems virtually ubiquitous. The anorectum also is the site of
local manifestations of more generalized disorders, such as inflammatory bowel disease.
Finally, because the rectum is a sexual organ for some people, sexually transmitted diseases
may occur at that site.

I. HEMORRHOIDS
A. Pathogenesis. Hemorrhoids are dilated veins within the anal canal and distal rec-
tum. External hemorrhoids are derived from the external hemorrhoidal plexus
below the dentate line and are covered by stratified squamous epithelium. Internal
hemorrhoids are derived from the internal hemorrhoidal plexus above the dentate
line and are covered by rectal mucosa.
Hemorrhoids are thought to develop in most instances as a consequence of
erect posture, straining at stool, heavy lifting, or childbirth. In some patients, por-
tal hypertension predisposes to hemorrhoids; rarely, hemorrhoids develop as a
result of an intraabdominal mass.
B. Clinical presentation
1. History. Hemorrhoids typically cause bleeding, which is detected as streaks of
red blood on the stool and toilet paper. Patients also may complain of anal itch-
ing or pain. However, severe pain is an unusual symptom unless the hemorrhoid
is thrombosed.
2. Physical examination. Inspection of the anus may reveal bluish, soft, bulging
veins indicative of external hemorrhoids or prolapsed internal hemorrhoids.
Nonprolapsed internal hemorrhoids cannot be seen externally and are difficult
to distinguish from mucosal folds by digital rectal examination unless they are
thrombosed. Thrombosed hemorrhoids usually are exquisitely tender.
C. Diagnostic studies. The anal canal and rectum should be examined by anoscopy
and sigmoidoscopy. Symptomatic hemorrhoids usually are accompanied by vary-
ing degrees of inflammation within the anal canal. At sigmoidoscopy, the anus and
rectum can be evaluated for other conditions in the differential diagnosis of rectal
bleeding and discomfort, such as anal fissure and fistula, proctitis and colitis, rec-
tal polyp, and cancer. Barium enema x-ray examination or colonoscopy should be
performed in patients over age 50 and in patients of any age whose stool remains
positive for occult blood after appropriate treatment for hemorrhoids.
D. Treatment. A high-fiber diet, stool softeners, and avoidance of straining at stool
and heavy lifting may be sufficient to treat mild hemorrhoidal symptoms. Warm
baths twice a day and anal lubrication with glycerine suppositories provide further
comfort. Addition of medicated suppositories, such as Anusol-HC (containing
hydrocortisone), may help reduce associated inflammation. However, steroid-
containing medications should be limited to 2 weeks of continuous use to avoid
atrophy of the anal tissues.
Additional treatment usually requires the expertise of a gastroenterologist or
surgeon. Rubber-band ligation is usually the first definitive treatment. The proce-
dure requires no anesthesia and produces excellent results in most patients.

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284 Part V: Specific Complaints and Disorders

Injection of hemorrhoids with sclerosing solutions, dilatation of the anal sphincter

under anesthesia, electrocoagulation, and laser coagulation are alternatives if rub-
ber banding is ineffective. In patients whose hemorrhoids are severe and refractory
to these treatments, surgical excision of the hemorrhoidal plexus may be necessary.
Rarely, surgical section of the internal anal sphincter is performed.

II. ANAL FISSURES

A. Pathogenesis. An anal fissure is a tear in the lining of the anus, usually resulting
from the difficult passage of hard stool. Some fissures are a consequence of a more
generalized bowel disorder, such as Crohn’s disease. Others result from the trauma
of anal intercourse or insertion of foreign bodies. Rarely, carcinoma of the anus
presents as an anal fissure.
More than 90% of fissures that are not associated with Crohn’s disease occur
in the posterior midline. The remainder occurs in the anterior midline. Fissures
associated with Crohn’s disease may occur at any location within the anal canal.
B. Clinical presentation. Anal fissures are painful, and the pain is exacerbated by
the passing of stool. The pain may lead to a cycle of retention of stool, formation
of hard stool, passage of hard stool, and aggravation of the fissure. Bleeding and
itching also are common. Anal fissures often coexist with hemorrhoids.
External examination by spreading the patient’s buttocks and anal orifice
may reveal the fissure. Digital examination usually is quite painful for the patient
and thus the rectal examination may be limited. Sometimes the fissure or a mass of
granulation tissue can be palpated. Preliminary application of a topical anesthetic
decreases the discomfort of the digital rectal examination and subsequent sigmoi-
doscopic examination.
C. Diagnostic studies
1. Anoscopy and sigmoidoscopy should be performed to make the definitive
diagnosis and to rule out other conditions mentioned in section I, in the dis-
cussion of hemorrhoids.
2. Scraping the fissure. If the cause of the fissure is suspected to be sexual, a
scraping of the fissure should be examined under dark field illumination to con-
sider the possibility of a syphilitic lesion.
3. Radiologic evaluation. Patients whose fissures fail to heal or who have fis-
sures that are not in the midline should undergo radiologic evaluation of the
large and small bowel for Crohn’s disease.
4. The treatment of anal fissure is similar to that of hemorrhoids: high-bulk diet,
stool softeners, warm baths, and lubricating suppositories. Most fissures heal on
this regimen. Chronic anal fissures that are not due to inflammatory bowel dis-
ease may require dilatation of the anus, sphincterotomy, or excision of the fissure.

III. FISTULAS AND ABSCESSES

A. Pathogenesis. A fistula is a tract lined by inflammatory tissue that usually has an
opening through the mucosa of the anus or rectum and another opening in the
perianal skin. Sometimes only one opening is evident. Fistulas are always infected
with local organisms. An abscess is a collection of pus within the perianal or
perirectal tissues, which may or may not be associated with a fistulous tract.
Factors that predispose to fistula or abscess formation include local infection of
the anal crypts, Crohn’s disease, trauma, cancer, and venereal disease.
B. Clinical presentation and diagnosis. A fistula or abscess may be painful and
cause fever. If the fistula is external, drainage of pus, mucus, or stool may be
evident. Physical examination may confirm the external location of the fistula
opening. A tender, firm, or fluctuant mass suggests an abscess. Anoscopy, sigmoi-
doscopy, and barium-contrast studies are indicated as described in section II.C.
C. Treatment. Although local treatment with warm baths, high-fiber diet, and stool
softeners may be palliative, definitive surgical drainage of the abscess or excision of
the fistula usually is indicated. An exception is a fistula associated with Crohn’s dis-
ease, which may respond to an elemental diet, metronidazole, or steroid therapy.
Broad-spectrum antibiotics are indicated for patients with fever, elevated white blood
cell count, or signs of systemic toxicity.
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Chapter 41: Hemorrhoids and Other Anorectal Disorders 285

IV. PROCTITIS
A. Pathogenesis. Proctitis is an inflammation of the rectal mucosa. It may be idio-
pathic or related to a specific cause, such as radiation or gonococcal infection.
B. Clinical presentation. Patients with proctitis typically complain of pain and
bleeding on defecation. Stools may be loose, but often they are well formed. In
fact, some patients move their bowels infrequently to avoid pain and thus become
constipated, which aggravates symptoms even more. Digital rectal examination
may reveal a small amount of bloody stool or mucus.
Idiopathic proctitis is a chronic, relapsing, localized condition that progresses
to ulcerative colitis in some patients. The appearance of an erythematous, friable,
sometimes hemorrhagic mucosa, however, is indistinguishable from that of ulcer-
ative colitis. Small ulcerations and pus suggest the possibility of gonococcal
proctitis. Ulcers and vesicles of the distal rectum, which may extend to the peri-
anal skin, suggest herpes proctitis.
C. Diagnostic studies. Sigmoidoscopy shows the inflammation to be limited to the
rectum, sometimes within several centimeters of the anus. Mucosal biopsy and
culture of rectal secretions should be obtained. More extensive bowel involvement
may be documented by barium enema or colonoscopy.
D. Treatment
1. Idiopathic proctitis. Treatment of idiopathic proctitis usually consists of
mesalamine enemas (i.e., Rowasa) or suppositories (i.e., Canasa) or steroid ene-
mas once or twice daily for 4 to 6 weeks. Patients should be instructed to lie in
the left decubitus position and gently insert a suppository or an enema before
bedtime and another in the morning after a bowel movement. Some patients
require one or two mesalamine or steroid enemas per day for prolonged periods
to control symptoms. Patients who have frequent recurrences of proctitis may
respond to prophylactic treatment with sulfasalazine (1 to 2 g b.i.d.) or a
mesalamine preparation (e.g., Asacol 800 mg t.i.d. or Colazal 2.25 g t.i.d.).
Steroid or mesalamine enemas also are somewhat effective in treating radiation
proctitis.
2. Infectious proctitis. Treatment of infectious proctitis is directed at the
causative agent. For example, gonococcal proctitis typically responds to aque-
ous procaine penicillin G, 4.8 million units intramuscular (IM), plus 1 g of oral
probenecid. For penicillin-allergic patients, tetracycline (orally, 1.5 g followed
by 0.5 g q.i.d. for 4 days) is effective.

V. RECTAL PROLAPSE
A. Pathogenesis. Rectal prolapse ranges in severity from prolapse of a small portion
of rectal mucosa to protrusion of the entire rectal wall through the anus (proci-
dentia). Straining at stool is thought to be causative, but pelvic surgery,
childbearing, and weak pelvic musculature are contributive factors.
B. Clinical presentation and diagnosis. Patients with rectal prolapse complain of
bleeding, passage of mucus, and irritation of the exposed mucosa. In some
patients, prolapse of the rectal mucosa or of a substantial portion of the rectum
may be observed. Other patients must strain to produce the prolapse. Poor anal
sphincter tone usually is evident on digital examination. Sigmoidoscopy and, in
most patients, barium enema are indicated to define the extent of irritated mucosa
and to rule out associated conditions.
C. Treatment. If the prolapse is mild and confined to the mucosa, the treatment
regimen is the same as for hemorrhoids. However, frank procidentia requires
operative treatment if the surgical risk is good.

VI. PROCTALGIA FUGAX

A. Pathogenesis and clinical presentation. Proctalgia fugax is fleeting pain in the
anorectum. The pain is intense, develops suddenly, and typically lasts for seconds to
minutes, although occasionally it persists for several hours. There is no known
cause. It probably is related to spasm of the musculature of the rectosigmoid or
levator muscles. Rarely, it is associated with mucosal inflammatory disease or
colonic tumors.
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286 Part V: Specific Complaints and Disorders

B. The diagnosis is made by the typical history of rectal pain and absence of physi-
cal findings. Rectal and sigmoidoscopic examinations should be performed to rule
out other treatable disorders.
C. Treatment is symptomatic, consisting of warm baths and, if symptoms are
frequent, analgesics and muscle relaxants. Because of the transient nature of the
disorder, however, it is often difficult to determine whether treatment has been
effective. The condition usually resolves spontaneously.

VII. PRURITUS ANI

A. Pathogenesis. Virtually everyone has experienced perianal itching. When the
itching becomes frequent or constant, patients seek medical attention. The causes
of pruritus ani are legion, including hemorrhoids, fissures, skin disorders, infec-
tions, parasites, neoplasms, excessive moisture, excessive dryness, irritation from
soap and other agents, and psychoneurosis.
B. Clinical presentation. When patients complain of perianal itching, a careful his-
tory of bowel habits, stool-wiping technique, use of cleansing or other local
agents, and ingestion of antibiotics should be obtained. Examination may be nor-
mal or may reveal erythema, excoriations, or maceration of the perianal skin.
C. Diagnostic studies. Rectal and sigmoidoscopic examinations should be per-
formed. Stool culture, examination of the stool for ova and parasites, and exami-
nation of the perianal skin for pinworms or Candida are performed when clini-
cally indicated.
D. Treatment depends on the diagnosis. If no specific cause can be determined, the
patient is advised to avoid all topical agents that might irritate the anus and to
consume a high-fiber diet. Patients should wipe the anus gently, not vigorously,
after defecation, using a moist cotton ball or cotton cloth. Calamine lotion or a
steroid cream (not ointment) may be applied to the anus several times a day.

VIII. TUMORS
A. Pathogenesis. Tumors of the anus sometimes are confused with other inflamma-
tory and infectious lesions. The most common anal tumor is epidermoid carci-
noma, but adenocarcinoma and malignant melanoma also can occur.
B. Clinical presentation and diagnosis. Patients complain of anal pain, bleeding,
itching, or presence of a mass. They may think that they are having more trouble
with their hemorrhoids. The diagnosis of neoplasm is suspected by visual inspec-
tion, digital examination, and anoscopy; it is confirmed by biopsy. A search for
local extension and metastatic disease is warranted. This typically includes routine
liver tests, chest x-ray, and computed tomography of the abdomen and pelvis.
C. Treatment. Small anal tumors can be treated by local excision. More extensive lesions
require the addition of radiation therapy or chemotherapy, or an abdominoperitoneal
resection of the rectum and anus.

IX. SEXUALLY TRANSMITTED ANORECTAL INFECTIONS. See Chapter 42.

Selected Readings
Beets-Tan RGH. Preoperative MR imaging of anal fistulas: Does it really help the surgeon?
Radiology. 2001;218:75.
Cheung O, et al. The management of pelvic floor disorders. Ailment Pharmacol Ther.
2004;19:481–495.
Diamant NE, et al. AGA technical review on anorectal testing techniques. Gastroenterology.
1999;116:735.
Dorsky R. Coping with the pain and annoyance of hemorrhoids. Dis Health Nutr. January/
February 2000:21.
Gosens MJEM, et al. Improvement of staging by combining tumor and treatment
parameters: the value for prognostication in rectal cancer. Clin Gastroenterol Hepatol.
2007;5(8):997–1003.
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Chapter 41: Hemorrhoids and Other Anorectal Disorders 287

Jones MP, Post JP, Crowell MD. High-resolution manometry in the evaluation of anorectal
disorders: a simultaneous comparison with water-perfused manometry. Am J
Gastroenterol. 2007;102:1–6.
Kang YS, et al. Pathology of the rectal wall in solitary ulcer syndrome and complete rectal
prolapse. Gut. 1996;38:587.
Koslin DB. Anal fistulae. Rev Gastroenterol Disord. 2001;1:56.
Madoff RD, et al. AGA technical review on the diagnosis and care of patients with anal
fissure. Gastroenterology. 2003;124:235–245.
Masderstein EL, et al. Surgical management of rectal prolapse. Nat Clin Pract Gastroenterol
Hepatol. 2007;4(10):552–561.
Rao SC. How useful are manometric tests of anorectal function in the management of
defecation disorders? Am J Gastroenterol. 1999;116:735.
Rao SC. Dyssynergic: disorders of the anorectum. Gastroenterol Clin North Am. 2001;
31:97–114.
Rao SSC. Diagnosis and management of fecal incontinence. Am J Gastroenterol. 2004;
99:1585–16.
Sentovic SM. Fibrin glue for anal fistulas: Long term results. Dis Colon Rectum. 2003;46:
498–502.
Sobhani I, et al. Prevalence of high-grade dysplasia and cancer in anal canal in human
papilloma virus-infected individuals. Gastroenterology. 2001;120:857.
Sotlar K, et al. Human papilloma virus type 16-associated primary squamous cell carcinoma
of the rectum. Gastroenterology. 2001;120:988.
Wald A, Fecal incontinence in adults. N Engl J Med. 2007;356:1648–1655.
79466_CH42.qxd 1/2/08 12:46 PM Page 288

42 SEXUALLY TRANSMITTED
ENTERIC DISORDERS

S ubstantial increases in the recognition and prevalence of sexually transmitted enteric

disorders have occurred over the past several decades, largely due to increasing freedom of
both heterosexual and homosexual expression. The acquired immunodeficiency syndrome
(AIDS) has further augmented the diversity and complexity of sexually related enteric dis-
orders. These disorders are summarized in Table 42-1. Gastrointestinal and hepatobiliary
disorders that are related to the human immunodeficiency virus (HIV) are discussed in
more detail in Chapter 43.

I. PATHOGENESIS. Most of the sexually related enteric disorders are infectious

(Table 42-1), although trauma may be a clinically significant factor in the pathogenesis
of anorectal disease, and neoplasm (Kaposi’s sarcoma, lymphoma) can complicate AIDS.
The transmission of infectious agents during sexual activity is to be expected, particularly
when one considers the variety of means of sexual expression—oral/oral contact, fellatio,
cunnilingus, anilingus, and anal intercourse, in addition to ordinary sexual intercourse.
Thus, it is no mystery that sexually related diseases occur, particularly in the oropharynx
and anorectum, but also elsewhere throughout the digestive system.

II. DIAGNOSIS. Knowledge of a patient’s sexual practices can be helpful but is not
necessary to make an etiologic diagnosis of one of the conditions listed in Table 42-1.

TABLE 42-1 Sexually Related Disorders of the Gastrointestinal Tract

Oropharyngeal disorders Condylomata acuminata

Gonococcal pharyngitis (papilloma virus)
Oral syphilis Traumatic injury
Herpes pharyngitis Liver disorders
Gastric disorders Gonococcal perihepatitis
Syphilitic gastritis Syphilitic hepatitis
Enteric disorders Hepatitis A; B; non-A, non-B
Campylobacter infections Cytomegalovirus hepatitis
Salmonellosis AIDS-related disorders
Shigellosis Infections with
Giardiasis Candida
Amebiasis Cryptosporidium
Anorectal disorders Isospora
Gonococcal proctitis Mycobacterium avium-intracellulare
Syphilis Kaposi’s sarcoma
Chlamydial infection Lymphoma
(lymphogranuloma venereum)
Herpes proctitis

288
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Chapter 42: Sexually Transmitted Enteric Disorders 289

A. Oropharyngeal disorders
1. Gonococcal pharyngitis can present with sore throat, exudate of the pharynx
and tonsils, and ulcerations of the tongue and buccal mucosa. However, some
patients with gonococcal infection of the oropharynx may be asymptomatic but
transmit the disease to others. If gonococcal infection is suspected, the lesions
should be cultured immediately.
2. Syphilis. The oral lesions of syphilis are elevated, round, sometimes ulcerated,
and usually painless. They occur most frequently on the lips but also may be
found on the tongue or tonsils, and elsewhere within the mouth and pharynx.
These lesions heal within several weeks but are superseded by the systemic signs
and symptoms of secondary syphilis, namely, fever, sore throat, lymphadenopa-
thy, pruritus, and skin lesions. A nonspecific pharyngitis may also be present.
The darkfield examination of the primary oral lesions may be confused by the
presence of normal oral spirochetes. Serologic tests may not be positive until the
secondary form of the disease appears. Aspiration of enlarged lymph nodes for
darkfield examination may give an early diagnosis.
3. Herpes pharyngitis. Patients with herpes pharyngitis have erythema and ulcer-
ations of the mouth, tongue, gingiva, and pharynx. Exudate and lym-
phadenopathy also may be present. The presence of a herpes infection in the
patient’s sexual partner makes the diagnosis more likely. Facilities to culture the
virus may not be available. The diagnosis can be inferred from serologic tests
directed against the herpes simplex virus.
B. Gastric disorders. Although the infectious agents that cause sexually related
enteric diseases may pass through the stomach, gastritis per se is not a feature of
those diseases. However, secondary syphilis, a rare complication, can involve the
stomach. In syphilitic gastritis, the mucosa becomes ulcerated and infiltrated with
chronic inflammatory cells. Patients complain of abdominal pain and vomiting.
Loss of weight is common. Spirochetes can be identified by darkfield examination
of mucosal biopsies. The diagnosis can be confirmed by serologic tests for syphilis.
The stomach also can be involved with lymphoma or with Kaposi’s sarcoma when
these conditions affect AIDS patients.
C. Enteric disorders. Patients with sexually transmitted enteric infections appear sim-
ilar clinically to those who contract the infection in some other manner. The diagno-
sis and management of infectious diarrheal conditions are discussed in Chapter 29.
D. Anorectal disorders
1. Gonococcal proctitis may present with anorectal pain, tenesmus, and a
mucopurulent discharge. At sigmoidoscopy, the rectal mucosa appears red and
contains pus and small ulcers. Mucosal biopsy shows nonspecific inflammation.
The diagnosis is made by Gram’s stain and culture of rectal aspirates or mucosal
biopsies. Many patients with anorectal gonococcal infection are asymptomatic
but are a source of infection to others.
2. Anorectal syphilis is characterized by a painless chancre, which often is mis-
taken for an anal fissure. The diagnosis of syphilis is based on a high index of
suspicion in a susceptible patient, darkfield examination of the lesion, and sero-
logic follow-up.
3. Chlamydia trachomatis can infect the rectum and intestine with either the
lymphogranuloma venereum (LGV) serotype or the non-LGV serotype. The
non-LGV infections are similar to infections caused by gonococci. They are
usually mildly symptomatic with anorectal discharge, tenesmus, anorectal pain,
and mild mucosal inflammation. In contrast, LGV infections typically cause
severe proctocolitis. Anorectal pain is severe and is accompanied by bloody
purulent discharge, tenesmus, and diarrhea. The rectal mucosa is friable and
ulcerated. The histologic appearance may be similar to that in Crohn’s disease,
with diffuse inflammation and granulomas. Stricturing and fistula formation
add to the confusion with Crohn’s disease. C. trachomatis can be isolated from
the rectum. Serologic tests of LGV infection confirm the diagnosis. Response to
treatment with tetracycline also is confirmatory of the diagnosis.
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290 Part V: Specific Complaints and Disorders

TABLE 42-2 Treatment of Sexually Related Gastrointestinal Infections

Infectious agent Suggested antibiotic Alternative antibiotic

Gonococcus
Oropharyngeal APPG, 4.8 million units TS (80 mg/400 mg),
Rectal IM
probenecid, 1 g p.o. 9 tablets daily  5 d
APPG, 4.8 million units Spectinomycin, 2 g IM
IM
probenecid, 1 g p.o.
Syphilis Benzathine penicillin G, Tetracycline, 500 mg p.o.
2.4 million units IM q.i.d.  15 d
Chlamydia
LGV Tetracycline, 500 mg p.o. Erythromycin, 500 mg p.o.
q.i.d.  21 d q.i.d.  21 d
Non-LGV Tetracycline, 500 mg p.o. Erythromycin, 500 mg p.o.
q.i.d.  7 d q.i.d.  7 d
Herpes simplex Acyclovir, 1 tablet Supportive therapy
5 times/d  10 d
Papilloma virus (condyloma) Podophyllin (10%–25%) Cryotherapy or surgery
on lesion every other day
Campylobacter Erythromycin, 500 mg Tetracycline, 500 mg
p.o. q.i.d.  7 d p.o. q.i.d.  7 d
Salmonella Antibiotic treatment not Ampicillin, 1 g intravenous
necessary except for q4h  10 d; TS, 2
severe cases tablets p.o. q12h  10 d
Shigella TS, 160 mg/800 mg Ampicillin, 500 mg
p.o. b.i.d.  7 d p.o. q.i.d.  7 d
Giardia Metronidazole, 250 mg Quinacrine hydrochloride,
p.o. t.i.d.  7 d 100 mg t.i.d.  7 d
Entamoeba Metronidazole, 750 mg Diiodohydroxyquin, 650 mg
p.o. t.i.d.  7 d p.o. t.i.d.  20 d
Candida (esophagitis) Fluconazole, Ketoconazole, 200 mg
50–100 mg  10 d p.o. b.i.d.
Cryptosporidium Supportive therapy only
in immunocompetent
patients
Spiramycin, 1 g p.o. q.i.d.
in patients with AIDS
Isospora Supportive therapy only
in immunocompetent
patients
Spiramycin, 1 gm
p.o. q.i.d. in patients
with AIDS
Mycobacterium Multidrug antituberculous
avium-intracellulare therapy

APPG, aqueous procaine penicillin G; TS, trimethoprim/sulfamethoxazole; LGV, lymphogranuloma

venereum; IM, intramuscular; p.o., orally; q.i.d., four times daily; t.i.d., three times daily; b.i.d., twice
daily; AIDS, autoimmune deficiency syndrome.
Modified from Quinn TC. Clinical approach to intestinal infections in homosexual men. Med Clin North
Am. 1986;70:611. Reprinted with permission.
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Chapter 42: Sexually Transmitted Enteric Disorders 291

4. Herpes can involve not only the anus and rectum but also the perianal skin, with
the typical herpetic vesicles and ulcerations. Patients complain of pain, rectal
discharge, and bloody stool. The diagnosis often can be made on clinical presenta-
tion alone. Histologic examination of rectal mucosal biopsies may reveal intranu-
clear inclusion bodies in addition to focal ulcers and perivascular mononuclear cell
infiltrates. Culture of the virus is diagnostic but may not be available. The serologic
diagnosis requires seroconversion or a fourfold or greater rise in antibody titer.
5. Condylomata acuminata, or anal warts, are caused by the human papilloma
virus and are common in people who practice anal intercourse. They appear as
small brownish papules around the anus.
6. Traumatic injury may have many causes and may take many forms. Dilatation
and stretching of the anus from anal intercourse can cause fissures and tearing of
the mucosa and underlying structures. The practice of inserting fingers, hands,
arms, or foreign objects into the rectum increases the likelihood of anal and rectal
trauma. The diagnosis of anorectal trauma is based on historical information unless
a foreign object is apparent. Traumatic and infectious disorders can coexist.
E. Liver disorders
1. Gonococcal perihepatitis is a consequence of spread of infection from the
fallopian tubes in women and through lymphatics or blood in both men and
women. The signs and symptoms are similar to those of acute cholecystitis,
namely, acute right upper abdominal pain that may radiate to the shoulder,
nausea and vomiting, and fever. Although the patient may or may not have
symptomatic pelvic gonorrhea, cultures of the uterine cervix for gonococcus
typically are positive. The condition must be differentiated from acute chole-
cystitis and other causes of acute abdominal pain (see Chapter 13).
2. Syphilitic hepatitis is an unusual manifestation of secondary syphilis. It is
thought to be due to an infiltration of the liver by spirochetes, which arrive
through the portal system from primary lesions in the rectum. The clinical picture
is one of hepatomegaly and obstructive jaundice. Liver biopsy is diagnostic when
it shows granulomas and spirochetes within the liver.
3. The hepatitis viruses and cytomegalovirus can be transmitted by sexual con-
tact. The diagnosis and management of these infections are discussed in Chapter 50.

III. TREATMENT. Effective treatment of the infectious causes of sexually related enteric
disease depends on the identification of the offending agent or agents and use of the
appropriate antibiotic regimen (Table 42-2). Supportive treatment may involve intra-
venous fluids and nourishment in patients who are unable to swallow or who have
severe diarrhea. There is no known effective therapy for Kaposi’s sarcoma. Lymphoma
may respond to chemotherapy or radiation therapy (see Chapter 32).

Selected Readings
Jones DJ, Goorney BP. ABC of colorectal diseases: Sexually transmitted diseases and anal
papillomas. BMJ. 1992;305:820.
Laughon BE, et al. Prevalence of enteric pathogens in homosexual men with and without
acquired immunodeficiency syndrome. Gastroenterology. 1988;94:984.
Owen WF Jr. The clinical approach to the male homosexual patient. Med Clin North Am.
1986;70:499.
Quinn TC. Clinical approach to intestinal infections in homosexual men. Med Clin North
Am. 1986;70:611.
Smith PD, et al. Gastrointestinal infections in AIDS. Ann Intern Med. 1992;116:63.
Surawicz CM, et al. Anal dysplasia in homosexual men: Role of anoscopy and biopsy.
Gastroenterology. 1993;105:658.
Weller ID. The gay bowel. Gut. 1985;26:869.
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43 GASTROINTESTINAL AND HEPATOBILIARY

DISEASES IN PATIENTS WITH HIV AND AIDS

Gastrointestinal Diseases Associated with Human Immunodeficiency Virus (HIV)

Infection
The treatment of human immunodeficiency virus (HIV) infection has dramatically
improved over the last several years with the use of combination therapy of potent anti-
retroviral agents including protease inhibitors. With this highly active antiviral therapy
(HAART), HIV replication can be profoundly suppressed and in some patients, circulating
HIV becomes undetectable. Even patients with advanced HIV disease, the CD4 lympho-
cyte count rises reflecting a redistribution of CD4 cells. Clinically, with regression of
immune suppression, patients become more immunocompetent, the risk for opportunistic
infections and processes becomes reduced, and overall survival is improved. Thus, at this
time the long-term prognosis is dictated by the severity of the immunodeficiency (absolute
number of CD4 cells) and the level of the circulation virus.
Because of HAART, there has been a major change in the management of oppor-
tunistic infections (OIs) in HIV and acquired immunodeficiency syndrome (AIDS). When
OIs are diagnosed and treated, both the OI and the underlying HIV infection are treated.
In fact, in some patients, treatment with HAART alone results in a remission of OI and
reduction of relapses. Because of the remarkable success of HAART in reconstitution of
the immune system in these patients, the etiology, diagnostic approach, and management
of HIV-associated gastrointestinal (GI) diseases learned in the pre-HAART era may not be
accurate at this time.
GI complaints and problems are still quite common in HIV-infected patients; how-
ever, etiology has shifted toward disorders not associated with HIV-induced immunodefi-
ciency. Also, some of the medications used in HAART regimens have been associated with
GI and hepatic side effects. Table 43-1 lists GI pathogens/diseases by location in HIV-
infected patients.

I. DISEASES OF THE ESOPHAGUS. Before HAART, approximately one third of HIV-

infected patients developed esophageal disease. In patients treated with HAART, the
frequency of OI of the entire GI tract, including the esophagus, has been dramatically
reduced. However, as with other OIs, the incidence of opportunistic disorders increases
as the immunodeficiency worsens. The esophagus may often be the site of the first
AIDS-defining opportunistic disease. OIs are the most common causes of esophageal
disease. However, cytomegalovirus (CMV) and idiopathic esophageal ulceration (IEU)
are rarely seen until the CD4 count falls below 100/mL. Almost all esophageal infec-
tions in patients with AIDS are treatable. A definitive diagnosis and treatment usually
results in better nutrition, weight gain, and a better quality of life for the patient.
A. Etiologies
1. Fungi. Prior to the use of HAART, Candidiasis was the most common cause of
esophageal disease in HIV-infected patients. Esophageal involvement by fungi
other than Candida is very rare.
2. Viruses. CMV is the most common cause of esophagitis in patients with AIDS.
In contrast to other immunocompromised states, such as in posttransplant
patients, infection with herpes simplex virus (HSV) is uncommon in HIV-
infected patients. In a prospective study of 100 patients infected with HIV, HSV
esophagitis was found only in 5% of these patients compared to a 50% preva-
lence of CMV esophagitis.

292
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Chapter 43: Gastrointestinal and Hepatobiliary Diseases 293

TABLE 43-1 Gastrointestinal Pathogens in HIV-Infected Patients

Site Organism

Esophagus Candida albicans

HSV
CMV
Stomach CMV
MAC
Small intestine Salmonella
Campylobacter
MAC
Cryptosporidium
Microsporidia (Enterocytozoon bieneusi)
Isospora belli
Giardia lamblia
Large intestine CMV
Adenovirus
Histoplasma
Shigella
Salmonella
Clostridium difficile
Campylobacter
MAC
Cryptosporidium
Microsporidia
Entamoeba histolytica
Anus HSV, Human papilloma virus

HIV, human immunodeficiency virus; HSV, herpes simplex virus; CMV, cytomegalovirus;
MAC, Mycobacterium avium complex.

3. Idiopathic esophageal ulcers (IEUs) are an important cause of dysphagia and

odynophagia in patients with AIDS. IEU is nearly as common as CMV
esophagitis, comprising about 40% of esophageal ulcers. The etiology of IEU is
unknown and includes disordered immune regulation, increased apoptosis,
local HIV infection, and unidentified viruses.
4. Gastroesophageal reflux disease (GERD), in the era of HAART, probably
represents one of the most common causes of esophageal disease.
5. Pill-induced esophagitis is not uncommon in HIV-infected patients on
HAART. Medications unique to these patients include zidovudine (AZT) and
zalcitabine (ddC).
B. Clinical presentation
1. The history is usually helpful in determining the cause and severity of the
esophageal disease. Difficulty swallowing (dysphagia), painful swallowing
(odynophagia), loss of appetite, and weight loss are the most common com-
plaints. When the pain is unilateral and localized to the neck or hypopharynx,
oropharyngeal rather than esophageal disease is likely.
2. Physical examination. The presence of oropharyngeal lesions may provide a
clue to the underlying cause of esophageal complaints. Approximately two
thirds of patients with esophageal candidiasis have concomitant thrush.
However, the presence of thrush does not necessarily indicate Candida
esophagitis. Also, Candida esophagitis may coexist with other esophageal dis-
eases in at least 25% of patients. Oropharyngeal ulcers are rarely associated
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294 Part V: Specific Complaints and Disorders

with esophageal ulcers. Kaposi’s sarcoma (KS) lesions may be seen in the
oropharynx and are associated with GI KS.
3. Laboratory tests. The stage of immunodeficiency determines the differential
diagnosis of esophageal disease. The levels of HIV viremia and CD4 lympho-
cyte count are the two most important laboratory tests. OIs of the esophagus
are uncommon until the CD4 count falls below 200/mm3. IEU and CMV
esophagitis are rarely seen until the CD4 count drops below 100/mm3.
4. Empiric therapy. Because candidiasis is the most common cause of esophageal
disease in HIV-infected patients, an empiric trial of antifungal therapy is reason-
able. Further diagnostic testing is then based on the clinical response. Empirical
therapy with fluconazole 200 mg per day followed by 100 mg per day for a 7- to
10-day treatment course is recommended. The clinical response of Candida
esophagitis to the treatment with fluconazole is rapid (within 3 days). If no sub-
stantial improvement occurs in 3 to 5 days, endoscopy is recommended. Most
patients who fail antifungal therapy do not have candidiasis, but rather esophageal
ulcers. Additional empirical trials such as antiviral therapy with acyclovir sodium
or ganciclovir sodium are discouraged. In patients with CD4 counts higher than
200/mm3 and with symptoms typical of GERD, a trial of gastric acid suppressive
therapy with high-dose, proton pump inhibiters is recommended.
5. Barium swallow/upper GI (UGI) series may document esophageal candidia-
sis or ulceration in symptomatic patients. However, because there are many
causes of esophageal ulcers in AIDS, patients will require endoscopic examina-
tion for biopsies.
6. Endoscopy is a means of directly visualizing the UGI mucosa as well as for
obtaining biopsies for histopathologic examination of the lesions visualized.
The endoscopic appearance of a lesion often suggests the diagnosis. Candidiasis
appears as cottage cheese–like plaques and coats most of the esophageal
mucosa. However, because Candida coexists with other lesions at least in 25%
of cases, multiple biopsies are required.
Viral esophagitis may present as diffuse esophagitis or small superficial
ulcers with HSV and as one or more large, well-circumscribed ulcers with
CMV. Biopsies of the ulcer margins and base are required for histopathologic
diagnosis. Immunohistochemical stains of the biopsies will increase the diag-
nostic accuracy. IEU may resemble CMV ulcers. Multiple biopsies of the ulcer
base and margins are required to exclude the presence of CMV. KS appears as
elevated blue-violatious nodules.
7. Treatment is to be directed to the etiology of the esophageal lesion. Esophageal
candidiasis responds well to fluconazole or itraconazole. Both agents are also
available in liquid formulation for patients who cannot swallow tablets or
capsules.
HSV esophagitis is treated with acyclovir sodium or valacyclovir
hydrochloride. For CMV disease, ganciclovir sodium is effective. The newer
drug, cidofovir, may be administered by a once-weekly injection. IEU may be
treated with either prednisone or thalidomide: The response rate is higher
than 90%. Patients should be treated or continued on HAART to help expedite
healing and to prevent relapse.

II. DISEASES OF THE STOMACH

A. Gastric lesions. The most common OI of the stomach is CMV, which usually
results in gastric ulceration. Gastric neoplasms include non-Hodgkin’s lymphoma
and KS. The stomach is the most common site in the GI tract for KS. Patients are
usually asymptomatic. Gastric lymphoma may present with epigastric pain, nau-
sea, and vomiting or bleeding. The prevalence of peptic ulcer disease with or with-
out Helicobacter pylori and gastric adenocarcinoma is the same as in the general
population.
B. Endoscopy with biopsies is the preferred diagnostic modality for gastric lesions. The
indications for endoscopy include likelihood of an underlying OI, severity of symp-
toms (nausea, vomiting, early satiety), and the possible need for endoscopic therapy.
C. Treatment should be directed to the cause of the problem.
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Chapter 43: Gastrointestinal and Hepatobiliary Diseases 295

III. DISEASES OF THE SMALL INTESTINE AND COLON

A. Diarrhea is a common complaint in patients with HIV infection especially in
patients with CD4 counts of less than 100/mm3. As with the esophagus, OI of the
intestines has decreased in prevalence as a cause of diarrhea in HIV-infected
patients. However, the overall incidence of diarrhea has not decreased at the same
rate because several of the antiviral agents used in HAART regimens can cause
diarrhea. In addition, patients with HIV infections are also susceptible to infection
by the same enteric pathogens that cause diarrhea in immunocompetent hosts. As
the CD count decreases, however, these patients become more susceptible to a
wide variety of OI that affect both the small intestine and the colon.
1. Etiologic agents. The most common identifiable causes of diarrhea in HIV-
infected patients are enteric bacteria (e.g., Shigella flexneri, Salmonella
enteritidis, Campylobacter jejuni, and Clostridium difficile. When the CD
count becomes less than 100/mm3, CMV, cryptosporidiosis, microsporidia,
Mycobacterium avium complex (MAC), and other OIs become more commonly
seen in these patients.
CMV is the most common viral agent identified from mucosal biopsy
specimens from HIV-infected patients with diarrhea. Other viruses reported to
involve the GI tract in patients with AIDS include adenovirus, rotavirus,
astrovirus, pecorino virus, and coronavirus. The clinical importance of these
viruses has not been well established.
Among the protozoa Cryptosporidium parvum and microsporidia
(Enterocytozoon bieneusi and Encephalitozoon intestinalis) are the most
potent causes of chronic diarrhea in AIDS patients.
MAC, which was very commonly seen in patients with AIDS, has become
rare in patients undergoing HAART. Neoplasms such as KS or lymphoma and
other OIs such as histoplasmosis do not lead to diarrhea.
2. Clinical presentation
a. History. Diarrhea resulting from enteritis or the involvement of the small
intestine is typically manifested by large-volume, watery stools associated
with dehydration, electrolyte disturbances, and malabsorption. Abdominal
pain and cramps are usually located in the periumbilical area. Associated
symptoms include nausea, vomiting, abdominal bloating, and borborygmi.
Diarrhea arising from colonic involvement and colitis is characterized
by frequent, small-volume stools, which often contain mucus, blood, and
pus. Symptoms include tenesmus, urgency, and rectoanal pain. Abdominal
pain is less likely to be crampy and is usually located in the lower quadrants.
b. Physical exam. Physical findings are nonspecific. Fever usually suggests
bacterial or mycobacterial infection. If CMV is suspected, funduscopic
examination may reveal retinitis. CMV colitis/ulcers are more common in
the ascending colon, thus the abdominal tenderness may be on the right
lower quadrant.
3. Diagnostic studies. The initial evaluation of the HIV-infected patient with
diarrhea must be tailored to the clinical setting, patient’s symptoms, physical
examination, and the CD4 count.
a. Stool studies should include examination for ova and parasites, culture for
bacteria, C. difficile toxin assay, and the presence of fecal leukocytes. The
positive yield of stool culture increases with repeated stool examination. If
fecal leukocytes are absent, additional stool studies should include a modi-
fied acid-fast stain to evaluate for Cryptosporidia, special stains for
microsporidia, and antigen for Giardia.
If MAC is suspected, blood cultures or bone marrow biopsy may be help-
ful in establishing disseminated MAC, but do not prove active GI involvement.
Entamoeba antibody titer is only useful in establishing invasive amebiasis (e.g.,
liver abscess) and not for colonic infection and colitis with ameba.
b. Radiologic studies. Neither barium enema nor small-bowel follow-through
examinations play a role in the evaluation of diarrhea in patients with AIDS.
Abdominal and pelvic computed tomography (CT) scan may reveal colonic
wall thickening suggesting colitis and the need for colonoscopy.
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296 Part V: Specific Complaints and Disorders

c. Endoscopic examination of the UGI tract and the colon are invaluable in
the evaluation of diarrhea in patients with AIDS. In addition to direct visu-
alization, biopsies are obtained for histologic examination.
4. Treatment. Drug-induced diarrhea must always be included in the differential
diagnosis of diarrhea in patients undergoing HAART. If diarrhea stops when
the retroviral agents are stopped and returns when they are restarted, one or
more of these drugs is implicated.
Even though CMV colitis responds to ganciclovir sodium in over 50% of
patients, effective therapy for many of the OIs in AIDS is lacking. So far, there
is no effective treatment for microsporidia and Cryptosporidia infection.
However, improvement of the immune function by HAART is essential and
may lead to remission of Cryptosporidia- and microsporidia-induced diarrhea.

Antimicrobial Therapy for Enteric Infections

TABLE 43-2
in HIV-Infected Patients

Organism Antimicrobial therapy

Bacteria
Campylobacter Erythromycin 250–500 mg p.o. q.i.d. for 7 d or ciprofloxacin
500 mg p.o. b.i.d. for 7 d
Salmonella Amoxicillin 1 g p.o. t.i.d for 3–14 d or trimethoprim/sulfamethoxazole
DS p.o. b.i.d. for 14 d or ciprofloxacin 500 mg p.o. b.i.d. for 7 d
Shigella Trimethoprim/sulfamethoxazole DS p.o. b.i.d. for 5–15 d or ampicillin
500 mg p.o. q.i.d. for 5 d or ciprofloxacin hydrochloride 500 mg
p.o. b.i.d. for 7 d
Clostridium difficile Metronidazole 500 mg p.o. t.i.d. for 7–10 d or vancomycin
hydrochloride 125–500 mg p.o. q.i.d. for 7–10 d
Fungi
Candida Ketoconazole 100–200 mg b.i.d. for 10–14 d or fluconazole
500–100 mg b.i.d. for 10–14 days for amphotericin B
0.3–0.6 mg/kg/body weight daily
Viruses
Herpes simplex Acyclovir 200–800 mg 5 times a day for 7 d or 5–12 mg/kg q8h for 7 d
Cytomegalovirus Ganciclovir 5 mg/kg IV b.i.d. for 14–21 d or foscarnet sodium
60 mg/kg IV q8h for 14 d, then 90–120 mg/kg daily; maintenance
6 mg/kg IV daily 5 d per week
Protozoa
Giardia Metronidazole 250 mg p.o. t.i.d. for 5 d or quinacrine hydrocholoride
100 mg t.i.d. for 5 d
Entamoeba Metronidazole 750 mg p.o. t.i.d. for 10 d, then iodoquinol 650 mg
t.i.d. for 20 d
Isospora Trimethoprim/sulfamethoxazole DS p.o. t.i.d for 10 d then twice
weekly for 3 weeks
Cryptosporidium Unknown (trials with azithromycin hydrochloride, letrazuril, and
paromomycin)
Microsporidia Unknown (trials with metronidazole and albendazole)
Mycobacteria
Mycobacterium Unknown (trials with clarithromycin 500–1000 mg p.o. b.i.d. for 2–4
avium-complex weeks and ethambutin 15–20 mg/kg/d, rifabutin 300–600 mg daily,
clofazimine 100–200 mg daily, ciprofloxacin hydrochloride 750 mg
daily, and amikacin 7.5 mg/kg daily or b.i.d.)

HIV, human Immunodeficiency virus; p.o., per os; b.i.d., twice daily; q.i.d., four times daily; t.i.d., three
times daily; IV, intravenous.
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Chapter 43: Gastrointestinal and Hepatobiliary Diseases 297

Antimicrobial therapy for enteric infections in HIV-infected patients is summa-

rized in Table 43-2. Symptomatic therapy with tincture of opium, Lomotil, and
Imodium is recommended. Octreotide has not proven to be beneficial in
patients with chronic unexplained diarrhea.

IV. HEPATOBILIARY DISEASE IN AIDS. Abnormal results of liver chemistry tests occur
in about 60% of patients with AIDS. Up to 80% of these patients have hepatomegaly,
and nearly 85% have histologic changes in hepatic parenchyma.
The spectrum of hepatobiliary disease in patients with AIDS is summarized in
Table 43-3. This spectrum includes viral hepatitis; granulomatous liver disease sec-
ondary to drugs; fungal, protozoan, bacterial, and mycobacterial infections; steatosis;
nonspecific portal inflammation; sinusoidal abnormalities including peliosis hepatis;
neoplasms such as KS and non-Hodgkin’s lymphoma; and biliary diseases including
acalculous cholecystitis, ampullary stenosis, and sclerosing cholangitis. These disor-
ders may be superimposed on previous hepatobiliary disease resulting from alco-
holism, intravenous (IV) drug abuse, and viral hepatitis.
A. Disorders
1. Viral infections (see also Chapter 50)
a. Hepatitis A virus (HAV) is transmitted through the fecal-oral route. It is
prevalent in both IV drug users and homosexual men. Many anti-HIV–
positive patients have anti-hepatitis A (IgG), which is the serologic evidence
of past exposure to hepatitis A virus, with full recovery. There is no chronic
form of HAV and no evidence that the clinical course of an acute HAV infec-
tion is altered in patients with AIDS. Treatment is supportive.
b. Hepatitis B virus (HBV) is transmitted parenterally by contaminated needles
and sexually from infected people. IV drug users and homosexual men are at
high risk of the development of HBV infection. In fact, approximately 90% of
patients with AIDS have serologic evidence of HBV infection, and 10% to 20%
are chronic carriers. Patients with AIDS and previous HBV infection have nor-
mal or slightly elevated serum transaminase levels. This is because HBV is not
directly cytopathic to the infected hepatocytes and the degree of inflammatory
response and liver damage is largely dependent on the host’s immunologic status.
Patients with HIV-induced immune suppression are likely to have less
inflammatory response and an improvement in the biochemical and histologic
features of chronic HBV infection. However, it has been noted that there
is increased replication of HBV in HIV-infected individuals, determined by an
increase in the HBV deoxyribonucleic acid (DNA) polymerase activity and an
increase in HBe antigen levels and HB core antigen–positive hepatocyte nuclei.

TABLE 43-3 Hepatobiliary Disorders in Patients with HIV Infection

Hepatitis Histoplasma capsulatum

Hepatitis A Microsporidia
Hepatitis B (acute and chronic) Biliary tract disease
Hepatitis C (acute and chronic) Ampullary stenosis
Hepatitis D (delta virus) Sclerosing cholangitis
Cytomegalovirus Cytomegalovirus
Epstein-Barr virus Cryptosporidium
Herpes simplex virus Candida
Drugs Acalculous chloecystitis
Granulomatous liver disease Neoplasms
Mycobacterium tuberculosis Lymphoma
Mycobacterium avium-intracellulare Kaposi’s sarcoma
Cryptococcus neoformans
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298 Part V: Specific Complaints and Disorders

Patients with AIDS who have acute hepatitis B have increased viremia
and an increased risk of the development of chronic hepatitis B. Patients
with hepatitis B who are also infected with HIV respond poorly to interferon
therapy, even in the absence of AIDS. The presence of HIV antibodies is also
associated with a suboptimal response to HBV vaccination in terms of both
the level of anti-HBs and the percentage of patients responding to the vac-
cine. Higher doses of the vaccine may need to be used in this population.
Measurement of HB surface antibody titers is recommended in HIV-positive
people to determine whether the desirable titer of greater than 10 milli-
International Units per liter (mIU/L) is present.
c. Delta hepatitis. Hepatitis delta virus (HDV) is a hepatotropic RNA virus
dependent on HB surface antigen for its replication and expression. It is
known to cause coinfection with HBV or superinfection in patients with
chronic hepatitis B. Patients with HIV infection have slightly higher serum
aminotransferase levels with HDV infection. Reactivation of HDV after HIV
infection has been reported.
d. Hepatitis C virus (HCV) infection and positive serologic studies for HCV anti-
body are often seen in patients infected with HIV. Most patients have HCV,
chronic active hepatitis, or cirrhosis. The response to antiviral therapy with
ribovirin and pegylated interferon has been poorer in these patients, as
compared to patients who are not co-infected with HIV. However, HCV
co-infection should be treated in the apprapriate patient.
e. Herpes simplex virus. More than 95% of homosexual men with AIDS have
serologic evidence of herpes simplex virus (HSV) infection. Patients with AIDS
may have HSV encephalitis, esophagitis, or orolabial or genital HSV infections
with pain, ulceration, and progressive tissue destruction. Hepatitis may occur
with widely disseminated HSV infection. In most of these conditions, patients
manifest orocutaneous or genital vesicles or both, ulcers, fever, hepatomegaly,
and leukopenia. Fulminant hepatitis may develop with overwhelming infection,
and patients may have coagulopathy, hepatic encephalopathy, and shock.
Diagnosis may be established by histopathologic examination of a liver biopsy
specimen. The virus may be cultured from the blood, urine, cutaneous lesions, or
liver. Mortality is very high despite therapy with acyclovir sodium or vidarabine.
f. Epstein-Barr virus infection. The course of hepatitis in patients with AIDS
who also have the Epstein-Barr virus has not been well characterized.
g. CMV infection usually produces subclinical disease in immunocompetent
adults. Occasionally patients have fever, hepatomegaly, and slightly elevated
aminotransferase levels. CMV infection may remain latent after primary
infection and recur with immunocompromise.
Approximately 95% of homosexual men have serologic evidence of
previous CMV infection. In HIV-infected patients, CMV may produce coli-
tis, esophagitis, pneumonitis, and retinitis. It is usually disseminated when
the liver is involved. In patients with CMV hepatitis, the serum alkaline
phosphatase and aminotransferase levels are moderately increased. Hepatic
involvement ranges from the asymptomatic carrier state to fulminant
hepatic necrosis. The diagnosis is made by liver biopsy in affected patients.
CMV commonly produces a parenchymal and portal mononuclear cell infil-
trate and focal hepatic necrosis. Occasionally granulomas are present.
Cytoplasmic inclusion bodies seen in the hepatocytes and in situ hybridiza-
tion and immune fluorescence techniques can rapidly detect CMV. CMV can
be cultured from urine, blood, and tissue from infected sites.
Treatment is with IV ganciclovir sodium, which may stabilize the clinical
course of patients with CMV infection but may cause neutropenia. Foscarnet
may be used as an alternative therapy without associated neutropenia.
2. Bacterial and mycobacterial infections
a. Mycobacterium avium-intracellulare (MAI) is the most common oppor-
tunistic pathogen causing hepatic infection in AIDS. It is usually found in
patients with AIDS who have had previous opportunistic infections. The pre-
sentation is often with fever, malaise, anorexia, weight loss, diarrhea,
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Chapter 43: Gastrointestinal and Hepatobiliary Diseases 299

hepatomegaly, and widely disseminated disease. The alkaline phosphatase

level is usually highly elevated, with mildly elevated transaminases.
The diagnosis is confirmed by liver biopsy and the typical findings of acid-
fast bacilli and poorly formed granulomas due to the suppressed activity of
T lymphocytes. The organism may be obtained from cultures of liver, blood,
lung, GI mucosa, bone marrow, and lymph nodes. The prognosis is poor due to
severe immunosuppression in the patients. Therapeutic trials using a four-drug
regimen consisting of rifampin, ethambutol, clofazimine, and ciprofloxacin
hydrochloride have given promising results in bacteremia with MAI.
b. Mycobacterium tuberculosis. As their immunosuppression progresses,
HIV-infected patients have an increased risk of the development of tubercu-
losis, usually from reactivation of a latent infection. In addition to the pul-
monary infection, extrapulmonary tuberculosis involving peripheral lymph
nodes, bone marrow, blood, and liver may occur. The liver involvement may
be biliary, with disseminated infection or with formation of granulomas and
frank abscesses. Hepatic failure may develop. Occasionally bile duct obstruc-
tion by tuberculosis or enlarged lymph nodes may present as cholestasis.
Infections with drug-resistant strains of tuberculosis are being reported, espe-
cially in patients living in inner-city settings.
Symptoms and signs include fever, night sweats, weight loss, produc-
tive cough, pleuritic chest pain, abdominal pain, lymphadenopathy,
hepatosplenomegaly, and jaundice. Chest x-rays may show only hilar or
mediastinal lymphadenopathy. The purified protein derivative (PPD) is
usually negative with concomitant cutaneous anergy. Serum alkaline phos-
phatase level is usually significantly elevated, but the transaminase and
bilirubin levels are only mildly elevated in most patients.
The diagnosis is usually made by culture of sputum, urine, blood,
lymph node, bone marrow, or liver tissue. Histologic stains for acid-fast
bacilli are not as sensitive. Liver biopsy may show granulomas, Kupffer’s cell
hyperplasia, focal necrosis, parenchymal inflammation, sinusoidal dilata-
tion, and occasionally peliosis hepatis.
Therapy includes isoniazid, rifampin, ethambutol, and pyrazinamide.
Although most patients respond well to therapy, adverse drug reactions are
common. The Centers for Disease Control and Prevention recommends that
HIV-seropositive patients with a history of exposure to tuberculosis, or with
a positive PPD even in the absence of active tuberculosis, receive prophylac-
tic isoniazid therapy for at least 6 months.
c. Other mycobacteria. Infections with atypical mycobacteria such as
Mycobacterium xenopi or Mycobacterium kansasii may rarely cause infec-
tion. Disseminated disease may occur in patients with hematologic malignan-
cies, chronic renal failure, or advanced immunosuppression. Hepatic infection
usually presents with hepatomegaly and greatly elevated serum alkaline phos-
phatase levels. Diagnosis requires positive cultures from infected tissues.
d. Salmonella. Patients with AIDS frequently have extraintestinal salmonellosis
with bacteremia and frequently relapse despite antibiotic therapy. Patients usually
have fever, headaches, diarrhea, nausea, abdominal pain, bloating, hepatomegaly,
and abnormal results on liver chemistry tests. Diagnosis may be established by
cultures of blood, stool, and liver tissue. Therapy includes ampicillin, chloram-
phenicol, trimethoprim/sulfamethoxazole, ciprofloxacin hydrochloride, or a
third-generation cephalosporin.
3. Fungal infections
a. Cryptococcus neoformans. Patients with AIDS who are infected with
C. neoformans usually have meningoencephalitis and pulmonary infections.
With hematogenous dissemination, cryptococcal hepatitis may develop. The
symptoms and signs are predominantly due to the neurologic, pulmonic, or
disseminated infection. Chronic low-grade fever, headache, altered senso-
rium, meningismus, cough, dyspnea, and pleuritic chest pain may be present.
Diagnosis can be made by cultures and histochemical stains of involved
tissue or by detection of cryptococcal antigen. Poorly formed granulomas
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300 Part V: Specific Complaints and Disorders

may be seen in liver biopsy specimens. Therapy includes amphotericin B,

flucytosine, and fluconazole. Patients with AIDS frequently relapse after ini-
tial therapy and may require chronic preventive therapy.
b. Histoplasma capsulatum. Hepatic histoplasmosis in patients with AIDS
usually develops from widely disseminated disease of which the origin is
often in the lungs. Most patients have either lived or traveled in endemic
areas such as midwestern United States river valleys or Puerto Rico.
Symptoms include severe weight loss, malaise, chronic fever, and some-
times cough and dyspnea. Cutaneous lesions, lymphadenopathy, and
hepatosplenomegaly may be present. Liver chemistry and serum alkaline
phosphatase levels are moderately elevated. The diagnosis may be made by
blood cultures or by biopsy of the bone marrow, liver, lymph node, or lung.
Smears with Gomori’s methenamine silver stain show the presence of bud-
ding yeast. Granulomas may also be present in the liver.
Treatment with amphotericin B often results in a dramatic response,
but the disease may recur. Prophylactic therapy with ketoconazole or flu-
conazole may be necessary.
c. Candida albicans. Hepatic candidiasis in patients with AIDS should be sus-
pected in the setting of dissemination from invasive esophagitis or another
source or after chemotherapy for lymphoma or leukemia. Patients may have
prolonged fever, right upper quadrant pain, tenderness, and hepatomegaly. The
serum alkaline phosphatase level is usually greatly elevated, compared to a mild
elevation in the transaminases. Microabscess may form in the liver and spleen.
These lesions may be seen on CT as radiolucent areas and on ultrasonography
as bull’s-eye lesions with central hyperechoic foci within hypoechoic lesions.
Diagnosis may be established by cultures of blood or liver and histo-
logic demonstration of granulomas and yeast forms or pseudohyphae with a
silver stain. Treatment includes amphotericin B, 5-fluorocytosine, ketocona-
zole, or fluconazole.
d. Other fungal infections. Systemic sporotrichosis with hepatic infection
has been reported in patients with AIDS, but it is rare. Coccidioidomycosis
may become systemic in immunosuppressed patients including those with
AIDS. In addition to pulmonary nodules seen on chest x-ray, the diagnosis is
usually made by histologic examination with periodic acid–Schiff (PAS) stain
of sputum, specimens obtained at bronchoscopy, bone marrow, and liver.
The organism may be cultured from tissues, blood, and urine. The liver
biopsy shows granulomas. Treatment of sporotrichosis and coccidioidomy-
cosis is with long-term therapy with amphotericin B.
4. Protozoan infections
a. Pneumocystis carinii. Diffuse interstitial pneumonia is the most common
serious opportunistic infection caused by P. carinii in patients infected with
HIV. Immunodeficient patients may have concomitant hepatic infection with
granuloma formation. These patients have elevated serum alkaline phos-
phatase and aminotransferase levels, usually associated with severe hypoal-
buminemia. Therapy is with trimethoprim/sulfamethoxazole or pentamidine.
b. Microsporidia. Homosexual men have a high incidence of exposure to
microsporidia, and immunosuppressed patients with AIDS are particularly
susceptible to development of GI infection. Hepatic infection is rare but may
occur. Histologic examination of the liver biopsy may show focal granulo-
mas in the portal areas. The parasites or their spores may be seen with spe-
cial stains within histiocytes and in extracellular locations.
c. Cryptosporidium. Infection of the liver with Cryptosporidium mainly
involves the gallbladder and the biliary tract (see section II.A.7).
5. Drug-induced hepatitis. Approximately 90% of patients who have AIDS take
at least one potentially hepatotoxic drug during the course of their illness.
Drug-induced hepatotoxicity tends to present subclinically. It is often difficult
to differentiate drug-induced hepatitis from that caused by infections or
malignancies. Withdrawal of hepatotoxic drugs may result in normalization of
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Chapter 43: Gastrointestinal and Hepatobiliary Diseases 301

the liver chemistry tests and clinical improvement. A liver biopsy or other
appropriate workup may be necessary to determine the precise nature of the
hepatobiliary abnormality in patients in whom the suspected drug is needed or
in those in whom withdrawal of the drug does not result in improvement.
6. Hepatic neoplasms
a. KS is the most common neoplasm found in patients with AIDS. It occurs pri-
marily in homosexual men, in whom it behaves as an aggressive malignancy
with visceral and cutaneous lesions. About one half of the patients have GI
lesions, which appear as violaceous macules on endoscopy. The lesions are
generally submucosal and may present with bleeding or obstruction.
About one third of the patients have hepatic involvement. The liver
chemistry tests may be normal, or there may be an elevation of the serum
alkaline phosphatase levels. On CT scan, hepatic lesions have a nonspecific
appearance. Unguided percutaneous liver biopsy is insensitive in the diagno-
sis of KS. Occasionally KS lesions can be seen on laparoscopy if the lesions
are superficial and anteriorly located. In general, hepatic involvement is
rarely documented antemortem.
Macroscopically, the lesions are multifocal and may occur at subcapsular
hilar and intrahepatic locations. Histologically, KS is seen as multifocal areas of
vascular endothelial cell proliferation with pleomorphic spindle-shaped cells
and extravasated red blood cells. Sinusoidal dilatation with vascular lakes may
be present. The clinical spectrum may include peliosis hepatis and angiosarco-
matous lesions.
Treatment includes radiotherapy or chemotherapy with vinblastine,
vincristine, or etoposide. Interferon therapy also may produce considerable
tumor reduction.
b. Lymphoma. In HIV-infected patients, the development of lymphoma is
considered a criterion for AIDS. Patients with AIDS, like other immunosup-
pressed patients, have an increased risk of the development of non-
Hodgkin’s lymphoma, often of B-cell origin. Patients with AIDS in whom
lymphoma develops are usually homosexuals.
Lymphoma in patients with AIDS is often extranodal with involvement
of unusual sites such as the central nervous system or rectum. Most patients
have multiorgan involvement. Primary hepatic lymphoma also may occur.
Patients initially may have lymphadenopathy, hepatomegaly, jaundice,
right upper quadrant pain, and systemic symptoms such as fever, malaise,
and night sweats.
Hyperbilirubinemia and considerable elevations of serum alkaline
phosphatase levels usually occur in advanced illness. CT and ultrasound are
helpful imaging techniques in the diagnosis of hepatic lymphoma. The
lesions are usually multifocal and may obstruct the biliary tract and result in
ductal dilatation.
Histologic examination of liver biopsy specimens obtained with CT or
laparoscopic guidance confirms the diagnosis. The lymphomas are usually
high grade and respond less well to chemotherapy than they do in immuno-
competent patients.
c. Other malignancies. Hepatic metastasis from cancers developing in other
sites has been seen in patients with AIDS. These include malignant
melanoma, adenocarcinoma, and small-cell cancers. The immunodeficiency
may permit dissemination to distant sites, including the liver.
7. Biliary tract disease. In addition to diseases of the biliary tract seen in
immunocompetent patients, opportunistic infections involving the gallbladder
and the biliary tract occur in patients with AIDS and may present with atypical
findings, sepsis, or acute abdomen.
a. Acalculous cholecystitis is rarely seen in immunocompetent people. It
is sometimes associated with total parenteral nutrition and biliary sludge.
In patients with AIDS, it may have a subacute clinical course or may present
with fever and right upper quadrant abdominal pain. Patients may also have
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302 Part V: Specific Complaints and Disorders

concurrent diarrhea. The disease is usually caused by CMV, Cryptosporidium,

or Candida.
Most patients do not have a leukocytosis. The levels of serum alkaline
phosphatase and transaminase are moderately elevated. Ultrasound and CT
typically show a dilated gallbladder with thickened wall and no gallstones.
Therapy is surgical excision of the inflamed gallbladder. Pathologic examina-
tion reveals an inflamed, edematous gallbladder wall with mucosal ulceration.
Often CMV inclusion bodies are seen near the mucosal ulcers. Coinfection
with bacteria, Cryptosporidium, and C. albicans may be present.
b. Cholangitis secondary to papillary stenosis (stenosis of the ampulla of
Vater) and sclerosing cholangitis-like findings are well-recognized complica-
tions in patients who have AIDS. Patients have fever, right upper quadrant
pain, and elevated serum alkaline phosphatase levels. CT and ultrasonogra-
phy are relatively insensitive in detecting these abnormalities. Retrograde
endoscopic cholangiopancreatography (ERCP) usually defines the lesions,
and endoscopic sphincterotomy, balloon dilation, and stent placement in the
strictures may treat and remove the obstruction to bile flow.
The infectious organisms causing periampullary, choledochal, and
cholangiolar narrowing and dilatation are CMV, Cryptosporidium,
Candida, MAI, and HIV. Lymphoma and KS may involve the ampulla and
the biliary tract, resulting in obstruction.
B. Diagnostic workup. When patients with AIDS have hepatobiliary disease, considera-
tions include, in addition to the conditions discussed previously, hepatic disease sec-
ondary to alcoholism, malnutrition, sepsis, hypotension, drugs, and previous viral
infections. Appropriate serologic studies should be obtained to document viral disease.
An ultrasound or CT examination of the liver may show ductal dilatation or
mass-occupying lesions. Patients with ductal dilatation or suspected ductal disease
should undergo ERCP. Mechanical decompression with sphincterotomy and stent
placement may eliminate the obstruction.
Biopsies of the involved areas should be cultured and examined histologically.
In patients with focal lesions, liver biopsy should be obtained under ultrasound or
CT guidance. Percutaneous liver biopsy is recommended when CT or ultrasound is
not helpful. In patients who have ascites, laparoscopic examination of the liver and
guided biopsy decrease the risk of complications that occur with percutaneous
biopsy techniques. Liver biopsy specimens should be cultured and histologically
examined with special stains. In about 50% of these patients, the liver biopsy helps
establish the diagnosis and provides a more rational basis for patient management.

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OCCULT OBSCURE
GASTROINTESTINAL BLEEDING 44

T he management of patients with acute gastrointestinal (GI) bleeding is discussed in

Chapter 14. Such patients typically have unequivocal evidence of bleeding, such as
hematemesis, hematochezia, or melena. However, other patients bleed slowly or intermit-
tently from lesions of the GI tract in a less dramatic manner or in amounts that are insuf-
ficient to be clinically evident but may be detected by testing of the stool for occult blood.
If bleeding is intermittent, detection and subsequent diagnosis are sometimes difficult.
Occult GI bleeding is usually more problematic in patients with occult bleeding disorders
(i.e., von Willebrand’s disease). Although the major worry of patients and physicians is
that occult bleeding is due to a cancer of the GI tract, the range of causes for the bleeding
is virtually the same as that for acute bleeding (see Table 14-1). Occult GI bleeding is often
attributed to therapy with anticoagulants or aspirin. However, neither warfarin nor aspirin
alone appears to cause positive fecal guaiac–based occult blood tests. A positive fecal
blood test of patients on warfarin, heparin, or aspirin should lead to formal evaluation of
the GI tract.

I. DETECTION OF OCCULT BLEEDING

A. Frequency of testing. The American Cancer Society recommends that people at
average risk for colon cancer (i.e., people without a history of colon polyps or can-
cer, without a strong family history of colon cancer, and without inflammatory
bowel disease) undergo yearly testing of the stool for occult blood beginning at age
40. People at higher than average risk should enter an appropriate surveillance
program, which may include occult blood testing and periodic sigmoidoscopy or
colonoscopy (see Chapters 37 and 39).
B. Method of obtaining stool for testing. If the stool obtained at digital rectal exami-
nation (DRE) is negative for occult blood, that is presumptive evidence that there is no
clinically significant blood in the stool, provided the patient is not taking vitamin C
(see section II.B.2.c). If the stool at DRE is positive for occult blood, however, one
does not know whether it is truly positive or is falsely positive due to the trauma of
the examination, dietary factors, or medications that may affect the test.
Interestingly, it has been shown in several studies that testing stool for occult blood
at the time of DRE does not increase the number of false-positive test results in
asymptomatic patients and promotes more compliance to screening. However, the
most reliable method of obtaining stool for occult blood testing is the following:
1. Give the patient three occult blood test cards. Each card has two windows for
testing stool, so the patient can submit six smears.
2. Instruct the patient to:
a. Avoid red meat and other foods with a high peroxidase content (e.g., broc-
coli, turnips, cauliflower, and uncooked cantaloupe, radish, and parsnips).
Foods with high peroxidase contents may give a false-positive test result
because the tests for occult blood depend on the pseudoperoxidase activity
of heme in stool.
b. Consume a high-fiber diet. A high-fiber diet is thought to promote larger
stools and perhaps “irritate” the surface of any potentially bleeding lesions.
This irritating function of fiber in the stool has not been proved.
c. Avoid vitamin C, iron preparations, aspirin, and other nonsteroidal anti-
inflammatory drugs. Vitamin C has been shown to give a false-negative test

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304 Part V: Specific Complaints and Disorders

result for occult blood because ascorbic acid inhibits the pseudoperoxidase
activity of heme. Aspirin and other nonsteroidal antiinflammatory drugs
may injure the gastric mucosa and cause bleeding, thus making the occult
blood test positive.
3. After 3 days of this regimen, the patient should smear stool on the two test win-
dows of a diagnostic card each day for the next 3 days (or the next three stools,
if stools are less frequent than daily) and return the cards to the physician.
Rehydrating the cards before testing increases the diagnostic yield.

II. DIAGNOSIS
A. Clinical presentation. Patients with occult blood in the stool typically feel well.
They may have symptoms related to the cause of the bleeding, for example, peptic
complaints, or abdominal discomfort due to a GI tumor, but they usually do not
have symptoms attributable to blood loss. They may be anemic (hemoglobin level
of less than 12 g/dL for women and less than 13 g/dL for men and serum ferritin
level of less than 45 mg/L) due to either the chronic loss of blood or, more likely,
the underlying disorder, or they may have normal levels of hemoglobin and hema-
tocrit. The presence of occult blood may be detected by routine screening exami-
nation or in response to the patient’s symptoms.
B. Diagnostic studies
1. Examination of the colon by colonoscopy is the preferred diagnostic study
in the evaluation of patients for occult GI bleeding. The use of flexible
sigmoidoscopy and air-contrast barium enema has been used as an alterna-
tive to colonoscopy; however, the sensitivity and specificity is less. Virtual
colonoscopy is in the process of development as an alternative to colonoscopy.
2. Examination of the upper GI tract. If the examination of the colon is nondi-
agnostic, examination of the upper GI tract is indicated. The clinician may elect
to study the UGI tract first if the patient’s history suggests UGI disease or lesion.
Endoscopy is the preferred method of studying the UGI tract for mucosal lesions.
3. Examination of the small intestine may be accomplished by radiologic or
endoscopic techniques. The most widely available technique is barium upper GI
and small-bowel series. Unfortunately, the diagnostic yield of this technique is
inferior to small-bowel enema or enteroclysis, which is more arduous and
not widely available. Enteroclysis is performed by passing a tube by mouth into
the proximal duodenum and instilling barium followed by air. This technique
provides an excellent air–barium contrast and is effective in detecting mass
lesions of the SI, but is ineffective in detecting mucosal lesions.
4. Enteroscopy is indicated for the evaluation of the SI for the detection of
mucosal lesions. Push enteroscopy is the usual technique used and entails a
perioral insertion of a push enteroscope or a pediatric colonoscope via the UGI
tract into the distal duodenum, jejunum and possibly into the ileum. Biopsy and
endoscopic therapy can be performed when a lesion is found. Sonde
enteroscopy involves the passage of a long enteroscope into the SI via the
upper GI tract and allowing peristalsis to carry it into the distal SI. The mucosa
is visualized as the sonde endoscope is slowly removed. It is a very uncomfort-
able procedure and does not allow biopsy or endoscopic therapy of the lesion.
Double balloon enteroscopy is available at specialized medical centers to
visualize the SI and obtain biopsies or apply therapeutic interventions.
Interoperative enteroscopy permits visualization of the SI by the use of
enteroscope or pediatric colonoscope that is advanced through the SI during
laparotomy. Push enteroscopy and interoperative enteroscopy have been
reported to detect abnormalities in up to 70% of patients.
5. More recently, the mucosa of the SI has been visualized by Pill-cam or capsule
endoscopy. The patient swallows the capsule that takes numerous pictures
along its course down the SI. These pictures are then retrieved by downloading
them via a computer.
6. Special studies. A small number of patients continue to bleed, usually
intermittently, from a source that defies identification, even after repeated
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Chapter 44: Occult Obscure Gastrointestinal Bleeding 305

evaluations. Unusual causes of bleeding must be considered in these patients,

and occasionally, extraordinary measures are required to make the diagnosis.
a. A technetium 99m sulfur colloid scan may show a Meckel’s diverticulum
that contains gastric mucosa. Although only about 20% of Meckel’s diver-
ticula contain gastric mucosa, these are the diverticula that ulcerate and
bleed. Bleeding from a Meckel’s diverticulum may be occult but typically is
more vigorous and sometimes intermittent.
b. Selective arteriography should be performed in patients with undiagnosed
occult GI bleeding, not to identify active bleeding but to determine whether
an abnormal vascular pattern suggests an angiodysplastic or neoplastic
lesion.

III. The treatment of occult GI bleeding depends on the cause. See the appropriate chapter.
Vascular ectasias of the SI are the most common source of bleeding in patients
with obscure GI bleeding. Endoscopic and surgical therapy is most successful with
large and discrete vascular ectasias. The treatment of diffuse and multiple vascular
ectasias are difficult and less successful. Hormonal therapy with estrogen and proges-
terone has been tried and has been noted to be successful in some reported cases, but
not in controlled studies.

Selected Readings
Amaro R, et al. Diagnostic and therapeutic options in obscure gastrointestinal blood loss.
Curr Gastroenterol Rep. 2000;2:395.
de Leusse A, et al. Capsule endoscopy or push enteroscopy for first-line exploration of
obscure gastrointestinal bleeding? Gastroenterology. 2007 Mar;132:855–862.
Goldstein JL, et al. Small bowel mucosal injury is reduced in healthy subjects treated with
celecoxib compared with ibuprofen plus omeprazole, as assessed by video capsule
endoscopy. Aliment Parmacol Ther. 2007 May 15;25:1211–1222.
Graham DY, et al. Visible small-intestinal mucosal injury in chronic NSAID users. Clin
Gastroenterol Hepatol. 2005;3(1):55–60.
Manner H, et al. Push-and-pull enteroscopy using the double balloon technique (double-
balloon enteroscopy) for the diagnosis of Meckel’s diverticulum in adult patients with
GI bleeding of obscure origin. Am J Gastroenterol. 2006;101:1152–1154.
Pennazio M, et al. Outcome of patients with obscure gastrointestinal bleeding after capsule
endoscopy: Report of 100 consecutive cases. Gastroenterology. 2004;126:643–653.
Qureshi WA. Current and future applications of the capsule camera. Nat Rev Drug Discov.
2004;3:447–450.
Rockey DC. Occult gastrointestinal bleeding. N Engl J Med. 1999;341:39.
Tiester SL, et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic
modalities in patients with obscure gastrointestinal bleeding. Am J Gastroenterol. 2005;
100(11):2407–2418.
Yamamoto H, et al. Clinical outcomes of double-balloon endoscopy for the diagnosis and
treatment of small-intestinal diseases. Gastroenterol Hepatol. 2004;2:1010–1016.
79466_CH45.qxd 1/2/08 12:55 PM Page 306

45 ACUTE PANCREATITIS

I. Acute pancreatitis is a discrete episode of inflammation resulting from intrapancre-

atic activation of digestive enzymes. It is a disease with a wide spectrum of severity,
complications, and outcome.
A. Acute edematous or interstitial pancreatitis. In this stage, the pancreatic
inflammation and disease is mild and self-limited in most patients. The inflamma-
tion results in interstitial edema. The parenchymal damage is minimal, and the
organ recovers its function after resolution of the inflammation.
B. Hemorrhagic or necrotizing pancreatitis. In some patients, the inflammation
may be extensive and progress to coagulation necrosis of the gland and the sur-
rounding tissues, leading to hemorrhagic or necrotizing pancreatitis. The mass of
inflamed pancreas containing necrotic tissue is referred to as a phlegmon.

II. COMPLICATIONS
A. Spread of the inflammatory process. The retroperitoneal location of the pan-
creas and the absence of a well-developed pancreatic capsule allow the inflamma-
tory process to spread freely. The activated pancreatic enzymes dissect through
the tissue planes and affect any of the following organs: the common bile duct,
duodenum, splenic artery and vein, spleen, pararenal spaces, mesocolon, colon,
mesentery of the small bowel, celiac and superior mesenteric ganglia, lesser omen-
tal sac, posterior mediastinum, and diaphragm. The peritoneal surfaces may be
involved with the inflammatory process, leading to exudation and fluid accumu-
lation in the peritoneal cavity (pancreatic ascites) and the lesser omental sac.
Involvement of the diaphragmatic lymphatics may lead to sterile pleural effusion
and pneumonitis.
Local effects of pancreatic enzymes and vasoactive materials include an
intense chemical burn of tissue leading to leakage of protein-rich fluid from the
systemic circulation into peritoneal and retroperitoneal spaces. This phenomenon
may lead to hypovolemia. Systemic effects of these circulating materials include
cardiovascular instability, respiratory failure, and renal failure.
B. Hemorrhage within or around the gland may dissect along tissue planes and lead
to a bluish discoloration in the periumbilical area (Cullen’s sign) or in the cos-
tovertebral angle (Turner’s sign).
C. Pseudocysts. Necrotic tissue, blood, pancreatic juice, and fat from disrupted
cells may accumulate within or adjacent to the pancreas, forming pseudocysts.
Pseudocysts may resolve spontaneously as the inflammation subsides. If the
pseudocyst is large or if there is a communication between the pseudocyst and a
ruptured pancreatic duct with continued secretion of pancreatic juices into the
enclosed space, the pseudocyst may not resolve.
D. Pancreatic abscesses. The secondary infection of a pancreatic phlegmon or
pseudocyst by enteric flora results in pancreatic abscess.
E. Fat necrosis may occur in peritoneal, retroperitoneal, and distant locations such
as in subcutaneous or intramedullary areas. Calcium salts (soaps) of free fatty
acids liberated from fatty tissue may precipitate in these areas.
F. Polyserositis and the adult respiratory distress syndrome. The entry of the
activated pancreatic enzymes (e.g., trypsin, elastase, phospholipase A) into the cir-
culation allows these potent digestive enzymes to attack distant sites.

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Chapter 45: Acute Pancreatitis 307

Polyserositis involving pericardial, pleural, and synovial surfaces may occur.

Left-sided pleural effusion is common. The pulmonary alveolar–capillary mem-
brane may be disrupted, forming hyalin membranes lining the alveolar surface. A
transudate fills the alveolar space and leads to a noncardiogenic pulmonary edema
or adult respiratory distress syndrome.
G. Disseminated intravascular coagulation and microthrombi. The release of acti-
vated pancreatic enzymes into the circulation may result in disseminated intravascu-
lar coagulation with formation of intravascular microthrombi. These thrombi may
affect the function of many organ systems. Pulmonary intravascular microthrombi
result in intrapulmonary right-to-left shunting and hypoxia. Microthrombi in the
glomerular capillaries, deposited in the mesangium and the glomerular basement
membrane, results in renal dysfunction of varying severity.
H. Circulatory shock may occur in severe instances due to third-spacing of fluid and
intravascular hypovolemia. If intravenous (IV) fluid replacement is inadequate,
hypovolemia and hypotension may intensify the pancreatitis.

III. ETIOLOGY. There are many conditions implicated as causative factors in the patho-
genesis of acute pancreatitis (Table 45-1).
A. Alcoholism and biliary tract disease. The two most common etiologic factors
associated with pancreatitis are alcoholism and biliary tract disease (gallstones).
These two factors account for 75% to 85% of all cases. In countries in which the
incidence of alcoholism and excessive alcohol use is high, such as the United States,
Australia, and South Africa, alcohol is the etiologic factor in more than 50% of
patients. In contrast, in countries in which alcoholism is less prevalent, such as
Britain and Israel, biliary tract disease is the most common cause of acute pancre-
atitis. The mortality of gallstone-associated pancreatitis is approximately 8% dur-
ing the first attack and 1% during subsequent attacks. Chronic pancreatitis with
pancreatic insufficiency rarely, if ever, occurs, even after multiple episodes of pan-
creatitis associated with gallstones.

TABLE 45-1 Causes of Acute Pancreatitis

Alcohol (ethanol, methanol) abuse (acute and chronic alcoholism)

Gallstones, biliary sludge (biliary tract disease)
Surgery (abdominal, cardiac, cardiopulmonary bypass, thoracic)
Trauma (blunt, penetrating)
Endoscopic retrograde cholangiopancreatography
Infections (viral: mumps, coxsackie, CMV, HSV, HIV; bacterial: Mycoplasma, Legionella,
Leptospira; fungal: Aspergillosis; parasitic: Salmonella, Mycobacterium, Toxoplasma,
Cryptosporidium)
Metabolic disorders (hypertriglyceridemia, pregnancy, hypercalcemia–hyperparathyroidism
Vasculitis, ischemia
Drugs (see Table 45-2)
Anatomic abnormalities in the area of the ampulla of Vater with possible obstruction (Crohn’s
disease, duodenal diverticulum, annular pancreas, pancreas divisum, choledochal cyst,
sphincter of Oddi dysfunction, ampullary neoplasm, pancreatic neoplasm, ampullary stenosis)
Penetrating gastroduodenal ulcer
Hereditary autoimmune factors
Miscellaneous (scorpion bite, parasites obstructing the pancreatic duct [Ascaris, fluke], severe
systemic hypotension, cholesterol embolization, Reye’s syndrome, fulminant hepatitis,
refeeding in eating disorders)
Renal failure
Renal transplantation
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308 Part V: Specific Complaints and Disorders

TABLE 45-2 Drugs Associated with Pancreatitis

Definitely associated Probably associated

Sulfonamides, sulfasalazine Ethacrynic acid

Estrogens (oral contraceptives) Chlorthalidone
Tetracyclines Methyldopa
Azathioprine L-Asparaginase
Mercaptopurine Procainamide hydrochloride
Furosemide Corticosteroids
Thiazides Nonsteroidal antiinflammatory drugs
Valproic acid Isoniazid
Ethanol Nitrofurantoin
Methanol Rifampin
Organophosphate insecticides Metronidazole
Pentamidine Erythromycin
ACE inhibitors 5-ASA
DDI Salicylates

DDI, 2
,3
-dideoxyinosine; ACE, angiotensin converting enzyme.

There is a well-documented association between excessive alcohol consump-

tion and pancreatitis. In most patients, the disease recurs many times, leading to
chronic pancreatitis with irreversible functional and structural damage of the
organ. Even though the mortality is considerably less than that of gallstone
disease–associated pancreatitis, all the complications of acute pancreatitis may
develop during the acute attacks.
B. Postoperative pancreatitis is infrequent but has a high mortality. It occurs after
cardiopulmonary bypass, thoracic, and abdominal surgical procedures. Operations
on and near the pancreas such as gastrectomy, biliary tract surgery, and splenec-
tomy are involved in most of the cases.
C. Endoscopic retrograde pancreatography. Pancreatitis may occur in less than
1% of cases after endoscopic retrograde pancreatography (ERCP). However,
hyperamylasemia is common after ERCP.
D. Blunt abdominal trauma is the most common cause of pancreatitis in children
and young adults.
E. Some metabolic disorders are implicated as causes of pancreatitis.
1. Hypertriglyceridemia may precede and cause pancreatitis. Patients with
some lipoprotein abnormalities, especially Frederickson type I, type IV, and
type V hyperlipoproteinemia, are at increased risk of development of pan-
creatitis. An abrupt increase in serum triglycerides to greater than 2,000
mg/dL can precipitate a bout of acute pancreatitis. This can occur in patients
with underlying hypertriglyceridemia who ingest either large amounts of
lipid and moderate amounts of alcohol or large amounts of alcohol or
who use birth control pills. Serum amylase may be normal in lipemic
serum. Dilutions should be requested to ascertain the correct level of serum
amylase.
2. Hypercalcemia from any cause can lead to acute pancreatitis. Causes of hyper-
calcemia include hyperparathyroidism, parathyroid adenoma or carcinoma,
myeloma, excessive doses of vitamin D, familial hypocalciuric hypercalcemia,
and hypercalcemia in patients receiving total parenteral nutrition (TPN) or
using calcium carbonate–containing antacids. Acute pancreatic necrosis is fre-
quent during hyperparathyroid crisis. Increased concentrations of calcium ions
in pancreatic secretion and pancreatic tissue might promote activation of
trypsinogen, initiating the proteolytic cascade.
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Chapter 45: Acute Pancreatitis 309

F. Organ transplantation. Pancreatitis may complicate renal and liver transplantation.

G. Pregnancy. Women in whom acute fatty liver of pregnancy develops in the third
trimester may also develop acute pancreatitis. However, 90% of instances of pan-
creatitis during pregnancy are associated with gallstones.
H. Infections. Viral agents, including mumps, hepatitis B, and Coxsackie virus group
B, and some bacteria (e.g., Mycoplasma pneumoniae) have been implicated as
causes for acute pancreatitis. Opportunistic protozoan, bacterial, and fungal
pathogens, which may involve the pancreas, include Cryptosporidium,
cytomegalovirus, Legionella pneumophila, and Salmonella species, Mycobacterium
avium, and tuberculosis.
I. Connective tissue diseases. Pancreatitis may occur in patients with some con-
nective tissue diseases, such as systemic lupus erythematosus (SLE), especially
those complicated with vasculitis.
J. Vasculitis, present in other disorders such as Henoch-Schönlein purpura, throm-
bocytopenic purpura, and necrotizing angiitis, may also be implicated as a cause of
acute pancreatitis.
K. Drugs have been associated with the development of pancreatitis in some patients.
Table 45-2 lists the drugs in two groups: those for which there is a definite associ-
ation and those for which the association is probable.
L. Anatomic abnormalities. Pancreatitis has been reported in patients with a num-
ber of anatomic abnormalities in the vicinity of the ampulla of Vater, possibly asso-
ciated with its obstruction, such as duodenal Crohn’s disease, duodenal diverticula,
choledochocele, choledochal cysts, duodenal intussusception, and sphincter of
Oddi dysfunction.
M. Pancreas divisum is a special condition that may lead to recurrent bouts of pan-
creatitis. Pancreas divisum results when the ducts of the embryologic ventral and
dorsal parts of the pancreas fail to fuse. Wirsung’s duct, which normally drains the
entire pancreas, only drains the uncinate process in these patients. The rest of the
pancreas is drained by the duct of Santorini through the minor papilla. In many of
the patients with pancreas divisum and recurrent pancreatitis, the minor papilla
has been found to be stenotic and may be implicated as the predisposing condition
for the development of pancreatitis.
N. Duodenal ulcer. Penetration of a duodenal ulcer into the pancreas may result in
local pancreatic inflammation. Even though there may be an elevation of serum
amylase, extensive pancreatitis usually does not develop.
O. Hereditary pancreatitis in an autosomal dominant transmission pattern has been
described in a number of families. Symptoms usually appear between the ages of
5 and 15 years and progress to chronic pancreatitis. There may be an increased
incidence of pancreatic adenocarcinoma in these families.
P. Miscellaneous causes. There are numerous other reported causes of pancreati-
tis including scorpion bite by Tityus trinitatis found in the West Indies and pan-
creatic duct obstruction by parasites such as flukes (Clonorchis sinensis) and
worms (ascaris). Systemic hypotension, cholesterol embolization, Reye’s
syndrome, and fulminant hepatic failure may also be associated with acute
pancreatitis. Refeeding pancreatitis may occur in patients with eating disorders
such as anorexia nervosa and bulimia.

IV. PATHOPHYSIOLOGY. The exact mechanism of the events that trigger the intrapancre-
atic activation of zymogens to active enzymes leading to autodigestion and inflammation
remains unknown. However, there is evidence that more than one mechanism is
involved. It is thought that ischemia, anoxia, trauma, infections, and endo- and
exotoxins set the stage for activation of trypsinogen to trypsin with further activation
of other zymogens to active enzymes, including phospholipase A, elastase, and lipase.
The enzymes, along with the detergent effect of bile acids, then digest cell membranes
and elastic fibers of blood vessels, leading to vascular damage with interstitial edema,
hemorrhage, and parenchymal cell and fat necrosis of the pancreatic and peripancreatic
tissues. Vasoactive substances such as bradykinin and histamine that are released lead to
vasodilatation and increased permeability resulting in more edema and inflammation.
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310 Part V: Specific Complaints and Disorders

One popular theory to explain the initiation of the autodigestion cascade sug-
gests obstruction to the outflow of pancreatic juice (i.e., with gallstone impaction at
the ampulla resulting in intraductal hypertension) and inhibition of acinar cell zymo-
gen secretion by exocytosis. In this setting, the zymogen-containing vacuoles in the
acinar cells fuse with lysosomes, which contain proteases. This results in enzyme acti-
vation within the combined vacuoles. These vacuoles rupture into the acinar cell,
resulting in acinar cell injury and death with consequent intra- and extraparenchymal
injury. Reflux of duodenal contents into the pancreatic duct, presence of a common
channel (communicating pancreatic and common bile duct) with or without impacted
gallstone, and occlusion of pancreatic blood vessels are other popular theories. Other
forms of ischemia may also lead to intracellular zymogen activation and result in
parenchymal damage.

V. PROGNOSTIC FACTORS IN ACUTE PANCREATITIS. Acute pancreatitis is a dis-

ease of varying severity. In most individuals, the disease is mild or moderate with full
recovery of the patient. However, in some individuals, the disease may be fulminant
with very high morbidity and mortality. Thus, it is important to identify factors that
increase the likelihood of a fatal outcome in patients with acute pancreatitis. Tables
45-3 and 45-4 summarize some of those factors. An increased mortality is observed
when three or more risk factors are present. These include hemoconcentration ele-
vated hematocrit, hypotension, need for massive fluid and colloid replacement
from third spacing of fluids, respiratory failure, and hypocalcemia. Patients
at high risk should be treated in an intensive care unit and may require surgical
intervention.

TABLE 45-3 Prognostic Factors in Acute Pancreatitis

On Admission
Age 55 y
WBC 16,000/L
Blood glucose 200 mg/dL (no diabetic history)
Serum LDH 350 IU/L (normal up to 225)
SGOT 250 Sigma Frankel units/L (normal up to 40)
Within 48 h
Age 55 y
WBC 15,000/L
Blood glucose 180 mg/dL (no diabetic history)
Serum urea 16 mmol/L (no response to IV fluids)
BUN rise 5 mg/dL
PaO2 60 mmHg
Serum calcium 8.0 mg/dL
Hematocrit fall 10%
Base deficit 4 mEq/L
Fluid sequestration 6 L
Serum albumin 3.2 gm/dL
Serum LDH 600 units/L (normal up to 255 units/L)
AST or ALT 200 units/L (normal up to 40 units/L)

WBC, white blood count; LDH, lactic dehydrogenase; SGOT, serum glutamic-oxaloacetic transami-
nase; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase;
IV, intravenous; Pao2, partial pressure of arterial oxygen.
From Imrie CW, et al. A single centre double-blind trial of trasylol therapy in primary acute pancreatitis.
Br J Surg. 1978;65:337; and Ranson JH, et al. Prognostic signs and the role of operative management
in acute pancreatitis. Surg Gynecol Obstet. 1974;139:69. Reprinted with permission.
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Chapter 45: Acute Pancreatitis 311

TABLE 45-4 Clinical Criteria for Severe Pancreatitis

Cardiac BP 90 mmHg, tachycardia 130, arrhythmia and other

ECG changes
Pulmonary Dyspnea, rales PO2 60 mmHg, adult respiratory distress
syndrome
Renal Urine output 50 mL/h, rising BUN and creatinine
Metabolic Calcium 8 mg/dL, albumin 3.2 g/dL
Hematologic Falling hematocrit, diffuse intravascular coagulation
Neurologic Irritability, confusion, CNS localizing signs
Abdominal Tense distention, fluid wave, ileus

BP, blood pressure; ECG, electrocardiogram; PO2, partial pressure of oxygen; BUN, blood urea
nitrogen; CNS, central nervous system.

VI. DIAGNOSIS
A. Clinical presentation
1. History. Abdominal pain is the most common complaint in acute pancreatitis.
It is usually located in the epigastrium, left upper quadrant, or periumbilical
area, and often radiates to the back, chest, flanks, and lower abdomen.
The pain is steady, dull, and boring in character. It is usually more intense
when the patient is supine and may lessen in the sitting position with the trunk
flexed forward and the knees drawn up. Patients also complain of nausea, vom-
iting, and abdominal distention secondary to ileus.
2. Physical examination. Patients with acute pancreatitis initially may present
with fever, tachycardia, and hypotension. Shock is common in severe instances
due to hypovolemia caused by third-space fluid sequestration (in retroperi-
toneal and other spaces) with increased vascular permeability and vasodilata-
tion and other systemic effects of proteolytic and lipolytic enzymes released
into the circulation. Jaundice may occur, due to obstructive cholelithiasis or,
more commonly, the compression of the intrapancreatic portion of the common
bile duct with edema of the head of the pancreas. Abdominal tenderness and
rigidity may be present. Bowel sounds are diminished or absent. The presence
of a bluish discoloration around the umbilicus (Cullen’s sign) and at the flanks
(Turner’s sign) suggests hemoperitoneum and results from hemorrhagic necro-
tizing pancreatitis.
Other findings such as pleural effusion (especially on the left side), pneu-
monitis and other pulmonary findings, such as ARDS, and subcutaneous fat
necrosis resembling erythema nodosum may be present. Tetany due to hypocal-
cemia is a rare finding.
B. Diagnostic studies
1. Laboratory studies
a. Serum amylase. Even though there is no definite correlation between the
severity of pancreatitis and the degree of serum amylase elevation, serum amy-
lase elevation is commonly equated to the presence of pancreatitis. However,
hyperamylasemia may be present in many other conditions, as summarized in
Table 45-5. Amylase is found in many organs, including salivary glands, liver,
small intestine, kidney, and fallopian tubes, and in various tumors such as car-
cinoma of the esophagus, lung, and ovary. In 75% of the patients with acute
pancreatitis, the serum amylase is elevated. Hyperamylasemia is noted within
the first 24 hours and persists for 3 to 5 days. Amylase levels normalize unless
there is extensive pancreatic necrosis, ductal obstruction, or pseudocyst
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312 Part V: Specific Complaints and Disorders

TABLE 45-5 Causes of Hyperamylasemia

Pancreatic trauma Ruptured ectopic pregnancy

Pancreatitis Ruptured or dissecting aortic aneurysm
Pancreatic pseudocyst Splenic rupture
Pancreatic abscess Renal insufficiency
Pancreatic cancer Diabetic ketoacidosis
Biliary tract disease Burns
Acute cholecystitis Salivary gland disease
Common bile duct obstruction Mumps
Perforated or penetrating peptic ulcer Carcinoma
Intestinal obstruction Lung
Intestinal ischemia or infarction Esophagus
Peritonitis Ovary
Acute appendicitis Macroamylasemia

formation. Serum amylase levels may be spuriously normal in patients with

hypertriglyceridemia and in patients with recurrent alcoholic pancreatitis.
b. Serum lipase levels are elevated in approximately 70% of patients. When
both serum amylase and serum lipase are determined, one enzyme is ele-
vated in 80% to 85% of the patients with acute pancreatitis, thus increasing
the diagnostic yield.
c. Urine amylase is increased in acute pancreatitis and may remain elevated
for 7 to 10 days after serum levels have returned to normal.
d. Leukocytosis (10,000–20, 0000/L) is frequent.
e. Hemoconcentration due to third-space fluid sequestration may lead to
hematocrit elevation to greater than 50%.
f. Hyperglycemia is not uncommon and may result from decreased insulin
and increased glucagon, catecholamine, and glucocorticoid release.
g. Hypocalcemia occurs in about 25% of patients. Its pathogenesis is multi-
factorial and most likely results from sequestration of calcium in saponified
fats as well as the presence of elevated levels of glucagon and calcitonin.
h. Serum bilirubin, alkaline phosphatase, and aminotransferase (alanine
[ALT], aspartate [AST]) levels may be transiently elevated and return to
normal in 4 to 7 days unless there is persistent biliary obstruction from gall-
stones or other causes.
i. Arterial hypoxemia may be present in 25% of patients. In some patients,
adult respiratory distress syndrome (ARDS) may develop. Cardiovascular
and electrocardiographic abnormalities may also occur, especially in severely
ill patients.
2. Radiologic studies. Several radiologic studies are useful in the diagnosis and
management of acute pancreatitis. These include flat film (kidneys, ureters, and
bladder [KUB]) of the abdomen, chest x-rays, ultrasonography, computed
tomography (CT), and ERCP.
a. The plain films are useful in excluding other diagnoses, such as perforated
viscus, mesenteric ischemia, or infarction. Findings suggestive of diffuse or
localized ileus and presence of ascites are nonspecific.
b. Ultrasound (US) and CT scans are helpful in determining the size and
appearance of the pancreas, the peripancreatic spread of the inflammation
and phlegmon, and the condition of the biliary tract. These noninvasive
techniques should be used to confirm clinically suspected disease and its
complications such as cholecystitis, choledocholithiasis, tumor, pseudocyst,
and ascites.
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Chapter 45: Acute Pancreatitis 313

When ileus is present, the US waves are scattered by the air in the
intestinal lumen, and a clear picture of the pancreas cannot be obtained.
However, US is the test of choice for documenting cholelithiasis and biliary
ductal dilatation. CT scan of the abdomen gives a clearer picture of the pan-
creas and the surrounding areas than US does and should be obtained when
there is a likelihood of severe pancreatitis (e.g., multiple positive Ranson’s
signs during the first 48 hours). If the CT scan is normal or shows mild pan-
creatic edema, the likelihood of a severe complication is remote even if many
of Ranson’s signs are positive. When a markedly swollen pancreas is seen
with or without fluid collections, the presence of extensive necrotic areas
within the pancreas (necrotizing pancreatitis) predisposes the patient to
secondary infection and higher risk of mortality. The distinction between
acute interstitial and necrotizing pancreatitis can be made if a CT scan is
obtained following the administration of IV contrast medium (dynamic CT
scan). In acute interstitial pancreatitis, the pancreas is well perfused and
uniformly enhanced by the intravascular contrast agent. If necrosis is pre-
sent, the areas of devitalized tissue are not perfused and are not enhanced.
The presence of air bubbles in the pancreatic and peripancreatic region
is strong evidence of pancreatic infection. When fever, elevated white blood
count, and clinical toxicity are associated with CT scan evidence of fluid col-
lections or necrotizing pancreatitis, CT-guided percutaneous aspiration,
staining, and culture of the obtained fluid may help to distinguish sterile
pancreatitis from pancreatic infection. When infection is suspected or
proved, surgical debridement may be lifesaving.
ERCP is generally contraindicated in patients with acute pancreatitis
except when an impacted common bile duct stone may be the cause of the
pancreatitis. Endoscopic sphincterotomy in these very ill patients may be
immediately therapeutic. ERCP is also useful in establishing the diagnosis
of pancreas divisum; annular pancreas; pancreatic cancer; periampullary,
ampullary, and pancreatic ductal abnormalities; and the possible communi-
cation of the pancreatic duct with pseudocysts. These studies are usually
performed after the patient has been clinically stabilized.
C. Differential diagnosis. Table 45-6 summarizes the differential diagnosis of
acute pancreatitis. It may be difficult to distinguish between acute cholecystitis,
ascending cholangitis, and pancreatitis, because they may present with similarly
elevated serum amylase and abnormal liver tests. US and dimethylphenylcar-
bamylmethyliminodiacetic acid (HIDA) scans may be helpful in differentiating
between these diseases. Gut ischemia, infarction, viscus perforation, aortic dis-
section, mechanical intestinal obstruction, myocardial infarction, and acute
appendicitis need to be promptly diagnosed and surgically treated.
D. Complications. See Table 45-7.

VII. TREATMENT. In most patients (85%–90%) with acute pancreatitis, the disease
is self-limited and resolves spontaneously. These patients are medically treated with

TABLE 45-6 Differential Diagnosis of Acute Pancreatitis

Acute cholecystitis Mesenteric ischemia/infarction

Biliary colic due to choledocholithiasis Vasculitis
Ascending cholangitis Dissecting aortic aneurysm
Perforated viscus Myocardial infarction
Penetrating peptic ulcer Pneumonia
Alcoholic hepatitis Renal colic
Viral hepatitis Acute appendicitis
Acute intestinal obstruction Diabetic ketoacidosis
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314 Part V: Specific Complaints and Disorders

TABLE 45-7 Complications of Acute Pancreatitis

Pancreatic Cardiovascular
Phlegmon Cardiogenic shock
Abscess Increased cardiac index
Pseudocyst Decreased systemic vascular resistance
Nonpancreatic Pulmonary
Inflammatory involvement of contiguous Hypoxemia
organs Pleural effusions
Obstructive jaundice Pulmonary infiltrates, atelectasis
Pancreatic ascites Adult respiratory distress syndrome
Intraperitoneal hemorrhage Renal
Thrombosis of splenic vein Decreased glomerular filtration rate and
Bowel infarction renal plasma flow
Gastrointestinal bleeding Acute tubular necrosis
Acute renal failure
Systemic
Hematologic
Metabolic
Disseminated intravascular coagulation
Hypocalcemia
Thromboses
Hyperlipidemia
Increased factor VII or fibrinogen
Hyperglycemia
Skin and musculoskeletal
Diabetes ketoacidosis
Erythema nodosum–like lesions
Nonketotic diabetic coma
Angiopathic retinopathy
Pancreatic encephalopathy
Polyarthritis

supportive care with special attention given to analgesia, maintenance of normal

intravascular volume, frequent monitoring of vital signs, and treatment of possible
complications of the disease.
A. Meperidine (Demerol) in a dosage of 50 to 100 mg every 4 to 6 hours IV or
intramuscular (IM) is better tolerated than morphine sulfate (MS), which may
induce spasm of the sphincter of Oddi. In cases of severe pain, MS may be
necessary.
B. The sequestration of fluid in the peripancreatic and retro- and intraperitoneal
areas reduce the circulating plasma volume in most patients. IV electrolyte and
colloid solutions should be given generously (i.e., 200–300 mL/L for the first 1–2
days) to replace the fluid deficit. Fluid volume status determination may require
Swan-Ganz catheter placement.
C. It is believed that by putting the pancreas “at rest” by reducing pancreatic secre-
tions, the pancreatic inflammation will be minimized. Patients usually are given
nothing by mouth, and the upper gastrointestinal tract is decompressed by naso-
gastric suction. The rationale for nasogastric suction is to decrease gastric secretion
and to prevent gastric contents from entering the duodenum. Nasogastric suction
with a double-lumen sump tube is used in patients with nausea, vomiting, and
ileus. It may not be necessary for the patient with mild disease.
D. No drugs have been shown to improve the course of acute pancreatitis. Clinical
trials using inhibitors of gastric acid secretion such as histamine-2 blockers or pro-
ton pump inhibitors also are no more effective than nasogastric suction.
Somatostatin or its analog octreotide may be beneficial by reducing pancreatic
enzyme secretion.
E. Prophylactic antibiotics are not recommended in interstitial pancreatitis.
Antibiotics should be reserved for patients with established infection. It is impor-
tant to recognize and treat with the appropriate antimicrobial therapy possible sec-
ondary infection of the injured pancreatic tissue (phlegmon, pseudocyst, and
abscess) or an obstructed biliary tract leading to ascending cholangitis.
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Chapter 45: Acute Pancreatitis 315

In several studies, prophylactic antibiotics were found to be helpful in pre-

venting either pancreatic infection or other infections among patients with
necrotizing pancreatitis.
F. Nutritional support of the patient with acute pancreatitis should not be neglected.
As the inflammation subsides, small feedings of a diet high in carbohydrate but
low in protein and fat may be initiated. It is important to advance the diet slowly.
The feedings should be stopped if symptoms return. Pancreatic secretion is stimu-
lated equally in patients given elemental diets and those given regular diets intra-
gastrically or intrajejunally. Parenteral administration of nutrition does not seem
to increase pancreatic secretion. Thus, in patients who cannot receive feedings
orally, parenteral nutritional support including intralipids should be instituted
after the first few days. In some studies intragastric or intrajejunal feedings have
shown decreased rate of infectious complications and should be preferred.
G. Patients with fulminant pancreatitis need intensive monitoring and therapy.
These patients have very large fluid requirements. Most patients have respiratory
insufficiency and acute respiratory distress syndrome and may require mechanical
respiratory support. Hypocalcemia and hypomagnesemia should be promptly
treated with IV replacement. Renal insufficiency and acute tubular necrosis are not
uncommon, and patients may require dialysis.
H. Patients with severe disease should be closely followed by a surgical team. In
patients with a deteriorating clinical condition, emergency laparotomy for
drainage of the necrotic pancreas and peripancreatic spaces may be attempted.
Some surgeons advocate subtotal pancreatectomy and a procedure to decompress
the biliary tract. Alternatively, in clinically deteriorating patients with necrotizing
pancreatitis demonstrated on CT scan, CT-guided percutaneous aspiration of the
necrotic pancreas may be attempted. Gram’s stain and culture should be performed
on the aspirated material. Positive bacterial findings necessitate surgical debride-
ment. In selected cases of infected necrosis, vigorous percutaneous drainage with
multiple large tubes have been successful in either delaying surgery until the patient
is a better surgical candidate or eliminating the need for surgery. Also, in selected
incidences of infected necrosis, there may be a role for endoscopic drainage, par-
ticularly if the necrosis has organized.
Imipenem and/or other antibiotics covering gut pathogens should be given.
In sterile necrosis, nonoperative medical management for the first 3 to 4 weeks is
recommended.

VIII. Pancreatic pseudocysts are collections of necrotic tissue, fluid, and blood that develop
in or near the pancreas over a period of 1 to 4 weeks after the onset of acute pancreati-
tis. They do not have a true capsule with an epithelial lining. A connection may be pre-
sent to a disrupted pancreatic duct. Most pseudocysts (90%) are solitary lesions located
in the body or tail of the pancreas. The main symptom is abdominal pain.
A. Pathogenesis. Most pseudocysts form during a severe episode of acute pancreati-
tis. Persistence of an elevated serum amylase level for more than a week after the
onset of pancreatitis may signal the formation of a pseudocyst. Other causes of
pancreatic pseudocyst include abdominal blunt trauma with disruption of a pan-
creatic duct, inadvertent surgical ductal trauma, and chronic pancreatitis.
Neoplastic cysts, such as cystadenoma or cystadenoma-carcinoma, account for
10% of cystic pancreatic masses.
B. Diagnostic studies. Abdominal US and CT scans are the best imaging techniques
used in the diagnosis of pancreatic pseudocysts. Serial scans help in following the
size and course of the cysts. ERCP may be required to assess the possible connec-
tion of the pseudocyst with the pancreatic duct.
C. Complications and treatment. Most pseudocysts tend to resolve spontaneously.
Symptomatic pseudocysts require decompression. This can be achieved by surgery
or by percutaneous catheter drainage or by endoscopic techniques. Endoscopic
and radiologic methods should be reserved for those institutions with extensive
experience in these techniques. The serious complications of pancreatic pseudo-
cysts are infection, perforation, and hemorrhage.
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316 Part V: Specific Complaints and Disorders

1. Infection. Patients with a pancreatic pseudocyst who have pain, fever, and
leukocytosis need to be evaluated for infection. Percutaneous aspiration under
US or CT guidance with Gram’s stain and culture of the aspirate helps in
confirming the diagnosis. Infected pseudocyst or abscess should be drained
externally.
2. Perforation. Rupture or leak of a pseudocyst into the peritoneal cavity or
retroperitoneum may result in shock and requires emergency surgery. The mor-
tality from this complication is very high.
3. Hemorrhage. A pseudocyst may erode into a viscus (e.g., stomach, small or
large bowel) or a blood vessel with subsequent hemorrhage. Angiography is
often necessary prior to surgery for proper diagnosis of this complication.

Selected Readings
Amar S, et al. Sorofenibinducod pancreatitis. Mayo Clin Proc. 2007;82(4):516.
Badalov N, et al. Drug induced acute pancreatitis: An evidence-based review. Clinical
Gastroenterol Heptatol. 2007;5(6):648–661.
Baron TH, et al. Acute necrotizing pancreatitis. N Engl J Med. 1999;340:1412.
Beger HG, et al. Surgical management of necrotizing pancreatitis. Surg Clin North Am.
1999;79:783.
Brown A, et al. Hemoconcentration is an early marker for organ failure and necrotizing
pancreatitis. Pancreas. 2000;20:367.
DeWaele JJ, et al. Emergence of antibiotic resistance in infected pancreatic necrosis. Arch
Surg. 2004;139(12):1371–1375.
Frakes JT. Biliary pancreatitis: A review emphasizing appropriate endoscopic intervention.
J Clin Gastroenterol. 1999;28:97.
Freeman ML. Pancreatic stents for prevention of post ERCP pancreatitis. Clin Gastroenterol
Hepatol. 2007;5(11):1354–1365.
Freeman ML, et al. Prevention of post-ERCP pancreatitis: A comprehensive review.
Gastrointest Endosc. 2004;59:845–864.
German Antibiotics in Severe Acute Pancreatitis Study Group. Prophylactic antibiotic
treatment inpatients with predicted severe acte pancreatitis. A placebo-controlled,
double-blind trial. Gastroenterology. 2004;126(4):997–1000.
Jacobsen BC, et al. A prospective, randomized trial of clear liquids versus low fat solid diet
as the initial meal in mild pancreatitis. Clin Gastroenterol Hepatol. 2007;5(8):946–951.
McClave SA, et al. Nutrition support in acute pancreatitis: A systematic review of the
literature. JPEN J Parenter Enteral Nutr. 2006;30:143–156.
Meier R, et al. ESPEN guidelines on enteral nutrition: pancreas. Clin Nutr. 2006;25:275–284.
Shankar S, et al. Imaging and percutaneous management of acute complicated pancreatitis.
Cardiovasc Intervent Radiol. 2004;27:567–580.
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CHRONIC PANCREATITIS 46

C hronic pancreatitis results from progressive destruction and fibrosis of the pancreas
with ongoing inflammatory lesions. The exocrine pancreatic tissue and function are lost
in the earlier stages, followed by the loss of endocrine parenchyma and function. The dis-
ease frequently is complicated in the early stages of its evolution by attacks of acute
pancreatitis, which are responsible for recurrent pain. After several years of ongoing
inflammation and fibrosis, pancreatic insufficiency develops, with resulting malabsorption,
steatorrhea, and diabetes mellitus. Acute attacks decrease and pain usually disappears.

I. CLASSIFICATION. Chronic pancreatitis may be classified into two forms that present
with specific lesions and have different causes.
A. Obstructive chronic pancreatitis is caused by the occlusion of pancreatic ducts,
which precedes the onset of pancreatitis. The occlusion may be the result of
tumors, scars of parenchymal inflammation, necrotic pseudocysts, or congenital
anomalies (e.g., annular pancreas, pancreas divisum). The lesions are found in
the part of the pancreas encompassing the occluded ducts. The ductal epithelium is
relatively preserved, and intraductal protein plugs and stones are not present.
Infiltrative and autoimmune diseases such as hemochromatosis and Sjögren’s
syndrome may also involve the pancreas, resulting in pancreatic insufficiency.
B. Chronic calcifying pancreatitis (CCP) is the most frequent cause (95% of all
instances) of chronic pancreatitis. It is significantly associated with chronic alcohol
consumption and is exacerbated by cigarette smoking and by diets high in protein
and high or low in fat.
Less frequently, CCP occurs with hyperparathyroidism and hypercalcemia, and
in some tropical countries (South India, Zaire, Nigeria, Brazil) it occurs in nonalco-
holic young people (average age, 12–20 years) of both sexes living in areas where
protein- and fat-poor diets are consumed. There is also a hereditary autosomal-
dominant form of CCP with variable penetrance. Pancreatic insufficiency from
cystic fibrosis may resemble CCP in morphology and presentation.
1. Morphology. CCP is characterized by the lobular, patchy distribution of lesions
of different intensity in neighboring lobules. Protein plugs are always found in
the ductal and acinar lumina, and in the later stages these form calcifications,
or calculi (pancreatic calcification). Atrophy of the epithelium and stenosis
of the ducts are common. Recurrent attacks of acute pancreatitis, retention
cysts, pseudocysts, and perineural inflammation are frequently associated.
The first visible lesions are protein precipitates or plugs in the lumina of
ducts and acini, which later calcify forming pancreatic stones. The ductal
epithelium in contact with the protein plugs or stones loses its basement mem-
brane, and the duct cells atrophy and disappear with the growth of periductal
connective tissue and fibrosis leading to fibrotic strictures. Distal to the strictures,
the exocrine tissue atrophies and disappears due to plugs, stones, and fibrosis.
When a partially obstructed duct is distended by pancreatic juice under pressure
of secretion, it may form an intrapancreatic cyst. These retention cysts may
grow and extend into peripancreatic tissue, forming retention pseudocysts.
Thus all lesions of chronic calcifying pancreatitis are thought to be secondary to
the formation of protein plugs and stones in the pancreatic ducts and ductules,
resulting in ductal obstruction, parenchymal inflammation, atrophy, and fibrosis.

317
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318 Part V: Specific Complaints and Disorders

2. Pathophysiology. The pathogenesis of pancreatic lithogenesis involves the

precipitation of both a fibrillar protein—a form of pancreatic stone protein
(PSP)—and calcium carbonate.
Normally the pancreatic juice is saturated with calcium. The precipitation
of calcium in the pancreatic juice is prevented by the presence of a group of
proteins, PSP-S2–5, synthesized and secreted by the acinar cells. PSP-S2–5 acts as a
calcium stabilizer of the pancreatic juice by blocking the growth sites of crys-
tals. In the pancreatic juice, PSP-S2–5 may be hydrolyzed by active trypsin to
give a shorter protein, PSP-S, which is insoluble at physiologic pH and does not
prevent calcium carbonate crystallization. PSP extracted from pancreatic plugs
and stones contain the same amino acid sequence as PSP-S1. The relative con-
centration of PSP is significantly decreased in the pancreatic juice of patients
who have CCP compared to normal controls; this is true even in the early stages
of the disease, before the appearance of calcification on abdominal x-rays. This
finding suggests that the formation of the calcified part of the stones is due to
a decreased secretion of PSP, the stabilizer of calcium in pancreatic juice. PSP
secretion is also decreased in hereditary chronic pancreatitis as well as in idio-
pathic and alcoholic forms; thus the condition may be either congenital or
acquired.
The lesions of the ductal epithelium caused by the protein plugs and stones
lead to transudation of protein- and calcium-rich interstitial fluid into ductal
lumina, increasing the calcium concentration in the pancreatic juice and result-
ing in increased intraductal calcium crystallization. As the diseased ducts
become obstructed by the precipitated protein and calcifications, the acini and
the lobule, which the ducts drain, become atrophic and fibrotic, resulting in
pancreatic parenchymal loss in a patchy distribution throughout the pancreas.
3. Role of alcohol consumption and diet. Acute recurrent pancreatitis is
thought to be a complication of the initial stages of CCP. It occurs in chronic
alcoholics who have recently increased their alcohol intake. Follow-up of these
patients shows that in most of them, pancreatic calculi (calcifications) develop
after a number of years.
Recurrent alcoholic pancreatitis progresses to overt pancreatic insuffi-
ciency at different rates in different people. However, there is a linear relation
between the average daily consumption of alcohol and the logarithm of the
risk. For a given amount of alcohol consumption, the risk increases with the
increased duration of consumption. Even small quantities (1–20 g of alcohol
per day) increase the risk. Rather than a statistical threshold of alcohol toxicity
for the pancreas, there is a continuous spectrum of individual thresholds. The
type of alcoholic beverage and the rhythm of alcohol consumption have no sig-
nificant influence on the risk of development of CCP.
Chronic alcohol ingestion increases the total protein concentration of pro-
tein in pancreatic juice but decreases the concentrations of PSP, citrate, bicar-
bonate, trypsin inhibitory protein, and the pH. Decreased citrate concentration
increases calcium availability. It is thought that the increased viscosity of the
pancreatic juice, due to increased protein content and decreased concentrations
of PSP and citrate, leads to formation of protein plugs and calcifications in
these patients.

II. DIAGNOSIS. The insidious nature of chronic pancreatitis delays the early diagnosis of
this disorder in many patients. Patients usually come to medical attention after con-
siderable damage has occurred to the gland. In most cases, it is difficult to differenti-
ate acute relapsing pancreatitis, in which the permanent pancreatic damage is mild to
moderate, from chronic relapsing pancreatitis.
A. Clinical presentations. Chronic pancreatitis is an insidious process of parenchy-
mal damage with necrosis and fibrosis of the gland. Approximately one half of the
patients present with episodes of acute pancreatitis superimposed onto the
damaged organ. One third of the patients may present with only abdominal pain.
Other patients may have jaundice, weight loss, malabsorption, steatorrhea,
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Chapter 46: Chronic Pancreatitis 319

diabetes mellitus, or upper gastrointestinal bleeding. Ten percent of the patients

never experience pain. The average age of the patient at initial diagnosis is 35 to
50 years.
1. Abdominal pain accompanying chronic pancreatitis is described as a steady,
boring, achy sensation usually associated with nausea with or without vomit-
ing. It is commonly present in the mid-epigastrium, but it may also be perceived
in the right or left upper quadrant or periumbilical area. It usually radiates to
the back, increases in the supine position, and decreases on sitting up and lean-
ing forward. Most patients require analgesics and may become addicted to
narcotics.
The course of the pain of chronic pancreatitis differs in different patient
groups. In most patients, it is a constant experience in the first 5 years after its
diagnosis. Thereafter, in about two thirds of the patients, it may resolve spon-
taneously or diminish in severity and frequency.
2. Malabsorption. Pancreatic exocrine function steadily diminishes with chronic
pancreatitis.
a. Fat and protein malabsorption becomes apparent after the loss of 90%
of the pancreatic secretory capacity. Protein malabsorption may be com-
pensated for with increased oral intake of protein without additional
abdominal discomfort to the patient. However, increased fat intake results
in more diarrhea and abdominal pain. The steatorrhea of chronic pancre-
atitis consists mainly of triglycerides (esterified fats) in contrast to steator-
rhea of sprue, which contains free fatty acids: The esterified fats are
hydrolyzed by pancreatic lipase to free fatty acids, but they are not
absorbed by the diseased intestinal mucosa. Stool volume is also smaller in
chronic pancreatitis, again due to the presence of esterified fats, because
hydroxylated free fatty acids are the secretagogues of colonic chloride and
water secretion.
b. Carbohydrate malabsorption is rare in chronic pancreatitis, because loss
of 97% of amylase secretion is necessary for maldigestion of starch.
c. Vitamin B12 malabsorption. Decreased pancreatic exocrine function does not
affect the absorption of bile salts, water- or fat-soluble vitamins, iron,
or calcium. However vitamin B12 malabsorption may occur in some patients
due to diminished secretion of trypsin. As vitamin B12 is ingested, a nonspe-
cific protein (R protein) found in the upper gastrointestinal secretions binds
with it and does not allow it to bind intrinsic factor (IF) from the stomach.
Normally, trypsin in the second portion of the duodenum cleaves off the R
protein and allows the association of vitamin B12 to intrinsic factor.
The IF–vitamin B12 complex is necessary for the active absorption of
the vitamin B12 at the terminal ileum. In chronic pancreatitis with diminished
levels of pancreatic proteases, especially trypsin, in the duodenal lumen, the R
protein is not cleaved off vitamin B12 and IF–vitamin B12 complex does not
form, leading to vitamin B12 malabsorption.
3. Diabetes mellitus. Along with exocrine insufficiency, endocrine insufficiency
with diminished insulin and glucagon release develops in these patients. Seventy
percent of the patients with pancreatic calcifications develop diabetes mellitus.
Microangiopathy and nephropathy do not seem to complicate diabetes mellitus
resulting from chronic pancreatitis. However, due to concomitant diminished
glucagon secretion, these patients are very sensitive to exogenous insulin and
may develop hypoglycemia even with low doses.
4. Physical examination. There are no specific findings in chronic pancreatitis.
Some patients have epigastric tenderness. A mass may be palpable if a palpable
pseudocyst exists. Patients with malabsorption may have weight loss but do not
present with signs of fat-soluble vitamin deficiency (vitamins A, D, E, and K)
such as night blindness, hypocalcemia, osteomalacia, and bleeding tendency.
Jaundice may exist in patients with common bile duct obstruction due to scar-
ring in the pancreatic head. In these patients, it may be difficult to differentiate
pancreatic cancer from chronic pancreatitis.
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320 Part V: Specific Complaints and Disorders

B. Diagnostic studies
1. Serum chemistry profile. There are no specific findings in the serum chemistry
profile in patients with chronic pancreatitis. Even during acute attacks, the
serum amylase or lipase level may not be elevated. The serum chemistry profile
may reflect concomitant liver disease. With obstruction of the common bile
duct, a cholestatic liver chemistry profile may emerge and should be confirmed
by imaging techniques.
2. Stool fat. Steatorrhea is best confirmed by 72-hour stool collection for quanti-
tative determination of fat. Most patients consuming 100 g of fat per day
excrete more than 10 g of fat per day. In advanced pancreatic insufficiency, stool
fat may reach 30 to 40 g per day.
3. Radiologic studies
a. Pancreatic calcifications are present on plain abdominal radiographs in
one third of patients with chronic pancreatitis.
b. Ultrasound and, especially, computed tomography (CT) scan provide for
more sensitive detection of pancreatic calcifications. The presence of pseudo-
cysts, ductal dilatation, and tumors can also be delineated.
c. Angiography. When a tumor is suspected, angiography may be helpful in
identifying neovascularity of the tumor, deviation of normal vascularity due
to tumor, or the lack of vascularity of the cystic lesions. When splenic vein
thrombosis has occurred, angiography demonstrates the site of occlusion and
the presence of gastric or esophageal varices.
d. Endoscopic retrograde cholangiopancreatography. Pancreatic ductal
anatomy is best delineated with endoscopic pancreatography: Dilatation,
cystic changes, strictures, and calculi are demonstrated. Most patients with
advanced chronic pancreatitis have a dilated common pancreatic duct with
intermittent sites of narrowing, creating the “chain of lakes” appearance on
the pancreatograms. The damage is also noted in the secondary ducts, with
dilatation and blunting leading to loss of the fine “acinarization.”
Endoscopic retrograde cholangiopancreatography (ERCP) may
also be helpful in the differentiation of pancreatic cancer from chronic pan-
creatitis. In pancreatic cancer, only that part of the duct involved with the
tumor is abnormal, in contrast to generalized abnormal changes seen with
chronic pancreatitis.
e. Endoscopic ultrasonography (EUS) may be used in instances of CCP in
which a tumor is suspected. The differentiation of sclerotic pancreatic cancer
from atrophic and fibrotic pancreatic parenchyma may be difficult with this
technique.
4. Tests of pancreatic exocrine function. Chronic pancreatitis or pancreatic
insufficiency can be determined with certainty only by demonstrating dimin-
ished exocrine function during adequate stimulation of the pancreas. These tests
may be necessary in situations in which no calcification is seen on radiographic
studies and the ducts appear normal on ERCP.
a. Secretin stimulation test. In this test, the duodenum is intubated under
fluoroscopy and the duodenal contents are aspirated, collected, and analyzed
after the patient receives intravenous secretin (1 U/kg of body weight) to
stimulate pancreatic water and bicarbonate secretion. The total output of
bicarbonate correlates well with the extent of pancreatic damage.
The addition of cholecystokinin to secretin, to stimulate exocrine
enzyme secretion (e.g., amylase or lipase), does not seem to increase the diag-
nostic accuracy. The secretin stimulation test is difficult to perform and
requires technical expertise. It is reliably performed in specialized medical
centers. The overall sensitivity is 74% to 90%.
b. The Lundh test meal provides for endogenous stimulation of pancreatic
exocrine secretion. After the patient is given a standard test meal, the
proximal jejunal fluid is aspirated for 2 hours and analyzed for trypsin.
This test is not as sensitive as the secretin stimulation test (sensitivity,
60%–90%).
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Chapter 46: Chronic Pancreatitis 321

c. Bentiromide test. Patients ingest 500 mg of N-benzoyl- L -tyrosyl-p-

aminobenzoic acid (bentiromide), a synthetic peptide, which is specially
cleaved by chymotrypsin to liberate PABA in the proximal small intestine.
PABA is normally absorbed, conjugated in the liver, and excreted in the urine.
Recovery of less than 60% of the liberated paraaminobenzoic acid (PABA)
from a 6-hour urine collection is considered to be abnormal and suggests
pancreatic insufficiency with decreased chymotrypsin output.
False-positive results may be obtained in patients with diffuse intestinal
disease resulting in diminished absorption of PABA, with chronic liver dis-
ease resulting in decreased conjugation of PABA, and with renal insufficiency
with reduced urinary output of PABA. The accuracy of the test may be
increased with a concomitant d-xylose test or by giving a small amount of
carbon 14–labeled PABA along with the test dose of the peptide. The ratio of
urinary PABA to 14C-PABA helps in differentiating false-positive results from
pancreatic insufficiency.
Even though this test does not seem to be as sensitive as the secretin test
in patients with mild pancreatic insufficiency, its ease of performance makes
it a desirable alternative. Its overall sensitivity is 37% to 90%.

III. LOCAL COMPLICATIONS. Chronic pancreatitis in a minority of patients may be com-

plicated by the development of pancreatic pseudocysts, abscess, ascites, common bile
duct obstruction, duodenal obstruction, and portal and splenic vein thrombosis. The
incidence of pancreatic cancer is not increased in patients with chronic pancreatitis.

IV. The treatment of chronic pancreatitis is mainly supportive and directed at the
complications.
A. Management of pain
1. In alcohol-related disease, alcohol and tobacco consumption should be
stopped. Patients should be advised to follow a diet with moderate fat and pro-
tein and high carbohydrate content.
2. In some instances pain relief may be obtained by small feedings and anal-
gesics. Many patients require narcotics.
3. Feedback control. Oral treatment with large doses of pancreatic enzymes has
been shown to decrease the abdominal pain experienced by patients with
chronic pancreatitis by inhibiting pancreatic exocrine secretion and allowing
the pancreas to rest. The presence of the proteases trypsin and chymotrypsin
within the lumen of the proximal duodenum exerts a feedback control on pan-
creatic exocrine secretion. The patients in whom pain responds to pancreatic
enzymes most readily are those with mild-to-moderate exocrine impairment.
The use of pancreatic enzymes has also been shown to heal pancreatic fistulas
and to decrease the frequency of attacks of acute, recurrent pancreatitis. The
doses used are similar to those used for the treatment of malabsorption (see
section IV.B).
4. Percutaneous injection of alcohol to destroy the celiac plexus has been
reported to relieve pain in some patients for as long as 6 months. Long-term
effects of this treatment have not been determined.
5. Surgery for relief of pancreatic pain is reserved for patients with intractable
and disabling pain unresponsive to any other mode of therapy. The surgical
procedures used depend on pancreatic and ductal anatomic abnormalities deter-
mined by preoperative CT scan and ERCP findings. In most patients, pain relief
is achieved for the short term. The long-term effectiveness of these procedures
in relieving pain is debated.
Drainage procedures are used when there is generalized or localized
pancreatic ductal dilatation, and partial resection of the gland is used when
there is no ductal dilatation or the abnormality is confined to a segment of the
pancreas.
a. Longitudinal pancreaticojejunostomy (the Puestow procedure). In this
procedure, the dilated pancreatic duct is filleted open longitudinally over the
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322 Part V: Specific Complaints and Disorders

length of the gland. A nonfunctioning segment of jejunum in a Roux-en-Y

loop is also opened longitudinally and sewn over the open duct to allow for
drainage of the pancreatic secretions.
b. Caudal pancreaticojejunostomy (DuVal procedure). When there is a duc-
tal obstruction in the body of the pancreas with distal duct dilatation, the
tail of the pancreas is resected and the remaining pancreas is placed in an
end-to-end fashion into a nonfunctioning segment of jejunum.
c. Sphincteroplasty of the sphincter of Oddi or Santorini has been used in
isolated strictures of these orifices (e.g., in pancreas divisum).
d. Pancreatic resection. In the absence of ductal dilatation and when abnor-
malities are confined to portions of the pancreas, 40% to 95% of the gland
may be resected. When the disease is confined to the head of the pancreas,
the Whipple’s procedure (pancreaticoduodenectomy) may be used. Total
pancreatectomy has been performed rarely when lesser procedures failed to
relieve pain.
Although the short-term success of these procedures in relieving pain
seems good, most patients experience pain recurrence. Also, pancreatic insuf-
ficiency and insulin-dependent diabetes mellitus become a problem after the
resection of 50% of the gland in most patients. Surgical manipulation of the
pancreas for relief of pancreatic pain should be reserved for truly refractory
pain, and drainage procedures, when possible, are preferred to resection
involving more than half of the gland.
B. Malabsorption. Steatorrhea is often an earlier and more severe problem than
azotorrhea in chronic pancreatitis because secretion of lipase and colipase
decreases earlier than that of the proteolytic enzymes. If steatorrhea is less than
10 g of fat per day, patients may do well with dietary restriction of fat. If the steat-
orrhea is greater than 10 g of fat per day, pancreatic enzyme supplementation is
recommended in addition to dietary fat restriction.
1. Pancreatic enzyme supplements. Pancreatic extracts may be used for
enzyme supplementation to reduce malabsorption. Table 46-1 lists some of the
commercially available pancreatic enzyme preparations.
To eliminate malabsorption, the concentration of enzymes delivered to the
duodenum need only be 5% to 10% of the concentration that is secreted into
the duodenum after maximal stimulation of the pancreas. This means that
approximately 30,000 IU of lipase must be present in the duodenum with each
meal. Most commercial preparations contain only 3,000 to 4,000 units of
active lipase per tablet. Therefore, if no lipase is inactivated in the stomach, six
to ten tablets are required per meal to eliminate steatorrhea. Lesser amounts
diminish but do not abolish steatorrhea.
The enzyme preparations are commonly given before each meal at the
following doses: Viokase, eight tablets; Cotazym, six capsules; Ilozyme,
four capsules; Pancrease MT16, three capsules; Creon, three capsules;
Entolase H.P., three capsules; and Zymase, three capsules. If the patient has
pancreatic pain, another one to two doses are given at bedtime. Although
pancreatic enzyme preparations are free of serious side effects, patients
ingesting large doses may complain of nausea, abdominal cramps, and peri-
anal excoriation. The high content of nucleic acids contained in the enzyme
preparations may result in hyperuricemia and kidney stones in some patients,
especially in children. Allergy to pork protein may develop and cause adverse
reactions.
Pancreatic lipase is irreversibly inactivated by a pH less than 4.0; there-
fore, it is important to maintain the gastric pH above 4.0 for at least 1 hour
postprandially. Because different patients have different rates of gastric acid
secretion, those who are achlorhydric or hypochlorhydric do well with the pre-
ceding dosages. However, in patients with normal gastric acid secretion, higher
dosages of the enzymes or adjuvant acid-suppressant therapy or both may be
necessary to keep the intragastric pH above 4.0 to deliver adequate active
enzyme concentrations to the small bowel.
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Chapter 46: Chronic Pancreatitis 323

TABLE 46-1 Commercial Pancreatic Enzyme Preparations

Enzyme content (Units)

Preparation Type Lipase Protease Amylase

Pancrelipase
Cotazym C 8,000 30,000 30,000
Cotazym-S ECMS 5,000 20,000 20,000
Festal II ECT 6,000 20,000 30,000
Ku-Zyme HP C 8,000 30,000 30,000
Pancrease ECMS 4,000 25,000 25,000
Pancrease MT4 ECMT 4,000 12,000 12,000
Pancrease MT10 ECMT 10,000 30,000 30,000
Pancrease MT16 ECMT 16,000 48,000 48,000
Pancrease MT25 ECMT 25,000 75,000 75,000
Viokase T 8,000 30,000 30,000
Zymase ECS 12,000 24,000 24,000
Pancreatin
Creon ECMS 8,000 13,000 30,000
Creon 25 ECMS 25,000 62,500 74,700
Pancreatin 8
T 22,500 180,000 180,000
Entozyme T 600 7,500 7,500

C, capsule; T, tablet; ECT, enteric-coated tablet; ECS, enteric-coated sphere; ECMT, enteric-coated
microtablet; ECMS, enteric-coated microsphere.

2. Adjuvant acid-suppressant therapy may be used to increase the gastric lumi-

nal pH and improve the survival of the exogenous enzymes during transit from
the stomach.
a. Sodium bicarbonate and aluminum hydroxide are the only antacids that
are effective in reducing steatorrhea; they are administered before or at the
beginning of the meal in a dosage that maintains intragastric pH above 4.0.
This seems to be 16.6 g per 24 hours for sodium bicarbonate and 18.4 g
per 24 hours for aluminum hydroxide gel. Other antacids, such as
magnesium aluminum hydroxide or calcium carbonate, tend to increase
steatorrhea.
Sodium bicarbonate 650 mg before and after meals has been effective,
especially with Viokase. If the patient is receiving a nighttime dose of the
enzymes, the dose of sodium bicarbonate is increased to 1,300 mg at bed-
time. Hypercalcemia and the milk–alkali syndrome have not occurred with
this regimen. Enteric-coated enzyme preparations should not be used with
sodium bicarbonate. They may release the contents of the microspheres in
the stomach with the loss of enzyme activity if used concomitantly with
sodium bicarbonate.
Magnesium- and calcium-containing antacids effectively increase
gastric pH but may aggravate steatorrhea by precipitating bile salts in the
duodenum and forming calcium and magnesium soaps from the undigested
free fatty acids, which increases intestinal secretion.
b. Gastric acid suppression with histamine-2 blockers or proton-pump
inhibitors. Adjuvant therapy with histamine-2 (H2) blockers and proton
pump inhibitors (PPIs) may be used. However, concurrent use of a pH-
sensitive, delayed-release pancreatic enzyme preparation and an H2 blocker
or a PPI could result in premature release of the enzymes in the stomach.
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324 Part V: Specific Complaints and Disorders

c. Enteric pH-coated pancreatic enzyme preparations are effective if the

intragastric pH remains at 4.0 to 5.0 and the duodenal pH above 6.0 to
allow for dissolution of the coating and release of the active enzymes.
These preparations have not been shown to be more advantageous than
the other preparations. The newer preparations (e.g., Creon) with smaller
microspheres may have better bioavailability in the duodenum.
Most patients with exocrine pancreatic insufficiency do quite well
with adequate enzyme replacement. The dosage of the enzymes should be
increased if symptoms are not alleviated.
C. Nutritional support. Patients with chronic pancreatitis tolerate small but frequent
feedings that are high in protein better than large feedings. In debilitated patients,
dietary supplements rich in protein should be used. If patients cannot tolerate
enteral feedings, parenteral nutrition may be given.
Medium-chain triglycerides (MCTs) may be substituted for long-chain
triglycerides to increase the total fat intake because MCTs are hydrolyzed much
more rapidly by pancreatic lipase, and some are absorbed while still intact into the
portal vein. MCT is sold as MCT oil for food preparation.
D. Bacterial overgrowth. As many as 25% of patients with chronic pancreatitis
have concomitant bacterial overgrowth in the small intestine. These patients may
need both pancreatic enzymes and antimicrobial therapy (e.g., tetracycline 500 mg
p.o. three or four times daily; metronidazole 250–500 mg p.o. three times daily for
7–14 days; Xifaxan 400 mg p.o. daily for 10 days before diarrhea and steatorrhea
can be effectively treated.
E. Diabetes mellitus. Patients who have diabetes mellitus with insulin deficiency as
a result of chronic pancreatitis also have concomitant glucagon deficiency. Thus,
these patients are very susceptible to hypoglycemia, and their insulin dosage needs
to be closely monitored.

Selected Readings
Adler DG, et al. The role of endoscopy in patients with chronic pancreatitis. Gastrointest
Endosc. 2006;63:933–937.
Cahen DL, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic
pancreatitis. N Engl J Med. 2007;356:676–684.
Dragonuv P, et al. Idiopathic pancreatitis. Gastroenterology. 2005;128(3):756–763.
Dragonuv P, et al. A 54-year-old man with abdominal pain attributed to chronic
pancreatitis. Clin Gastroenterol Hepatol. 2007;5(3):302–306.
Eleftheriadis N, et al. Long term outcome after pancreatic stenting in severe chronic
pancreatitis. Endoscopy. 2005;37:223–230.
Elta GH. Is there a role for the endoscopic treatment of pain from chronic pancreatitis?
N Engl J Med. 2007;356:727–729.
Etemad B, et al. Chronic pancreatitis: Diagnosis classification and new genetic developments.
Gastroenterology. 2001;120:682–707.
Frey CF, et al. Comparison of local resection of the head of the pancreas combined with
longitudinal pancreatic jejunostomy (Frey procedure) and duodenum-preserving
resection of the pancreatic head (Berger procedure). World J Surg. 2003;27:1211–1230.
Gabrielli A, et al. Efficacy of main pancreatic duct endoscopic drainage in patients with
chronic pancreatitis, continuos pain, and dilated duct. Gastrointest Endosc. 2005;61:
576–581.
Lankish MR, et al. The effect of small amounts of alcohol on the clinical course of chronic
pancreatitis. Mayo Clin Proc. 2001;76:242–251.
Lowenfel AB, et al. Risk factors for cancer in hereditary pancreatitis study group. Med
Clin North Am. 2000;84:565–593.
Morinville V, et al. Recurrent acute and chronic pancreatitis: Complex disorders with a
genetic basis. Gastroenterol Hepatol. 2005;1(3):195–205.
Norton ID, et al. The role of transabdominal ultrasonography, helical computed
tomography and magnetic resonance cholangiopancreatography in diagnosis and
management of pancreatic disease. Curr Gastroenterol Rep. 2000;2:120.
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Chapter 46: Chronic Pancreatitis 325

Palanivelu C, et al. Laparoscopic lateral pancreatic jejunostomy: A new remedy for an old
ailment. Surg Endosc. 2006;458–461.
Pickartz T, et al. Autoimmune pancreatitis. Nat Clin Pract Gastroenterol Heptatol.
2007;4(6):314–323.
Pitchumoni CS. Pathogenesis of alcohol-induced chronic pancreatitis: Facts, perceptions
and misperceptions. Surg Clin North Am. 2001;81:379–389.
Ralmondo M. What is the role of EUS in screening for chronic pancreatitis? Nat Clin Pract
Gastroenterol Hepatol. 2007;4(10)530–532.
Toskes PP. Alcohol consumption and chronic pancreatitis. Mayo Clin Proc. 2001;76:241.
Whitcom DC, et al. Mechanisms of disease: Advances in understanding the mechanisms
leading to chronic pancreatitis. Nat Clin Pract Gastroenterol Hepatol. 2004;1(1):46–52.
79466_CH47.qxd 1/2/08 1:29 PM Page 326

PANCREATIC CANCER, AMPULLARY

47 CANCER, CYSTIC TUMORS, AND
NEUROENDOCRINE TUMORS
OF THE PANCREAS

E xocrine pancreatic cancer accounts for 95% of all the cancers that arise in the
pancreas. Between 75% and 95% of exocrine pancreatic cancers arise from the ductular
epithelium. Other cancers, such as acinar cell carcinoma, giant cell carcinoma, adenosqua-
mous carcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic tumor, muci-
nous ductal ectasia, intraductal papillary neoplasm, fibrosarcoma, leiomyosarcoma, and
lymphoma are rare and account for less than 10% of the exocrine tumors.
Islet cell tumors of the pancreas make up approximately 5% of the carcinomas of
the pancreas. These tumors often manifest themselves by the hormones they secrete.
Tumors secreting gastrin, insulin, glucagon, vasoactive intestinal polypeptide (VIP), pan-
creatic polypeptide (PIP), neurotensin, and somatostatin may present as single tumors or as
part of multiple neoplasm syndromes.

I. ADENOCARCINOMA OF THE PANCREAS

A. Epidemiology. The prevalence of adenocarcinoma of the pancreas is nine to ten
per 100,000 persons in most Western countries. It is the fourth most common
cause of death from carcinoma in males (after lung, colon, and prostate) and the
fifth in females (after breast, colon, lung, and ovary). It can occur at any age but is
most commonly seen in the sixth to eighth decades of life. It is more common in
men than in women (1.3:1), in blacks than in whites (incidence 15.2/100,000 black
men), and in Jews than in non-Jews.
There has been an increase in the incidence of pancreatic cancer in the last
30 years. Various substances have been implicated as possible etiologic factors.
The risk of pancreatic cancer developing is increased 1.5 times in cigarette smok-
ers. The risk increases as the number of cigarettes smoked increases, and the excess
risk levels off 10 to 15 years after smoking cessation.
Diets rich in fat, red meat, or both have been implicated as risk factors. There
seems to be a protective effect of diets rich in fruits and vegetables, carotenoids,
and selenium. Other risk factors include history of peptic ulcer surgery (partial
gastrectomy); cholecystectomy, possibly by increasing cholecystokinin (CCK)
secretion; chronic pancreatitis (mostly hereditary and tropical types); hereditary
nonpolyposis colorectal cancer; ataxia-telangiectasia; Peutz-Jeger syndrome; famil-
ial breast cancer; familial atypical multiple mole melanoma; and prolonged expo-
sure to the gasoline derivatives 2-naphthylamine and benzidine and metal dusts.
There is no conclusive evidence that drinking alcohol is related to the development
of pancreatic cancer.
B. Pathophysiology. Adenocarcinoma of the pancreas forms a dense, fibrotic
mass in the pancreas associated with a desmoplastic reaction. Seventy percent of
the lesions are located in the head; the remainder is in the body and the tail of the
gland or are multifocal or diffusely infiltrate the gland. By itself, the tumor may
not cause symptoms. However, because the pancreas, which is a retroperitoneal
organ without a mesentery, lies close to the porta hepatis, common bile duct, duo-
denum, stomach, and colon, the tumor mass may impinge on or penetrate into any
of these structures and cause symptoms.
Pancreatic cancer metastasizes widely. It spreads locally by direct extension
and to distant sites by lymphatic and vascular channels. It also invades nerves and

326
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Chapter 47: Pancreatic Cancer 327

nervous plexuses, especially in the celiac and mesenteric areas. The most common
sites of extralymphatic metastasis are the liver, peritoneum, lungs, intestines,
adrenals, kidneys, bones, and the diaphragm. Pancreatic tumors other than ductal
adenocarcinomas (e.g., cystadenocarcinomas, islet cell tumors) often have a more
indolent course. Tumors such as carcinomas of the breast, lung, thyroid, kidney,
ovary, uterus, and prostate, and melanomas may metastasize to the pancreas and
present as mass lesions in the organ.
C. Diagnosis
1. Clinical presentation
a. History. The early symptoms of pancreatic cancer are vague and nonspe-
cific. The most common symptoms are abdominal pain, back pain, weight
loss, anorexia, nausea, jaundice, diarrhea, malabsorption, depression, and
abdominal mass.
i. An insidious weight loss with anorexia and nausea, accompanied by
upper abdominal pain radiating to the back, is the most common pre-
sentation. Greater than 90% of the patients initially have jaundice.
Common bile duct obstruction by a tumor in the head of the pancreas
may result in jaundice while the mass is still small. Tumors located in the
body and tail of the organ may result in jaundice in later stages either
by extension or due to metastasis to the porta hepatis or the liver
parenchyma.
ii. Up to 70% of the patients may present with diabetes mellitus or glucose
intolerance. The decreased or delayed insulin secretion is thought to
arise from loss of B cells due to the desmoplastic reaction of the tumor.
iii. Migratory thrombophlebitis (Trousseau’s sign) may be a mode of
presentation. However, this entity is not specific for pancreatic cancer. It
may occur with other malignancies such as carcinomas of the stomach,
colon, ovary, and lung.
iv. A minority of the patients may also present with a picture of acute
pancreatitis, cholangitis, gastrointestinal bleeding, polyarthritis,
and skin nodules due to fat necrosis.
b. The physical examination in most instances is not helpful. The major find-
ings in a subpopulation of patients are jaundice, palpable gallbladder, epi-
gastric mass, and nodular liver if metastases are present.
c. Warning signs for early diagnosis. The initial symptoms of pancreatic
cancer are usually ignored by the patient (patient delay) and the physician
(physician delay). The mean duration of symptoms before diagnosis in most
series is 3 to 4 months. Most of the tumors are unresectable and, therefore,
the disease is fatal. The following warning signs may facilitate an early diag-
nosis of this malignancy:
i. Recent upper abdominal or back pain consistent with retroperitoneal
lesion.
ii. Recent upper abdominal pain or discomfort with negative gastrointestinal
investigations.
iii. Jaundice with or without pruritus.
iv. Weight loss greater than 5% of normal body weight.
v. Unexplained acute pancreatitis.
vi. Unexplained onset of diabetes mellitus.
d. Differential diagnosis. A variety of malignant and benign disorders of other
organs may present with features similar to pancreatic cancer. Also, it is
important to remember that pancreatic cancer may coexist in a patient with
a common benign disorder such as gallstones or peptic or diverticular dis-
ease, and normal contrast studies of the gastrointestinal tract, serum
chemistries, and hemogram do not rule out the presence of pancreatic cancer,
especially if the tumor is small.
2. Diagnostic studies
a. Laboratory tests. There are no specific laboratory tests for the early detec-
tion of pancreatic cancer. If there is involvement of the liver or the biliary
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328 Part V: Specific Complaints and Disorders

tract, this will be reflected in the serum chemistries. The serum amylase and
lipase in most instances are normal. A subgroup of patients has elevated
blood glucose levels.
b. Tumor markers. Various serologic tumor markers including tumor associated
antigens, enzymes, and hormones have been investigated for early detection of
pancreatic cancer. These are carcinoembryonic antigen (CEA), CA 19-9,
alpha-fetoprotein, pancreatic oncofetal antigens, pancreatic ribonuclease, and
galactosyl transferase isoenzyme II. The sensitivity and specificity of these
assays have not been adequate for early diagnosis of this disease.
The most extensively studied serum marker is CA 19-9, which is used
widely. It is not specific for pancreatic cancer, however, because it also can
be elevated in other gastrointestinal tumors such as those in the bile ducts
and colon. Because levels of CA 19-9 are frequently normal in the early
stages of pancreatic cancer, the test is not reliable for use in screening. The
presence of high levels may help differentiate between benign diseases of the
pancreas and pancreatic cancer. When the pancreatic cancer is completely
resected, the CA 19-9 levels fall, suggesting that it is a useful marker for
follow-up surveillance.
The ratio of testosterone to dihydrotestosterone is below 5 (normal is 10)
in more than 70% of men with pancreatic cancer, presumably because of
increased conversion of testosterone by the pancreatic tumor. This ratio may
be more sensitive than CA 19-9 in detecting smaller pancreatic cancers and
more specific than the other markers.
c. Ultrasound and computed tomography. Ultrasonography usually is the
first examination for suspected pancreatic cancer. Computed tomography
(CT) with intravenous (IV) contrast is used when satisfactory imaging is not
obtained with ultrasound (US). These two techniques are by far the most
sensitive and specific for pancreatic disease. They both demonstrate
enlargement of the gland, alteration in contour or consistency of the gland,
the presence of masses, and biliary or pancreatic duct dilatation. CT scans
may also delineate peripancreatic nodal enlargement as well as invasion of
other organs and vessels. Metastasis to the liver and porta hepatis may be
detected.
US and CT are complementary in imaging the pancreas. The lesions in
the head of the pancreas are seen well by US, whereas those in the body and
tail are detected better by CT scan. However, small lesions, especially in the
body or tail, may be missed by both techniques. Helical thin section CT scan
with IV contrast and CT angiography (CTA) increase the diagnostic yield.
d. Magnetic resonance imaging, contrast-enhanced magnetic resonance
imaging (MRI) using IV gadolinium–DPTA is useful for detecting small
pancreatic tumors. Ductal size is evaluated by magnetic resonance
cholangiopancreatography (MRCP). MR arteriography (MRA) has obvi-
ated the need for angiography and improves the examination of the pancreas
for tumor. Fat-saturation MRI is especially valuable in looking for suspected
tumors in a pancreas that is not enlarged.
e. Endoscopic retrograde cholangiopancreatography (ERCP). The diagno-
sis of pancreatic cancer by ERCP depends on radiographic demonstration of
pancreatic duct stenosis or obstruction caused by the tumor. An accompa-
nying cholangiogram may further delineate abnormalities along the course
of the common bile duct. It can also visualize and differentiate ampullary
and duodenal carcinomas. In experienced hands, it has greater than 90%
sensitivity and specificity in providing a definitive diagnosis of pancreatic
cancer.
In addition, biopsies of periampullary tissue and cytologic examina-
tion of aspirated pancreatic juice may increase the diagnostic yield further.
ERCP is usually performed if an abnormality is noted on the US or CT scan
or if an abnormality is suspected but cannot be demonstrated by these
methods.
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Chapter 47: Pancreatic Cancer 329

In addition to diagnosis, ERCP may be used to place stents in the

obstructed biliary and pancreatic ducts to relieve obstruction and palliate
patients with unresectable tumors.
f. Endoscopic ultrasonography (EUS). The pancreas may be visualized
clearly with this method from the lumina of the duodenum, antrum, and
gastric fundus to localize pancreatic cancers that are too small to be seen by
CT or transabdominal US. Associated lymph nodes and vascular involve-
ment are accurately demonstrated. The sensitivity of EUS compares favor-
ably with that of CT and angiography. Staging of pancreatic cancer with
EUS may become routine before selection of therapy. EUS guided fine-needle
aspiration allows cytologic evaluation.
g. Angiography. Celiac and superior mesenteric angiography with selective
cannulation of the pancreatic vessels may provide a sensitive diagnostic tool.
However, this invasive technique is best used to determine resectability of
the tumor before surgery. Arterial encasement, venous occlusion, and tumor
vascularity can be visualized, and angiography may save the patient an
unnecessary abdominal exploration. If a tumor is resectable, the arterial
blood supply and anatomic variations of the foregut vasculature can be
delineated by angiography to help in the planning of surgery.
h. Cytologic diagnosis. Direct percutaneous fine-needle aspiration can
be performed with US, CT, EUS, or angiographic guidance. The aspirated
material is used for cytologic examination. This technique may provide the
tissue diagnosis and allow differentiation of lymphoma or endocrine
tumors from adenocarcinoma without surgery; it is especially useful in
elderly patients in whom the morbidity and mortality of laparotomy are
high.
The drawbacks of this procedure are that a negative result cannot
exclude the presence of a malignant tumor, especially if the tumor is small,
and that tumor seeding may occur along the needle tract with possible peri-
toneal spread of the tumor.
i. Percutaneous transhepatic cholangiogram. In patients with obstructive
jaundice with dilated bile ducts, percutaneous transhepatic cholangiogram
(PTC) may visualize the common bile duct and the site of its obstruction.
A drainage catheter may then be introduced percutaneously for biliary
decompression.
j. Laparoscopy. The most common sites of distant metastasis from pancreatic
cancer are the liver, the peritoneum, and the omentum. These lesions, which
may be too small to be detected by CT, may be directly visualized by
laparoscopy. Because the presence of these metastases contraindicates
surgery, laparoscopy may help increase the accuracy of staging.
D. Treatment. To decide on the appropriate mode of treatment for pancreatic cancer,
a staging system has been devised.
Stage I: confined to pancreas alone.
Stage II: involving only neighboring structures.
Stage III: involving regional lymph nodes.
Stage IV: including liver and other distant spread.
Regardless of the mode of therapy chosen, all patients need to receive intensive
supportive and nutritional therapy, either enteral or parenteral, as indicated. The
importance of emotional support in this disease, both to the patients and their fami-
lies, cannot be overstated. Optimal therapy requires a multidisciplinary approach by
a team that includes a medical oncologist, an interventional radiologist, a gastroen-
terologist, a radiotherapist, an internist and a pain management specialist.
1. Surgery
a. Definitive surgery. In a large series of patients with pancreatic cancer, only
5% to 22% had a resectable tumor at the time of diagnosis. The standard
operation for pancreatic cancer is pancreaticoduodenectomy (the
Whipple’s operation) or a modification of this procedure. The Whipple’s
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330 Part V: Specific Complaints and Disorders

operation consists of en bloc removal of the duodenum, a variable portion of

the distal stomach, and the jejunum, gallbladder, common bile duct, and
regional lymph nodes, followed by pancreaticojejunostomy and gastroje-
junostomy. Vagotomy should be performed if more than 60% of the stomach
is removed. Total pancreatectomy does not offer better results; however, it
produces exocrine insufficiency and brittle diabetes, which is difficult to
manage. In the United States, a less extensive operation that preserves the
pylorus and avoids postgastrectomy symptoms is being used with no appar-
ent compromise of long-term survival. In most of these patients, the cancer
is at the head of the pancreas.
The 5-year survival of patients who undergo pancreatic resection is
17% to 24% in large centers. There may be a better prognosis for some sub-
groups of patients such as those with smaller tumors (
2 cm in diameter),
patients without lymph node metastases or major vessel involvement, and
those with no residual tumor. In such patients, the 5-year survival may be as
high as 57%. The mortality of pancreaticoduodenectomy is less than 5% in
many centers, and there are fewer complications than previously due to both
technologic and procedural advances.
b. Palliative surgery
i. Biliary obstruction. In patients with unresectable tumors of the head
of the pancreas with biliary obstruction, a bypass procedure may be
performed to decompress the biliary tract. The choice of operation
depends on the location of the obstruction: A cholecystojejunostomy,
choledochojejunostomy, or hepatojejunostomy may be done. Because
approximately one third of the patients with ductal adenocarcinoma of
the head of the pancreas eventually have duodenal obstruction, a gastro-
jejunostomy may be performed at the same time to spare the patient a
second laparotomy.
Mean postoperative mortality after biliary bypass is about 20%
with an average survival of 5.4 months. In debilitated patients, a percu-
taneous or endoscopically placed biliary stent may decompress the bil-
iary tract and reduce the morbidity and the length of hospitalization.
The success rate of stents is more than 85% with less than 1% to 2%
mortality. Patients treated with stents may have more frequent hospital
admissions for stent occlusion, recurrent jaundice, and infection.
However, the new, expandable metal stents seem to avoid these compli-
cations. Duodenal obstruction can be treated only by surgery.
ii. Cancer of the body or tail of the pancreas is invariably diagnosed at
a late stage. It is very important, however, to rule out endocrine cancer
in these instances by tissue diagnosis because endocrine tumors are much
more amenable to treatment and have a much better prognosis. See
Section IV.
iii. Abdominal and back pain. Most patients with pancreatic cancer com-
plain of debilitating abdominal or back pain. The injection of phenol
or absolute alcohol around the celiac plexus for the relief of pain is
helpful in some patients. This procedure can be done operatively dur-
ing laparotomy or percutaneously. Narcotics and radiotherapy may
also be used.
2. Chemotherapy. Most patients with stages I and II and some with stage III
disease who are reasonable surgical candidates should be treated surgically.
However, some patients with stages III and IV disease have been treated with
single- or multiple-agent chemotherapy with variable results. The drugs used
are 5-fluorouracil (5-FU), mitomycin, carmustine (BCNU), lomustine
(CCNU), methyl CCNU, streptozotocin, and Gematabine (Gemzar).
Response rates have been 20% to 40% in small series. Combination
chemotherapeutic regimens are also being tested. Additional controlled stud-
ies are needed in this area before chemotherapy can become an established
treatment of this disease.
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Chapter 47: Pancreatic Cancer 331

3. Radiation therapy alone has not been unequivocally successful in the treatment
of nonresectable localized cancer of the pancreas. However, the combination of
radiation therapy (4,000–6,000 rad) with chemotherapy (using 5-FU) has been
found to result in enhanced radiation therapeutic efficiency. In one study, the
survival was increased from 5.5 months to 11 months. Newer radiation tech-
niques using iodine 125 directly implanted into the tumor tissue and neutron
beam radiation show promise in the treatment of unresectable cancer of the
pancreas.
4. Intraoperative radiation therapy offers the possibility of delivering higher
doses of radiation to the pancreatic cancer with less risk of injury to the adjacent
organs. In most centers, a single dose of 20 Gy is delivered to the surgically
exposed cancer by an electron beam through a field-limiting cone. Median sur-
vivals of 13 to 16 months have been reported with excellent local control. Five
percent of patients have lived 3 to 8 years. Relief of pain has been achieved in
50% to 90% of these patients. Unfortunately, in 30% of these patients unavoid-
able irradiation of the duodenum may result in bleeding, obstruction, and per-
foration. In most patients, therefore, protective gastrojejunostomy is performed
at the same time as the intraoperative radiation.

II. AMPULLARY CARCINOMA. Ninety percent of ampullary or periampullary tumors

are adenocarcinomas of pancreatic ductal origin and arise as a periampullary mass
from the area of interface of the pancreaticobiliary ductal system, the ampulla of
Vater, the pancreas, and the duodenum. They are considered separately from pancre-
atic cancer because of better resectability and prognosis.
A. Clinical presentation. Most patients are elderly, in the sixth or seventh decade of
life, and present with anorexia, weight loss, malaise, abdominal pain, and pro-
gressive jaundice (obstructive.) Iron deficiency anemia and cholangitis may be
present. Recurrent acute pancreatitis of no identifiable etiology may be the presen-
tation in some patients.
B. Diagnosis of ampullary carcinoma is facilitated by UGI endoscopy and biopsy of
tumor for histologic examination and EUS. For staging of tumor depth of invasion
and presence of nodal spread, utilize IV contrast enhanced CT and MRI of the
abdomen, MRCP, and ECRP.
C. Treatment. Tumors confined to the ampulla that do not invade the muscularis
propria on EUS may be resected endoscopically or preferably by surgical approach.
Pancreaticoduodenectomy is the most effective and definitive treatment for peri-
ampullary carcinoma. Small tumors with metastases have a good prognosis.

III. Cystic tumors of the pancreas are a heterogeneous group of pancreatic neoplasms
that include mucinous cystic neoplasms (50%), serous cystoadenomas (30%), intra-
ductal papillary mucinous neoplasms (12%), papillary cystic tumors (3%), and other
tumors (5%).
A. Mucinous cystadenomas are cystic lesions more commonly seen in the body
and tail of the pancreas and occur more commonly in women. They are often
asymptomatic and may be found during an abdominal US or CT examination. If
there is a mass in the wall of the cystic lesion, CT or EUS guided fine-needle aspi-
ration may be necessary for a diagnosis of cystadenocarcinoma. The aspirated
fluid is usually viscous. Elevated levels of carcinoembryonic antigen (CEA) in the
cyst fluid indicate malignancy. Surgical resection is indicated for malignant
lesions.
B. Serous cystadenomas may occur in any part of the pancreas. They are well-
circumscribed, solitary, cystic lesions. On EUS or CT guided fine-needle aspira-
tion the fluid has low viscosity and low levels of amylase and CEA. Elevated CEA
indicates malignancy. In some cases, CT shows a cystic lesion, especially in the
head and neck of the pancreas, that has a honeycomb appearance with an area of
central fibrosis and calcification (stellate, or star shaped). Small serous cystade-
nomas may be monitored; larger ones and those which are malignant should be
resected.
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332 Part V: Specific Complaints and Disorders

C. Mucinous ductal ectasia or intraductal papillary mucinous neoplasm

(IPMN) or ductal ectasia or ductal ectatic mucinous cystadenoma is fre-
quently seen in the head of the pancreas. It often causes dilatation and filling of
the main pancreatic duct or its side branches with thick viscous mucus. When
the tumor is localized to a branch of the duct, then it may resemble a cluster of
grapes. On ERCP, the dramatic picture is of a patulous ampulla of Vater with
extruding mucus. Some patients are asymptomatic, but others may complain of
abdominal pain and others may have a long history of recurrent acute pan-
creatitis associated with steatorrhea and glucose intolerance. The appropriate
treatment is surgical resection to relieve symptoms and to prevent invasive
carcinoma.
D. Papillary cystic neoplasm (solid and cystic tumor) or solid and papillary
neoplasm of the pancreas is a rare tumor mostly seen in young women. Palpable
abdominal mass may be present. It may be asymptomatic or may cause abdominal
pain. In symptomatic cases surgery may be indicated.

IV. PANCREATIC ENDOCRINE TUMORS. Pancreatic endocrine tumors are relatively

rare. The incidence in the United States is less than 1 per 100,000 persons. These
tumors may arise sporadically in persons with multiple endocrine neoplasia type I
(MEN I). MEN I is an autosomal dominant syndrome associated with mutations in the
MEN I tumor suppressor gene. It is characterized by multiple neuroendocrine tumors
involving the parathyroid, pituitary gland, and pancreas, especially with gastrinomas
and insulinomas. In rare cases, pancreatic endocrine tumors may be associated with
Von Hippel–Lindau disease.
A. Clinical presentation. The clinical presentation of pancreatic endocrine tumors is
related to the symptoms of the specific hormonal hypersecretion. The best charac-
terization of these syndromes are those associated with insulinoma, glucagonoma,
gastrinoma, VIPoma, somatostatinoma and PPOma, the nonfunctioning pancre-
atic neuroendocrine tumors associated with high serum levels of pancreatic
polypeptide.
1. Insulinomas have an incidence of 1 to 4 cases per 1 million persons per year.
Ten percent of these patients also have MEN I. The predominant symptoms are
due to hypoglycemia (blood sugar levels
50 mg/dL) with inappropriately high
insulin levels. Patients may present with intermittent confusion, sweating,
nausea, vomiting, weakness, and even loss of consciousness. In most
cases, the tumors are diagnosed before they become 2.5 cm and before they
metastasize.
The diagnosis is confirmed by the detection of elevated fasting serum
insulin, C-peptide levels, and the tolbutamide test. Endoscopic ultrasound
(EUS) is the preferred imaging modality for the detection of the tumor.
Intraoperative ultrasound is used to locate the tumor.
The initial management is dietary modification and administration of dia-
zoxide. For isolated tumors, the tumors are enucleated surgically. In patients
with MEN I, a subtotal pancreatectomy may be undertaken due to the risk of
multiple tumors and a higher rate of recurrence.
2. Glucagonomas are among the rarest of the pancreatic endocrine tumors.
Eighty percent are sporadic and 20% are associated with MEN I. The age of
occurrence is the seventh decade of life. Glucagonomas may be associated with
diabetes mellitus. Most of the patients present with necrolytic migratory ery-
thema characterized by raised erythematous patches beginning in the perineum
and then involving the trunk and extremities. Plasma glucagon levels exceed
1,000 picograms per milliliter (pg/mL).
Tumors are usually visible on CT scan and most patients present with
metastases. Initial treatment involves use of somatostatin analogs. Those that
are refractory may be treated with intravenous infusion of amino acids. Surgery
may be curative with isolated tumors or palliative.
3. Gastrinomas and Zollinger—Ellison syndrome (ZES) is characterized by
elevated gastrin levels and gastric acid hypersecretion resulting in peptic
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Chapter 47: Pancreatic Cancer 333

ulcer disease (PUD), GERD, diarrhea, and abdominal pain. A positive secretin
test (see Chapter 24) may be necessary to confirm the diagnosis. The majority
of gastrinomas are found in the “gastrinoma triangle” which is an area
bounded by the cystic and the common bile ducts, the duodenum, the sur-
rounding lymph nodes, or in the pancreas. EUS and somatostatin scintigraphy
may help in the localization of the tumor(s) preoperatively; however, intraoper-
ative palpation and duodenectomy is usually necessary. Proton pump inhibitors
are highly effective in controlling the symptoms of associated gastric acid
hypersecretion.
4. VIPomas present with the Verner–Morrison syndrome or pancreatic cholera
characterized by profound diarrhea, hypokalemia, and achlorhydria. The
syndrome is due to the ectopic secretion of vasoactive intestinal peptide (VIP).
VIP causes enterocyte intercellular elevation of cyclic AMP, resulting in intesti-
nal smooth muscle relaxation, inhibition of electrolyte absorption, and pro-
found secretory diarrhea.
VIPomas often present in fifth decade of life. The diagnosis is based on the
presence of elevated serum VIP levels. Most tumors are visualized with CT scan
or MRI, EUS, or somatostatin scintigraphy. Surgical resection is used for local-
ized disease to reduce tumor burden in patients with metastases. Somatostatin
analogs are effective in suppressing VIP secretion and controlling the secretory
diarrhea.
5. Somatostatinomas and PPOmas may be associated with diabetes mellitus,
hypochloridemia, and diarrhea. PPOmas are associated with high serum levels
of PP. Although high levels of PP do not cause symptoms, the tumors cause
symptoms from tumor bulk. Most patients have metastatic disease at the time of
diagnosis; however, surgical resection is curative in patients in the early stage of
the disease.

Selected Readings
Alberts SR, et al. Treatment options for hepatobiliary and pancreatic cancer. Symposium
of solid tumors. Mayo Clin Proc. 2007;82(5)628–637.
Arvanitakis M, et al. Predictive factors for pancreatic cancer in patients with chronic
pancreatitis in association with K-RSA gene mutation. Endoscopy. 2004;36(6):
535–542.
Brugge WR, et al. Cystic neoplasms of the pancreas. N Engl J Med. 2004;351:1218–1226.
Brugge WR, et al. Diagnosis of pancreatic cystic neoplasms: A report of the cooperative
pancreatic cyst study. Gastroenterology. 2004;126:1330–1336.
Dewitt J, et al. Comparison of endoscopic ultrasound and computed tomography for the
preoperative evaluation of pancreatic cancer: a systematic review. Clin Gastroenterol
Hepatol. 2006;4:717–725.
Farnell MB, et al. Pancreas cancer working group. A prospective randomized trial
comparing standard pancreatoduoderectomy with extended lymph aderectomy in
resectable pancreatic head adenocarcinoma. Surgery. 2005;138:618–628.
Giovannini M, et al. Endoscopic ultrasound-guided cystogastrostomy. Endoscopy.
2003;35:239–245.
Handrich SJ, et al. The natural history of the incidentally discovered small simple
pancreatic cyst: Long-term follow-up and clinical implications. Am J Roentgenol.
2005;184:20–23.
Kalady MF, et al. Pancreatic duct strictures: Identifying risks of malignancy. Ann Surg
Oncol. 2004;11(6):555–557.
Kim JE, Lee KT, et al. Clinical usefulness of carbohydrate antigen 19-9 as a screening test
for pancreatic cancer in an asymptomatic population. J Gastroenterol Hepatol.
2004;19:182–186.
Li D, et al. Pancreatic cancer. Lancet. 2004;363:1049–1057.
Maire, F, et al. Differential diagnosis between chronic pancreatitis and pancreatic cancer:
Value of the detection of KRAS II mutations in circulating DNA. Br J Cancer. 2002;
87(5):551–554.
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334 Part V: Specific Complaints and Disorders

Maire F, et al. Intraductal papillary mucinous tumors of the pancreas: The perioperative
value of cytologic and histopathologic diagnosis. Gastrointest Endosc. 2003;58:
701–706.
Norton ID, et al. The role of transabdominal ultrasonography, helical computed
tomography and magnetic resonance cholangiopancreatography in diagnosis and
management of pancreatic disease. Curr Gastroenterol Rep. 2000;2:120.
Somagyi L, et al. Diagnosis and staging of islet tumors of the pancreas. Curr Gastroenterol
Rep. 2001;2:159.
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JAUNDICE AND INTERPRETATION 48

OF LABORATORY LIVER TESTS

L aboratory tests have an important role in the recognition of liver disease and deter-
mination of the nature and extent of the liver dysfunction. There is no one specific test for
assessment of liver disease. However, the combination of a number of tests that assess dif-
ferent parameters of liver physiology obtained serially over time and interpreted within the
clinical context may serve in establishing the diagnosis and prognosis and help in follow-
ing the course of the hepatic dysfunction. The most useful laboratory tests in liver disease
may be grouped into three categories. These are tests that reflect (a) liver cell injury and
necrosis, (b) synthetic function of the liver, and (c) cholestasis from intra- or extra-
hepatic biliary obstruction or infiltrative processes in the liver, or both.

I. SERUM ENZYMES AS MARKERS OF HEPATOCELLULAR INJURY AND NECROSIS

A. Serum transaminases. The transaminases, or aminotransferases, are a group of
enzymes that catalyze the transfer of an amino group from amino acid to ketoacid.
The two transaminases whose activities are measured most frequently in the assess-
ment of liver disease are serum glutamic-oxaloacetic transaminase (SGOT), or
aspartate aminotransferase (AST), and serum glutamic-pyruvic transami-
nase (SGPT), or alanine aminotransferase (ALT). Both ALT and AST require
pyridoxal-5
-phosphate as cofactor. They are found in the liver, skeletal, and car-
diac muscle, kidney, brain, pancreas, lung, leukocytes, and erythrocytes. High con-
centrations of ALT are found only in the liver.
Both of these enzymes are normally present in the serum. Normal values
are less than 40 U/L. When tissues rich in transaminases are damaged or
destroyed, the enzymes are released into the circulation. The increment in the
serum activities reflects the relative rates at which the enzymes enter and leave
the circulation.
Serum transaminases are sensitive indicators of liver cell damage. SGPT, or
ALT, is a cytosolic enzyme, whereas SGOT, or AST, is both cytosolic and microso-
mal. The serum activity of these enzymes is increased in any form of liver cell
injury, including viral-, drug-, or toxin-induced hepatitis; metastatic carcinoma;
heart failure; and granulomatous and alcoholic liver disease. Rebounds of
transaminase values or persistent elevations usually indicate recrudescences of
hepatic inflammation and necrosis. Therefore, their serial determination reflects
the clinical activity of the liver disease.
In the jaundiced patient, values greater than 300 to 400 U/L usually indicate
acute hepatocellular disease. Extrahepatic obstruction usually does not cause as
high a rise in serum transaminases. Values less than 300 U/L in a jaundiced patient
are nondiagnostic and can occur with acute and chronic hepatocellular diseases as
well as with obstructive jaundice. The largest elevation, in excess of 1,000 U/L, is
observed in viral hepatitis, in acute toxic or drug-induced liver injury, in prolonged
hypotension, and in acute common bile duct (CBD) obstruction.
The SGOT/SGPT ratio is most useful in detecting patients with alcohol-related
liver disease. In these individuals, the SGOT/SGPT ratio is usually greater than 2,
due to the decreased concentration of SGPT in the hepatocyte cytosol and serum of
alcoholic patients. Patients with alcoholic liver disease are deficient in pyridoxal-
5
-phosphate, a coenzyme necessary for the synthesis of aminotransferases in the
liver, particularly ALT.

335
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336 Part V: Specific Complaints and Disorders

The degree of elevation of the serum transaminase activity has a low prog-
nostic value. Rapid recovery may occur in cases of toxic hepatitis, in shock-related
liver cell injury, or with relief of acute CBD obstruction, even with values greater
than 3,000 U/L. In contrast, in most patients with cirrhosis and in those with ter-
minal liver failure, values may be near normal.
Transaminase elevations are not specific for liver disease; they may also be
elevated in patients with cardiac and skeletal muscle damage as well as after stren-
uous exercise such as jogging, running, and working out. The extent of enzyme
elevation with muscle disease is usually less than 300 U/L except in acute rhab-
domyolysis. However, with severe muscle injury, other enzymes such as aldolase
and creatine phosphokinase (CPK) are also elevated.
Uremia may depress aminotransferase levels. This effect is reversible after
dialysis, suggesting that a dialyzable inhibitor of the aminotransferase reaction is
in the serum of uremic patients.
Lactic dehydrogenase (LDH) is a cytoplasmic enzyme found in most normal
and malignant tissues. Of the five isoenzymes of LDH (1–5), the electrophoretically
slowest one (LDH-5) corresponds to the liver. LDH is much less sensitive than the
aminotransferases in measuring liver cell injury, even when isoenzyme analysis is
used. It is most sensitive in revealing myocardial infarction and hemolysis.

II. TESTS OF BIOSYNTHETIC FUNCTION

A. Serum proteins. The liver is the major source of most of the serum proteins.
Albumin, fibrinogens and other coagulation factors, plasminogen, transferrin,
ceruloplasmin, haptoglobin, and -globulins are all synthesized by the parenchy-
mal cells of the liver. -globulins, on the other hand, are not synthesized in the
liver but by lymphocytes and plasma cells.
Serum proteins are determined in the laboratory using several techniques.
The most useful ones are the fractional salting-out techniques and paper elec-
trophoresis. Salting-out methods, which are used in most chemistry profiles (e.g.,
SMA-12), separate and quantitate albumin and globulins, whereas electrophoretic
techniques separate and give values for albumin, 1-, 2-, -, and -globulins.
Higher values for albumin are usually obtained by the salting-out method.
Electrophoretic methods permit a more detailed fractionation of serum proteins by
their migration due to their net charge in an electric field (Fig. 48-1).
In most forms of liver disease, there is a decrease in the concentration of serum
albumin and other serum proteins synthesized in the liver and a rise in globulins.
The magnitude of the serum protein alterations depends on the severity, extent, and
duration of the liver disease. Albumin has a relatively long half-life (t1/2  17 
days). Thus its level may not change in acute disease. The rise in globulins, mainly

Figure 48-1. Electrophoretic pattern of

normal serum.
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Chapter 48: Jaundice and Interpretation of Laboratory Liver Tests 337

-globulins, in liver disease is due to a decrease in the antigen-filtering function of

the diseased liver. A serum albumin value of less than 3 g/dL (normal range,
3.5–5.0 g/dL) and serum globulins greater than 4 g/dL (normal range, 2.0–3.5 g/dL)
usually suggest chronic or progressive liver disease. Hypoalbuminemia and hyper-
globulinemia are characteristically noted in cirrhosis and tend to be more marked
than in acute hepatic diseases. A normal albumin level with a polyclonal hyper-
gammaglobulinemia may be seen in well-compensated cirrhosis.
Deficiency or absence of serum 1-globulins may be seen in patients with a form
of liver disease associated with the accumulation of 1-antitrypsin in hepatocytes.
Information obtained from protein fractionation suggests the extent of hepa-
tocellular damage and has prognostic significance. In a patient with cirrhosis, an
increase in the albumin value of 2 to 3 g/dL toward normal with treatment implies
an improvement in the hepatic function and a more favorable prognosis than if
there were no rise despite therapy.
Protein determination has limited clinical value for several reasons. It is not a
very sensitive indicator of liver disease; thus, it has limited value for differential
diagnosis, and abnormal values may be seen in other, nonhepatic disorders.
B. Prothrombin time (PT). The liver synthesizes all the clotting factors except factor
VIII. It is also involved in the clearance of the clotting factors and dissolution of
the formed clot. The serum activities of several clotting factors are useful indica-
tors of hepatic synthetic function.
The one-stage PT, which reflects the activities of prothrombin, fibrinogen,
and factors V, VII, and X, is dependent on both hepatic synthesis of these factors
and availability of vitamin K. Prolongation of PT (normal range, 11.5–12.5
seconds) by 2 seconds or more is considered abnormal.
A prolonged PT is not specific for liver disease. It may be present in congen-
ital deficiencies of coagulation factors, in states of consumption of coagulation fac-
tors, and with ingestion of drugs that affect the coagulation cascade. PT is also
prolonged in patients with hypovitaminosis K due to obstructive jaundice, steator-
rhea, prolonged dietary deficiency, or intake of antibiotics that alter the bowel
flora as well as due to poor utilization of vitamin K in parenchymal liver disease.
Parenteral injection of vitamin K (10 mg subcutaneously) normalizes the PT in
24 hours in most patients, except those with parenchymal liver disease.
Although PT is not a very sensitive index of liver disease, it has a high prog-
nostic value, especially in acute hepatocellular disease. Prolongation of PT more
than 5 to 6 seconds heralds the onset of fulminant hepatic necrosis. In alcoholic
liver disease as well as other chronic hepatocellular diseases, prolongation of PT by
more than 4 to 5 seconds that does not respond to parenteral vitamin K therapy
indicates poor long-term prognosis.

III. TESTS OF CHOLESTASIS

A. Enzymes
1. Serum alkaline phosphatase. Alkaline phosphatases are enzymes that cat-
alyze hydrolysis of organic phosphate esters at an alkaline pH. These enzymes
are found in many tissues. The serum enzyme is principally derived from three
sources: (a) the hepatobiliary system: the bile canalicular surface of the hepato-
cytes and biliary epithelium; (b) bone: the osteoblasts; and (c) the intestinal
tract: the brush border of the intestinal mucosal cells (10% of the total serum
enzyme). The enzyme has a half-life of about 7 days in the body.
The alkaline phosphatase activity in individuals 18 to 60 years of age is
higher in men than in women. After 60 years of age, the level increases in both
genders and may be higher in women than men. It is much higher in children
than in adults and corresponds to bone growth and osteoblastic activity. In
pregnancy, placental phosphatase may cause doubling of serum alkaline phos-
phatase, especially in the third trimester.
In a patient with elevated alkaline phosphatase, the hepatobiliary system,
bone, and occasionally the small intestine and kidney may be the source of the
increased enzyme activity. To determine the source of the elevated enzyme,
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338 Part V: Specific Complaints and Disorders

several approaches may be used. Polyacrylamide gel electrophoretic separation

of isoenzymes is the most accurate. The heat susceptibility of the enzyme from
different sources seems to be different. The heat stability at 56°C for 15 minutes
decreases in the following order: the placenta, liver, and bone. Unfortunately,
there is overlap, and results are difficult to interpret and not diagnostically useful.
The preferred approach to differentiate hepatobiliary enzyme from others
is to measure the serum activity of another, similar enzyme elevated in liver dys-
function, such as 5
-nucleotidase, -glutamyltanspeptidase, or leucine aminopep-
tidase. However, lack of elevation of these enzymes in the setting of elevated
alkaline phosphatase does not rule out liver disease because these enzymes do
not necessarily rise in parallel with alkaline phosphatase.
Hepatobiliary alkaline phosphatase synthesis and leakage into the circula-
tion seem to be mediated by bile acids. In intra- and extrahepatic biliary
obstruction, alkaline phosphatase is elevated before jaundice develops. Values
may be 3 to 10 times normal with a minimal rise in the transaminases. In
hepatocellular diseases that primarily affect the liver parenchyma (cirrhosis,
hepatitis), the alkaline phosphatase may not rise or may rise minimally with a
concomitant large rise in transaminases.
Serum alkaline phosphatase elevation (2–10 times normal) is also helpful
in the early diagnosis of infiltrative diseases of the liver, including granuloma-
tous involvement with tuberculosis, sarcoidosis, fungal infection, tumors (pri-
mary or metastatic), and abscesses.
In summary, the major value of the serum alkaline phosphatase measure-
ment is in differentiation of hepatocellular liver disease from obstructive liver
diseases such as bile duct obstruction with stones, tumors, strictures, or granu-
lomas within or outside the liver parenchyma (Table 48-1).
2. 5
-Nucleotidase. This enzyme is another phosphatase found in many tissues
but primarily located in the liver in the canaliculi and sinusoidal membranes.
Serum values are elevated (normal range, 0.3–3.2 Bodansky units) in hepato-
biliary diseases with a spectrum of abnormality similar to that found for alka-
line phosphatase. It is specific for the liver and is not influenced by gender or
race, but values increase with age, reaching a plateau after age 50. It does not
rise in bone disease or in pregnancy. Serum 5
-nucleotidase may be particularly
helpful in the diagnosis of liver disease in childhood and in pregnancy.
5
-Nucleotidase and alkaline phosphatase are both valuable in the diagno-
sis of biliary obstruction and hepatic infiltrative or space-occupying lesions. Even
though the correlation between the two enzymes is high, the values may not rise

TABLE 48-1 Causes of an Isolated Alkaline Phosphatase Elevation

Primary or metastatic tumor of liver or bone

Granulomatous liver disease
Hodgkin’s disease
Non-Hodgkin’s lymphoma
Inflammatory bowel disease
Primary biliary cirrhosis
Hepatic abscess and intraabdominal infections
Congestive heart failure
Hyperthyroidism
Diabetes
Any bone disease with rapid turnover
Partial extrahepatic bile duct obstruction
Sclerosing cholangitis
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Chapter 48: Jaundice and Interpretation of Laboratory Liver Tests 339

proportionately in individual patients, and rarely 5
-nucleotidase may be normal

in the presence of elevated hepatic alkaline phosphatase. Like alkaline phos-
phatase (AP), 5
-nucleotidase may be used to screen for liver metastases and to
follow their evolution. In screening for liver metastases, it seems to have a higher
predictive value and lower rate of false-positives than -glutamyl transpeptidase,
alkaline phosphatase, or a combination of the three.
3. Leucine aminopeptidase. This protease has been demonstrated in all human
tissues but especially in the liver in the biliary epithelium. It is not elevated in
bone disease, and the values are similar in both adults and children. In preg-
nancy, however, the values rise progressively, reaching a peak at term.
Serum leucine aminopeptidase is at least as sensitive as alkaline phos-
phatase and 5
-nucleotidase in the diagnosis of biliary obstructive, space-
occupying, and infiltrative diseases of the liver. There is controversy regarding
its specificity for these disorders versus hepatic parenchymal disease. However,
values greater than 450 U/L are rarely seen in patients with hepatocellular
disease such as cirrhosis or hepatitis.
4. -Glutamyl transpeptidase (GGT). This enzyme is particularly found in the
liver, pancreas, and kidney. Values are comparable in both genders after age 4.
Serum activity does not rise due to pregnancy or bone diseases.
Elevated values are found in diseases of the liver, biliary tract, and pan-
creas. The degree of elevation of serum GGT is comparable in various liver dis-
eases; thus, it has limited value in the differential diagnosis of jaundice. GGT
values are elevated in individuals who have alcoholic liver disease or who ingest
large quantities of alcohol and use barbiturates or phenytoin. A GGT/AP value
greater than 2.5 is highly suggestive of alcohol abuse. Its serum values are
diminished by female sex hormones, including those in birth control pills.
B. Serum bilirubin reflects the capacity of the liver to transport organic anions
and to metabolize drugs. The formation of bilirubin from heme is essential for
mammalian life because it provides the body with the main means of elimination
of heme. Eighty percent of the circulating bilirubin is derived from heme of hemo-
globin from senescent red blood cells destroyed in the reticuloendothelium of the
bone marrow, spleen, and liver. Ten percent to 20% of the bilirubin comes from
other sources such as myoglobin, cytochromes, and other heme-containing pro-
teins processed in the liver. Initially, heme is oxidized at the alpha position to the
green pigment biliverdin, which is then reduced at the gamma position to bilirubin.
Bilirubin is virtually insoluble in aqueous solutions. In blood, it is reversibly
but tightly bound to plasma albumin at a 1:1 ratio. Unbound bilirubin diffuses
into tissues and can cross the blood–brain barrier; it may cause kernicterus and
jaundice in infants. Sulfonamides, salicylates, free fatty acids, x-ray contrast media,
diuretics, hypoxia, and acidosis have the ability to displace bilirubin from its bind-
ing site on albumin.
1. Processing of serum bilirubin by the hepatocyte. Newly formed bilirubin is
removed from the circulation very rapidly by the liver. Normally, the plasma
bilirubin concentration is less than 1 mg /dL. The processing of the serum biliru-
bin load by the hepatocyte occurs in four steps. These are uptake, cytosolic
binding, conjugation, and secretion.
a. Uptake of bilirubin by the hepatocyte occurs with the dissociation of the
albumin–bilirubin complex facilitated by hepatocyte plasma membrane pro-
teins with subsequent translocation of bilirubin into the hepatocyte through
a saturable protein carrier, which also binds other organic anions but not
bile salts.
The hepatocellular uptake system operates well below saturation, and
uptake does not limit bilirubin excretion. Approximately 40% of the biliru-
bin taken up by the hepatocyte after a single pass refluxes unchanged back
to the plasma. This reflux may increase in hyperbilirubinemia.
b. Cytosolic binding. Once in the hepatocyte, bilirubin binds to two cytosolic
proteins: ligandin and Z protein. The binding limits the reflux of bilirubin back
to the plasma and delivers it to the endoplasmic reticulum for conjugation.
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340 Part V: Specific Complaints and Disorders

c. Conjugation of bilirubin involves its esterification with glucuronic acid to

form, first, a monoglucuronide, then a diglucuronide. The principal enzyme
involved is uridine diphosphate (UDP)–glucuronyl transferase. Administration
of microsomal enzyme inducers such as phenobarbital, glutethimide, and
clofibrate causes increased activity of this enzyme. Conjugation renders
bilirubin water-soluble and is essential for its elimination from the body in
bile and urine. Most of the conjugated bilirubin excreted into bile in humans
is diglucuronide with a lesser amount of monoglucuronide.
d. Secretion of conjugated bilirubin from the hepatocyte to the bile
canaliculi involves a specific carrier and occurs against a concentration gra-
dient. The carrier is shared by other anions, including anabolic steroids and
cholecystographic agents, but not bile acids. In fact, bile acids facilitate biliru-
bin secretion. Secretion is the rate-limiting step in the transfer of bilirubin
from plasma to bile.
Conjugated bilirubin is excreted in bile as a micellar complex with cho-
lesterol, phospholipids, and bile salts. Bacteria in the colon deconjugate and
convert it to a large number of urobilinogens. A minor portion of these pig-
ments is absorbed into plasma through the enterohepatic circulation and is
excreted in the urine; the rest is excreted in the stool.
2. Urinary bilirubin. Unconjugated bilirubin is not excreted by the kidney.
Conjugated bilirubin may be excreted in the urine in considerable amounts
when there is conjugated hyperbilirubinemia. Only the conjugated bilirubin
not bound to albumin can be filtered through the glomerulus and appear in
the urine. Compounds such as salicylates, sulfisoxazole, and bile salts that
displace bilirubin from its binding site on serum albumin augment its renal
excretion.
Detection of bilirubin in the urine implies the presence of hepatobiliary
disease. Absence of bilirubin in the urine of a jaundiced patient suggests uncon-
jugated hyperbilirubinemia.
3. Serum bilirubin
a. Measurement. Serum bilirubin is measured by van den Bergh’s diazo reac-
tion. Unconjugated bilirubin requires the presence of alcohol for the diazo
reaction and gives an indirect van den Bergh’s reaction. Conjugated bilirubin
reacts directly without alcohol. Total serum bilirubin is measured with the
diazo reaction carried out in alcohol, where both the conjugated and the
unconjugated bilirubin react with the reagent. The conjugated bilirubin is
then measured from the diazo reaction carried out without alcohol. The dif-
ference represents the concentration of the unconjugated bilirubin.
b. The serum concentration of bilirubin depends on a balance between the
rate of production and hepatic removal of bilirubin.
i. Increased bilirubin levels may result from overproduction of bilirubin;
impaired hepatic uptake, binding, conjugation, or secretion; and leakage
of the bilirubin from damaged cells or bile ducts. Hyperbilirubinemia
results in clinical jaundice at a serum bilirubin concentration greater than
2.0 to 2.5 mg/dL.
ii. Unconjugated hyperbilirubinemia results from overproduction or
defective hepatic uptake or conjugation, whereas conjugated hyper-
bilirubinemia results from decreased hepatic secretion (excretion) or
leakage of the conjugated bilirubin due to diffuse liver injury or impair-
ment of biliary flow at the canalicular or bile duct level.
Unconjugated hyperbilirubinemia is present when the total serum
bilirubin is greater than 1.2 mg /dL and the direct fraction is less than
20% of the total serum bilirubin. Causes of hyperbilirubinemia are sum-
marized in Table 48-2.

IV. UNCONJUGATED HYPERBILIRUBINEMIA

A. Hemolysis causes increased production of bilirubin. When the excretory capacity
of the liver is exceeded, serum levels of unconjugated bilirubin rise. Reduction of
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Chapter 48: Jaundice and Interpretation of Laboratory Liver Tests 341

TABLE 48-2 Causes of Hyperbilirubinemia

Unconjugated Conjugated

Increased bilirubin production Hereditary disorders

Hemolytic anemia Dubin-Johnson syndrome
Hemoglobinopathies Rotor syndrome
Enzyme deficiencies Hepatocellular disease
Autoimmune Viral hepatitis
Disseminated intravascular A; B; non-A, non-B; D; Epstein-Barr virus;
coagulation cytomegalovirus
Ineffective erythropoiesis Chronic hepatitis
Pernicious anemia Cirrhosis
Blood transfusions Drug-induced liver injury
Hematoma Alcohol-induced liver injury, fatty liver,
Hereditary disorders hepatitis, cirrhosis
Gilbert syndrome Infiltrative diseases
Crigler-Najjar syndromes type I, II Tumors (primary, metastatic), infections
Drugs (tuberculosis, parasites, abscess)
Drug-induced cholestasis
Recurrent jaundice of pregnancy
Extrahepatic cholestasis, cholecystitis,
choledocholithiasis, cysts, tumors,
pancreatic disease (cysts, carcinoma,
chronic pancreatitis)
Postoperative jaundice
Sepsis
Parenteral nutrition
Primary biliary cirrhosis
Sclerosing cholangitis

red cell survival to one-half normal does not cause elevation of serum bilirubin. A
sixfold increase in red cell destruction results in serum bilirubin elevation to less
than 5 mg/dL.
In hemolytic hyperbilirubinemia, there may be a concomitant increase in con-
jugated bilirubin levels. However, if conjugated bilirubin is in excess of 15% of the
total bilirubin level, hepatic dysfunction must also be present.
B. Ineffective erythropoiesis. Patients with hematologic disorders characterized by
abnormalities of heme biosynthesis have increased bilirubin turnover without
increased extramedullary red cell destruction. These disorders include iron-deficiency
anemia, pernicious anemia, thalassemia, sideroblastic anemia, lead poisoning, and
erythropoietic porphyria.

V. HEREDITARY UNCONJUGATED HYPERBILIRUBINEMIA. There is no definite evi-

dence that abnormalities of hepatic uptake or cytosolic binding of bilirubin result in
hyperbilirubinemia. However, deficiency of hepatic bilirubin UDP–glucuronyl trans-
ferase is known to result in unconjugated hyperbilirubinemia. The degree of enzyme
deficiency allows this disorder to be divided into three types: Gilbert syndrome and
Crigler–Najjar types I and II.
A. Gilbert syndrome. Gilbert syndrome may be the most common cause of mild
unconjugated hyperbilirubinemia. It is present in up to 5% to 7% of white adults
in the United States and Western Europe. These patients have a partial deficiency
in bilirubin glucuronyl transferase. Some patients also have decreased uptake of
bilirubin and organic anions and a mild compensated hemolytic state.
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342 Part V: Specific Complaints and Disorders

The syndrome is inherited as an autosomal dominant trait with incomplete

penetrance and is characterized by mild, persistent unconjugated hyperbilirubine-
mia. The disorder usually does not become obvious until the second decade and
often is diagnosed incidentally during a physical or laboratory examination. The
serum bilirubin range is 1.3 to 3.0 mg/dL, rarely exceeding 5 mg/dL. The hyper-
bilirubinemia fluctuates and increases with fasting, surgery, fever, infection, exces-
sive alcohol ingestion, and intravenous (IV) administration of glucose solutions.
The other liver enzymes and the histologic studies of the liver are normal. Bilirubin
monoglucuronide is the dominant pigment in the bile.
The diagnosis of Gilbert syndrome is made in patients with no systemic symp-
toms, no overt hemolysis, and normal liver serum tests and histologic studies.
Patients with this disorder when placed on a 300-kcal diet without lipids for 24 to
48 hours have an elevation of their serum bilirubin by 100% or by 1.5 mg/dL. Also,
administration of phenobarbital (180 mg/day in divided doses for 2 weeks) decreases
the serum bilirubin levels by enhancing the activity of the glucuronyl transferase.
B. Crigler-Najjar type I syndrome is an extremely rare disorder with an autosomal
recessive inheritance. It appears early in life with hyperbilirubinemia ranging from
24 to 45 mg/dL. In most infants, it is associated with kernicterus and cerebral dam-
age. These patients lack the hepatic bilirubin glucuronyl transferase, and adminis-
tration of microsomal enzyme inducers such as phenobarbital does not influence
bilirubin levels. The patients have normal liver histologic studies and a normal liver
enzyme profile but colorless bile. Phototherapy may transiently reduce the bilirubin
level, but most affected individuals die within the first year of life with kernicterus.
A few patients survive to the second decade, when encephalopathy develops.
C. Crigler-Najjar type II syndrome. Patients with this disorder have a partial defi-
ciency of the glucuronyl transferase. This disorder is inherited as an autosomal
dominant trait with incomplete penetrance. Serum unconjugated bilirubin levels
are in the range of 6 to 25 mg/dL. The bile is rich in monoconjugates. Jaundice
may not be apparent until adolescence, and neurologic complications are rare.
As in Gilbert syndrome, hyperbilirubinemia increases with fasting or removal
of lipid from the diet. Liver histology and serum liver enzymes are normal. These
patients also respond to treatment with phenobarbital, with the reduction of their
bilirubin to less than 5 mg/dL.
D. Acquired deficiency of glucuronyl transferase. Neonatal jaundice may be
aggravated or prolonged in infants treated with drugs such as chloramphenicol or
vitamin K, or exposed to pregnane 3--20-diol in breast milk due to inhibition of
transferase activity. Hypothyroidism delays normal maturation of this enzyme and
prolongs neonatal jaundice in these infants.

VI. CONJUGATED HYPERBILIRUBINEMIA. In jaundice from liver or biliary tract disease,

both conjugated and unconjugated bilirubin levels are elevated, and the urine contains
bilirubin. With bile duct obstruction, the level plateaus between 10 and 30 mg/dL.
Levels greater than 30 mg/dL are more likely in patients with hepatocellular disease.
Urinary excretion is the main means of obtaining bilirubin homeostasis in obstructive
jaundice. Intra- or extrahepatic causes of jaundice cannot be differentiated on the basis
of total serum bilirubin or the proportion of conjugated bilirubin. Fractionation of
plasma bilirubin helps to distinguish predominantly unconjugated from conjugated
hyperbilirubinemia. The most common causes of cholestasis are listed in Table 48-3.
A. Familial conjugated hyperbilirubinemia
1. Dubin-Johnson syndrome. This chronic intermittent form of jaundice is an
autosomal recessive disorder with elevation of both the conjugated and the
unconjugated serum bilirubin. Most patients are mildly jaundiced, but levels
may be as high as 30 mg /dL. Patients exhibit normal liver enzyme profiles;
however, histologically a yellow-black pigment is seen in the hepatocytes. This
melaninlike substance is found in the lysosomes. The liver may be slightly
enlarged and may be tender.
The principal defect in these patients is reduced ability to transport organic
anions except for bile salts from the liver cell into the bile. Pregnancy and oral
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Chapter 48: Jaundice and Interpretation of Laboratory Liver Tests 343

TABLE 48-3 Causes of Cholestasis

Extrahepatic Intrahepatic

Biliary Drugs
Gallstone Hormones
Stricture Pregnancy
Cyst Viral hepatitis
Diverticula Alcohol hepatitis
Carcinoma Hodgkin’s disease, lymphoma
Bile duct Sarcoidosis
Ampulla of Vater Primary biliary cirrhosis
Lymph node involvement Sclerosing cholangitis
Pancreas Sepsis
Carcinoma Parenteral nutrition
Pseudocyst Postoperative
Chronic pancreatitis Dubin-Johnson syndrome
Rotor syndrome

contraceptives, which reduce hepatic excretory function, may unmask Dubin-

Johnson syndrome by producing overt jaundice. These patients also have an
abnormality in coproporphyrin excretion. The urine shows greater copropor-
phyrin I than III levels, which is a reversal of the normal pattern.
2. Rotor’s syndrome. This benign disorder is inherited as an autosomal reces-
sive trait with defects in hepatic uptake and storage of conjugated bilirubin.
There may be an additional excretory defect or a decrease in the intrahepatic
binding of bilirubin, allowing conjugated bilirubin to reflux into the plasma.
The hyperbilirubinemia is usually less than 10 mg/dL. Other liver enzyme tests
and liver histology are normal. There is no pigment in the hepatocytes. The uri-
nary coproporphyrin levels are higher than normal, and coproporphyrin I may
be greater than III but not as great as in Dubin-Johnson syndrome. The pattern
of coproporphyrin excretion is similar to that seen in other hepatobiliary
disorders.
B. Recurrent jaundice of pregnancy. In a minority of pregnant women, usually
after the seventh week of gestation but most commonly in the third trimester, an
intrahepatic cholestasis occurs with jaundice and pruritus. The serum bilirubin
level remains less than 8 mg /dL but is accompanied by considerably elevated alka-
line phosphatase and cholesterol levels and mildly abnormal transaminases.
Histologically, there are varying amounts of intrahepatic cholestasis but minor
parenchymal cell changes.
These patients have an increased sensitivity to the cholestatic (antiexcretory)
effects of estrogenic and progestational hormones. The condition is benign and
needs to be differentiated from fatty liver of pregnancy, which can be fatal. Pruritus
responds to treatment with cholestyramine. The condition usually recurs with sub-
sequent pregnancies, but all of the abnormalities revert back to normal promptly
after delivery.
C. Drug-induced cholestasis
1. The use of oral contraceptives in some women may result in intrahepatic
cholestasis and jaundice due to the inhibitory effect of these drugs on hepato-
cellular biliary excretion. The liver function abnormalities resolve after the drug
is discontinued, and chronic liver dysfunction does not occur.
2. Male sex hormone analogs such as methyltestosterone may produce cholesta-
tic jaundice and may result in chronic liver disease and biliary cirrhosis.
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344 Part V: Specific Complaints and Disorders

3. Many drugs produce cholestasis and liver cell injury, which may be accompa-
nied by allergic manifestations such as fever, rash, arthralgia, and eosinophilia.
D. Postoperative jaundice. The cause of postoperative jaundice is multifactorial.
Most patients have bilirubin pigment overload from blood transfusion with
decreased red cell survival and resorption of blood from hematomas and large
ecchymoses. Concurrent use of drugs may cause hepatic dysfunction, injury, or
cholestasis. Hypotension, hypoxemia, sepsis, and shock contribute to impaired
hepatic function. Renal insufficiency may decrease urinary excretion of conjugated
bilirubin and enhance the degree of jaundice.
The hyperbilirubinemia may reach 30 to 40 mg/dL, with most of the bilirubin
being conjugated. Serum alkaline phosphatase level may be elevated up to 10-fold,
but the transaminases are usually only moderately elevated. Liver biopsy in most
instances shows intrahepatic cholestasis. The course of the jaundice depends on the
general condition of the patient. As the entire organ systems recover, the jaundice
subsides and liver function returns to normal.
E. Sepsis from any source in the body may result in conjugated hyperbilirubine-
mia and mild-to-moderate elevation of the transaminases and alkaline
phosphatases.
F. Hepatocellular disease. The most common disorders associated with jaundice
are hepatitis and cirrhosis. With injury to the hepatocytes, all the steps in bilirubin
metabolism are affected. Because secretion is the rate-limiting step, most of the
bilirubin is conjugated. The hyperbilirubinemia in hepatocellular disease usually
does not plateau and may exceed 60 mg/dL.
1. The major causes of intrahepatic cholestasis are
a. Alcohol-related liver disease.
b. Drugs (phenothiazines, sulfonylureas, allopurinol, azathioprine, thiazides,
acetaminophen, and aspirin).
c. Viral hepatitis (acute and chronic A, B, non-A, non-B, delta, Epstein-Barr
virus, cytomegalovirus, and others).
d. Toxic hepatitis.
e. Sepsis.
f. Infiltrative disorders (sarcoid, lymphoma, tuberculosis, primary or metastatic
malignancy, sickle cell disease).
2. Laboratory studies
a. In intrahepatic cholestasis, the laboratory tests reflect abnormal liver
function (Table 48-4).
b. In viral hepatitis, the transaminases may be elevated to 10 to 50 times nor-
mal (see Chapter 49).
c. In alcoholic liver disease, the alkaline phosphatase usually rises up to
about five times normal, SGOT (AST) is elevated less than 10 times normal,
and the SGPT (ALT) is lower than the SGOT (AST). The SGOT/ SGPT ratio
is usually 2:1 to 3:1 (see Chapter 51).
d. In drug-induced cholestasis, bilirubin may not be high, but there is
usually a dramatic rise in alkaline phosphatase with a slight rise in transam-
inases (see Chapter 53).
3. The course of the jaundice depends on the general condition of the patient.
As the entire organ systems recover, the jaundice subsides and liver function
returns to normal.
G. Extrahepatic cholestasis
1. Causes
a. Extrahepatic biliary obstruction due to stones, strictures, lymphadenopa-
thy, or tumors can occur anywhere along the route of the bile ducts from the
hilum of the liver to the duodenal papilla. Gallstone disease accounts for
most of the benign extrahepatic obstruction. Most of these patients have an
abrupt onset of jaundice. The disease ranges from biliary colic to acute chole-
cystitis and ascending cholangitis, especially with CBD stones.
b. Cancer. Pancreatic cancer, cholangiocarcinoma, adenocarcinoma of the
duodenum and ampulla of Vater, metastatic or primary liver tumors, and
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Chapter 48: Jaundice and Interpretation of Laboratory Liver Tests 345

TABLE 48-4 Patterns of Laboratory Studies in Cholestatic Disease States

Bilirubin Alkaline SGOT SGPT

Disease (mg/dL) phosphatase (AST) (ALT) Albumin

Alcoholic 0–20 5  nl 10  nl 2  nl nl or sl ↓
liver disease
Acute viral 0–20 nl–3  nl 10–50  nl 10–50  nl nl
hepatitis
Drug-induced 5–10 2–10  nl nl–5  nl 10–50  nl nl
intrahepatic
cholestasis
Common bile duct 0–10 nl–10  nl nl–10  nl nl–10  nl nl
obstruction
Malignant 5–20 2–10  nl nl nl nl
common bile
duct obstruction

SGOT, serum glutamic-oxaloacetic transaminase; AST, aspartate aminotransferase; SGPT, serum

glutamic-pyruvic transaminase; ALT, alanine aminotransferase; nl, normal; sl ↓, slightly depressed.

enlarged nodes at the porta hepatis are common causes of extrahepatic bil-
iary obstruction and jaundice.
2. Laboratory studies
a. In general, patients with gallstone disease have less hyperbilirubinemia
than those with intrahepatic cholestasis or extrahepatic malignant obstruc-
tion. The serum bilirubin is usually less than 20 mg/dL. The alkaline phos-
phatase may be elevated up to 10 times normal. The transaminases may
abruptly rise about 10 times normal and decrease rapidly once the obstruc-
tion is relieved.
b. In pancreatic cancer and other obstructive cancers, the serum bilirubin
may rise to 35 to 40 mg/dL, the alkaline phosphatase may rise up to 10
times normal, but the transaminases may remain normal. See Table 48.4 for
additional patterns of laboratory studies.

VII. DIAGNOSTIC STUDIES. The history, physical examination, and laboratory tests are
usually not sufficient to make the diagnosis of the underlying disorder causing the jaun-
dice. Additional diagnostic procedures are needed to arrive at a definitive diagnosis.
A. Noninvasive techniques
1. An abdominal flat plate (kidneys, ureters, bladder [KUB]) obtained in the
radiology department is the first test to be done on a patient with jaundice.
Aside from providing information on other organs in the abdomen, it may
show calcified gallstones, a “porcelain” gallbladder, air in the biliary tract, or
air in the gallbladder wall.
2. Ultrasonography. In most patients, the ultrasound should be the first proce-
dure performed. It identifies with 95% accuracy the presence of extrahepatic
bile duct obstruction, because the ducts proximal to the obstruction are usu-
ally dilated. It is a sensitive test for revealing stones in the gallbladder, but it
fails to show small stones or strictures in the bile ducts. CBD stones are visu-
alized reliably by ultrasound only in about one third of such patients.
Ultrasound may also demonstrate tumors, cysts, or abscesses in the pancreas,
liver, and other structures near the biliary tract. Ultrasound is limited in
patients who are obese, who have had a recent barium study, or who have a
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346 Part V: Specific Complaints and Disorders

large amount of bowel gas. Absence of ductal dilatation on ultrasound does

not exclude extrahepatic obstruction. Nondilated ducts caused by early, inter-
mittent, or incomplete biliary obstruction; tumor encasement; sclerosing
cholangitis; or the presence of cirrhosis of the liver may result in negative
ultrasound results. Duct diameters measured by ultrasound are normal in
25% to 40% of patients with documented CBD stones. The significance of
CBD dilatation in postcholecystectomy patients is controversial. If an abnor-
mality of the bile ducts is suspected in such patients, direct visualization tech-
niques (e.g., endoscopic retrograde cholangiopancreatography or percutaneous
transhepatic cholangiography) should be used to allow both strictured and
dilated areas to be evaluated.
3. Computed tomography (CT) of the abdomen provides excellent visualiza-
tion of the liver, gallbladder, pancreas, kidneys, and retroperitoneum. It can
differentiate between intra- and extrahepatic obstruction with 95% accuracy.
However, CT may not define incomplete obstruction caused by small gall-
stones, tumors, or strictures. CBD stones are seen in only 30% of patients.
4. Cholescintigraphy (dimethylphenylcarbamylmethyliminodiacetic acid
[HIDA] scan). When there is a suspicion of acute cholecystitis with cystic
duct obstruction and ascending cholangitis with CBD obstruction even in the
presence of a very elevated serum bilirubin level, the scintiscan may help pro-
vide the diagnosis. The nuclear scan is done following a single IV injection of
a technetium 99m derivative of iminodiacetic acid (IDA). If the scintiscan
demonstrates a patent CBD by the presence of the radionuclide within the
small bowel but no filling of the gallbladder or the cystic duct within 2 hours
after the injection of the tracer, acute cholecystitis or cystic duct obstruction
is diagnosed. However, if the radionuclide fills the biliary tract and does not
appear in the duodenum within 2 hours of injection, CBD obstruction is
inferred.
5. Radionuclide scanning. The visualization of the liver by the 99mT c-sulfur
colloid scan is dependent on the uptake of 99mTc-sulfur colloid by the Kupffer’s
cells of the liver. Space-occupying lesions, such as liver abscesses, cysts, and
primary and metastatic tumors, appear as filling defects, whereas chronic hepa-
tocellular disease (e.g., cirrhosis) with portal hypertension is associated with
patchy uptake of the radionuclide with increased uptake by the spleen and bone
marrow. This test is limited by its ineffectiveness in demonstrating small space-
occupying lesions (i.e., 2–3 cm). It is most helpful in estimating liver size and
in implicating the presence of cirrhosis in patients with normal or abnormal
liver chemistries.
6. The oral cholecystogram is an old test that may be useful in patients with low-
grade jaundice to demonstrate the presence of radiopaque or radiolucent stones
in the gallbladder as well as to help assess gallbladder function. However, non-
visualization of the gallbladder may be due to a bilirubin level of 3 mg/dL,
chronic liver disease, chronic gallbladder disease, the absence of a gallbladder, or
failure of the patient to ingest the contrast material, to absorb it, or to remain in
the fasting state.
7. The IV cholangiogram has been associated with a high frequency of allergic
reactions and failure to visualize the biliary tract if the bilirubin is 2 mg /dL. Its
use is not recommended.
8. Magnetic resonance cholangiopancreatography (MRCP) is a newer nonin-
vasive technique for visualization of the biliary and pancreatic ductal system. It
is especially useful in patients who have contraindications for endoscopic ret-
rograde cholangiopancreatography (ERCP). Excellent visualization of biliary
anatomy is possible without the invasiveness of ERCP.
B. Invasive techniques
1. Liver biopsy. Percutaneous liver biopsy is a safe, bedside procedure of low
cost. It is helpful in evaluating the following: hepatocellular injury of unknown
cause; hepatomegaly; fever of unknown origin; hepatic defects demonstrated by
ultrasound, CT, or radionuclide scanning; and chronic hepatitis. It is also used
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Chapter 48: Jaundice and Interpretation of Laboratory Liver Tests 347

for staging of malignant lymphoma and confirming the diagnosis and assessing
the severity of suspected alcoholic liver disease. A 2-cm piece of liver tissue is
needed to ensure accurate diagnosis; however, a sampling error can be expected
10% of the time despite an adequate amount of tissue. Liver biopsy may be
very helpful in evaluating the patient with cholestatic jaundice but only after
extrahepatic bile duct obstruction has been ruled out. Contraindications include
an uncooperative patient, hydatid cyst disease, suspected vascular lesion of
the liver, right-sided pleural effusion, infection of the biopsy site, and clinically
significant coagulopathy (i.e., PT 4 seconds prolonged and platelet count
75,000).
2. Laparoscopy (peritoneoscopy) can be performed with local anesthesia and
allows direct visualization of the liver. It may be helpful in the diagnosis of por-
tal hypertension, cirrhosis, and liver tumors in difficult cases and also allows for
visually directed liver biopsies.
3. Percutaneous transhepatic cholangiography (PTC) is performed in the radi-
ology department. Contrast material is injected directly under fluoroscopy into
the intrahepatic biliary tract through a 22- to 23-gauge, 15-cm-long Chiba or
skinny needle passed percutaneously from a right lateral intracostal approach.
It allows the visualization of the intrahepatic bile ducts. An adequate study
should be obtained in up to 75% of the patients with nondilated ducts and in
more than 90% of patients with dilated ducts as diagnosed by a previous ultra-
sound or CT scan. The complication rate ranges from 1% to 10%.
The patients must be cooperative and have good bleeding parameters with
a PT within 3 seconds of control and a platelet count greater than 50,000.
Prophylactic antibiotics should be used in patients with suspected obstruction
and infection. After the procedure, patients must be monitored for possible
bleeding or leakage of bile into the peritoneum.
This procedure may be used therapeutically to decompress the biliary tract
nonsurgically with the placement of a stent through an area of obstruction from
malignancy or benign stricture of the bile duct. The drainage may be external
or internal into the small bowel. The success rate is variable, and the procedure
should be considered palliative for poor-risk patients or those with nonre-
sectable masses.
4. Endoscopic retrograde cholangiopancreatography (ERCP) is the procedure
of choice when obstruction of the pancreatic or distal CBD is suspected by
ultrasound or CT scan. The duodenal lumen and papilla are visualized, and
contrast material is injected into the pancreatic and bile ducts under fluoro-
scopic guidance. The technique is successful greater than 90% of the time
whether the ducts are dilated or not. Visualization of the pancreatic duct may
reveal chronic pancreatitis, pseudocyst, or tumor causing the obstruction;
stones, strictures, and tumors causing obstruction of the bile ducts also may be
delineated.
ERCP allows for biopsies of the periampullary duodenum and the
papilla for tissue diagnosis. It may also be used as a therapeutic procedure in
patients with recurrent or retained CBD stones. A sphincterotomy can be
performed by cautery with incision of the papilla, relieving the obstruction
and allowing the gallstones to pass into the duodenum. Retrieval of gall-
stones may also be accomplished with intraductal balloon or baskets or after
intraductal crushing using special catheters. Nasobiliary stents may be placed
in the CBD to allow drainage, and permanent biliary stents may be placed in
the obstructed ducts as palliation in instances of inoperable carcinomatous
obstruction.
5. Angiography. Visualization of the hepatic arterial and venous circulation is
helpful in evaluating portal hypertension and determining the vascular supply,
vascularity, and surgical resectability of a mass lesion in the liver.

VIII. SUMMARY. The algorithm shown in Figure 48-2 summarizes the diagnostic workup
for the evaluation of jaundice.
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348 Part V: Specific Complaints and Disorders

Figure 48-2. Interpretation of laboratory liver tests in patients with jaundice. (R/o, rule out or
exclude.)

Selected Readings
Balisteri WF, et al. Intrahepatic cholestosis: summary of an American Association for the
study of liver diseases single topic conference. Hepatol. 2005;42:222–235.
Heathcote EJ. Diagnosis and management of cholestatic liver disease. Clin Gastroenterol
Hepatol. 2007;5(7):776–782.
Mendes FD, et al. Abnormal hepatic biochemistries in patients with inflammatory bowel
disease. Am J Gastroenterol. 2007;102(2):344–350.
Pratt DS, et al. Evaluation of abnormal liver enzyme results in asymptomatic patients.
N Engl J Med. 2000;342:1266.
Sorbi D, et al. An assessment of the role of liver biopsies in asymptomatic patients with
chronic liver test abnormalities. Hepatology. 1999;30(suppl):487A.
Vuppalanchi R, et al. Etiology of new-onset jaundice: How often is it caused by
idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol. 2007
Mar;102:558–562.
Wong K, et al. The diversity of liver diseases associated with an elevated serum ferritin.
Can J Gastro. 2007;20:467–470.
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GALLSTONES 49

I. ANATOMY AND PHYSIOLOGY

A. The biliary tract starts at the hepatocyte canaliculi, which empty into biliary
ductules. Larger ducts join the right and left hepatic ducts, which drain into the
common hepatic duct (CHD) at the porta hepatis. When the cystic duct from the
gallbladder joins the CHD, the common bile duct (CBD) is formed. The CBD is
usually 8 cm long and 0.5 to 0.9 cm in diameter. It passes behind the first portion
of the duodenum, through a groove in the head of the pancreas, and empties into
the second portion of the duodenum at the ampulla of Vater. Distally the pancre-
atic duct may join the CBD before it also empties into the ampulla.
B. The gallbladder, a pear-shaped distensible organ, 4
8 cm in size with a normal
capacity of 30 to 50 mL, lies in a fossa on the visceral surface of the liver on a line
separating the right and left hepatic lobes. When distended with acute inflamma-
tion, the fundus comes in close contact with the anterior abdominal wall in the
right upper quadrant near the ninth and tenth costal cartilages, giving rise to the
Murphy’s sign. Posteriorly, it abuts the first and second portion of the duodenum
and the hepatic flexure of the colon. Thus, extension of the inflammation of the
gallbladder may lead to spontaneous fistulas into these hollow organs.
C. Bile flow. Bile, formed by the hepatocytes (600 mL per day), consists of water,
electrolytes, bile salts, cholesterol, phospholipids, bilirubin, and other organic
solutes. The gallbladder stores and concentrates bile during fasting. Approximately
90% of the water and the electrolytes are resorbed by the gallbladder epithelium,
resulting in bile rich in organic constituents. The stratification of this bile into a
density gradient is thought to play a role in gallstone formation.

II. Gallstone disease is a major health problem in the United States. It affects approxi-
mately 20% of adult Americans. Gallstones are formed by the precipitation of insol-
uble bile constituents: cholesterol, polymerized bilirubin, bile pigments, calcium salts,
and proteins. Gallstones are classified into cholesterol, black pigment, and brown pig-
ment stones. Cholesterol stones are most frequent in industrialized societies. Black
pigment stones occur in patients with chronic hemolytic disorders, and brown pig-
ment stones are associated with impaction in the biliary tract. These stones are more
prevalent than cholesterol stones in the Far East. Cholesterol stones may be pure,
large (2.5 cm), solitary or mixed (70% cholesterol), multiple, smooth, and faceted.
Black and brown stones contain less than 25% cholesterol and are multiple and irreg-
ular. They contain polymerized bilirubin and calcium salts (bilirubinate, phosphate,
and fatty acids). All types of gallstones may become calcified. The calcification is usu-
ally central in pigment stones and peripheral in cholesterol stones.
A. Pigment stones (black and brown)
1. Epidemiology. Clinically, black pigment stones are more prevalent in three
major settings: hemolytic states, cirrhosis, and the elderly. In the United States,
approximately 30% of gallstones are pigment (mostly black) stones. The inci-
dence is age-dependent: Pigment stones are more common in the sixth and sev-
enth decades. In Asia, biliary tract parasitism with Clonorchis sinensis and
Ascaris lumbricoides, biliary ductal stasis, and chronic or repeated spasm at the
sphincter of Oddi as a result of widespread use of opium may contribute to the
increased prevalence (approximately 70%) of brown pigment cholelithiasis.

349
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350 Part V: Specific Complaints and Disorders

2. The pathogenesis of black pigment stone formation is not clear; however,

there seems to be an increased concentration of the insoluble, unconjugated
bilirubin and poorly soluble bilirubin monoglucuronide in the bile of these
patients. Abnormal motor function of the gallbladder and reduced bile salt con-
centration may also contribute to the pathogenesis. Infections with organisms
such as Escherichia coli reduce biliary pH and deconjugate bilirubin glu-
curonide, which may create a nidus for gallstone formation.
B. Cholesterol gallstones
1. Risk factors
a. Heredity. The prevalence of cholesterol gallstones varies in different popu-
lations. There is a strong correlation between the percentage of cholesterol
saturation of gallbladder bile and gallstone formation, as in Pima Indian
women in whom the prevalence reaches 80%. Thus hereditary mechanisms
are important.
b. Age. Gallstones may be found at all ages, but the incidence increases
with age.
c. Gender. Women, starting at puberty, have a two to three times greater risk
of developing gallstones compared to men.
d. Pregnancy. Supersaturation of bile with impaired gallbladder emptying
during pregnancy due to an increase of estriol, progesterone, and other sex
hormone levels increases the incidence of cholelithiasis.
e. Use of exogenous estrogens. There is increased cholelithiasis among
users of exogenous estrogens and progesterone, as in birth control pills and
in postmenopausal estrogen replacement. The condition could be secondary
to gallbladder stasis induced by these hormones and to reduced bile flow
and altered lipid composition of bile.
f. Diabetes. The increased prevalence of cholelithiasis in diabetes is largely
due to obesity and increased biliary cholesterol secretion.
g. Obesity. The bile of obese people is more lithogenic due to excessive cho-
lesterol secretion caused by increased cholesterol synthesis.
h. Rapid weight loss. Regardless of the method of weight loss, up to 25% of
patients who lose weight rapidly will develop symptomatic gallstones. With
weight loss, cholesterol is mobilized from peripheral adipose tissue and
secretes into bile leading to cholesterol supersaturation. Also, the stimulus
for gallbladder contraction from dietary fat is diminished leading to gall-
bladder stasis. Weight fluctuation is also a risk factor for gallstones.
i. Hyperlipidemia. Patients with type I and IV hyperlipidemia have a high
risk of cholesterol gallstone formation.
j. Cystic fibrosis and pancreatic insufficiency. Malabsorption of bile salts
decreases the bile salt pool and increases the lithogenicity of bile, leading to
cholelithiasis.
k. Ileal disease, bypass, or resection. Extensive disease of the distal small
intestine as in Crohn’s disease, or surgical resection of the distal ileum
impairs bile salt resorption and predisposes to gallstone formation due to
decreased bile acid pool.
l. Drugs. Clofibrate used in the treatment of hyperlipidemia decreases serum
cholesterol by inhibiting cholesterol synthesis. This stimulates tissue mobiliza-
tion and increases cholesterol secretion into bile. Bile becomes more lithogenic,
leading to cholelithiasis. The somatostatin analog octreotide predisposes to
gallstone formation by inducing gallbladder stasis.
m. Diet. A high-calorie diet, refined carbohydrates, and diets high in polyun-
saturated fatty acids predispose to cholelithiasis. Increased dietary fiber
seems to decrease the risk of cholelithiasis. Weight-reduction diets with
severe caloric restriction leading to rapid weight loss also may result in
cholelithiasis.
n. Genetic factors. The prevalence of gallstones is highest in the American
Indian tribes, especially the Pima Indians of Arizona. By the age of 30, 80%
of Pima women have gallstones. There is also a high prevalence of gallstones
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Chapter 49: Gallstones 351

in Chile. In addition to genetic factors, it is thought that this high preva-

lence in Chile is due partly to the high intake of beans, which adversely
affects biliary cholesterol saturation. Gallstones are more common in first-
degree relatives of patients with gallstones than in the general population.
o. Spinal injury, especially high spinal section, is associated with a high inci-
dence of gallstones, probably secondary to gallbladder stasis.
p. Total parenteral nutrition promotes gallbladder stasis and the formation
of sludge and gallstones with prolonged use.
q. Truncal vagotomy may be a risk factor for cholelithiasis secondary to
decreased gallbladder motility.
2. Cholesterol gallstone formation. The first step in the formation of gallstones
is the secretion by the liver of bile supersaturated with cholesterol. Cholesterol
in dilute hepatic bile is transported in spherical vesicles of phospholipid and
cholesterol into the biliary tract and the gallbladder. Hepatic bile is concen-
trated in the gallbladder.
The second step in gallstone formation is crystallization. The precipitation
of cholesterol crystals initiates the formation of gallstones. When the gallbladder
bile becomes abnormally supersaturated with cholesterol, nucleation, floccula-
tion, and precipitation of cholesterol crystals occur, leading to the initiation of
gallstone formation. The excessive presence of promoters of crystallization and
relative deficiency of inhibitors of crystallization are also thought to be impor-
tant in the initiation of nucleation and crystal formation. The promoters and
inhibitors are most likely proteins such as mucous glycoprotein. The growth of
the crystals to macroscopic stones is further facilitated by the gallbladder mucus.
Patients who have cholesterol gallstones may have defects leading to the
production of abnormally supersaturated bile due to an absolute increase in the
secretory rate of biliary cholesterol or an absolute decrease in the secretory rate
of biliary bile salts, lecithin, and phospholipids. Changes in the concentration
of one of the key promoters of crystallization, mucous glycoprotein, are medi-
ated by mucosal prostaglandins (PGs). Aspirin and nonsteroidal antiinflamma-
tory drugs (NSAIDs), by decreasing PG synthesis, also prevent microcrystal and
gallstone formation, especially in obese people undergoing weight reduction
through dieting.
Gallbladder motor dysfunction and stasis also contribute to gallstone for-
mation and may be a primary phenomenon.
3. Clinical presentation. Long-term studies have shown that at least one half of
the individuals with gallstones remain asymptomatic, one third experience
severe symptoms, and one fifth experience serious complications.
a. The complications of cholelithiasis include the following:
i. Cystic duct obstruction, leading to
a) Colic.
b) Acute cholecystitis.
c) Cholangitis, sepsis.
d) Perforation, peritonitis.
e) Fistulization, gallstone ileus.
ii. Choledocholithiasis, which may cause
a) Obstructive jaundice.
b) Cholangitis, sepsis.
c) Acute pancreatitis.
d) Stricture formation.
iii. There is some evidence to suggest that gallstones and chronic cholecys-
titis also may predispose to carcinoma of the gallbladder.
b. Biliary colic. Dyspeptic symptoms such as heartburn, fat intolerance, and
increased “gas” (bloating, flatulence, and belching) are not symptoms spe-
cific to gallbladder disease. Biliary colic is pain arising from a distended gall-
bladder due to obstruction of the cystic duct with a gallstone. Commonly,
the “attacks” follow heavy meals. The pain is felt mostly in the right upper
quadrant and may radiate to the epigastrium, back, or shoulder. It may be
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352 Part V: Specific Complaints and Disorders

mild or severe, lasts 1 to 6 hours, and usually is accompanied by nausea and

vomiting. At times, when the cystic duct obstruction is transient, biliary
colic is relieved spontaneously. However, prolonged cystic duct obstruction
with a gallstone usually results in acute cholecystitis, cholangitis, and their
complications.
c. Prognosis. Both complications and mortality from gallstones increase with
age and with passage of time. The first attack may be severe, especially in
the elderly and patients with other serious illness. Because the mortality for
these patients from complications of gallstones may be as high as 15% to
20%, elective surgery should be considered when asymptomatic gallstones
are found. Surgery is also recommended for patients with symptoms or com-
plications of cholelithiasis.
4. Differential diagnosis. Other causes of severe upper abdominal pain need to
be considered in the differential diagnosis of biliary colic. These causes include
acute myocardial infarction, ruptured aortic aneurysm, perforated peptic ulcer,
pneumonia, pneumothorax, pleurisy, intestinal obstruction, intestinal ischemia,
pancreatitis, and renal colic.
5. Diagnostic studies. The demonstration of gallstones by ultrasound is currently
the best diagnostic test, having the highest sensitivity (90%–95%) and specificity
(98%). An oral cholecystogram may also demonstrate gallstones as well as gall-
bladder contractile function after ingestion of fat; however, this test is not as sen-
sitive as ultrasound. Computed tomography (CT) scan of the gallbladder is much
more sensitive than conventional radiography in detecting gallstone calcium.
However, ultrasound is more sensitive than CT in detecting gallbladder sludge
and stones.
Endoscopic retrograde cholangiopancreatography (ERCP) is useful in
identifying CBD stones. It is not specific for the diagnosis of gallbladder stones.
Magnetic resonance cholangiopancreatography (MRCP) is a nonin-
vasive method to screen for CBD stones as well as for strictures and cystic
anomalies of the CBD and bile duct dilatation. The reported sensitivity is 70%
to 100% and specificity is 80% to 100%.
6. Management of symptomatic but uncomplicated gallstone disease
a. Pain relief. The immediate treatment of biliary colic is symptomatic. Pain
relief is usually achieved with narcotic analgesics, excluding morphine, and
antiemetics.
b. Laparoscopic cholecystectomy is the recommended treatment for long-
term management. If choledocholithiasis is suspected, preoperative ERCP
with sphincterotomy or intraoperative cholangiography may be necessary.
Open cholecystectomy is reserved for patients who have contraindications
to the laparoscopic procedure. In the average patient, the mortality of elec-
tive cholecystectomy is less than 1%. The risk increases in patients with dia-
betes, renal insufficiency, cardiovascular disease, respiratory disease, and
cirrhosis of the liver.
c. Extracorporeal shock-wave lithotripsy (ESWL) is not currently used in
the United States for uncomplicated gallbladder stones. In centers where
ESWL is available, it may be used for problematic CBD stones not cleared by
ERCP. ESWL in combination with oral bile acid therapy has been used for
patients who are not surgical candidates and who have single or small cho-
lesterol gallstones and a functioning gallbladder. Gallstones are localized by
three-dimensional ultrasound, then extracorporeal shock waves are focused
and fired on the gallstones and fragmentation is achieved. Up to three ses-
sions may be needed to achieve fragmentation of the gallstones into pieces
smaller than 3 mm. It is expected that these fragments pass spontaneously
into the duodenum or dissolve by oral bile acids. Oral bile acid therapy may
need to be continued for several months. Approximately 20% of patients
develop biliary colic and 25% subsequently undergo cholecystectomy. Other
side effects include pancreatitis (1%), local pain, petechia and bruising, and
microscopic hematuria.
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Chapter 49: Gallstones 353

d. Gallstone dissolution with oral bile acid therapy is based on the theory
that cholesterol stones should dissolve in bile rendered unsaturated with
respect to cholesterol by increasing the concentration of bile salts. Gallstone
clearance may not depend completely on stone dissolution. Cholesterol-rich
stones can disintegrate as they dissolve, and the resultant fragments might
pass out of the gallbladder in the bile via the cystic duct and into the CBD
and duodenum.
The first bile acid used orally was chenodeoxycholic acid (CDCA).
CDCA decreases the cholesterol saturation of bile by lowering cholesterol
secretion, thus bringing about a gradual dissolution of cholesterol stones. In
a controlled trial using 12 to 15 mg/kg per day (approximately 1 g daily),
the stones dissolved in 40% to 60% of the selected patients during 2 years
of continuous therapy.
i. Contraindications. Dissolution therapy is contraindicated in the presence
of any of the following:
a) Pigment stones
b) Calcified stones
c) Stones larger than 1.5 to 2.0 cm
d) Multiple stones
e) Nonopacifying gallbladder on oral cholecystogram
f) Obesity
g) Pregnancy or women who may become pregnant
h) Concomitant liver disease
i) Severe symptoms
j) Nonresponders by oral cystography after 9 months of therapy
k) Poor patient compliance
7. Side effects. The most common side effect is secretory diarrhea induced by
the bile acid in the colon. Occasionally, gallstones become small enough during
therapy to pass into and obstruct the cystic or CBD, resulting in inflammation.
Minor liver enzyme elevations may occur in 7% of the patients without any
significant structural changes in liver histology. There may be a modest rise in
plasma and low-density lipoprotein (LDL) cholesterol.
8. Maintenance of therapy. CDCA therapy needs to be maintained indefinitely
in all patients because the bile reverts to its previous supersaturated state in
1 to 3 weeks after cessation of the therapy, and stones recur within 6 to
48 months.
9. Ursodeoxycholic acid (UDCA) is more potent than CDCA in lowering biliary
cholesterol secretion and saturation. It also has fewer side effects. It does not
affect the serum LDL levels or liver chemistry tests. A UDCA dosage of
10 mg/kg per day is optimal and equivalent to a CDCA dosage of 15 mg /kg per
day. In some patients, stone rim calcifications may occur and limit dissolution.
10. The combination of UDCA and CDCA is at least as effective and free of side
effects as monotherapy with UDCA and is less expensive. The dosage of
CDCA is reduced to 7.5 mg / kg per day, and UDCA is used at a dosage of
5 mg /kg per day.

III. CHOLECYSTITIS
A. Acute calculous cholecystitis. Inflammation of the gallbladder is associated with
gallstones in more than 90% of cases. It is a common problem, presenting as an
acute abdomen, especially in middle-aged women. Acute calculous cholecystitis is
caused by obstruction of the cystic duct either by an impacted stone or by the edema
and inflammation caused by the passage of a stone to the CBD and duodenum. The
obstructed gallbladder becomes distended, and the walls become edematous,
ischemic, and inflamed. Secondary infection with enteric organisms complicates the
inflammation and may lead to cholangitis and sepsis.
1. Diagnosis
a. Clinical presentation. The pain of acute cholecystitis usually starts in the
right upper quadrant or epigastrium as a colicky pain followed by local signs
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354 Part V: Specific Complaints and Disorders

and symptoms of inflammation. It may radiate to the flanks, intrascapular

regions, and right shoulder. Nausea and vomiting are also common. Physical
examination reveals a tender right upper quadrant, especially at the tip of
the ninth costal cartilage during inspiration (Murphy’s sign). The gallbladder
may be palpable. Abdominal rigidity represents peritoneal inflammation.
Fever, tachycardia, and tachypnea are common. Jaundice suggests obstruc-
tion of the CBD and may be present in one third of the patients.
b. The differential diagnosis includes acute appendicitis, pancreatitis, hepatitis,
pneumonia, pyelonephritis, perforated peptic ulcer, and myocardial infarction.
c. Diagnostic studies
i. Laboratory studies. Leukocytosis of 10,000 to 15,000/L with a shift
to the left usually accompanies acute cholecystitis. Elevation of the serum
amylase is not uncommon without the presence of concomitant pancre-
atitis. Elevation of alkaline phosphatase and bilirubin levels usually sug-
gests obstruction of the CBD due to either an impacted stone or edema
and inflammation as a result of the passage of a stone. Alanine amino-
transferase (ALT) and aspartate aminotransferase (AST) elevations sug-
gest concomitant parenchymal cholangitis.
ii. Ultrasonography is the test of choice in demonstrating gallstones, thick-
ening of the gallbladder wall, and pericystic fluid. If the CBD is
obstructed, dilatation of the biliary tract may be present.
iii. Biliary scintigraphy (i.e., dimethylphenylcarbamylmethyliminodi-
acetic acid [HIDA] or PIPIDA scan) uses technetium 99m–labeled deriv-
atives of iminodiacetic acid excreted in the bile. In healthy individuals,
scans obtained 15 to 30 minutes after intravenous (IV) injection demon-
strate the filling of the bile ducts and the gallbladder and passage of the
radionuclide to the CBD and small intestine. In acute cholecystitis due to
an obstructed cystic duct, the gallbladder does not fill. Parenchymal liver
disease and high bile duct obstruction may lead to failure of imaging of
the extrahepatic biliary tract. False-positive scans may occur in chronic
cholecystitis, and false-negative scans have been reported in acalculous
cholecystitis. In general, the sensitivity of this test is very high.
2. Treatment
a. The patient should be admitted to the hospital. Oral intake should be
stopped and, in those with severe nausea and vomiting, a nasogastric sump
tube should be inserted to aspirate gastric contents with low suction.
IV fluid and electrolytes should be provided. Antibiotic therapy to cover enteric
organism may be used if secondary infection is suspected after appropriate
cultures are obtained.
b. Cholecystectomy is the definitive treatment for acute cholecystitis. Most
patients can be treated with laparoscopic cholecystectomy. Extensive previ-
ous laparotomy with scarring may render laparoscopy impossible in some
cases. Controversy as to the timing of the surgery still exists for uncompli-
cated cases; however, most surgeons prefer early intervention, within
5 days of onset of symptoms, rather than waiting 6 to 8 weeks. In elderly
patients with other systemic diseases, such as congestive heart failure,
the operation may need to be delayed. Preoperative ERCP may be per-
formed in selected patients if CBD stones are suspected. Sphincterotomy
and stone extraction eliminate the need for operative CBD exploration.
Cholecystectomy should be performed acutely in cases of emphysematous
cholecystitis in which the gallbladder walls and bile ducts contain gas. The
infective organisms are the gas-forming bacteria, such as Clostridium,
E. coli, and other anaerobes.
c. Cholecystostomy. In severe illness, when laparotomy is contraindicated, a
cholecystostomy may be performed. Cholecystostomy involves evacuation
of the gallbladder of the stones and infected bile and placement of a Foley
catheter into the gallbladder for drainage to outside the body. When the
patient is stable, a tube cholangiogram should be performed to assess the
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Chapter 49: Gallstones 355

patency of the biliary system and the presence of possible residual stones. If
these abnormalities are detected, cholecystectomy should be performed
when possible.
3. Complications
a. Perforation is the most serious complication of acute cholecystitis. It may
be localized or may extend into the peritoneal cavity with subsequent peri-
tonitis or into an adjacent hollow organ, such as the stomach, duodenum, or
colon with formation of a cholecystenteric fistula. Surgical intervention is
necessary in all cases.
b. Gallstone ileus is a form of mechanical intestinal obstruction caused by the
impaction of a large gallstone that has entered into the intestine from a
cholecystenteric fistula. The obstruction may be intermittent as the stone
moves along the intestine until permanent obstruction occurs. Most obstruc-
tions occur in the ileum. Colonic obstruction is rare except at sites of
previous narrowing due to another disease process, such as diverticular or
inflammatory bowel disease. Gallstone ileus requires prompt diagnosis and
laparotomy.
c. Mirizzi syndrome. Rarely, a gallstone impacted in the cystic duct or the
neck of the gallbladder may cause a localized obstruction of the common
hepatic duct from direct pressure or inflammatory changes around the duct.
The obstruction can cause right upper quadrant pain, jaundice, recurrent
cholangitis, and possibly a fistula between the two ducts.
Ultrasound examination may show dilated ducts above the point of
obstruction as well as the stone. ERCP or percutaneous transhepatic cholan-
giography (PTC) confirms the site of obstruction. CT scan may be helpful in
defining the stone and differentiating it from tumor or mass. Surgery is
required in most instances.
B. Acute acalculous cholecystitis is a particularly severe form of inflammation of
the gallbladder that occurs in the absence of cholelithiasis. There is a high inci-
dence of necrosis, gangrene, and perforation of the gallbladder in this group of
patients. The mortality may be as high as 50% if diagnosis is delayed and prompt
therapy not instituted.
Most of the patients are elderly or debilitated as a result of coexisting disease
or trauma. The condition is also seen in patients of all ages in the intensive care
unit, after surgery, or on total parenteral nutrition. Absence of oral intake associ-
ated with gallbladder stasis, sludge formation, and increased biliary pressure due
to narcotic drugs that increase the tone at the sphincter of Oddi may contribute to
its pathogenesis.
1. Diagnosis
a. Clinical presentation. Bile is usually infected with enteric bacteria, which
may lead to sepsis. The clinical presentation may be nonspecific, and the
diagnosis requires a high index of suspicion. Most patients complain of
abdominal pain, nausea, and vomiting. Fever and chills may be present.
Serum bilirubin, alkaline phosphatase, ALT, and AST may be elevated. There
is usually a moderate leukocytosis (10,000–20,000 cells/L) with a left shift.
Serum amylase may be elevated.
b. Diagnostic studies. The diagnostic test of choice in acute acalculous
cholecystitis is ultrasound of the gallbladder, which identifies a distended
gallbladder with thickened walls and biliary sludge. Nuclear scans with
HIDA or PIPIDA may give equivocal results in these debilitated patients and
are not reliable.
2. Treatment. Successful management of acute acalculous cholecystitis
requires prompt diagnosis and early surgical intervention. Patients should be
treated with antibiotics to cover enteric organisms and enterococci.
Cholecystectomy is the surgical procedure of choice. Cholecystostomy is not
recommended because, in most cases, the gallbladder is necrotic or gan-
grenous and its total removal is necessary to prevent perforation and other
complications.
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356 Part V: Specific Complaints and Disorders

IV. CHOLEDOCHOLITHIASIS
A. Pathogenesis. Stones in the bile ducts may be primary (develop in the duct) or
secondary (originate in the gallbladder). If they are discovered after cholecystec-
tomy, they may have been overlooked (retained) or may have formed after the
surgery (recurrent).
1. Primary bile duct stones are rare in Western countries. They are more com-
mon in the Orient and are often associated with biliary infections and parasitic
infestations. They are usually pigment stones.
2. Secondary bile duct stones. Because 10% to 15% of patients with choles-
terol gallstones also have stones in the CBD, it is thought that most CBD stones
in the Western countries originate from the gallbladder. In fact, 95% of patients
with ductal stones also have stones in the gallbladder.
3. Stones found in the bile ducts after cholecystectomy may be retained or may
have formed de novo. Bile stasis associated with partial obstruction or marked
dilatation of the duct may promote choledocholithiasis. Recurrent stones are
often formed from bile pigments.
B. Diagnosis
1. Clinical presentation
a. Choledocholithiasis may present in the following ways:
i. Biliary colic–abdominal pain
ii. Obstructive jaundice
iii. Cholangitis
iv. Pancreatitis
v. Hemobilia
b. The biliary obstruction caused by cholelithiasis and the ensuing increased
biliary pressure and diminished bile flow result in the morbidity associated
with duct stones. The rate of progression of the obstruction, its degree, and
concomitant bacterial contamination of the biliary tract determine the sever-
ity of the syndrome. Thus acute obstruction usually causes colic with or
without concomitant pancreatitis; gradual obstruction may present as jaun-
dice. Cholangitis and abscess formation may follow if obstruction is not
relieved. Chronic biliary obstruction, if not relieved, may give rise to sec-
ondary biliary cirrhosis resulting in hepatic failure and portal hypertension.
c. Signs and symptoms. The most common complaint is right upper abdom-
inal or epigastric pain, which is usually associated with nausea and vomit-
ing. Jaundice, which may be fluctuating or progressive, is also common. If
obstruction is severe, dark urine and pale stools may develop. Fever and
chills, if present, will signal cholangitis or abscess formation.
2. Diagnostic studies
a. Laboratory studies. Elevation of alkaline phosphatase and bilirubin levels
is the hallmark of ductal obstruction. Serum amylase may be elevated with-
out concurrent pancreatitis. Elevation of transaminases (ALT, AST) may be
seen transiently with passage of a stone. If it persists, along with leukocyto-
sis, cholangitis is suspected.
b. Ultrasonography is the initial diagnostic test of choice in the workup of
gallstone disease. Aside from the presence of stones in the gallbladder, dilata-
tion of the biliary tract secondary to obstruction of the bile ducts is clearly
seen on ultrasound. If the obstruction occurs acutely, dilatation may not be
present.
In patients who have undergone cholecystectomy, slight dilatation of
the CBD (up to 0.8 cm) may be acceptable without the presence of distal
obstruction.
c. Biliary scintigraphy using 99mT c-labeled HIDA or PIPIDA may show
obstruction of the CBD in 85% to 90% of cases. In a positive scan, if the
cystic duct is patent, the passage of the radionuclide into the gallbladder and
the major ducts but not into the small bowel is noted within 1 to 4 hours.
d. CT scan is an excellent method to demonstrate CBD stones, especially those
with calcium.
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Chapter 49: Gallstones 357

e. MRCP has excellent sensitivity and specificity in visualizing the CBD for
stones as well as detecting other structural abnormalities such as ductal dila-
tion, sclerosing cholangitis and cystic abnormalities.
f. ERCP demonstrates the location of the stone or stones in the bile ducts and
is preferred in patients with suspected CBD obstruction without intrahepatic
ductal dilatation. Endoscopic examination of the upper gastrointestinal tract
and the duodenal ampullary orifice helps rule out pathology in these areas.
Endoscopic sphincterotomy has replaced operative sphincteroplasty in
patients with retained or recurrent CBD stones discovered after cholecystec-
tomy. In most cases, CBD stones smaller than 1.5 cm spontaneously pass
into the duodenum after endoscopic sphincterotomy. Stones larger than
1.5 cm can be fragmented and removed with special ERCP catheters, baskets,
and balloons. This technique can also be used therapeutically in debilitated
patients with CBD stones and intact gallbladders when cholecystectomy and
bile duct exploration are medically contraindicated. If an impacted CBD
stone is the cause of the pancreatitis, endoscopic removal by sphincterotomy
is the preferred immediate mode of therapy. In all cases in which an
obstructed CBD is manipulated, broad-spectrum IV antibiotic coverage must
be provided to the patient to prevent sepsis.
g. PTC may be used diagnostically and occasionally therapeutically in some
patients. If obstruction of the CBD and dilatation of the intrahepatic biliary
tract has been demonstrated by ultrasound, the location and the nature of
the obstruction can be delineated by PTC. Furthermore, it is possible to
relieve the obstruction, even if temporarily, by the insertion of a stent, espe-
cially in debilitated patients in whom surgery is contraindicated. Dissolution
of CBD cholesterol stones by infusion of solvents such as monooctanoin
with a catheter percutaneously placed above the stone or attempts at dis-
lodging and mobilizing the stone and facilitating its passage into the duode-
num or withdrawing it percutaneously may be considered for therapy for
such patients. Patients should be treated with IV broad-spectrum antibiotics
before such attempts.
C. Treatment. In symptomatic patients presenting with stones in the gallbladder and
the CBD, the treatment of choice is laparoscopic cholecystectomy and endoscopic
stone extraction via ERCP pre- or postoperatively. Cholecystectomy and CBD
exploration are reserved for patients with contraindications to the laparoscopic
procedure or who require abdominal exploration. If stones are found in the CBD
during CBD exploration, they should be removed, and a drainage procedure such
as a sphincteroplasty or choledochoenterostomy may be performed to allow the
passage of any residual stones into the gut. In these instances, a T tube is placed in
the CBD to decompress the biliary duct and to allow the performance of postop-
erative cholangiograms.
In approximately 2% of the patients, a residual CBD stone is demonstrated
on postoperative cholangiograms. These residual stones may be extracted either
percutaneously through the T tube or endoscopically by means of ERCP. In situ
dissolution of cholesterol stones with monooctanoin or MBTE infusion has also
been successful in selected patients. If these methods fail, endoscopic sphinctero-
tomy and stone removal or reoperation may be necessary.

V. Obstructive cholangitis is an inflammation of the bile ducts associated with enteric

bacterial infection in the setting of biliary obstruction. Obstruction may be sec-
ondary to CBD stones, biliary strictures, choledochal cysts, biliary fistulas, stenosis
of biliary–enteric anastomoses, and occasionally malignancy. Mechanical manipula-
tion of the biliary ducts (i.e., during PTC, ERCP, or T-tube studies) may also result
in cholangitis.
The most common organisms found in the bile in cholangitis are E. coli,
Klebsiella, Proteus, Enterobacter, Pseudomonas, Streptococcus fecalis, and Clostridium.
The spillage of the bacteria into the bloodstream often gives rise to bacteremia and sep-
sis. When infection is severe, invasion of the liver parenchyma may occur, resulting in
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358 Part V: Specific Complaints and Disorders

abscess formation. Recurrent infection and inflammation of the bile ducts may result
in strictures, areas of dilatation, and intraductular calcium bilirubinate stone formation.
Secondary biliary cirrhosis and portal hypertension may be late sequelae.
A. Diagnosis
1. Clinical presentation. Patients usually present with intermittent abdominal
pain, fever, chills, and jaundice. Dark urine and pale stools suggest the presence
of biliary obstruction.
2. Diagnostic studies. Leukocytosis with a shift to the left and elevation of
serum alkaline phosphatase and bilirubin levels are common. Serum ALT, AST,
and amylase levels are usually elevated.
B. Treatment. When cholangitis is suspected, prompt diagnosis and relief of the
obstruction is essential. Patients should be given IV antibiotics for enteric organ-
isms to prevent sepsis.
Ultrasonography, ERCP, PTC, and abdominal CT scan may be necessary
to diagnose the extent, nature, and location of the obstruction. The choice of defin-
itive treatment for relief of the obstruction depends on the findings. Surgery or
other less invasive techniques such as PTC or ERCP may be required.

Selected Readings
Agrawal S, et al. Gallstones, from gallbladder to gut: Management options for diverse
complications. Postgrad Med. 2000;108:143.
Chuang CZ, et al. Physical activity, biliary lipids and gallstones in obese subjects. Am
J Gastroenterol. 2001;96:1860.
deLedinghen V, et al. Diagnosis of choledocholithiasis: EUS or magnetic resonance
cholangiography? A prospective controlled study. Gastrointest Endosc. 1999;49:26.
Donovan JM, et al. Physical and metabolic factors in gallstone pathogenesis. Gastroenterol
Clin N Am. 1999;28:75–97.
Germanos S, et al. Clinical update: surgery for acute cholecytitis. Lancet. 2007;369:
1774–1776.
Ko C, et al. Gallbladder disease. Clin Perspect Gastroenterol. March /April 2000:87.
Kolla SB, et al. Early vs delayed laparoscopic cholecystectomy for acute cholecystitis:
a prospective, randomized trail. Surg Endos. 2004;18:1323–1327.
Mendez SN, et al. Intestinal motility and bacterial overgrowth in patients with gallstones.
Gastroenterology. 2001;120:1310.
Mulholland MW. Progress in understanding acalculus gallbladder disease. Gastroenterology.
2001;120:570.
Peng WK, et al. Role of laparoscopic cholecystectomy in the early management of acute
gallbladder disease. Br J Surg. 2005;92:586–591.
Schirmer BD. Cholelithiasis and cholecystitis. J Long Term Eff Med Implants. 2005;
15:329–338.
Shaffer EA. Gallbladder sludge: What is its clinical significance? Curr Gastroenterol Rep.
2001;3:166.
Throwridge RL, et al. Does this patient have acute cholecystitis? JAMA. 2003;299:80–86.
Tsai CJ, et al. Long-term intake of dietary fiber and decreased risk of cholecystectomy. Am
J Gastroenterol. 2004;99:1364–1370.
Tsai CJ, et al. Dietary protein and risk of cholecystectomy in a cohort of US women: The
Nurses Health Study. Am J Epidemiol. 2004;160:11–18.
Tsai CJ, et al. Glycemic load, glycemic index, and carbohydrate intake in relation to risk
of cholecystitis in women. Gastroenterology. 2005;129:105–112.
Verma D, et al. EUS vs MRCP for detection of choledocholithiasis. Gastrointest Endosc.
2006;64:248–254.
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VIRAL HEPATITIS 50

H epatitis can be defined as the constellation of symptoms and signs resulting from
hepatic inflammation and hepatic cell necrosis. If the insult is acute and occurs in a previ-
ously asymptomatic individual, the term acute hepatitis can be applied. The most com-
mon causes of acute hepatitis are viruses, toxins, and alcohol. Occasionally other disease
entities such as Wilson’s disease, leukemias, and lymphomas with acute infiltration of the
liver may give rise to a clinical picture of acute hepatitis. Viruses, however, are the major
etiologic agents of acute liver injury.
Systemic infection with several viruses results in hepatic inflammation and cell death.
Viruses that cause hepatitis have been classified as hepatitis A (HAV), B (HBV), C (HCV),
delta (HDV), and E (HEV). However, in some individuals, infection with the Epstein-Barr
virus (EBV) or cytomegalovirus (CMV) also results in acute hepatitis.
In most patients, acute viral hepatitis presents as an acute illness characterized by the
abrupt onset of malaise, fever, anorexia, nausea, headache, abdominal discomfort, and pain.
Jaundice, itching, dark-colored urine, and light-colored stools often cause the patient to seek
medical attention. At this stage, the disease caused by different viruses is usually indistin-
guishable; serologic studies and viral DNA or RNA determination by polymerase chain reac-
tion (PCL) may provide the only means of identification. Pertinent factors regarding the five
forms of acute and chronic viral hepatitis are summarized in Tables 50-1 and 50-2.

I. HEPATITIS ASSOCIATED WITH EPSTEIN-BARR VIRUS

A. Pathogenesis. EBV is a herpes virus and is the causative agent of infectious
mononucleosis (IM). Although clinical jaundice occurs in approximately 5% of
the cases of IM, hepatitis caused by this virus may be as common as that from
HAV and HBV. However, the hepatitis in IM is usually mild and is accompanied
by other clinical features of IM.
1. In most individuals, the natural primary infection with EBV occurs asympto-
matically in childhood, conferring lifelong immunity to IM in the form of IgG
antibodies to EBV. In the industrialized countries, 50% to 60% of the children
by age 5 and more than 80% of the individuals by age 20 acquire seropositiv-
ity to EBV. Infection tends to occur earlier in lower socioeconomic groups, but
symptomatic disease is frequent in college students who were not exposed to
EBV in childhood. In adults, symptomatic disease develops in one half of the
cases and may be severe in older individuals.
2. Transmission of the virus occurs through contact with infected saliva. The
virus is found in saliva droplets and in the epithelial cells. Blood transfusions
have been implicated in a few cases.
3. In most cases, the virus initially infects oropharyngeal epithelial cells with
secondary infection of the B lymphocytes with further dissemination of the
virus. The incubation period is usually 4 to 7 weeks. The virus can be isolated
from oral secretions in 80% of patients with acute IM. The EBV genome is
incorporated into some infected B lymphocytes, which incite a cytotoxic T-cell
proliferation and response, seen in the peripheral blood smear as the atypical
mononuclear cells of IM. Although the cellular and hormonal response brings
the infection under control, infection persists in a subpopulation of B lympho-
cytes. In fact, EBV can be isolated from the saliva of 15% to 20% of asympto-
matic adults. Persistent and reactivated infections are rare but do occur.

359
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360 Part V: Specific Complaints and Disorders

TABLE 50-1 Five Forms of Viral Hepatitis

Hepatitis

A B C D E

Virus HAV HBV HCV HDV HEV

Family Picornavirus Hepadnavirus Flavivirus Satellite Calicivirus
Size 27 nm 42 nm 30–60 nm 40 nm 32 nm
Genome ssRNA dsDNA ssRNA ssRNA ssRNA
Length 7.8 kb 3.2 kb 10.5 kb 1.7 kb 8.2 kb
Acute 0.2% 0.2%–1.0% 0.2% 2%–20% 0.2%
mortality
Chronicity None 2%–7% 50%–70% 2%–70% None
Spread Fecal-oral Parenteral Parenteral Parenteral Fecal-oral
Sexual ? Sexual ? Sexual
Perinatal
Antigens HAV Ag HBsAg HCV Ag HDV Ag HEV Ag
HBcAg
HBeAg
Antibodies Anti-HAV Anti-HBs Anti-HCV Anti-HDV Anti-HEV
Anti-HBc
Anti-HBe
Viral HAV-RNA HBV-DNA HCV-RNA HDV-RNA Viruslike
markers DNA polymerase particles

HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV,
hepatitis E virus; ssRNA, single-stranded RNA; dsDNA, double-stranded DNA; kb, kilobase; Ag, antigen.
From Hoofnagle JH, DiBisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin
Liver Dis. 1991;11:74. Reprinted with permission.

TABLE 50-2 Serologic Diagnosis of Acute Viral Hepatitis*

Disease Serologic results Comments

Hepatitis A IgM anti-HAV Reasonably specific

Hepatitis B HBsAg Can be negative (early loss)
IgM anti-HBc Indicates acute hepatitis
Hepatitis C Anti-HCV Can appear late in disease
Hepatitis D HBsAg and anti-HDV Anti-HDV can appear late in disease
IgM anti-HBc present Coinfection
IgM anti-HBc absent Superinfection
Hepatitis E All negative History of exposure

HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBc, hepatitis B core; HCV, hepatitis C
virus; HDV, hepatitis D virus.
*Initially four tests should be obtained: IgM anti-HAV, IgM anti-HBc, HBsAg, and anti-HCV. In some
situations, further testing for anti-HDV and anti-HCV are needed (see text).
From Hoofnagle JH, DiBisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin
Liver Dis. 1991;11:11. Reprinted with permission.
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Chapter 50: Viral Hepatitis 361

B. Clinical presentation. In patients 15 to 30 years old, IM classically presents with

fatigue, malaise, fever, anorexia, distaste for food and cigarettes, nausea, vomiting,
and headache. Periorbital edema and a rash may be present. Sore throat is com-
mon and may be caused by a secondary infection with
-hemolytic Streptococcus.
Lymphadenopathy and splenomegaly are present in about half of the cases. Ten
percent to 15% of the patients have hepatomegaly, and 5% develop jaundice.
Hemolytic anemia may be present.
Occasionally in IM, the hepatitis may be the predominant presentation, espe-
cially in older patients, and may last 1 to 2 months. In some cases, the clinical
presentation of fever, right upper quadrant pain, jaundice, and elevated alkaline
phosphatase may mimic extrahepatic obstruction.
1. Diagnostic studies. Mild elevation of transaminases (more than twice nor-
mal) and alkaline phosphatase is common. Serum bilirubin is 1 to 8 mg/dL.
The hepatitis is usually milder than seen with other viruses. Severe jaundice,
liver failure, coagulopathy, and encephalopathy are rare.
In the acute disease, 60% of the patients have an absolute lymphocytosis,
and 50% have the “atypical mononuclear cells.” The monospot test has a
specificity of 99% and a sensitivity of 80%. It may be negative initially in one
sixth of the patients and should be repeated. The heterophil antibody is more
sensitive and is positive in 90% of the patients. EBV-specific serology (IgM
antibody [Ab]) allows for definitive diagnosis but may be negative in early mild
IM. A single high virus-specific antibody (IgG) does not reliably distinguish
current from previous infection.
C. Treatment. Currently there is no specific treatment for IM hepatitis.
Corticosteroids may be of value in severe acute pharyngitis for the edema but do
not provide any benefit for other manifestations of IM including hepatitis.
Acyclovir sodium has been used in a few cases of persistent severe IM with some
clinical improvement.

II. CYTOMEGALOVIRUS INFECTIONS OF THE LIVER

A. Pathogenesis. CMV is a common infectious agent resulting in asymptomatic
infection in most individuals. Occasionally, an IM-like illness or hepatitis may
occur. In immunosuppressed patients, a severe disseminated infection can result
with multisystem disease and a high mortality. CMV infection in acquired immun-
odeficiency syndrome (AIDS) is discussed in Chapter 43. Transmission is through
close contact with infected saliva, urine, and occasionally blood.
Once an infection occurs, the virus persists and cannot be eradicated from
the host. The viral genome is incorporated into the host cells and remains latent
most of the time. Occasionally, CMV reactivates and is shed in the patient’s saliva
and urine. In a normal host, these reactivations are controlled by the immune
response, but they may present as opportunistic infections in immunocompro-
mised and allograft patients. Viremia in these patients may result in hepatitis as
well as infections of other organs. Reinfection is also possible with a different
strain of CMV; thus, individuals may bear more than one type of CMV in their
cells, which may reactivate at different times.
B. Diagnosis
1. Virus identification. CMV can be cultured from the urine, saliva, blood, and
other tissues of infected individuals. The proper laboratory should be consulted
ahead of time to expedite the proper method of sampling and delivery of the
specimens for best results.
2. Immune response. Primary infection is usually diagnosed by seroconver-
sion. CMV-specific IgG antibody is absent in the acute serum and positive
later in the disease course. If an acute sample is not collected, high-titer IgG
will not be diagnostic of an acute infection. However, CMV-specific IgM
antibodies will be diagnostic for the presence of acute infection. In recurrent
infections, virus isolation may be required for diagnosis. None of the normal
hosts and only one third of the allograft patients has a rise in IgM titers during
CMV recurrences.
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362 Part V: Specific Complaints and Disorders

3. Liver disease
a. Primary CMV infections. In patients with primary CMV infections, sub-
clinical liver involvement may be common with a mild rise in liver enzyme
levels. In others, a mild, self-limited hepatitis with a mild or moderate rise
in liver enzymes is present. There may be accompanying hemolysis and atyp-
ical mononuclear cells in the peripheral blood smear.
b. CMV from blood transfusions. In these instances, the virus is thought to
be present in blood leukocytes including neutrophils. The onset of disease is
3 to 6 weeks after transfusions. Hepatitis in most patients is accompanied
by a mononucleosislike disease.
c. Transplant patients. In most patients who have undergone transplanta-
tion, CMV is found to be a common cause of acute hepatitis. CMV may
enter the patient through the transplanted organ or transfusions, or it may
be reactivated during immunosuppression. In these patients, chronic infec-
tion of the liver may also exist without producing disease.
d. Liver biopsy specimens may be cultured for CMV. Histologically, liver
parenchyma contains the owl-eye inclusions in the hepatocytes and may
contain noncaseating granulomas or granulomatous changes.
e. It is debatable whether CMV can cause massive hepatic necrosis. There is
no evidence that CMV causes chronic liver disease in normal hosts.
However, in immunocompromised patients (e.g., in patients with AIDS), the
hepatobiliary infection may be extensive and chronic. Concomitant liver
infections with CMV and HBV have been described.
C. Treatment. In proven cases, intravenous (IV) therapy with ganciclovir sodium
may be helpful. Doses used vary from 2.5 mg/kg q8h for 20 days to 5 mg/kg q12h
for 14 days. Treatment may need to be continued indefinitely (see Chapter 43) in
patients with AIDS.

III. HEPATITIS A. Infections with HAV account for approximately 25% of the clinical
hepatitis cases diagnosed in industrialized nations. It occurs both sporadically and in
epidemics. In general, it causes less morbidity and mortality than hepatitis virus types
B, C, and delta.
A. Pathogenesis. HAV is endemic in underdeveloped countries, where infections
usually occur in children and are clinically inapparent. The outcome of the infec-
tion seems to depend on the age of the patient and the infecting dose of the virus.
The disease is of shorter duration and milder in children. Adults may present with
clinically significant disease; fulminant hepatitis occurs with a frequency of 1 to 8
per 1,000 cases. HAV is a 27-nm, nonenveloped RNA enterovirus and belongs to
the group picornavirus. All strains of the virus identified to date belong to one
serotype. The infection is acquired by the fecal-oral route and can be isolated from
the liver, bile, stools, and blood during the late incubation period and acute pre-
icteric phase of the disease. Fecal viral shedding and viremia diminish once jaun-
dice occurs.
B. Diagnosis
1. Clinical presentation. The typical course of a case of acute hepatitis A is
shown in Figure 50-1. Hepatitis A has an incubation period of from 2 to 7
weeks with a mean of 4 weeks. In clinically apparent cases, there is an abrupt
onset of symptoms. Malaise, fever, anorexia with aversion to food and ciga-
rettes, nausea, and abdominal pain are frequent. Within a few days after the
onset of symptoms, there is a marked rise in serum alanine aminotransferase
(ALT), aspartate aminotransferase (AST), and bilirubin levels, resulting in jaun-
dice. In approximately 25% of the cases, hepatosplenomegaly is noted.
2. The duration of the illness is usually less than 1 month, but elevated serum
transaminases have been recorded for as long as 6 months.
3. Complications from hepatitis A are rare. A cholestatic phase may occur in
some patients and may mimic obstructive jaundice. Relapses have been seen
within 4 to 15 weeks of recovery from the disease and may be precipitated by
exertion or alcohol intake. The disease may last 16 to 40 weeks. There may be
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Chapter 50: Viral Hepatitis 363

Figure 50-1. Typical course of acute hepatitis A. ALT, alanine aminotransferase; HAV, hepatitis A
virus; anti-HAV, antibody to HAV. (From Hoofnagle JH, DiBisceglie AM. Serologic diagnosis of acute
and chronic viral hepatitis. Semin Liver Dis. 1991;11:74. Reprinted with permission.)

complications from immune complex formation and deposition. There is no

evidence that HAV causes a chronic carrier state or chronic liver disease; how-
ever, chronic carriers of HBV can be infected with HAV.
4. Serology. The development of serologic assays for hepatitis A antigen (HAAg)
and antibody (Haab) has allowed for accurate diagnosis of HAV infection.
HAAg can only be detected in the stool and possibly the blood of viremic
patients shedding the virus in the preclinical stages of the disease.
High titers of HAV-specific IgM antibody develop in all patients by the
time of clinical presentation. Thus, the presence of anti-HAV IgM in a jaun-
diced patient confirms the diagnosis of hepatitis A. The titers of IgM antibody
decline over the next few months. IgG antibodies are slower to appear but can
be detected in all patients after 3 weeks of disease. The presence of HAV IgG
antibody in a patient in the absence of HAV IgM antibody denotes previous
infection with HAV with full recovery.
C. The treatment of hepatitis A is supportive. Most patients do not require hospi-
talization. Patients should receive good nutrition and abstain from alcohol and
other hepatotoxic agents. Enteric precautions are recommended to prevent fecal-
oral transport. In patients with severe cholestatic hepatitis A, steroid therapy may
be beneficial. Prednisone 40 mg daily may be given for several weeks and gradu-
ally tapered.
D. Prophylaxis. Administration of normal serum immunoglobulin has been shown
to provide protection if given before exposure to the virus or during the incuba-
tion period of the disease.
1. Postexposure prophylaxis of 0.02 mg/kg is recommended for household and
sexual contacts of patients with hepatitis A within 2 weeks of exposure. Similar
prophylaxis is recommended for staff and members of daycare centers and
institutions providing custodial care. It is not recommended for contacts in
schools, offices, factories, and hospitals unless there is a problem with hygiene.
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364 Part V: Specific Complaints and Disorders

2. Travelers to endemic areas should receive prophylaxis, with the dose of the
immunoglobulin dependent on the intended period of stay. For travel of less
than 2 months’ duration, 0.02 mL/kg should be given, and 0.06 mL/kg for
longer periods.
3. Vaccine. Over the last several decades, the incidence of HAV infection has been
decreasing in industrialized countries. Because infection in early childhood is
becoming less common, a population of susceptible adolescents and adults, in
whom hepatitis A can be more severe, is emerging. Passive immunization with
serum immune globulin (IG) has a limited duration of protection of approxi-
mately 3 months. For a longer duration of protection, active immunization with
a vaccine is required. Clinical trials with a killed whole virus vaccine have been
successful, and the vaccine is now available. The vaccine is administered in three
doses intramuscularly into the deltoid muscle at 0, 1, and 6 months. A recom-
binant complementary DNA vaccine for this RNA virus is also available.
A combination vaccine (Twinrit-Galaxo Smith Kline) containing 20 g of
HBsAg protein (Energix –B) and 720 ELISA units of inactivated Hep A virus
(HAV VIX) provides dual protection with three injections at 0, 1, and 6 months.

IV. HEPATITIS B (HB). There are about 2.5 billion people worldwide infected with
HB virus (HBV), of these about 350 million persons are chronic carriers and 4 mil-
lion new HBV infections occur yearly. The highest prevalences of HBV (about
15%) are in the Far East and Southeast Asia, Middle East, Africa, and among
Alaskan natives and Pacific Islanders. HBV causes acute and chronic liver disease
and liver cancer.
HBV is spread parenterally (horizontal transmission) or by intimate contact
since HBV is found not only in blood, but also in semen, saliva, and other body secre-
tions. It is believed that transmission in Asia is perinatal (vertical transmission)
from mother to infant.
The risk factors for transmission include high-risk sexual activity (multiple sex-
ual partners, homosexual activity as in men having sex with men), injection drug use,
hemodialysis, living or being born in an endemic area, and working in the health care
profession.
There are eight genotypes (A–H) of HBV. Genotype A is found in Europe and
North America, genotype B and C in the Far East and Southeast Asia, and genotype D
mainly in southern Europe, Africa, and India. The clinical significance of genotypes
are enfolding (i.e., genotype A and B are more sensitive to treatment with interferon
than genotypes C and D).
A. HBV is a DNA virus belonging to a class of animal viruses called hepadna viruses.
These viruses are hepatotropic, tend to cause persistent infections, and have been
associated with the development of hepatocellular carcinoma. HBV is unique among
human viruses in its genomic and antigenic structure and its replicative cycle.
The structure of HBV is shown in Figure 50-2. It consists of an outer shell
made up of a protein (HBsAg) and a complex inner core. The complex inner core
or the nucleocapsid core is a 27-nanometer (nm) icosahedral structure that consists
of 180 copies of viral core protein (HBcAg) surrounding the viral DNA (genome)
and virally encoded DNA polymerase. HBcAg protects the viral genome from

Figure 50-2. Structure of hepatitis B virus. (From

Hoofnagle JH, Schafer DF. Serologic markers of hepati-
tis B virus infection. Semin Liver Dis. 1986;6:1. Reprinted
with permission.)
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Chapter 50: Viral Hepatitis 365

Figure 50-3. Structure of the HBV genome. The thick lines are the DNA strands, and the open
reading frames that code for proteins are indicated outside the DNA. Black boxes indicate the start
sites of the open reading frames. (From Foster GR, Carman WF, Thomas HC. Replication of hepati-
tis B and delta viruses: Appearance of viral mutants. Semin Liver Dis. 1991;11:122. Reprinted with
permission.)

degradation by exogenous nucleases. Figure 50-3 depicts the structure of the HBV
genome.
The HBV genome is composed of circular DNA of approximately 3,200 base
pairs with a complete negative strand and an incomplete complementary positive
strand. The negative strand contains overlapping genes that encode structural pro-
teins (surface proteins and their derivatives and core) and two replicative proteins
(polymerase and X). HBV is unique among DNA viruses in that it replicates in a
way similar to that of the RNA retroviruses such as the human immunodeficiency
virus (HIV) via an RNA intermediate.
Once HBV is blood borne in the host, the replication cycle begins with the
attachment of HBV to the hepatocyte cell membrane and entry into the hepatocyte
cytoplasm. The virus is then uncoated and the nucleocapsid and the viral DNA are
transported into nucleus. Once in the nucleus, the viral genome is repaired by fil-
ing in the gap in the positive-strand DNA and forming the covalently closed circu-
lar DNA (cc cDNA.) Thus, complexly double-stranded HCV DNA is formed.
Synthesis of cc cDNA is catalyzed by the viral DNA polymerase.
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366 Part V: Specific Complaints and Disorders

The cc cDNA is the template for synthesis of genomic and subgenomic

transcripts, catalyzed by host RNA polymerase. Genomic or pregenomic
RNA thus formed then acts as the template for future DNA minus-strand
synthesis.
Viral RNA transcripts are then transported into the cytoplasm and their
translation into proteins yields the viral envelope, core, precore protein, and viral
DNA polymerase. Viral Packaging encapsidation occurs in the cytoplasm.
Encapsidation involves the assembly of the viral core consisting of 180 molecules
of core proteins and the synthesis of the viral DNA by reverse transcription. The
template for the minus strand is pregenomic mRNA and the template for the plus
strand is minus-strand DNA. The two DNA strands of HBV are made sequentially
rather than simultaneously as occurs in conventional DNA replication. Once the
DNA synthesis is completed, the template RNA is degraded by specific RNAase
which resides in the viral polymerase.
After replication is complete, the viral core is either transported into the
nucleus or passes through the endoplasmic reticulum and Golgi apparatus where
the core acquires the envelope proteins before exportation from the cell by
exocytosis.
Early in HBV infection, some of the nucleocapsid cores are transported back
to the nucleus where synthesis of the plus strand is completed and stable cc cDNA
molecules are formed. The cc cDNA molecules form a reservoir of transcriptional
templates so that after cell division of the infected hepatocytes, infection will be
propagated to daughter hepatocytes. When the HBV infection is well established,
nucleocapsid cores are preferentially exported from the hepatocytes facilitating the
horizontal spread of infection throughout the liver.
Integration of HBV-DNA either intact or more frequently in fragments into
the host genome does occur in chronic HBV infection and is implicated in hepatic
carcinogenesis.
B. Pathogenesis. At the entry of HBV and its invasion of hepatocytes, viral proteins
are expressed on the hepatocyte membrane. These proteins are recognized by the
host immune systems, both the humoral and the cellular arms. If the host immune
response to the infected hepatocytes is strong enough to destroy all the involved
cells, “hepatitis” results in clearance of the virus.
However, if the immune response is inadequate to completely obliterate the
infected hepatocytes, an ongoing viral infection ensues with varying degrees of
hepatic inflammatory response.
If the HBV infection occurs perinatally (i.e., by vertical transmission, before
the immune system of the infant is fully developed), an inadequate immune
response is mounted and viral persistence results (immune tolerance).
C. Serology. Infection with HBV results in an overproduction of HBsAg outnum-
bering the intact virus by 10 million to 1. Assays to detect various HBV-related
antigens and antibodies in the serum of infected individuals are summarized in
Figure 50-4.
Hepatitis B e antigen (HBeAg) is an internal antigen of HBcAg particles
that can be detected in the serum of patients with high levels of circulating HBV.
HBeAg is found only in HBsAg-positive serum and signals active ongoing infec-
tion and infectivity. HBcAg is found only within the infected hepatocytes and
not in the serum. The hepatitis B antibodies (Ab) are described in the following
sections.
D. HBV infection. Infection with HBV may present in one of six clinical states: acute
hepatitis, immune tolerant state, chronic hepatitis, inactive asymptomatic
carrier state, and cirrhosis and hepatocellular carcinoma. Infection with HBV
in older children and adults can lead to several outcomes.
Approximately two thirds of the individuals infected with HBV have a tran-
sient subclinical infection, followed by rapid clearance of the virus with a strong
immune response, production of high titers of HBsAb, and permanent immunity.
HBcAb is also produced in these individuals but does not confer or suggest
immunity.
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Chapter 50: Viral Hepatitis 367

Figure 50-4. Typical course of acute hepatitis B. Initially, HBV-DNA can be detected by blot
hybridization, but as the disease resolves, only low levels can be detected using polymerase chain
reaction. ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e
antigen; HBV-DNA, hepatitis B virus DNA; anti-HBc, antibody to hepatitis B core antigen; anti-HBe,
antibody to HBeAg; anti-HBS, antibody to HBsAg; PCR, polymerase chain reaction. (From Hoofnagle
JH, DiBisceglie AM. Serologic diagnosis of acute and chronic viral hepatitis. Semin Liver Dis.
1991;11:75. Reprinted with permission.)

E. Acute hepatitis. The outcomes of HBV infection are outlined in Figure 50-5.
About one fourth of individuals with HBV infection develop clinically apparent
acute hepatitis. The incubation period, or time between exposure and onset of
symptoms, is 1 to 6 months. During this time, there is active viral replication, and
the patient’s serum becomes positive for HBsAg, DNA, and HBcAb IgM.
1. Clinical presentation. Before jaundice and typical clinical findings of hepatitis
become apparent, these patients may present with rash, neuralgia, arthralgia,
arthritis, glomerulonephritis, and polyarteritis nodosa, vasculitis, mixed cryo-
globulinemia, pericarditis, pancreatitis, and aplastic anemia. These disease
states are believed to result from circulating antigen-antibody complexes.
2. Laboratory tests
a. As the patient becomes symptomatic, there is a concomitant rise in serum
ALT and AST (5–20 times normal) and a moderate elevation of the serum
alkalie phosphatase (2–10 times normal). These enzymes represent hepato-
cellular damage. Serum bilirubin may reach very high levels (30 mg/dL).
Prothrombin time (PT) and partial thromboplastin time (PTT) levels
may also become abnormal depending on the severity of the liver disease.
b. Serum HBV-DNA becomes undetectable in these patients within 1 to 8 weeks
after the onset of symptoms. HBcAg also disappears soon after the peak of
serum transaminase. HBsAg usually remains detectable in the serum through-
out the illness and may persist even into convalescence. This is because the
initial HBsAg titers are very high, and because HBsAg has a long half-life of
8 days, it may take months to clear it to undetectable levels.
c. HBcAb is present in high titers in the serum of infected patients with HBV
when jaundice appears. The initial antibody is of IgM type; with recovery,
the IgM type disappears, and the IgG HBcAb titers reach high levels and
persist for life.
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368 Part V: Specific Complaints and Disorders

0%
70

-3
%

%
10
-9
0%

Figure 50-5. Outcomes of acute hepatitis B virus infection in adults. (From Hoofnagle JH, Schafer DF.
Serologic markers of hepatitis B virus infection. Semin Liver Dis. 1986;11:1. Reprinted with
permission.)

d. HBeAb appears when HBeAg becomes negative and often disappears within
a few months or years.
e. HBsAb arises during recovery after HBsAg has cleared. There is usually a
“window” period between the disappearance of HBsAg and the appearance
of HBsAb. The only way to make the diagnosis of acute hepatitis in these
individuals is to show the presence of HBcAb (IgM type). A minority of the
patients (5%–15%) who clear HBV and recover normally never develop
HBsAb. However, most of these individuals have positive IgM HBcAb.
f. In some patients (10%), HBV clearance is very rapid, and HBsAg levels may
be absent at the onset of symptoms. These acutely ill patients have positive
IgM HBcAb titers and may have detectable HBeAg levels. These variations
are more common in both mild and fulminant disease.
g. HBV-DNA can be detected and measured quantitatively with specific assays.
The hybridization assay measures replicating HBV-DNA whereas the ampli-
cation assay performed using the polymerase chain reaction (PCR) measures
HBV-DNA nonspecifically.
3. Prognosis. In patients who can mount a vigorous immune response, the virus
is cleared, and recovery is within a few months (1–6 months). A minority of the
patients with acute hepatitis (1%–5%) develop fulminant hepatic failure (FHF)
due to massive hepatic necrosis. The prognosis in these patients is poor and
depends on hepatic regeneration.
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Chapter 50: Viral Hepatitis 369

The risk of HBV infection becoming chronic varies with the age of the
patient at the initial infection. In an immunocompetent adult, the risk is 5%,
in an immune compromised adult 50%, in early childhood 50%, and in the
newborn 90%.
F. Chronic HBsAg carrier state and chronic hepatitis
1. Clinical course and serology. About one tenth of adult patients infected with
HBV do not clear the virus and remain HBsAg positive. Some of these patients
develop chronic progressive hepatitis, and others may remain in a clinically qui-
escent “carrier” state. Figure 50-6 summarizes the serologic course of chronic
type B hepatitis in immune competent adults.
a. In patients who develop chronic type B hepatitis, the initial pattern of HBV
markers is similar to that in patients with acute, self-limited hepatitis.
However, in patients with ongoing active disease, HBeAg and HBV-DNA
persist and accompany elevated serum transaminases even after 6 months of
symptomatic disease.
b. In most patients, the initial disease is mild, and some patients may be
anicteric and symptomatic. These patients may present with only nonspecific
symptoms of anorexia and fatigue and mild-to-moderate elevation of liver
tests.
c. IgM HBcAb levels remain elevated in chronic active type B hepatitis. As the
disease wanes, the titers diminish with an increase in IgG HBcAb.
d. Patients who remain HBsAg positive do not produce specific HBsAb.
However, in 20% to 40% of HBsAg carriers, there may be low levels of
HBsAb directed toward HBsAg subdeterminants not present in the serum.
e. The course of chronic HBV infection varies. The activity of the liver disease
and the serologic markers change over time. In approximately one half of
these patients, HBeAg disappears and is replaced by HBeAb. Concomitantly,
there is a flare of the hepatitis with elevated ALT and AST levels and loss of

Figure 50-6. Representative course of chronic hepatitis B in which acute infection is followed by
chronic infection. Ultimately, there is a remission in disease when seroconversion from HBeAg to anti-
HBe occurs. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV-DNA, hepatitis B virus
DNA; HBsAg, hepatitis B surface antigen; PCR, polymerase chain; anti-HBc, antibody to hepatitis B
core antigen; anti-HBe, antibody to HBeAg. (Hoofnagle JH, DiBisceglie AM. Serologic diagnosis of
acute and chronic viral hepatitis. Semin Liver Dis. 1991;11:75. Reprinted with permission.)
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370 Part V: Specific Complaints and Disorders

DNA from serum. This is followed by marked improvement of liver histol-

ogy and a decrease in serum transaminases. The transition from the viral
replicative phase, suggested by the presence of HBeAg, to the nonreplicative
phase, suggested by the presence of HBeAb, is marked by an increased
immune response of the patient to clear viral replication.
f. HBsAg persists in the serum of most of these patients even though there may
be no evidence of viral replication. These individuals are referred to as the
“healthy HBsAg carriers” or they are in the immune tolerant state.
g. If the HBV infection has occurred in adulthood, approximately 1% of the
patients also clears the HBsAg and becomes HBsAb positive. Because previ-
ous liver damage has occurred in these patients, they are usually left with
some degree of cirrhosis. These individuals account for some of the patients
with “cryptogenic” cirrhosis.
h. In some patients, chronic HBV infection remains in the viral replicative
stage. This may be continuous, with positive HBeAg titers; or intermittent or
low grade, with undetectable HBeAg. The latter pattern is more common in
the Far East and with HBV infection early in life.
Integration of HBV-DNA into the hepatocyte DNA occurs during
chronic HBV infection and persistent viral replication. This may be a neces-
sary step in the development of hepatocellular carcinoma in patients with
previous HBV infection.
i. In 10% to 30% of the patients with chronic HBV hepatitis, cirrhosis devel-
ops accompanied by its complications of portal hypertension, esophageal
varices, ascites, and encephalopathy. The level of IgM HBcAb correlates
with the activity of the chronic hepatitis. High titers are found in severe
exacerbations, moderate titers in moderately active disease, and low titers in
mild cases. Patients who are healthy HBsAg carriers with no evidence of
active liver disease have no detectable IgM HBcAb titers.
2. The determining factors for development of chronic hepatitis after HBV
infection are (a) the age of the individual when initially infected, (b) the
immune status of the host, (c) gender, and (d) the severity of the acute infection.
Ninety percent to 95% of infected neonates and about 30% to 50% of
children but only 1% to 10% of adults develop chronic disease. Women are
less affected than men, and the disease becomes chronic much more frequently
in patients undergoing hemodialysis, in other intrinsically or iatrogenically
immunocompromised patients, and in those with HIV coinfection. The severity
of the initial disease appears to have little predictive value when the age of
onset and the host immune status are taken into account.
3. Reactivation of quiescent chronic HBV infection occurs spontaneously or,
more frequently, in individuals following the withdrawal of immunosuppressive
drugs (e.g., chemotherapy, steroids, organ transplantation). In some patients,
reactivation may precipitate fulminant hepatic necrosis. Most individuals with
reactivation have positive HBsAg titers without positive HBeAg titers. In some
patients, if the prior presence of HBsAg was not known due to subclinical acute
disease, reactivation may be regarded as the initial acute infection. In these indi-
viduals, HBeAg, DNA and IgM HBcAb all may become positive. The initial loss
of HBeAg in the carrier does not necessarily represent resolution of the infec-
tion, which suggests that HBV infection may become latent as the herpesvirus
infections do. Recent data suggest that HBV may infect and reside quietly in the
lymphocytes in the spleen of previously infected individuals.
4. HBV mutants. HBV polymerase is an RNA/DNA transcriptase that lacks a
proofreading function. During viral replication, it frequently transcribes its
template incorrectly, creating mutant viruses. Many of these mutants are inca-
pable of forming infectious virions. However, several infectious HBV mutants
have been identified by PCR. One of these mutants contains a point mutation
in the gene coding the “surface” protein in the highly antigenic “a” determi-
nant of HBsAg. This mutation alters the antigenic properties of the HBV, allow-
ing it to escape the protective effects of the HBV vaccine.
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Chapter 50: Viral Hepatitis 371

Another mutant of HBV has been identified in patients who have active
hepatitis B but lack HBeAg. These hepatitis B virions have a point mutation in
the precore gene. This mutation prevents the synthesis of the precore-core pro-
tein and abolishes the formation of HBeAg, which modulates viral infection.
Lack of HBeAg expression on the infected hepatocytes prevents immunologic
recognition and destruction of these infected cells, resulting in chronic active
hepatitis.
5. Superinfection. HBV carriers may develop hepatic superinfections with other
hepatotropic viruses. Sudden increases in the serum transaminases may repre-
sent superinfection with HAV, HCV, or HDV.
a. HAV infection may be a superinfection or simultaneous coinfection and is
usually associated with more severe and fulminant hepatitis.
b. HCV superinfections may be difficult to document accurately due to the
delay of detectability of HBcAb in acute HCV infections. However, the diag-
nosis can be made in the face of increased serum transaminases with reduc-
tion of HBsAg titers due to viral interference, and negative tests for IgM
HBcAb, IgM HAV, and anti-HDV. HCV DNA titers should be measured in
ongoing hepatitis.
c. HDV superinfection is discussed in section V.
d. Nonviral causes. It should always be kept in mind that sudden increases in
the serum transaminases may result from nonviral causes, such as drug and
alcohol hepatotoxicity, shock, congestive heart failure, right ventricular fail-
ure, and extrahepatic biliary obstruction.
6. The differential diagnosis of HBsAg-positive acute viral hepatitis is sum-
marized in Table 50-3.
7. Primary hepatocellular carcinoma (HCC). In the parts of the world where
HBV infection is endemic (e.g., Far East, sub-Saharan Africa), PHC is the lead-
ing cause of death from cancer. It appears that persistent HBV infection is the
leading cause of PHC. This suggests that HBV is an oncogenic virus. The pres-
ence of cirrhosis is not necessary for transformation into HCC.
a. Predisposing factors. Some of the predisposing factors for development
of HCC are race (e.g., Asians, Inuits), age at infection (especially infancy
and early childhood), chronic-persistent infection, and the presence of envi-
ronmental cocarcinogenic factors, such as ingestion of ethanol, cigarette
smoking, and possibly exposure to aflatoxin.

TABLE 50-3 Differential Diagnosis of HBsAg-Positive Acute Viral Hepatitis

Diagnosis Suggestive features

Acute hepatitis B IgM anti-HBc

Acute delta hepatitis (coinfection) IgM anti-HBc and anti-HDV
Chronic hepatitis B with
Acute hepatitis A IgM anti-HAV
Delta hepatitis (superinfection) Anti-HDV
Acute hepatitis C Anti-HCV
Reactivation Change in HBV markers
Other acute liver injury Drug or alcohol history
Evidence of other liver disease

HBc, hepatitis B core; HDV, hepatitis delta virus; HAV, hepatitis A virus; HCV, hepatitis C virus; HBV,
hepatitis B virus.
Adapted from Hoofnagle JH, Schafer DF. Serologic markers of hepatitis B virus infection. Semin Liver
Dis. 1986;6:1. Reprinted with permission.
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372 Part V: Specific Complaints and Disorders

b. Pathogenesis. It is thought that the integration of HBV-DNA into the

DNA of the hepatocyte leads to alterations in cellular gene expression and
cellular transformation. The resulting clones of transformed cells may
become autonomous and form HCC.
c. Diagnosis. Early clinical detection of HCC is difficult. However, determi-
nation of elevation of serum alpha-fetoprotein (AFP) levels and demonstra-
tion of a mass in the liver by ultrasonography (US) or computed tomogra-
phy (CT) scanning, or magnetic resonance imaging (MRI) are used currently
on a yearly basis with reasonable success. Tissue diagnosis can be made by
needle biopsy of the liver under US or CT guidance.
G. Treatment
1. Acute HBV infection. The treatment of acute HBV infection is supportive.
Most patients recover promptly. Those in whom FHF develops require inten-
sive care with appropriate treatment of the accompanying complications.
2. Chronic HBV infection. Advances have been made in the last decade in diag-
nosis and the treatment of chronic HBV infection. Chronic HBV infection is
diagnosed by confirming the presence of HBsAg at least on two occasions 6 or
more months apart. Serum transaminase levels, serologic tests, quantitative
HBV-DNA level, and the liver histology can be used to categorize patients
as belonging to one of the three phases of chronic hepatitis B infection
(Table 50-4). These phases are immune tolerant, immune reactive, and
inactive carrier.
It is important to note that patients do not remain in one of these groups
indefinitely. Thus, the liver enzymes, HBV-DNA levels, and HBeAg and HBsAg
status should be repeated every 6 to 12 months to detect changes in the status
of the patient.
Patients in the immune tolerant phase are characterized by having nor-
mal or minimally elevated transaminases, minimal to no necroinflammatory
activity on liver biopsy, positive HBeAg and negative HBeAb, and high HBV-
DNA levels (105 copies/mL) Patients in this phase rarely respond to antiviral
therapy and usually do not progress to severe liver disease. Antiviral therapy is
not currently recommended for patients in the immune tolerant phase.
However, many individuals in the immune tolerant phase will eventually enter
a more active phase called the immune reactive phase. This is heralded by a
rise in the transaminase levels and decreased HBV-DNA levels. Antiviral ther-
apy is recommended at this phase of the disease.

TABLE 50-4
Clinical Characteristics of Three Phases
of Chronic HBV Infection

Immune reactive
Immune
Clinical profile Inactive carrier tolerant HBeAg
HBeAg Mutant

HBeAg    
HBeAb    
HBV-DNA by 104 105 105 104
PCR
(copies/mL)
ALT Normal Normal Elevated Elevated
Liver biopsy Inactive Inactive Active Active
Treatment Not Not Recommended Recommended
recommended recommended
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Chapter 50: Viral Hepatitis 373

If the patient appears to be in the immune tolerant phase and has normal
transaminases, HBV-DNA 100,000 copies/mL, but has evidence of necroin-
flammation or fibrosis on liver biopsy, antiviral therapy is recommended.
There are data suggesting that high HBV-DNA levels may be associated
with increased risk of hepatocellular carcinoma (HCC) even in patients with no
active inflammation in the liver. This may be a reason to treat patients with
HBV-DNA greater than 10,000 copies/mL. However, this is still controversial
since there is no evidence currently that lowering HCV-DNA levels decreases
the risk of HCC in patients with normal transaminases. A family history of
HCC should lower the threshold for initiation of therapy in these patients.
In the immune reactive phase patients have variable degrees of elevation
of the transaminases, evidence of necroinflammatory changes on liver biopsy, and
often high HBV-DNA levels (105 copies/mL). Patients in this phase are the ones
most likely to benefit from antiviral therapy since, if left untreated, the ongoing
necroinflammatory activity will more likely progress to cirrhosis and HCC.
In the immune reactive phase, most patients are HBeAg positive and HBeAb
negative. However, there is a subgroup of patients who are HBeAg negative and
HBeAb positive despite high levels of HBV-DNA. This type of infection is referred
to HBeAg mutant infection. The mutation in these viruses occurs in the precore
or core promoter region of the HBV genome giving rise to a strain of HBeAg that
is incapable of producing HBeAg despite ongoing viral replication. Evolution of
this strain usually follows a period of active disease. Approximately 30% to 50%
of these patients intermittently have normal transaminases and low HBV-DNA
levels. Patients infected with the HBeAg mutant virus are less likely to transition
to an inactive state and appear to be at a greater risk of chronic liver disease com-
plications even with lower HBV-DNA levels (104 copies/mL). Antiviral therapy
in these patients often results in lowering HBV-DNA and transaminase levels and
results in histologic improvement. However, disease activity returns if antiviral
therapy is stopped. Thus, most of these patients require lifelong therapy.
It is important to differentiate between patients infected with HBeAg
mutant virus from inactive carriers who are also HBeAg negative and HBeAb
positive. Inactive carriers have persistently low HBV levels (104 copies/mL)
and normal transaminases.
Inactive carrier state is characterized by normal transaminases, positive
HBeAb, negative HBeAg, no evidence of inflammatory activity on liver biopsy,
and very low nondetectable levels (104 copies/mL) of HBV-DNA.
In this phase progression of liver damage does not occur and reactivation
is uncommon. These patients do not require antiviral therapy. However, these
patients should be followed clinically every 6–12 months.
Reactivation of viral replication and active HBV hepatitis may occur if the
patients are treated with chemotherapy, corticosteroids, or other agents that
may cause immunosuppression. Antiviral treatment of HBV should be insti-
tuted promptly with active disease.
The goal of therapy for chronic HBV infection ideally is to “cure” the
patient by completely eradicating the HB virus. This is seldom possible.
However, in a minority of patients, conversion from HBsAg to HBsAb may
occur spontaneously or during other antiviral therapies.
Achievable qualitative goals include symptomatic improvement, prevention
of long-term complications of chronic liver disease such as cirrhosis and HCC,
reduction of morbidity and mortality, and prevention of spread of infection of
HBV to others. Quantitatively, the goals of therapy include the suppression or
loss of HBV-DNA, seroconversion from HBeAg positivity to HBeAb positivity,
normalization of transaminases, and histologic improvement on liver biopsy.
a. Interferons (IFN) are endogenous glycoproteins with antiviral, antiprolifera-
tive, and immunoregulatory properties. Interferon-, derived from leuko-
cytes, and interferon-
, derived from fibroblasts, are similar and occupy the
same receptor on the target cells. Interferon-, derived from T cells, is differ-
ent and occupies a different receptor. Interferon has properties that have an
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374 Part V: Specific Complaints and Disorders

impact on both viral replication and host HLA class I expression. These
effects enhance the recognition of the infected hepatocytes by cytolytic T
lymphocytes. Thus, both the antiviral and the immunoregulatory effects of
interferons are necessary for effective antiviral therapy of chronic hepatitis B.
b. Recombinant interferon- has been used with some success in the treat-
ment of chronic HBV. In several studies, when 5 million units of IFN- were
given subcutaneously (SC) every day or 10 million units three times weekly
for 4 to 6 months, approximately 28% to 35% of patients experienced a
sustained loss of HBV-DNA, compared with none of the untreated, control
patients. The loss of HBV-DNA is noted to occur after 6 to 12 weeks of
interferon therapy and is accompanied by an acute hepatitislike elevation of
aminotransferase activity, which suggests enhanced cytolytic T-cell (CTL)
activity against virus-infected hepatocytes.
Outside of the above studies, treatment of patients with chronic HBV
with recombinant IFN- has not been very successful. The drug and treat-
ment are poorly tolerated by patients and the above results have not been
duplicated.
c. In more recent studies, treatment with Pegasys or PEG-IFN2b (polyethylene
glycol interferon-2b) at a dose of 180 g/week administered subcuta-
neously for 12 months gave more promising results (32% HBeAg serocon-
version to HBeAb and 3% HBsAg conversion to HBsAb). Patients with
HBV genotypes A and B seem to have greater success with PEG-IFN ther-
apy than with the other HBV genotypes. Also, combination therapy or the
addition of a nucleoside (i.e., Lamivudine, to PEG-IFN therapy) did not
increase the therapeutic yield.
d. Side effects of interferon therapy. The side effects of interferon therapy
are systemic flulike symptoms, bone marrow suppression, autoimmune
phenomena (e.g., autoimmune thyroiditis, asymptomatic appearance of
autoantibodies), and infections related to granulocytopenia, and psychiatric
disturbances, especially depression.
e. Nucleoside and nucleotides. Lamivudine is the first oral nucleoside
analog approved by the FDA to treat HBV infection. It works by inhibiting
HBV-DNA replication when HBeAg-positive patients are treated with
lamivudine at a dose of 100 mg/d over 1 year. HBeAb seroconversion is
observed in approximately 15% to 18% of patients. Longer duration of
therapy has been associated with higher HBeAb conversion rates. However,
the treatment with lamivudine has limited efficacy due to the development
of HBV-YMDD mutants that are resistant to the drug. The rate of resis-
tance is 20% at the end of the first year of treatment and goes up to 70%
in 3 or 4 years. Relapses of active hepatitis are common with the develop-
ment of YMDD mutants and/or after discontinuation of therapy. In addi-
tion, the development of lamivudine resistance also negatively impacts the
ability of the virus to respond to newer, more potent antiviral drugs.
Adefovir dipivoxil is an oral nucleotide that inhibits HBV-DNA repli-
cation by suppressing HBV-DNA polymerase. One-year therapy of HBeAg-
positive patients with adefovir 10 mg daily results in 12% seroconversion to
HBeAb, and the seroconversion increases up to 40% after 4 years of therapy.
Determination of early response to therapy (by 6 months) is recommended
since 50% of patients may not respond as indicated by a decrease of HBV-
DNA viral load to 4/log copies/mL.
Resistance to adefovir is less than that toward lamivudine (1.5%–2%
per year); however, it rises to 20% to 25% after 5 years of treatment.
Fortunately, adefovir-resistant mutants are sensitive to lamivudine and ade-
fovir is active against lamivudine-resistant strains of HBV. Resistant patients
are treated with combination therapy. Adefovir as well as lamivudine may
be used effectively in the treatment of HBeAg-negative patients. Monitoring
of renal function is recommended during therapy.
Entecavir is a newer nucleoside analog approved by the FDA for use
in the treatment of both HBeAg-positive and -negative patients. It has more
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Chapter 50: Viral Hepatitis 375

potent antiviral activity against HBV than lamivudine and adefovir at doses
of 0.5 mg or 1 mg daily taken orally. Approximately 20% of HBeAg-positive
patients achieve HBe antibody seroconversion by the end of 1 year of treat-
ment. The response increases up to 54% by the end of the second year of
therapy with no emergence of resistance. Histologic improvement has also
been demonstrated in these patients. In patients infected with lamivudine-
resistant HBV mutants, 1-mg daily dose is effective. Unfortunately, up to 7%
of patients infected with HBV resistant to lamivudine may also be cross-
resistant to entecavir as well. Entecavir has no antiviral activity against HIV.
Tenofovir is a nucleotide analog which has been used in HIV treat-
ment. It has been shown to be effective for the treatment of HBV and
lamivudine-resistant HBV. It has a more potent treatment potential than
adefovir with no side effects. It is ideal for treatment of patients coinfected
with both HBV and HIV. However, resistant HBV develops similarly to
Lamivudine after 2 years of therapy.
Newer agents include telbivudine 600 mg daily, an oral nucleoside
analog that has been shown to have superior therapeutic benefit compared
to lamivudine 100 mg daily in HBeAg-positive and -negative patients. So for
no resistance has been seen after 2 years of therapy.
Clevudine and pradefovir are also close to being approved by FDA
for the treatment of chronic HBV infection.
In summary, there is currently no standard therapy for patients with
chronic HBV infection who are in immune reactive phase. In selected
patients, especially those who were infected after early childhood and with
no contraindication for interferon therapy, a one-year course of therapy
with pegylated interferon alfa-2-a may provide a good chance of HBeAg
seroconversion with a finite duration of treatment. This treatment has been
shown to be more effective in patients infected with HBV genotype A.
In others, the most potent oral antiviral agent available with no or low
resistance profile should be selected. In patients who clear HBV-DNA and
achieve seroconversion of HBeAg to HBeAb, 6 to 12 months of further ther-
apy is recommended. For patients with HBeAg-negative chronic infection,
oral therapy with a nucleotide that has the least resistance profile should be
selected since the treatment is expected to be indefinite.
Patients who have developed lamivudine resistance should be treated
with combination therapy of adefovir or tenofovir or switched to entecavir
at 1 mg daily. It is expected that combination therapy will be used in most
patients in the future.
H. Hepatitis B vaccine and prophylaxis
1. Hepatitis B vaccine. HBV infection as acute or chronic disease is a major
public health problem throughout the world. In Asia and Africa, HBV infection
occurs primarily perinatally or in childhood, resulting in a 10% to 15% rate of
chronic infection in the adult population. In the developed countries where the
infection occurs mostly in adults, the chronic infection rate is lower (1%–10%)
but still results in sizable morbidity and mortality.
Hepatitis B vaccine is indicated for immunization against infection caused
by all known subtypes of HBV. Because hepatitis D (caused by the delta virus)
does not occur in the absence of HBV infection, it can be expected that hepati-
tis D will also be prevented by hepatitis B vaccination. Immunization is recom-
mended for people of all ages, especially those who are or will be at increased
risk of exposure to HBV (Table 50-4).
a. The first-generation hepatitis B vaccines are derived from the plasma of
chronic HBsAg carriers who are HBeAg negative. The vaccines are composed
of purified HBsAg and induce protective HBsAb but no antibodies to the other
HBV antigens. They have been available since 1980 and have been considered
both effective and safe. Due to new concerns about the safety of this human
plasma-derived vaccine, however, it is no longer in use in the United States.
b. The second-generation hepatitis B vaccines are manufactured using
other methods (i.e., using HBsAg produced by other cell lines or organisms
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376 Part V: Specific Complaints and Disorders

through recombinant DNA technology). The recombinant hepatitis B vaccine

produced from yeast has been studied for safety and efficacy in humans and
is as good as the plasma-derived hepatitis B vaccine. It has replaced the
plasma-derived vaccine in the United States and is administered to children
as part of the complete vaccination schedule.
There are two recombinant hepatitis B vaccines currently in use in the
United States. Engerix-B contains 20 mg/mL, and Recombivax HB, 10
mg/mL of HBsAg protein. The dose for Engerix-B for neonates and children
up to 10 years is 0.5 mL (10 mg), and for older children and adults, 1.0 mL
(20 mg) is administered to the deltoid muscle at 0, 1, and 6 months. The
vaccine is administered SC if the patient has a bleeding diathesis (e.g., hemo-
philia or a coagulopathy). An alternative dosing schedule with injections at
0, 1, and 2 months may be used for some populations (e.g., neonates born
of HBV-infected mothers, others who have or might have been exposed to
HBV, and travelers to high-risk areas). On this alternative schedule, an addi-
tional dose at 12 months is recommended for infants born of infected moth-
ers and for others for whom prolonged maintenance of protective titers is
desired. For hemodialysis patients, the dose is increased to 40 mg (2 mL)
because the vaccine-induced protection is less complete and may persist only
as long as antibody levels remain above 10 mIU/mL.
Recombivax HB is given in a similar dosing schedule to Engerix-B
(0, 1, and 6 months) using different volumes (Table 50-5).
Protection against HBV infection by hepatitis B vaccines correlates well
with HBsAb response produced in the host. Protection may not be complete
before the antibody develops in the first few months after the first dose of the
vaccine. The efficacy is increased if the intramuscular injection is given in the
deltoid muscle rather than in the buttock. After immunization, 95% of healthy
individuals develop the HBsAb. The antibody response depends on the indi-
vidual’s age and immune competence; younger persons respond better than
older persons. Children and neonates respond quite well; however, immuno-
deficient patients such as those on hemodialysis or chemotherapy do not respond
as well as healthy individuals. Most persons have substantial HBsAb levels
even 5 years after their initial vaccination. The duration of the persistence cor-
relates with the level of antibody response after the immunization. Thus, the
timing of the booster doses remains controversial. However, levels of antibody
below 10 mIU/mL sample-to-negative-control (S/N) counts per minute by
radioimmunoassay may not be protective. This level may be used as a guide in
individuals susceptible to the HBV infection for booster administration.
Interestingly, in healthy individuals even vaccines with minimal or unde-
tectable HBsAb long after vaccination appear to be protective against clinically
apparent HBV and chronic HBV infection. Based on the apparent long-term
protection provided by vaccination and the absence of data demonstrating that
booster immunization has an advantage over natural exposure, the U.S. Public
Health Service has issued no recommendations for booster vaccination for
healthy people. Hemodialysis patients and patients with immunosuppression
may need booster injections when serum levels of HBsAb fall below 10 mIU/mL.
The recommended booster dose of Engerix-B is 10 mg for neonates
and children up to 11 years of age, 20 mg for older children and adults, and
40 mg for hemodialysis patients. The dose of Recombivax-B for booster
injection for hemodialysis patients is 40 mg; for other age groups, the dose
is the same as in the initial injections.
A combination vaccine (Twinrix-Glaxo Smith Kline) containing
20 g of HBsAg protein (Energix-B) and 720 ELISA units of inactivated
hepatitis A virus (Havrix) provides dual protection against infection with
HVA and SBV with three injections spaced 0, 1, and 6 months apart. It is
indicated for all individuals with risk of both HAV and HBV infection.
It is recommended that all children receive HAV and HBV vaccination
routinely.
 79466_CH50.qxd

TABLE 50-5 Recommended Dose and Schedule of Hepatitis B Vaccines

Recombivax HB
1/2/08

Group Formulation 0 mo 1 mo 6 mo

Birth through 10 years of age 10 g/mL 0.25 mL (2.5 g) 0.25 mL (2.5 g) 0.25 mL (2.5 g)
11–19 years of age 10 g/mL 0.5 mL (5 g) 0.5 mL (5 g) 0.5 mL (5 g)
1:32 PM

20 years of age 10 g/ml 1.0 mL (10 g) 1.0 mL (10 g) 1.0 mL (10 g)
Hemodialysis patients 40 g/mL 1.0 mL (40 g) 1.0 mL (40 g) 1.0 mL (40 g)
Infants born to HBsAg-positive mothers 10 g/mL 0.5 mL (5 g)  0.5 mL (5 g) 0.5 mL (5 g)
0.5 mL HBIG
Page 377

Engerix-B

Group Formulation 0 mo 1 mo 2 mo/6 moa 12 mob

Birth through 10 years of age 20 g/mL 0.5 mL (10 g) 0.5 mL (10 g) 0.5 mL (10 g)
11 years of age 20 g/mL 1.0 mL (20 g) 1.0 mL (20 g) 1.0 mL (20 g)
Hemodialysis patients 20 g/mL 2.0 mL (40 g) 2.0 mL (40 g) 2.0 mL (40 g)
Infants born to HBsAg-positive mothers 20 g/mL 0.5 mL (10 g)  0.5 mL (10 g) 0.5 mL (10 g) 0.5 mL (10 g)
20 g/mL 0.5 mL HBIG
HBIG prophylaxis-postexposure 0.06 mL/kg

aSee Section VI for choice of 2 mo versus 6 mo for third dose.

bSee Section VI for indication.
HB, hepatitis B; HBsAg, hepatitis B surface antigen; HBIG, hepatitis B immune globulin.

377
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378 Part V: Specific Complaints and Disorders

2. Immune prophylaxis. Hepatitis B vaccine alone is recommended for preexpo-

sure prophylaxis of susceptible individuals. When there is both an immediate
and a long-term risk, hepatitis B immune globulin (HBIG) and hepatitis B vac-
cine (passive–active immunization) should be given in separate injection sites.
This is recommended for people who have been exposed to HBV (a) through
percutaneous (needle stick), ocular, or mucous membrane exposure to blood
known or presumed to contain HBsAg; (b) from human bites by known or pre-
sumed HBsAg carriers that penetrate the skin; or (c) following intimate sexual
contact with known or presumed HBsAg carriers. The HBIG (0.06 mL/kg)
should be given intramuscularly as soon as possible after exposure—within
24 hours if possible. Hepatitis B vaccine (Engerix-B, Recombivax HB) should
be given intramuscularly at a separate site within 7 days of exposure, and sec-
ond and third doses should be given 1 and 6 months, respectively, after the first
dose. An alternative schedule for Engerix-B is 0, 1, and 2 months.

V. HEPATITIS D (THE DELTA AGENT). The hepatitis D virus (HDV) was discovered in
Italy by Mario Rizzetto in 1977 during an investigation of the distribution of the HBV
antigens in liver biopsy specimens of patients chronically infected with HBV. He
described a new antigen in the nuclei of infected hepatocytes that was obligatorily asso-
ciated with HBsAg. This new antigen was named delta. Subsequently, large amounts of
this antigen were extracted from the liver of a patient with chronic HBV infection and
the delta agent. Using this antigen, a specific and sensitive radioimmunoassay was
developed for the detection of both the delta antigen in liver biopsy specimens and the
antibody directed at the delta antigen in the serum of infected individuals.
A. Epidemiology. HDV has a global distribution. It has been found to be endemic in the
Mediterranean basin, southern Italy, eastern Europe, the Middle East, Asia, western
Africa, Australia, New Zealand, islands in the South Pacific, and the Amazon basin.
Epidemics of HDV have been reported in North and South America, Colombia, and
Venezuela. In endemic regions, transmission occurs from close person-to-person con-
tact with transmucosal exchange of body fluids. Perinatal transmission is rare. In
nonendemic areas such as northern Europe and North America, transmission is by
direct inoculation from infected blood products. Any population that has a high fre-
quency of HBV infection is vulnerable to HDV infection, especially IV drug abusers,
hemophiliacs, hemodialysis patients, homosexual men, and prisoners.
B. Pathogenesis. HDV is a defective hepatotropic RNA virus that requires the pres-
ence of HBV as a “helper virus” for its pathogenicity. It replicates only in hosts
who have a concomitant HBV infection. HDV is a 36-nm spherical particle con-
taining the D antigen and a single-stranded RNA molecule in the interior, which is
coated by HBsAg on the exterior. The structure of HDV is shown in Figure 50-7.

Figure 50-7. The delta agent. HBsAg, hepatitis B surface antigen; RNA, ribonucleic acid. (From
Hoofnagle JH. Delta hepatitis and the delta agent in the American Association for the Study of Liver
Diseases: Hepatobiliary disease–current concepts and controversies [postgraduate course] 1983.)
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Chapter 50: Viral Hepatitis 379

HDV seems to have a direct cytopathic effect on hepatocytes rather than causing
immune-mediated hepatocyte damage, as results from HBV infection.
Individuals who are immune to HBV are protected from HDV infection.
However, persons who are susceptible to both HBV and HDV infection (negative for
all markers of HBV and HDV) and who are carriers of HBsAg may get hepatitis D.
C. Acute coinfection. In patients simultaneously exposed to HBV and HDV, coin-
fection occurs. The disease is usually self-limited, and the clinical course resembles
that of classic acute hepatitis from HBV. Occasionally, coinfection results in exten-
sive liver damage and FHF. This occurs more commonly in IV drug abusers. The
diagnosis of coinfection with HBV and HDV is best made by the detection of
positive titers for IgM HDV antibody, HBsAg, and IgM HBcAb, HBV-DNA and
HDV-RNA (available only in research labs) in the patient’s serum.
The coinfection may manifest itself as a single bout of elevated transaminases
or more frequently as a biphasic illness with two separate transaminase peaks sep-
arated by weeks or even months. Expression of the disease due to HDV must wait
for hepatocytes to be infected first by HBV. If the inoculations with the two viruses
are close in time, HDV overwhelms the synthesis of HBV gene products in the
HBV- and HDV-infected cells and causes the first bout of hepatitis. The second
bout of hepatitis is caused by HBV expression. If the two peaks are very close in
time, massive hepatic necrosis may occur and may be fatal to the patient. If the two
bouts are separated by months, the first bout is usually from HDV. In either event,
both viruses usually are cleared, and the patient completely recovers and develops
both an HDVAb and HBsAb. Figure 50-8 summarizes the course of a case of acute
HDV coinfection.
D. Superinfection. In chronic carriers of HBsAg, HDV superinfection usually causes
severe liver disease, even FHF. In fact, 60% of FHF cases thought to be from HBV
are actually due to HDV superinfection. Because most of the hepatocytes are
already infected by HBV and contain HBsAg, HDV disseminates extensively and

Figure 50-8. Typical course of acute delta hepatitis coinfection. ALT, alanine aminotransferase;
HBsAg, hepatitis B surface antigen; HDV-RNA, hepatitis delta virus ribonucleic acid; anti-HDV,
antibody to HDV; anti-HBs, antibody to HBsAg. (From Hoofnagle JH, DiBisceglie AM. Serologic diag-
nosis of acute and chronic viral hepatitis. Semin Liver Dis. 1991;11:79. Reprinted with permission.)
79466_CH50.qxd 1/2/08 1:32 PM Page 380

380 Part V: Specific Complaints and Disorders

causes massive hepatic necrosis. Clinically, the disease may resemble fulminant type
B hepatitis but can be recognized to be D hepatitis superinfection with the serologic
presence of a strong IgM and IgG HDAb response and negative IgM HBcAb.
Anti-HDV arises late during acute HDV and is usually not detectable in serum
at the onset of symptoms. In some cases of self-limited hepatitis D, anti-HDV is not
detectable. For these reasons the serologic diagnosis of acute hepatitis D is often
unsatisfactory and requires testing of both acute- and convalescent-phase serum
samples. HDV antigen is present in both the serum and the liver of infected patients.
Immune blotting for serum HDV antigen is available only in the research setting.
However, the HDV antigen is detectable in the nuclei of hepatocytes and weakly in
the cytoplasm in almost all patients with chronic hepatitis D. It has been detected
in many pathology laboratories by a variety of immunostaining techniques, which
can be applied to formalin-fixed, paraffin-embedded sections.
The hepatitis in these individuals tends to become chronic in almost all cases.
In fact, very few patients clear both HBV and HDV after the superinfection. In
HDV superinfection of HBsAg carriers, patients with negative HBcAg serology are
probably the only ones in whom chronic HDV infection develops.
E. Chronic hepatitis D is characterized by a history of acute hepatitis. If the patient
was a “silent carrier” of HBsAg, this acute illness may be the first episode of
hepatitis for the patient. If the patient had chronic hepatitis from HBV, the disease
may be thought of as an exacerbation or a superimposed hepatitis. Figure 50-9
summarizes the typical course of acute delta hepatitis superinfection.
Unfortunately, chronic HDV infection accelerates the progression of liver dis-
ease both in patients with ongoing chronic liver disease from HBV and in silent
carriers of HBsAg. Most patients develop chronic active hepatitis, which often
progresses to cirrhosis over a short span of time. The detection of high titers of
anti-HDV is strongly suggestive of chronic HDV.

Figure 50-9. Typical course of acute delta hepatitis superinfection. ALT, alanine aminotransferase;
HDV-RNA, hepatitis delta virus ribonucleic acid; HBsAg, hepatitis B surface antigen; anti-HDV, anti-
body to HDV. (From Hoofnagle JH, DiBisceglie AM. Serologic diagnosis of acute and chronic viral
hepatitis. Semin Liver Dis. 1991;11:79. Reprinted with permission.)
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Chapter 50: Viral Hepatitis 381

F. Treatment. Currently there is no specific therapy for delta hepatitis, and the treat-
ment for all forms of the disease is supportive. Steroids and other immunosup-
pressive drugs have not been effective. Interferon- 9 MU three times weekly
results in initial response in 50% of patients, but biochemical and virologic
responses are rarely sustained. Monitoring of interferon- therapy in chronic HDV
is best accomplished by sequential testing for HDV-RNA in serum or in the liver.
Currently, the control of delta infection depends on its prevention. Because
HDV infection requires the helper function of HBV, prevention of HBV infection
and the HBsAg carrier state will also prevent HDV infection. Thus, the hepatitis B
vaccine helps prevent new HBV and HDV infections. However, the large number
of people carrying the HBsAg remains at risk for development of delta hepatitis.
A vaccine against HDV is not yet available.

VI. HEPATITIS C
A. Epidemiology. Hepatitis C virus (HCV), identified in 1988 is a single-stranded
enveloped RNA virus that belongs to the Flaviviridae family. It appears to be
responsible for most instances of parenterally transmitted non-A, non-B hepatitis.
The virus seems to mutate frequently and appear in many subtypes. Table 50-6
summarizes the differential diagnosis of elevated liver tests suggesting non-A, non-B
hepatitis other than hepatitis C.
HCV is associated with transfusions of contaminated blood and blood prod-
ucts such as plasma, factor VIII, factor IX, fibrinogen, cryoprecipitate, and immune
globulin prior to 1990. HCV is also transmitted by IV drug abuse, hemodialysis,
and organ transplantation. It appears to be transmitted rarely by familial, sexual,
or maternal–infant exposure. Heterosexual transmission seems to be much less
frequent than homosexual transmission of the virus.
Health care workers exposed to a patient or the blood of a patient infected
with HCV may acquire hepatitis C either from an accidental needle stick or with-
out such an incident; however, the risk in such cases seems to be less than 10%.
This occurrence has been documented in dialysis and oncology units and in
plasmapheresis centers. Sporadic instances of hepatitis C occur and may account
for 6% to 36% of the sporadic cases of hepatitis seen in urban areas. There may
be unnoted percutaneous exposure among such patients (i.e., with use of intranasal
cocaine, tattooing, body piercing, and exposure to blood through sharing tooth-
brushes, razors, or other personal items).

Differential Diagnosis of Elevated Liver Tests

TABLE 50-6
Suggesting Non-A, Non-B Hepatitis

Disease Diagnostic features

Mononucleosis Lymphocytosis, IgM anti-VCA, Monospot

Cytomegalovirus Lymphocytosis, anti-cytomegalovirus
Syphilis VDRL test
Cholangitis History and clinical course
Drug injury History of drug intake
Autoimmune chronic active hepatitis Antinuclear antibody, immunoglobulins
Ischemic liver injury History, lactic dehydrogenase levels
Budd-Chiari syndrome History
Wilson’s disease History, ceruloplasmin, copper

Anti-VCA
antibody to the viral capsid antigen of Epstein-Barr virus.
From Hoofnagle JH, Schafer DF. Serologic markers of hepatitis B virus infection. Semin Liver Dis.
1986;6:1. Reprinted with permission.
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382 Part V: Specific Complaints and Disorders

Vertical transmission of HCV from mother to child is uncommon (5% except

for persons coinfected with HIV [50%]). Maternal HCV Ab crosses the placenta
and HCV Ab may be detected in the child up to 1 year after birth. To detect active
infection in the child, the presence of HCV-RNA by PCR needs to be determined.
Cesarean section decreases the transmission of HCV from the mother to the child.
The disease is found worldwide and appears to be almost as common in eco-
nomically developed countries as it is in underdeveloped countries.
HCV preferentially replicates in hepatocytes; however, replication extrahep-
atic sties also have been demonstrated. HCV inherently has a high mutation rate
that results in considerable heterogeneity throughout its genome. It is classified
into 6 genotypes that are genetically distinct groups of viral isolates that have
arisen during the evolution of the virus. There are also 40 subtypes (i.e., a, b).
In the United States, genotype 1 is most prevalent (approximately 70% of
HCV infections) and is associated with lower response rates to interferon therapy
than the other genotypes. Genotype 2 accounts for 15% and genotype 3 for
10% of the HCV-infected patients in the United States. Genotype 4 is the most
common genotype in Egypt and the Middle East. Genotype 5 is found in South
Africa, and genotype 6 in Southeast Asia. Regardless of ethnicity, those infected
with type 1 HCV are found to have higher circulating levels of HCV and a greater
likelihood of developing cirrhosis and HCC.
B. Clinical presentation
1. Acute hepatitis
a. The mean incubation period for transfusion-associated hepatitis C is 7 to
8 weeks with a range of 2 to 26 weeks. Shorter incubation periods of 1 to
2 weeks have also been recorded.
b. The acute illness associated with hepatitis C usually cannot be distinguished
from hepatitis caused by other heterotropic viruses. However, it tends to be
less severe. Usually patients complain of flulike symptoms, easy fatigability,
malaise, and anorexia with occasional nausea and vomiting; fever, arthral-
gia, and skin rash are rare.
c. Approximately 25% of patients with hepatitis C are icteric. Jaundice usually
lasts less than a month. The serum transaminase (ALT, AST) levels are only
moderately elevated (800 IU/L).
d. Transient agranulocytosis and aplastic anemia have been observed in
patients with hepatitis C.
e. A clinical feature characteristic of hepatitis C is its episodic, fluctuating pat-
tern of serum transaminase (ALT, AST) activity. Periods of elevation of these
enzyme levels are interrupted by months of normal or near-normal levels of
liver enzyme activity (Fig. 50-10).
2. Chronic disease
a. Long-term follow-up studies in patients with hepatitis C have revealed that
at least 90% of patients infected with HCV have chronic disease. The dis-
ease may continue to appear to resolve both biochemically and histologi-
cally, followed by intermittent or constant elevation of serum transaminases.
Persistent viremia can prevail in the presence or absence of elevated ALT
activity. In fact, spontaneous total resolution of the disease may occur in
only a small proportion of infected individuals.
b. The progression to chronic hepatitis cannot be predicted from the clinical or
biochemical severity of the acute illness. Anicteric as well as icteric disease
may become chronic.
c. In most studies, the frequency of development of chronic liver disease from
transfusion-associated hepatitis C is 85% to 90%. When biopsied, approxi-
mately 70% to 80% of these patients have chronic active hepatitis, and 10%
to 20% have cirrhosis. The chronic active hepatitis in these patients is pro-
gressive and progresses to cirrhosis in most cases over 10 to 30 years.
d. Cofactors such as concomitant alcoholism, hemochromatosis, and chronic
hepatitis B coinfection with HIV are important contributors to progressive
liver disease and cirrhosis in patients with chronic hepatitis C.
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Chapter 50: Viral Hepatitis 383

Figure 50-10. A case of acute hepatitis C that progressed to chronic infection and disease. ALT,
alanine aminotransferase; HCV-RNA, hepatitis C virus ribonucleic acid; anti-HCV, antibody to hepati-
tis C virus; PCR, polymerase chain reaction. (From Hoofnagle JH, DiBisceglie AM. Serologic diag-
nosis of acute and chronic renal hepatitis. Semin Liver Dis. 1991;11:78. Reprinted with permission.)

e. Several studies have linked essential mixed cryoglobulinemia (EMC) (an

immune complex vasculitis associated with joint, skin, and sometimes kid-
ney involvement), porphyria cutanea tarda (PCT), and lymph-proliferative
diseases such as lymphoma and lymphocytic leukemia with HCV infection.
3. Hepatitis C and hepatocellular carcinoma. There is convincing evidence that
HCV infection is associated with the development of hepatocellular carcinoma.
Several patients have been reported to develop hepatocellular carcinoma 9 to 18
years after the onset of transfusion-associated hepatitis C.
C. Diagnosis
1. Serologic tests. Serologic assays are used for screening for HCV infection and
for first-line diagnosis. There are two types of anti-HCV (HCVAb) assays, the
enzyme immunoassay (EIA) and the recombinant immunoblot assay (RIBA).
Both detect antibodies to different HCV antigens. Three successive generations
of EIAs have resulted in increased sensitivity in detecting HCVAb and thus,
with the third-generation EIA confirmatory, RIBA testing is rarely needed.
2. Virologic tests. Currently there is no method available for culturing HCV
from serum samples. Viral detection is accomplished by amplification methods
for HCV-RNA such as with the polymerase chain reaction (PCR). Qualitative
PCR testing for HCV-RNA is very sensitive and can detect as few as 100 viral
copies/mL within one week of infection with HCV. The quantitative PCR test-
ing allows the measurement of serum HCV-RRN levels (viral load) and are
used in assessing the effectiveness of antiviral therapy.
3. Histopathologic examination of liver biopsy specimens from HCV-infected
patients has been standardized to differentiate and quantitate inflammation and
fibrosis. These are expressed in fractions of 0-4/4, with the high numerator used
for increasing severity.
D. Treatment of chronic HCV. There is no vaccine against HCV and there is no reli-
able postexposure prophylaxis. So prevention of spread of HCV depends on diag-
nosing and treating persons who are likely to be infected. Infected patients should
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384 Part V: Specific Complaints and Disorders

be vaccinated against HAV and HBV because of the high risk of severe liver disease
if superinfection occurs with these viruses.
1. Monotherapy. Treatment of chronic HCV infection is based on parenteral
interferon (IFN) therapy. Initially, the treatment consisted of IFN monotherapy
using 3 million units given subcutaneously three times per week for 6 months
and yielded about 10% end of treatment response (ETR). However, with this
therapy, there is a 90 % relapse rate 6 months after cessation of therapy, giv-
ing a sustained viral response (SVR) of about 3%. When this treatment was
extended to 12 months, the SVR increased to about 10%.
2. Combination therapy
a. Combination therapy using IFN- with ribavirin, an oral guanosine nucleoside
analog, has been shown to greatly improve sustained response rates in naive
and relapsing patients. In treatment of naive patients with IFN- at a dose of 3
million units given sc three times a week, in combination with oral ribavirin 800
to 1,200 mg per day for 12 months, achieves sustained virologic response rates
of approximately 30%. These rates are higher (up to 40%–50%) for patients
with low viral loads and with HCV genotypes II and III. In patients with HCV
genotypes II and III, combination therapy for 24 weeks achieves the same effi-
cacy as combination therapy administered for 48 weeks. The impact of combi-
nation therapy on interferon monotherapy nonresponders is less impressive.
b. The current standard of therapy for a patient with chronic HVC is a
combination of pegylated interferon and ribavirin.
The addition of polyethylene glycol (PEG) to interferon increases the
half-life of the drug in the patient, thereby allowing once-weekly adminis-
tration. When pegylated IFN therapy is combined with oral ribavirin, the
rate of SVR is greatly increased especially in patients with HCV genotype 1.
The optimal dose of PEG interferon--2b (PEG-IFN) is 1.5 g/kg per week
sc and for PEG interferon--2a (Pegasys) is 180 g per week sc. The pre-
ferred ribavirin dose is weight-based (10.6 mg/kg) for PEG-IFN and with
Pegasys it is 1,000 to 1,200 mg per day.
For naive patients with HCV genotype 1 infection, treatment is recom-
mended for 48 weeks. Early viral response is assessed by quantitative deter-
mination of HCV-RNA by PCR (viral load) at the end of the first month. In
patients who have undetectable viral load after one month of therapy, the
SVR is 90%.
For patients with undetectable viral load at 3 months of therapy or
those with a 2 log drop in the viral load, the SVR is in the range of 48%.
Patients with HCV genotypes 2 and 3 with the same treatment plan
have SVR 80% after treatment.
Patients who fail to respond to above therapy or those who relapse after
treatment may be offered therapies involving longer duration of therapy, higher
ribavirin and interferon doses, and/or treatment with consensus interferon
(Infergen) which is a synthetic interferon at a dose of 15 g sc daily and
ribovirim for 48 weeks. These treatments are still under study and are evolving.
c. There are numerous side effects of interferon and ribavirin therapy. Aside
from the flulike symptoms, fatigue, and depression, interferon causes
cytopenia and autoimmune thyroiditis. Ribavirin causes hemolytic anemia
and psychiatric and mood disorders and insomnia. It is paramount that
these side effects are treated promptly and effectively for patients’ comfort
and to ensure patient compliance. Growth factors, especially erythropoietin
is being used in many patients to alleviate anemia. Patients with mood dis-
orders or changes need to be treated with appropriate drugs and should be
followed by mental health professionals as needed.
Patients with HIV and HCV coinfection should be treated for HCV as
well as HIV.
Since ribavirin is teratogenic, patients who are taking ribavirin and are
sexually active need to use barrier contraception during the treatment and
6 months posttherapy.
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Chapter 50: Viral Hepatitis 385

Newer oral agents are being developed to enhance the eradication of

HCV in infected patients. Polymerase and protease inhibitors and other
antiviral drugs show promise. However, these agents, when used alone, have
not been shown to be effective in achieving SVR due to the rapid develop-
ment of viral resistance. When added to the current regimen of interferon
and ribavirin-based therapies, though, they seem to enhance SVR and also
possibly shorten the treatment duration.

VII. The hepatitis E virus (HEV) is a small (27–30 nm) RNA virus that causes acute epi-
demics of enterically transmitted hepatitis in underdeveloped areas of the world. HEV
is transmitted by the fecal-oral route and is associated with contamination of food or
water sources.
A. Diagnosis. HEV antigen can be detected in the liver, bile, and stool during the
incubation period and symptomatic phase of hepatitis E. Anti-HEV can be detected
by immune electron microscopy in serum during acute illness. Titers of anti-HEV
rise during convalescence; however, immunity to reinfection may not be absolute.
HEV-RNA has been cloned. Recombinant immunoassays are being developed for
both anti-HEV and HEV antigen. Diagnosis of acute HEV can be made in patients
presenting with acute hepatitis with a recent history of living in or travel to
endemic areas of the world (Central and South America, Mexico, Asia, Africa, and
the Middle East) and absence of serologic markers of acute hepatitis A, B, and C.
B. Clinical course. HEV causes an acute hepatitis in adults with varying severity. In
pregnant women, especially in the third trimester, it is associated with high
mortality—approximately 10% to 35% of instances. HEV infection does not lead
to chronic hepatitis or to the carrier state.

Selected Readings
Berg T, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks
of peginterferon-alpha-2a plus riboviron. Gastroenterology. 2006;130:1086–1097.
Chen CJ, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B DNA
level. JAMA. 2006;295(1):65–73.
Derenci P. Predictors of response to therapy for chronic hepatitis C. Semin Liver Dis. 2004;24(suppl
2):25–31.
Fartoux L, et al. Effect of prolonged interferon therapy on the outcome of hepatitis C virus-related
cirrhosis: A randomized trial. Clin Gastroenterol Hepatol. 2007;Apr;5:502–507.
Hoofnagle JH, et al. Management of hepatitis B: summary of a clinical research workshop. Hepatology.
2007;45:1056–1075.
Krawczynski K, et al. Hepatitis E virus: Epidemiology, clinical and pathological features, diagnosis and
experimental animal models. In: Thomas HC, Lemon S, Zuckerman AJ, eds. Viral Hepatitis. 3rd ed.
Malden, Mass.: Blackwell; 2005:624–634.
Lok ASF. Navigating hepatitis B treatments. Gastroenterol. 2007;132:1586–1594.
Lok ASF and McMahon BJ. AASLD practice guidelines: Chronic hepatitis B. Hepatology. 2007;
45:507–539.
McLean OR, et al. Acute Hepatitis C: Diagnosis and management. Pract Gastroenterol. 2007;(Sept)66–77.
Niro GA, et al. Peglyated interferon alpha-2b as monotherapy or in combination with ribovirin in
chronic hepatitis delta. Hepatology. 2006;44:713–720.
Oldfield EC, et al. The A’s and B’s of vaccine—Preventable hepatitis: Improving prevention in high risk
adults. Rev Gastroenterol Disord. 2007;7(1):1–21.
Pungpapong S, et al. Natural history of hepatitis B virus infection: an update for clinicians. Mayo Clin
Proc. 2007;82(8):967–975.
Re VL, et al. Prevalence, risk factors, and outcomes for occult hepatitis B virus infection among HIV-
infected patients. J Acquir Immune Defic Syndr. 2007;44:315–320.
Sarazin C, et al. A normal hepatitis C virus protense inhibitor, plus pegylated interferon alpha-2b for
genotype 1 nonresponders. Gastroenterology. 2007;132:1270–1278.
Shiffman ML, et al. Peginterferon Alpha-2a and Riborvirin for 16 or 24 weeks in HCV genetype 2 or 3.
N Eng J Med. 2007;357:124–134.
Shresthas MR, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med.
2007;356:895–903.
Sorjano V, et al. Core of patients with HIV and Hepatitis C virus. AIDs. 2007;21(9):1073–1089.
Zeuzem S, et al. Efficacy of 24 week treatment with peginterferon alpha—2b plus ribovirin in patients
with chronic hepatitis C infected with genotype 1 and low pretreatment virimia. J Hepatol.
2006;44:97–103.
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51 ALCOHOLIC LIVER DISEASE (ALD)

I. EPIDEMIOLOGY. The association of alcohol abuse and liver damage has been known
since the time of the ancient Greeks. The availability of alcoholic beverages, licensing
laws, and economic, cultural, and environmental conditions all influence both per
capita alcohol consumption and mortality from alcohol-related liver disease.
Alcoholism is, in part, inherited, and aberrant alcohol-drinking behavior is genetically
influenced. The risk factors that may affect the susceptibility to development of alco-
holic liver disease include genetic factors, malnutrition, female gender, and viral agents
(hepatitis virus B, C, and D).
Ninety percent to 95% of people with chronic alcohol consumption develop
fatty liver. In almost all instances, this lesion is thought to be reversible on cessation
of alcohol intake. Ten percent to 30% of individuals go on to perivenular sclerosis
(collagen deposition in and around central veins). Ten percent to 35% of chronic alco-
holics, however, have acute liver injury that may become recurrent or chronic. Some
of these patients recover, but 8% to 20% go on to sinusoidal, perivenular, and peri-
central fibrosis and cirrhosis. Even during the inflammatory stage without the pres-
ence of cirrhosis, patients may have portal hypertension, ascites, and esophageal
varices.

II. RELATION OF CIRRHOSIS TO ALCOHOL CONSUMPTION. The alcohol content of

various beverages is shown in Table 51-1. The development of alcoholic cirrhosis cor-
relates with the quantity and duration of alcohol consumption. For men, the relative
risk of cirrhosis has been estimated to be 6 times greater when consumption is 40 to
60 g of alcohol per day than when it is up to 20 g per day, and 14 times greater at 60
to 80 g per day. The average “cirrhogenic” dose has been calculated to be 40 to 80 g
of ethanol per day consumed for approximately 10 to 12 years.
In a case-controlled study in men, the relative risk for cirrhosis was 1.83 for men
consuming 40 to 60 g of absolute alcohol per day compared to men consuming fewer
than 40 g per day. The relative risk rose to 100 for men consuming more than 80 g
per day. The average cirrhogenic and threshold doses are lower in women than in
men. Binge drinking compared to drinking with meals and beer and spirits compared
to wine drinking increases the risk for ALD.

III. ETHANOL METABOLISM

A. Absorption, distribution, and elimination. In a healthy man, about 100 mg of
ethanol per kilogram of body weight is eliminated in an hour. Heavy alcohol con-
sumption for years may increase the rate of ethanol elimination up to 100%.
Ethanol is absorbed from the gastrointestinal tract, especially the duodenum
and jejunum (70%–80%), by simple diffusion because of its small molecular size
and low solubility in lipids. The rate of absorption is decreased by delayed gastric
emptying and by the presence of intestinal contents. Food delays gastric absorp-
tion, producing a slower rise and lower peak value of blood alcohol in fed than in
fasting patients.
The systemic distribution of alcohol is very rapid. In organs with a rich blood
supply, such as the brain, lungs, and liver, alcohol rapidly equilibrates with the
blood. Alcohol is poorly lipid-soluble. At room temperature, tissue lipids take up
only 4% of the quantity of alcohol dissolved in a corresponding volume of water.

386
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Chapter 51: Alcoholic Liver Disease (ALD) 387

TABLE 51-1 Alcohol Content of Various Beverages

Alcohol concentration* Alcohol in standard

Beverage (g/100 mL) measures

Beer 3.9 13.3 g; 12-oz bottle/can

Red wine 9.5 11.0 g/glass; 71 g/bottle
Rosé 8.7 10.0 g/glass; 65 g/bottle
White wine, dry 9.1 10.0 g/glass; 64 g/bottle
White wine, medium 8.8 10.0 g/glass; 62 g/bottle
White wine, sweet 10.2 11.0 g/glass; 71 g/bottle
White wine, sparkling 9.9 11.0 g/glass; 74 g/bottle
Port 15.9 124 g/bottle
Sherry, dry 15.7 123 g/bottle
Sherry, medium 14.8 115 g/bottle
Sherry, sweet 15.6 122 g/bottle
Vermouth, dry 13.9 122 g/bottle
Vermouth, sweet 13.0 100 g/bottle
Cherry brandy 19.0 148 g/bottle
Hard liquor 70% 31.7 240 g/bottle; 7.5 g/single-shot
(brandy, gin, whiskey)

*Percentage alcohol
0.078  g alcohol/100 mL.

Key: 1 fl oz  30 mL; 1 pint  470 mL; 1 wine bottle  757 mL.

In an obese person, therefore, the same amount of alcohol per unit of weight gives
a higher blood alcohol concentration than in a thin person. The mean volume of
distribution of ethanol is less in women than in men, resulting in higher peak
blood concentrations and greater mean areas under the ethanol concentration–
time curves.
In humans, less than 1% is excreted in the urine, 1% to 3% via the lungs,
and 90% to 95% as carbon dioxide after it is oxidized in the liver.
B. Chemical metabolism
1. Alcohol dehydrogenase. Although most of the ingested ethanol is metabo-
lized by the liver, other tissues such as the stomach, intestines, kidney, and
bone marrow cells oxidize ethanol to a small extent. There is an alcohol
dehydrogenase (ADH) present in the mucosa of the stomach, jejunum, and
ileum, which results in a considerable first-pass metabolism of alcohol. The
gastric ADH activity is less in women than in men and decreases with chronic
alcoholism.
In the liver, the main pathway for ethanol metabolism is by its oxidation
to acetaldehyde by ADH. Alternative pathways of oxidation in other subcellu-
lar compartments are also present. Multiple molecular forms of ADH exist,
and at least three different classes have been described on the basis of structure
and function. Various ADH forms appear in different frequencies in different
racial populations. This polymorphism may explain, in part, individual varia-
tion in the rate of acetaldehyde production and first-pass elimination.
The hepatic metabolism of ethanol proceeds in three basic steps. First,
ethanol is oxidized within the hepatocyte cytosol to acetaldehyde. Second,
acetaldehyde is oxidized to acetate via catalysis mainly by aldehyde dehydroge-
nase (ALDH) in the mitochondria. Third, acetate ALDH is released into blood
and is oxidized by peripheral tissues to carbon dioxide and water.
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388 Part V: Specific Complaints and Disorders

When ethanol is oxidized to acetaldehyde via ADH, nicotinamide-adenine

dinucleotide (NAD) is required as a cofactor and is reduced to NADH during
the reaction, resulting in an increase in the liver of the NADH/ NAD ratio. This
increase in the redox state of the liver has serious metabolic effects such as inhi-
bition of hepatic gluconeogenesis, impairment of fatty acid oxidation, decrease
in citric acid cycle activity, and increase in conversion of pyruvate to lactic acid
resulting in lactic acidosis.
2. The microsomal ethanol oxidizing system (MEOS) is located in the endo-
plasmic reticulum (ER) of the hepatocyte. It is a cytochrome P-450-, NADPH-
(reduced nicotinamide-adenine–dinucleotide phosphate), and oxygen-dependent
enzyme system that oxidizes ethanol to acetaldehyde. Because chronic con-
sumption of ethanol leads to the proliferation of the ER, the activity of the
MEOS is also increased (induction). However, its quantitative contribution to
the total ethanol metabolism is still controversial. The current nomenclature for
MEOS is P45011E1. In addition to ethanol, this enzyme system oxidizes other
alcohols, carbon tetrachloride (CCl4), and acetaminophen (Tylenol).
3. ALDH rapidly metabolizes acetaldehyde to acetate. Multiple molecular forms of
ALDH have been demonstrated. Two major hepatic ALDH isoenzymes (I and II)
exist in humans. The mitochondrial isoenzyme (ALDH I) has been reported to
be missing in about 50% of liver specimens in Japanese people. The deficiency
of ALDH I in Asians has several metabolic and clinical consequences.
4. Change in hepatic redox state. When ethanol is oxidized to acetaldehyde in
the hepatocyte cytosol via ADH, NAD is required as a cofactor. NAD is reduced
to NADH. Also, ALDH-mediated conversion of acetaldehyde to acetate requires
NAD conversion of NADH in the mitochondria. Thus, both the cytosolic and
mitochondrial redox states are altered. This effect is manifested by respective
increases of both liver and blood lactate to pyruvate and of -hydroxybutyrate to
acetoacetate ratios. This state leads to inhibition of hepatic gluconeogenesis, fatty
acid oxidation, and citric acid cycle activity, which may clinically exhibit as fatty
liver, hypoglycemia, and lactic acidosis (Fig. 51-1).
5. Alterations in metabolism of ethanol, acetaldehyde, and acetate during
chronic alcohol consumption. Chronic ethanol consumption enhances ethanol
clearance except in the presence of clinically significant liver damage or severe
food restriction. This effect is attributed to increased ADH activity, MEOS
activity, a hypermetabolic state in the liver, and possible increased mitochondr-
ial reoxidation of NADH, which is the rate-limiting step in ethanol elimination
and metabolism. The explanation for increased ethanol elimination by corti-
costeroids is the induced increase in NADH conversion to NAD as a result of
steroid-induced gluconeogenesis.

Figure 51-1. Metabolic consequences of change in hepatic redox state secondary to oxidation
of ethanol.
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Chapter 51: Alcoholic Liver Disease (ALD) 389

In healthy people, almost all the acetaldehyde formed during ethanol oxi-
dation is effectively oxidized in the liver. However, detectable concentrations of
acetaldehyde have been found in the peripheral blood of chronic alcoholics and
in Asians, who experience alcohol-related flushing. The unusually high blood
acetaldehyde levels found in severely intoxicated, chronic alcoholics are thought
to result from an increased rate of ethanol oxidation of ADH and a decrease in
the liver ALDH activity associated with both liver injury and chronic ethanol
consumption.

IV. PATHOGENESIS OF ALCOHOLIC LIVER INJURY

A. Hepatocyte injury. Alcoholic liver injury is multifactorial. Ethanol causes physi-
cal changes. It “fluidizes” all biologic membranes including hepatic mitochondria,
endoplasmic reticula, and cell surface membranes by changing their lipid composi-
tion. There is an increase in the cholesterol ester content of plasma membranes and
a decrease in the enzyme activity of such enzymes as succinic dehydrogenase and
cytochromes a and b, and in the total respiratory capacity of the mitochondria.
Chronic alcohol consumption also potentiates the release of alkaline phosphatase
and -glutamyl peptidase from liver plasma membranes.
In addition to the metabolic effects resulting from the changed redox state
and the inhibition of fatty acid oxidation during the oxidation of ethanol
(Fig. 51-1), acute large doses of ethanol mobilize fat from adipose tissue to the
liver. Administration of ethanol with a high-fat diet potentiates alcoholic fatty liver.
This effect is attenuated with chronic alcohol consumption.
B. Acetaldehyde is thought to be the major initiating factor in the pathogenesis of
alcoholic liver damage. It has been shown to form covalently bound adducts with
hepatocyte proteins. Acetaldehyde-protein adducts could inhibit hepatic protein
secretion, impair biologic functions of proteins, and combine with tissue macro-
molecules and thereby cause severe tissue injury. Acetaldehyde may also initiate
lipid peroxidation via the generation of free radicals. Normally, free radicals are
inactivated by glutathione. However, acetaldehyde may bind with glutathione or
with cysteine and inhibit the synthesis of glutathione, which may contribute to the
depression of liver glutathione seen in chronic alcoholics; this reaction may also
increase lipid peroxidation.
Humoral immune response by production of antibodies to acetaldehyde
adducts, microtubules, and other proteins may play a role in the liver injury. There
is also some evidence that cytotoxic reactions mediated by mononuclear cells may
take place to increase cellular damage.
Chronic alcohol consumption induces the MEOS, which also contributes to
increased acetaldehyde production. However, MEOS induction also enhances oxy-
gen consumption and potentiates hypoxia, especially in the centrolobular (perivenous)
area because the P45011E1 is predominantly localized to this area in the lobule.
The induction of P45011E1 also increases hepatotoxicity of other chemicals such
as CCl4 and acetaminophen, which may contribute to the liver injury, especially in
zone 3 (perivenular zone).
In addition to the accumulation of fat in the hepatocytes with chronic alcohol
consumption, there is also an accumulation of protein in and around hepatocytes
such as microtubular protein (alcoholic hyalin) and exportable proteins secondary
to impairment of their synthesis and transport out of hepatocytes. The result is an
additional decrease in the sinusoidal area and perfusion of hepatocytes.
C. Hepatic fibrogenesis. Alcohol-induced hepatocyte necrosis and inflammation
may trigger fibrogenesis and the development of cirrhosis. However, ethanol itself
and its metabolites also have significant effects on collagen metabolism and fibro-
genesis. Thus alcoholic hepatitis is not a necessary step in the development of
cirrhosis.
Chronic alcohol consumption has been associated with the induction and
proliferation of perisinusoidal and perivenular mesenchymal cells called Ito cells
and of myofibroblasts, which produce increased amounts of types I, III, and IV col-
lagen and laminin. Myofibroblasts are contractile cells and may contribute to scar
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390 Part V: Specific Complaints and Disorders

contraction and portal hypertension in cirrhosis. Ito cells and myofibroblast

processes extend into the space of Disse around the hepatocytes, and their concen-
trations correspond to the degree of collagen formation in the space of Disse.
Fibronectin formation is also stimulated; the fibronectin may form a skeleton for
collagen formation. The increased collagenization of the space of Disse results in
reduction of the fenestration between sinusoids and the space of Disse and, there-
fore, may isolate the hepatocyte from its blood supply. These changes also increase
the resistance to blood flow and contribute to increased portal pressure.
Perivenular and perisinusoidal fibrosis has a predictive value for the development
of alcoholic cirrhosis. The presence of alcoholic hepatitis and steatosis also corre-
lates with the development of cirrhosis.
Various cytokines including tissue necrosis factor (TNF), interleukin-2 and
interleukin-6, transforming growth factors (TGF- and -), and platelet-derived
growth factor (PDGF) all seem to contribute to stimulation and transformation of
Ito cells and reinforcement of liver cell injury.
D. Nutritional factors in alcoholic liver disease. The role of nutritional factors in the
development of alcoholic liver injury has been controversial. However, it is thought
that protein-calorie malnutrition may contribute to liver injury. Because of the meta-
bolic alterations caused by ethanol and because of the present liver injury, however,
the malnutrition noted in people with chronic ethanol abuse may be, in part, sec-
ondary rather than primary. There is some evidence that a high-protein diet and
phenyl phosphatidylcholine (extracted from soybeans) have a protective effect on the
liver in alcohol-induced cirrhosis.

V. DIAGNOSIS
A. Clinical presentation. Alcoholic hepatitis (AH) is an acute or chronic illness
associated with severe chronic alcoholism, involving extensive hepatocellular
necrosis, inflammation, and scarring. It is extremely variable in clinical presenta-
tion and may be superimposed on other forms of alcoholic liver disease such as
fatty liver and Laënnec’s cirrhosis.
Alcoholic liver disease may occur without any symptoms. The most common
complaints in symptomatic patients with alcoholic hepatitis are anorexia, nausea,
vomiting, and abdominal pain, especially in the right upper quadrant. Most
patients lose weight due to anorexia and nausea. One fourth of patients have fever.
Fever may be due to severe liver damage in the absence of an infection; however,
infections should be excluded in these immunocompromised patients. Jaundice,
when present, is usually mild, but in 20% to 35% of the patients who present with
a cholestatic picture, it is severe. Diarrhea and symptoms related to complications
of portal hypertension such as ascites, peripheral edema, and esophageal varices
are less common. Most patients with acute hepatitis have a tender and somewhat
enlarged liver. Jaundice, splenomegaly, ascites, peripheral edema, spider angiomata,
palmar erythema, parotid enlargement, gynecomastia, testicular atrophy, finger
clubbing, and Dupuytren’s contractures may also be present.
B. Diagnostic studies
1. Laboratory studies
a. The most characteristic laboratory findings in acute alcoholic hepatitis are
elevated serum transaminases and bilirubin. Serum glutamic-oxaloacetic
transaminase (SGOT, or aspartate aminotransferase [AST]) levels are usually
2 to 10 times normal. Values greater than 500 U/L are rare. Serum glutamic-
pyruvic transaminase (SGPT, or alanine aminotransferase [ALT]) levels are
also elevated, but they are increased less than SGOT levels. The reduced
SGPT levels may be related to mitochondrial injury in alcoholic hepatitis.
The SGOT/SGPT ratio in alcoholic hepatitis is usually greater than 1.
b. Serum alkaline phosphatase level is moderately elevated in at least one
half of the patients. In patients presenting with a cholestatic picture, the
elevation may be marked.
-Glutamyltranspeptidase (GGTP) activity is
also often elevated in alcoholic hepatitis. This enzyme is quite sensitive for
alcoholic injury.
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Chapter 51: Alcoholic Liver Disease (ALD) 391

c. Serum globulins are often increased, and, interestingly, IgA levels are
disproportionately elevated compared to the other immunoglobulins. Serum
albumin levels may be normal initially in well-compensated and well-nourished
patients but are usually decreased.
d. Because the liver is the main site of synthesis of the coagulation factors, in
severely ill patients the prolongation of prothrombin time by greater than
7 to 10 seconds predicts a poor prognosis.
e. The hematologic parameters are usually abnormal in alcoholic hepatitis.
Leukocytosis with a shift to the left is common. Anemia and thrombocy-
topenia are usually present. Platelet count of 100 usually indicates the
presence of cirrhosis. Aside from the fact that alcohol is toxic to the bone
marrow, patients may have hypersplenism, disseminated intravascular coag-
ulation (DIC), and bone marrow suppression from their acute and chronic
disease state.
f. Other causes of liver injury should be ruled out by appropriate serologic
tests and a careful drug history. Acetaminophen even in therapeutic doses
may be toxic in alcoholic patients. Aspirin and acetaminophen levels may be
helpful in selected patients.
g. Hepatitis C infection increases the risk of developing cirrhosis in ALD.
This is also true in reverse. Thus, patients with ALD should be tested for
hepatitis C antibody and if the test is positive, treatment of hepatitis C
should be recommended.
2. Ultrasound. Even though the diagnosis may be easily established in most
patients from the history, physical examination, and blood work, it may be
helpful in some patients, especially in those presenting with the picture of
cholestasis, to obtain an abdominal ultrasound to rule out biliary tract disease,
ascites, and the presence of hepatocellular carcinoma. Some patients may
require computed tomography (CT) scan of the abdomen and endoscopic ret-
rograde cholangiopancreatography (ERCP).
3. Liver biopsy should be performed early in the course of the disease in most
patients to confirm the diagnosis and to stage the severity of the liver injury.
With deterioration of liver function (excessive prolongation of the prothrombin
time or the presence of ascites), liver biopsy may not be possible later in the
disease process.
Microscopic examination of the liver biopsy is essential for classification
of the alcoholic injury with regard to steatosis, early fibrosis, alcoholic hepati-
tis, or Laënnec’s cirrhosis. In patients with alcoholic hepatitis, pathologic fea-
tures may include the following:
a. The hepatocellular necrosis is mainly centrilobular but may be panlobu-
lar. Hepatocytes in various stages of degeneration are usually present. Many
hepatocytes are swollen, balloonlike, or vacuolated and often contain a fib-
rillar material or alcoholic hyalin called Mallory bodies. This cytoplasmic
material, even though commonly seen in patients with alcoholic hepatitis, is
not limited to this disease. It has also been reported in diseases such as
hepatoma, Indian childhood cirrhosis, and liver disease in patients with
intestinal bypass surgery, obesity, diabetes, and drug reaction. Occasionally
it is seen in primary biliary cirrhosis, primary sclerosing cholangitis, and
Wilson’s disease.
b. The inflammatory exudate consists predominantly of polymorphonuclear
(PMN) leukocytes in addition to some mononuclear cells. PMNs are seen in
portal tracts and sinusoids and are usually concentrated in areas of hepato-
cellular necrosis with or without alcoholic hyalin. In 50% to 75% of the
cases, rosettes of PMNs are seen around degenerating hepatocytes contain-
ing Mallory bodies. This finding constitutes the hallmark of the disease.
c. Fibrosis is usually extensive and seen early in the disease. It frequently sur-
rounds the central veins and extends into the perisinusoidal areas. The
stellate fibrosis often remains after inflammation resolves and leads to
micronodular cirrhosis.
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392 Part V: Specific Complaints and Disorders

d. Fatty infiltration is commonly seen in patients with alcoholic hepatitis. The

extent of steatosis depends on recent alcohol intake, dietary fat, and the con-
comitant presence of obesity or diabetes.
e. Severe cholestasis may be seen in one third of patients. In these patients,
in addition to pericentral injury and scar formation, there is marked peri-
portal necrosis, inflammation, and destruction of small bile ducts.
f. Hemosiderosis may be seen in some of these patients.

VI. CLINICAL COURSE. In patients with steatosis only, abstinence from alcohol may lead
to resolution of the liver injury. However, if perivenular and sinusoidal fibrosis is pre-
sent, abstinence may halt further damage, but the scarring may remain.
Alcoholic hepatitis is a disease of varying severity. The overall mortality is 10%
to 15%. Healing is slow, and most patients require 2 to 8 months for recovery after
stopping consumption of alcohol. The disease usually worsens after the first several
days, regardless of the initial presentation. Patients may have encephalopathy and
other complications during this stage, such as gastrointestinal bleeding from
esophageal varices, gastritis or peptic ulcers, coagulopathy or DIC, infections espe-
cially of the urinary tract and lungs, spontaneous bacterial peritonitis, and hepatore-
nal syndrome. A combination of serious complications often leads to death of the
patient.
Many patients with a history of chronic alcoholism have episodes of acute alco-
holic hepatitis superimposed on existing cirrhosis. It is thought that repeated bouts of
alcoholic liver injury, necrosis, and fibrosis lead to extensive scarring and Laënnec’s
cirrhosis.

VII. TREATMENT. The most important component of therapy of alcoholic liver disease
is strict abstinence from alcohol. Alcohol is the most common cause of liver dis-
ease in the Western world. In many countries, the incidence of alcoholic liver disease
is increasing at a time when the incidences of other liver disorders are remaining
steady or declining.
A. Supportive therapy. The mainstay of therapy for alcoholic hepatitis is support-
ive. Most patients require bed rest. Seriously ill patients should be admitted to an
intensive care unit. If complications of portal hypertension exist, they should be
promptly treated. Infections and concomitant pancreatitis should be ruled out or
appropriately treated.
B. Diet. Alcohol intake should be strictly forbidden. Patients should be given
thiamine, folic acid, and multivitamins. The electrolyte, calcium, magnesium,
phosphate, and glucose levels should be strictly monitored and corrected.
Protein-calorie malnutrition is present in most patients. The energy expen-
diture and protein degradation are increased. Insulin resistance is a ubiquitous
finding. This causes fat to be preferred over carbohydrate as an energy source.
Frequent feedings with a high-carbohydrate, high-fiber, and low-fat diet may
decrease insulin resistance and improve nitrogen balance. In patients who cannot
eat, enteral tube feedings may be given with standard formulas. Special formula-
tions such as Hepatic-Aid may be reserved for the small minority of patients for
whom encephalopathy remains a major problem after a fair trial of standard ther-
apy. Patients should receive sufficient daily calories to provide basal energy expen-
diture (BEE)
1.2 to 1.4 total kcal or 25 to 30 kcal/ kg of ideal body weight.
Thirty percent to 35% of total calories should be given as fat and the remainder as
carbohydrate. Protein should not be restricted below 1 mg/kg unless encephalopa-
thy necessitates further restriction.
In patients in whom enteral therapy is not possible, parenteral nutrition
should be given promptly following guidelines similar to those outlined for enteral
nutrition. The use of solutions rich in branched-chain amino acids such as
HepatAmine is controversial and is not necessary except in cases of hepatic
encephalopathy and coma.
C. Alcohol withdrawal. Initially, symptoms of alcohol withdrawal may be present.
Alcoholic seizures and delirium tremens should be prevented by strict attention to
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Chapter 51: Alcoholic Liver Disease (ALD) 393

the patient’s metabolic status and by the careful administration of benzodiazepines.

Because the metabolism of these drugs is altered in the presence of the “sick” liver
and encephalopathy may easily be induced, reduced doses of diazepam or chlor-
diazepoxide should be used; oxazepam is preferable and may be used in regular
doses.
D. Controversial therapies. Other therapies used in the treatment of alcoholic
hepatitis are still controversial. They should be used only in carefully selected and
controlled settings.
1. Corticosteroids—prednisone or prednisolone—given for 4 to 6 weeks at
40 mg have been shown in several studies to improve mortality in severely ill
patients with alcoholic hepatitis and encephalopathy. No benefit has been
reported for less seriously ill patients.
An equation has been developed to assess the severity of alcoholic hepatitis:

Discriminant function (DF)  4.6
PT (sec)  control PT

 serum bilirubin

where PT  prothrombin time

DF greater than 32 has been equated with severe disease. Using DF, several
multicenter trials have confirmed the usefulness of prednisone in severely ill
patients. Hepatic encephalopathy was noted to be a predictor of early mortal-
ity. Based on these studies, corticosteroid therapy for 28 days may reduce early
mortality in severely ill patients with alcoholic hepatitis.
2. Anticytokine therapy. Serum levels of tumor necrosis factor (TNF) as well as
IL-1, IL-6, and Il-8 are elevated in AH and correlate with mortality.
a. Pentoxifylline has been shown to reduce the production of TNF-2, IL-5, IL-10
and IL-12. In an animal model it has been shown to reduce portal pressure in
cirrhosis. In a study with 101 patients with severe AH, pentoxifylline
400 mg t.i.d. was compared to placebo and the in-hospital mortality was lower
in patients receiving pentoxifylline. The difference in mortality between the two
groups suggests a number needed to treat of 4.7 which is identical to the num-
ber comparing the use of steroids to placebo in patients with severe AH.
b. Infliximab (IgG monoclonal antibody to TNF) has been used in two small
uncontrolled pilot studies and suggested a benefit. However, in a trial inflix-
imab at 10 mg per kg in combination with prednisolone 40 mg per day
resulted in a higher incidence of death due to increased risk of infections.
c. Etanercept, a P75-soluble TNF receptor: FC fusion protein neutralizes sol-
uble TNF. In a small study of 13 patients with severe AH, etanercept ther-
apy for 2 weeks increased the 30-day survival rate to 92%; however, in 23%
of patients etanercept therapy had to be prematurely discontinued due to
infection, GI bleeding, or hepatic decompensation.
3. Antioxidants
a. Vitamin E alone or in combination with other antioxidants may improve
outcome of patients with AH.
b. Sadenosylmethionine (SAMe) is a precursor of cysteine, one of the amino
acids of the tripeptide glutathione, and is produced in the body from methio-
nine and adenosine triphosphate by the enzyme SAMe synthetase. This
enzyme’s activity is decreased in patients with cirrhosis and results in a low
level of glutathione. SAMe given to patients with Child’s A or B cirrhosis
decreased the 2-year mortality rate from 29% to 12%.
4. Silymarin, the active ingredient in milk thistle, is thought to exert hepato-
protective actions through free-radical scavenging and immunomodulatory
effects. In patients with alcoholic liver disease, improvement in liver chemistry
tests and liver histology is thought to be the result of decreased lipid peroxida-
tion and lymphocyte proliferation.
5. Anabolic steroids might benefit patients with alcohol-related liver disease
because of their effects on protein and nucleic acid synthesis. A number of tri-
als have been undertaken to assess the effects of these drugs. Currently, there is
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394 Part V: Specific Complaints and Disorders

no consensus as to their value in any stage of alcoholic liver disease. Moreover,

long-term use may promote peliosis hepatis and hepatocellular carcinoma.
6. Propylthiouracil (PTU) at doses of 300 mg per day for 45 days has been tried
in patients with mild-to-moderate alcoholic hepatitis. Therapy with PTU may
reverse the relative tissue anoxia in the centrilobular zone of the liver by
decreasing the rate of oxygen consumption. Patients receiving PTU in several
studies recovered more rapidly than controls. The effect of PTU on severely ill
patients is not known.
7. Colchicine has been advocated for therapeutic use in alcoholic liver disease
because of its antiinflammatory, antimicrotubular, and antifibrotic actions;
however, its effectiveness has not been established.
8. Potential new therapies. Thalidomide, misoprostol, adiponectin, and probi-
otics have all been shown in preliminary studies to have anticytokine proper-
ties. Also, leukocytapheresis or other extracorporeal recirculating systems to
remove cytokines are being studied; therapies inhibiting apoptosis may also be
beneficial.
E. Liver transplantation. The suitability of patients with alcoholic liver disease as can-
didates for liver transplantation has been debated since the advent of transplantation
programs. Clear guidelines are still lacking. Abstinence from alcohol is associated, in
most patients, with improved liver function and prolonged survival. However,
progressive liver failure develops in some patients despite abstinence. Because no
effective therapy exists for decompensated alcoholic cirrhosis, patients with end-
stage disease should be considered for liver transplantation. Unfortunately, the
demand for donor livers exceeds the availability, and thus transplantation cannot, at
present, supply each deserving patient. In patients referred for liver transplantation,
it is important to rule out other alcohol-related medical problems, such as car-
diomyopathy, pancreatitis, neuropathy, and malnutrition, which may worsen the
overall prognosis. Posttransplant compliance with the medical regimen, continuation
of strict abstinence from alcohol, and the availability of family or social support
systems are important. When liver transplantation has been carried out, the out-
comes have been good and do not differ substantially from those reported in patients
with nonalcoholic liver disease.

Selected Readings
Bridle K, et al. Hepcidin is down regulated in alcoholic liver injury: implications for the
pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res. 2006;30:106–112.
Clouston AD, et al. Steatosis as cofactor in other liver diseases: Hepatitis C virus, alcohol,
hemochromatosis, and others. Clin Liver Dis. 2007;11(1):173–189.
Foody W, et al. Nutritional therapy for alcoholic hepatitis: New life for an old idea.
Gastroenterology. 2001;120:1053.
Kapadia C. Alcoholic steatosis: The Kupfer cell—A villain? Gastroenterology. 2001;120:581.
Purohit V, et al. Role of S-adenosylmethionine, folate, and betaine in the treatment of
alcoholic liver disease: summary of a symposium. Am J Clin Nutr. 2007;86(1):14–24.
Tilg H, et al. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med.
2000;343:1467.
Yipw W, et al. Alcoholic liver disease. Semin Diagn Pathol. 2007;23:149–160.
79466_CH52.qxd 1/2/08 1:33 PM Page 395

NONALCOHOLIC FATTY LIVER DISEASE 52

I. DEFINITION. Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver

diseases with histologic features of alcohol-induced liver disease that occurs in indi-
viduals who do not consume significant quantities of alcohol. The spectrums of the
liver diseases include hepatic steatosis (fatty liver); nonalcoholic steatohepatitis
(NASH) with histologic evidence of hepatitis, hepatocellular injury, necrosis, and fibro-
sis; and cirrhosis with eventual portal hypertension and other complications includ-
ing hepatocellular carcinoma.
NAFLD is believed to be one of the most common causes of abnormal liver
chemistry tests in American adults. It is thought to be the major cause of cryptogenic
cirrhosis. Ten percent to 20% of patients with NASH progress to cirrhosis or end-
stage liver disease in a decade or more. The survival of patients with NAFLD is lower
than in general population.
Clinically, NAFLD should be a diagnosis of exclusion. It should be suspected as a
cause of chronic liver disease in patients who deny alcohol consumption and have neg-
ative serologic tests for active viral, congenital, and acquired causes of liver disease.
Hepatis C virus (HCV) or hepatitis G virus infections are not implicated as
causes of NAFLD; however, NAFLD may increase the severity of HCV-related liver
disease. Obesity-related steatosis seems to have deleterious effects similar to those of
alcohol-induced steatosis on HCV-infected patients, exacerbating the liver damage.
In the United States the prevalence of NAFLD is estimated to be 20% and NASH
3%. The prevalence of NAFLD is 50% in people with diabetes, 74% in obese per-
sons, and nearly 100% in morbidly obese individuals. NAFLD affects both adults and
children: 2.6% of all children and 22.5% to 52.8% of obese children. Evidence for an
association between arterial hypertension and atherosclerosis is accumulating. In fact,
NAFLD is an independent risk factor for cardiovascular mortality.

II. ASSOCIATED CONDITIONS. Conditions associated with NAFLD include Type 2 dia-
betes mellitus, obesity, and dyslipidemia, all of which are related to metabolic syndrome.
A. Obesity. Obesity is the condition most often reported to be associated with
NAFLD. Obesity is described in 40% to 100% of patients with NASH. NASH has
been documented in 9% to 36% of obese patients. The prevalence and severity of
hepatic steatosis has been noted to be directly proportional to the grade of obesity,
and the severity of NASH has been noted to be proportional to the degree of hepatic
steatosis. The distribution of body fat seems to be important in the development of
hepatic steatosis. In one study, a significant correlation was found between the
degree of hepatic steatosis and waist-to-hip ratio, suggesting a relationship between
visceral and intraabdominal fat and accumulation of fat in the liver.
B. Hyperglycemia, insulin resistance, hyperinsulinemia, glucose intolerance,
and Type 2 diabetes mellitus have been described in 25% to 75% of adult patients
with NASH.
C. Hyperlipidemias, including hypertriglyceridemia and hypercholesterolemia or
both, have been found to be present in 20% to 80% of patients with NASH.
D. Most patients with NASH seem to have multiple risk factors including obesity,
Type 2 diabetes mellitus, and hyperlipidemia.
E. Other risk factors include female gender, rapid weight loss, acute starvation, total
parenteral nutrition, and small-bowel diverticulosis.

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396 Part V: Specific Complaints and Disorders

F. Genetic conditions associated with NAFLD include Wilson’s disease, homo-

cystinuria, tyrosinemia, a-beta- and hypobetalipoproteinemia, and Weber–Christian
disease.
G. Surgical procedures associated with NAFLD, particularly NASH, include gas-
troplasty for morbid obesity, jejunoileal bypass, extensive small-bowel resection,
and biliopancreatic diversion.
H. Drugs. The use of a number of drugs has been implicated in the development of
NAFLD. The list includes glucocorticoids, amiodarone, synthetic estrogens, tamoxifen
citrate, 4,4
-diethylaminoethoxyhexesterol (DHEAH), isoniazid, methotrexate, per-
hexiline maleate, tetracycline, puromycin, bleomycin, dichloroethylene, ethionine,
hydrazine, hypoglycin, l-asparaginase, azacytidine, azauridine, and azaserine. Chronic
industrial exposure to petrochemicals has also been reported as a risk factor for
NAFLD.

III. DIAGNOSIS
A. Clinical findings
1. Symptoms. Most patients with NAFLD are asymptomatic; however, fatigue,
malaise, or vague right upper quadrant pain or discomfort may cause patients
to seek medical attention.
2. Signs. Hepatomegaly may occur in up to 75% of patients. Splenomegaly may
be present in 25% of patients. Stigmata of portal hypertension and cirrhosis
occur rarely. In a subset of patients with NAFLD, especially in association with
certain drugs and toxins (i.e., certain nucleoside analogs, antimitotic agents, or
tetracycline) fulminant hepatic failure may develop rapidly. Cirrhosis may
develop rapidly in patients with steatosis and inborn errors of metabolism (i.e.,
tyrosinemia).
3. Laboratory findings. Laboratory features of NAFLD are nondiagnostic. Mild-
to-moderate increases in serum aminotransferases (alanine [ALT] and aspartate
[AST]) are the predominant laboratory abnormalties reported in patients with
NASH. Typically, the liver test abnormalities are noted during routine testing or
when patients seek medical attention for other complaints. However, liver
enzymes are not always sensitive markers for NASH because some patients
present with normal transaminases in the presence of severe liver disease. Also,
there is no significant correlation between the degree of serum aminotrans-
ferase elevation and the histologic findings and severity of the hepatic inflam-
mation or fibrosis. Serum ALT levels are often higher then AST levels, in
contrast to the pattern seen in alcoholic hepatitis in which the AST/ALT ratio is
higher and serum alkaline phosphatase levels may be mildly elevated; serum
bilirubin and albumin levels are usually normal. Prolongation of prothrombin
time (PT) is suggestive of hepatic decompensation. A small percentage of
patients with NASH may have positive low-titer antinuclear antibody (ANA)
levels. However, antimitochondrial antibody (AMA), antibody to hepatitis C
virus, and hepatitis B surface antigen are negative, and serum ceruloplasmin
and antitrypsin levels are normal. Elevated serum ferritin and transferrin satu-
ration seem to occur commonly in patients with NASH. Men with NASH may
have higher iron stores than women. One third of patients with NASH may
have one or two copies of the Cys282Tyr mutation in the HFE gene (genetic
marker for hemochromatosis). Trends toward more severe hepatic fibrosis in
patients with NASH with this gene mutation have been reported.
4. Imaging modalities. Several noninvasive imaging techniques including abdom-
inal ultrasound (US), computerized tomography (CT), and magnetic resonance
imaging (MRI) can reveal hepatic steatosis. None of the tests are significantly
sensitive for the detection of hepatic inflammation or fibrosis. CT and MRI
may be helpful only when extrahepatic manifestations of cirrhosis and portal
hypertension (i.e., ascites, splenomegaly, varices) are present. Thus, none of
these imaging modalities is sensitive or specific enough to definitively establish
the diagnosis of NASH or reliably grade its severity.
5. Liver biopsy is the only diagnostic test for confirming the clinical suspicion of
NAFLD and NASH, staging the severity of the liver disease, and determining
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Chapter 52: Nonalcoholic Fatty Liver Disease 397

the extent of fibrosis. It is still uncertain as to whether liver biopsy is essential

in the average patient, because biopsy results may not change clinical manage-
ment. Liver biopsy should be considered for patients with metabolic syndrome
and for patients with persistently elevated liver enzymes despite optimal treat-
ment of associated metabolic conditions.
B. Histology. NAFLD is histologically indistinguishable from alcoholic liver disease.
Histologic stages of NAFLD include steatosis, steatohepatitis, and cirrhosis. Steatosis
involves macrovesicular fat accumulation in the hepatocytes. NASH histology
includes macrovesicular steatosis, lobular inflammation, hepatocyte degeneration,
hepatocyte ballooning, and hepatic fibrosis. Steatosis may be diffuse or located pri-
marily in the central zones of hepatic lobules. Parenchymal inflammation of varying
degrees is present in all cases and the cellular infiltrate may consist of neutrophils,
mononuclear cells, and lymphocytes. Hepatocyte necrosis with ballooning and
cellular dropout, Mallory’s hyaline, and Councilman’s bodies may be present.
Stainable iron may be present in 15% to 65% of patients. Pericellular, peris-
inusoidal, and periportal fibrosis have been described in 35% to 85% of patients
with NASH. The extent of fibrosis may vary considerably from patient to patient,
ranging from mild fibrosis around small veins or groups of cells (chicken-wire
fibrosis) to extensive, severe fibrosis with bridging of portal tracts and central
veins and distortion of the hepatic architecture. Cirrhosis is found at initial liver
biopsy in 7% to 16% of patients with NASH and is indistinguishable from
Laënnec’s cirrhosis.

IV. The pathogenesis of NAFLD is complex, potentially involving multiple tissues

including the liver, adipose tissue muscle, and other peripheral tissues. Adipose tissue
and insulin resistance play a dominant role in the pathogenesis of NAFLD. It is known
that visceral adipose tissue stores and mobilizes lipids. In the presence of caloric excess,
adipose stores respond pathologically and affect the rates of both lipogenesis and
lipolysis and results in an increased release of free fatty acids (FFA) from adipose tis-
sue into the circulation. This then influences the accumulation of lipids in the liver and
striated muscle. During this process cytokines are released and impair insulin signal-
ing and reduce insulin-mediated glucose uptake into muscle. Also, an impaired insulin
signal in the liver decreases glucose utilization and promotes glucose production,
increasing hepatic glucose output. In addition, the availability of FFA in the liver stim-
ulates de novo lipogenesis and FFA esterification. This is accompanied by impaired
apolipoprotein (Apo) B100 and the formation of very low density lipoprotein (VLDL).
All of these factors trigger lipid accumulation and oxidation in the liver, oxidative
stress, the release of inflammatory cytokines, and hepatic stellate cell activation.
In summary, although the specific mechanisms involved in the pathogenesis of
NASH are not completely clear, it is thought that NASH develops as a consequence of
a two-hit process. The first hit is steatosis, and the second hit involves oxidative stress
and proinflammatory cytokines which induce progressive liver disease. There is
increasing evidence that the adipokines released from white adipose tissue seem to
mediate the second hit involved in the pathogenesis of NAFLD and NASH.
Adiponectin is an adipokine with antiinflammatory properties. It also increases
insulin sensitivity, regulates hepatic FFA metabolism, and reverses hepatic stellate cell
activation. Low levels of adiponectin are strongly associated with visceral adiposity,
hyperlipidemia, and insulin resistance. Leptin, another adipokine, is proinflammatory.
It enhances hepatic fibrogenesis by increasing the expression of transforming growth
factor B (T6F-B) and hepatic stellate cell activation. Tumor necrosis factor (TNF)
and interleukin (IL)-6 are proinflammatory cytokines also produced by visceral
adipose tissue. These cytokines play a central role in insulin resistance by impairing
insulin signaling in hepatocytes and promoting inflammation. They also have a nega-
tive influence on the immune system. Resistin and angiotensin are two other factors
that may contribute to the pathogenesis of NAFLD.

V. NATURAL HISTORY AND PROGNOSIS. The natural history of NAFLD is related to

its histopathology. Simple steatosis does not appear to be a progressive disease; how-
ever, approximately 20% of patients with NAFLD–NASH progress to cirrhosis.
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398 Part V: Specific Complaints and Disorders

Although NASH is generally thought to be a clinically stable disease in most

patients, it can progress to significant liver disease in a subgroup of patients. The risk fac-
tors for developing fibrosis and cirrhosis with NASH include older age, metabolic syn-
drome, obesity, diabetes mellitus, and AST/ALT higher than 1. Liver-related mortality has
been found in 11% of patients with NAFLD with hepatic fibrosis who were followed up
for 10 years. NAFLD may be as important as alcohol or HCV infection in causing cir-
rhosis in the United States. In fact, orthotopic liver transplantation is currently being per-
formed for decompensated liver disease caused by NAFLD. Better understanding of the
mechanisms involved in the pathogenesis of NAFLD is expected to help identify patients
with hepatic steatosis who are at high risk of developing progressive liver disease, portal
hypertension, and other complications of cirrhosis including hepatocellular carcinoma.

VI. TREATMENT. Currently, there is no effective therapy for NAFLD. Available treatment
modalities attempt to eliminate the factors that are commonly associated with
NAFLD. Weight loss, treatment of hyperglycemia, hyperlipidemia, and discontinua-
tion of alcohol and potentially toxic drugs such as corticosteroids, estrogens, amio-
darone, and perhexiline are recommended. Treatment for morbid obesity (i.e.,
bariatric surgery) should be considered. In small, short-term studies, the use of
ursodeoxycholic acid, vitamin E, gemfibrozil, betaine (a metabolite of choline),
N-acetylcysteine, and metformin resulted in improvement in liver chemistry tests and
hepatic steatosis, but no significant change in histological grade of inflammation or
fibrosis has been observed.
Thiazolidinediones (TZDs) (i.e., pioglitazone [Actos] and rosiglitazone
[Avandia]) is a class are drugs known as “insulin sensitizers” since they allow the adi-
pose and muscle cells to become more sensitive to insulin and allow better uptake of
serum glucose into these cells. In ongoing studies, TZDs show promise in reversing
NASH, especially in the diabetic patients. (Avandia has been removed from the U.S.
market for increasing cardiac risk factors.)
Newer treatment modalities using anticytokine (e.g., TNFa antibodies, antioxi-
dants, glutathione prodrugs, and insulin sensitizers) are being evaluated. Patients with
NAFLD who develop hepatic decompensation should be evaluated for liver transplan-
tation. In a number of patients, NASH has been observed to recur after successful liver
transplantation.

Selected Readings
Day CP. From fat to inflammation. Gastroenterology. 2006;130:207–210.
Ekstedt M, et al. Long-term followup of patients with NAFLD and elevated liver enzymes.
Hepatology. 2006;44:865–873.
Farrell GC, et al. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatol.
2006;43(2 suppl I):S99–S112.
Gholam PM, et al. Nonalcoholic fatty liver disease in severely obese subjects. Am J
Gastroenteraol. 2007 Feb;102:399–408.
Hubscher SG. Histological assessment of nonalcoholic fatty liver disease. Histopathology.
2006;49:450–465.
McClaine CJ, et al. Good fat/bad fat. Hepatology. 2007;45:1343–1346.
79466_CH53.qxd 1/2/08 1:33 PM Page 399

DRUG-RELATED HEPATIC INJURY 53

M ore than 1,100 drugs and herbal remedies have been reported to cause liver injury.
Drug-induced liver injury can mimic almost all patterns of liver injury seen in humans.
Among causes of acute liver failure, drug-induced liver injury accounts for more than 50%
of them. The injury can be hepatocellular necrosis, cholestatic disease, deposition of
microvesicular fat in hepatocytes, or mixed patterns. In most cases, the damage is caused by
toxic metabolites of the drug or immune response to the drug or its metabolites. It may result
in chronic hepatitis and cirrhosis. Antimicrobials, psychotropic drugs, lipid-lowering agents
and nonsteroidal antiinflammatory drugs (NSAIDS), phenytoin, propylthiouracil antituber-
culosis drugs, sulfa compounds, and disulfirams are implicated most often. Table 53-1 is a
partial list of drugs for which liver chemistry test monitoring is recommended. For the major-
ity of drugs the risk of drug-induced liver injury is in the range of 1:104–105 in the United
States. The risk is greater in women and the elderly, and the risk varies depending on the
nutritional and other susceptibility characteristics of the patients and the drug class.

I. HEPATOCELLULAR NECROSIS. Drug-induced hepatocellular necrosis is clinically

indistinguishable from cell injury from other causes such as viruses or ischemia. Thus
it is important to obtain a drug history and note the presence of any hypersensitivity
reactions such as rash or eosinophilia.
A. The diagnosis is usually established by a history of drug ingestion and the elimi-
nation of other possible causes such as viruses or ischemia by appropriate serology
and clinical data.
1. The severity of the disease can range from minimal symptoms to fulminant
hepatic failure. In fact, 20% to 50% of patients with fulminant hepatic failure
have drugs, especially acetaminophen, as the cause of their liver failure.
2. Laboratory studies. Serum glutamic-oxaloacetic transaminase (SGOT, or
aspartate aminotransferase [AST]) and serum glutamic-pyruvic transaminase
(SGPT, or alanine aminotransferase [ALT]) levels are elevated (2–30 times
normal). These enzymes leak into the circulation from the cytoplasm of dam-
aged or dying hepatocytes. The alkaline phosphatase and albumin levels are
usually affected to a lesser extent. Serum bilirubin levels and the increase in
prothrombin time (PT) correlate with the severity of the liver damage.
3. A percutaneous liver biopsy performed early in the course of the disease can
be helpful in identifying the type and extent of injury.
a. Drugs such as carbon tetrachloride, acetaminophen, and halothane cause
injury to the centrilobular or perivenular area.

TABLE 53-1 Drugs Recommended for Liver Chemistry Monitoring

Piroxicam, diclofenac, sulindac, aspirin, pyrazine, fluconazole, itraconazole, dapsone, isoniazid,

rifampin, labetalol hydrochloride, amiodarone hydrochloride, atorvastin calcium, lovastatin, nicotinic
acid, valproic acid, carbamazepine, phenytoin, tolcapone, tacrine hydrochloride, rosiglitazone
maleate, pioglitazone hydrochloride, methotrexate, propylthiouracil

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400 Part V: Specific Complaints and Disorders

b. Drugs such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), thi-

azide diuretics, nicotinic acid, clofibrate, gemfibrozil, oxacillin, sulfon-
amides, rifampin, ketoconazole, fluorocytosine, zidovudine, isoniazid,
tacrine, trazodone, calcium channel blockers, beta blockers, and methyldopa
cause diffuse parenchymal injury similar to viral hepatitis.
c. Valproic acid, amiodarone, and intravenous tetracycline can cause extensive
microvesicular fat infiltration of the hepatocytes and liver failure, as seen in
Reye’s syndrome or fatty liver of pregnancy.
B. Treatment consists of prompt discontinuation of the offending drug and support-
ive measures. In most cases, patients recover over weeks to months. However,
fatality in fulminant cases is still significant.

II. CHOLESTASIS. Drug-induced cholestasis is due to impairment of bile secretion by

the hepatocytes. It may be caused by a change in the chemical and physical properties
of the hepatocyte membranes as with estrogen and 17C-alkyl-steroids. In addition,
drugs, directly or by their toxic metabolites, may induce cholestasis by their effects on
cytoskeletal elements, inhibition of membrane Na-K-ATPase, or immunologic damage
to the hepatocytes or to the small bile ducts. Drugs most commonly involved in
cholestatic liver injury are phenothiazines, tricyclic antidepressants, erythromycin,
carbamazepine, cyproheptadine, tolbutamide, captopril, phenytoin, trimethoprim-
sulfamethoxazole, sulfasalazine, and lipid-lowering drugs.
A. Diagnosis. Patients with drug-induced cholestatic liver disease may present with
clinical and laboratory findings very similar to those in intra- or extrahepatic bile
duct obstruction, septic cholangitis, or acute cholecystitis.
1. Clinical presentation and laboratory studies. Fever, pain, and tenderness in
the upper abdomen (especially in the right upper quadrant), jaundice, and pru-
ritus are commonly present. The serum alkaline phosphatase level is usually
significantly elevated (2–10 times normal), with a mild increase in serum
transaminases. Conjugated hyperbilirubinemia may be severe (2–30 mg/dL).
There may be an accompanying rash or other signs of hypersensitivity.
2. Diagnostic studies. Ultrasound should be performed in most patients to rule
out possible bile duct obstruction. Endoscopic retrograde cholangiopancreatog-
raphy (ERCP), percutaneous transhepatic cholangiography (PTC), or computed
tomography (CT) may be necessary in difficult cases.
3. Liver biopsy should be considered if the diagnosis cannot be made with the
preceding clinical data. Histology usually shows cholestasis with or without
inflammation. Microscopic cholangitis, infiltration of the portal tracts with
inflammatory cells, and limited hepatocellular necrosis may be present.
B. Treatment is supportive. Prompt withdrawal of the drug is essential.

III. MIXED-PATTERN LIVER INJURY. In most cases, drug-induced liver injury causes a
combination of cholestasis and hepatocyte necrosis. Patients usually have moderate
elevation of the serum transaminases, bilirubin, and alkaline phosphatase levels. Most
of these reactions are the result of hypersensitivity to the drug and affect only a few
susceptible individuals.
A. Phenytoin (Dilantin) toxicity resembles viral mononucleosis. Patients present
with fever, lymphadenopathy, and a tender liver. The liver biopsy shows portal
lymphocytic infiltration and spotty necrosis of parenchymal cells.
B. Drugs such as quinidine, allopurinol, nitrofurantoin, diltiazem, and many others
cause a granulomatous reaction with some hepatocytic necrosis.
C. For a detailed list of drugs and their liver toxicity see the article by Lewis in the
Selected Readings.

IV. AMIODARONE HEPATOTOXICITY. Recently three cardioactive drugs—amiodarone,

perhexiline maleate, and colalgia (4,4
-diethylaminoethoxyhexestrol)—have been
found to cause liver injury resembling alcoholic hepatitis.
A. Pathogenesis. Amiodarone has been reported to cause corneal and skin deposits,
hypo- and hyperthyroidism, pulmonary infiltrates and interstitial fibrosis, peripheral
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Chapter 53: Drug-Related Hepatic Injury 401

neuropathy, and hepatomegaly with transaminase elevation in 20% to 40% of the

patients receiving the drug. Liver histology in these patients resembles that of alco-
holic hepatitis. There may be bile duct proliferation, fibrosis, and cirrhosis. Electron
microscopy shows the presence of trapped phospholipids in secondary lysosomes.
Amiodarone has been found to accumulate in acidic lysosomes and to competitively
inhibit lysosomal phospholipases and phospholipid degradation leading to accumula-
tion of phospholipids in lysosomes of liver cells. The relation of this phospholipidosis
to the formation of a state resembling alcoholic liver injury and cirrhosis is not known.
Amiodarone has a long half-life and a large volume of distribution. The blood
levels remain elevated, and the drug is present in the liver for months after the drug
is stopped. The hepatotoxicity is usually clinically insidious. It usually develops
after a year of therapy but can occur after 1 month.
B. Diagnosis. Liver disease is diagnosed by the findings of hepatomegaly, a moder-
ate rise in serum transaminases, and occasionally elevated bilirubin. Liver biopsy
with histologic and electron microscopic examination may be necessary.
C. Treatment and clinical course. Therapy is supportive after discontinuation of
the drug. Even though hepatomegaly usually reverses in time, the liver disease may
progress, leading to cirrhosis and its complications.

V. ASPIRIN HEPATOTOXICITY. Aspirin (ASA) and other salicylates have been noted to
cause liver injury in patients with rheumatic and collagen vascular diseases such as
juvenile and adult rheumatoid arthritis, rheumatic fever, and systemic lupus erythe-
matosus. Normal subjects and patients with nonrheumatic diseases such as orthopedic
problems may also be affected.
A. Pathogenesis. The blood level of the drug (5 mg/dL) and the duration of intake
(6 days to weeks) seem to play an important role in the production of liver dam-
age. The injury appears to be a cumulative phenomenon, appearing after many
days of intake of large therapeutic doses. A single, toxic overdose of aspirin pro-
duces little or no hepatic injury.
Patients with rheumatic and collagen vascular disorders may be more sus-
ceptible to liver injury with aspirin than others. This may be due to the presence
of hypoalbuminemia allowing higher serum levels of unbound aspirin, underlying
liver damage, and possibly altered metabolism of the salicylates. The mechanism
of hepatic injury seems to be intrinsic toxicity of the salicylate moiety rather than
host idiosyncrasy to the drug. Salicylate choline and sodium salicylate also can
induce hepatic injury. The liver disease is usually mild, acute, and reversible.
Lowering the dose of ASA without totally discontinuing its use may be sufficient
to reverse the injury. There is strong evidence to suggest that aspirin in the setting
of a viral infection may provoke the development of Reye’s syndrome in children.
1. Clinical presentation. Clinical manifestations of hepatic injury are not promi-
nent. Most patients remain asymptomatic. Some patients complain of anorexia,
nausea, and mild abdominal distress. Almost all patients are anicteric.
The liver disease is usually mild. However, encephalopathy, severe coagu-
lopathy, and fatal liver failure have been reported. There is no established
evidence that aspirin causes chronic liver injury.
2. Diagnostic studies. Serum transaminases are usually moderately elevated (2–10
times normal). In 10% of the individuals, SGOT levels are greater than 100
IU/mL. The SGOT (AST) levels are usually higher than the SGPT (ALT) levels.
The alkaline phosphatase levels are usually normal or only modestly elevated.
Serum bilirubin levels have been elevated only in about 3% of the reported cases.
3. Treatment is supportive. In most instances, it is not necessary to discontinue
the drug for reversal of liver injury. Decreasing the dosage to attain blood lev-
els less than 15 mg/dL seems to be sufficient.

VI. ACETAMINOPHEN HEPATOTOXICITY. Acetaminophen (Tylenol or Paracetamol) is

an analgesic-antipyretic with few side effects when taken in therapeutic doses in most
individuals. However, it is a potent hepatotoxin leading to hepatic necrosis when
taken in large overdoses.
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402 Part V: Specific Complaints and Disorders

Most instances of acetaminophen-related liver injury result from a large, single

overdose (10 g or 30 regular-strength or 15–20 extra-strength tablets) taken in a
suicide attempt. Multiple small doses taken with therapeutic intent can reach a total dose
large enough to produce liver injury. Alcoholics have an enhanced susceptibility to liver
injury from a single dose as low as 3 g or multiple therapeutic dosages (4–8 g per day for
2–7 days). Preexisting hepatic disease, malnutrition, and wasting diseases may also pre-
dispose patients to hepatic injury from acetaminophen with multiple therapeutic doses.
A. Pathogenesis. Following oral ingestion in therapeutic doses, acetaminophen is
rapidly absorbed, and peak plasma concentrations are reached in 30 to 60 minutes. It
is metabolized primarily in the liver by conjugation (70% to 80%) with glucuronide
or sulfate, which are excreted in the urine. About 5% to 10% of the drug is oxidized
to catechol metabolites and 3-hydroxy- and 3-methoxy-acetaminophen. Another 5%
to 10% of the drug is processed by the cytochrome P-450 mixed-function oxidase
(MFO) system and converted to a reactive metabolite N-acetyl-p-benzoquinone imine
(NAPQI). Normally, this toxic intermediate reacts with the cysteine moiety of cytoso-
lic glutathione and is excreted in the urine as thioethers. If the toxic metabolite is in
excess of the cellular glutathione, it binds to vital hepatocyte proteins, leading to cell
death. Figure 53-1 summarizes the metabolism of acetaminophen.

Figure 53-1. Major metabolic pathways of acetaminophen. (From Nelson SD. Molecular mecha-
nisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis. 1990;10:268. Reprinted with
permission.)
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Chapter 53: Drug-Related Hepatic Injury 403

1. Likelihood of hepatic injury. The likelihood that a large dose of aceta-

minophen will lead to hepatic injury depends on the following:
■ Age of the patient
■ Total quantity ingested
■ Blood level achieved
■ Rate of disposition
■ Activity of the P-450 MFO system
■ Adequacy of glutathione stores
a. Age of the patient. Acetaminophen overdose in young children is generally
associated with a much lower incidence of hepatotoxicity than in adults.
b. Total quantity ingested. The toxic total single dose in most instances is
greater than 15 g. However, lower single doses of 3 to 6 g have been toxic in
some situations.
c. Blood level achieved. There is a correlation between blood levels at 4 and
10 hours after ingestion and the severity of the liver injury. If the blood levels
exceed 300 mg/dL at 4 hours, the injury is often severe. Levels below 150
mg/dL are usually nontoxic. A nomogram that helps predict liver damage
associated with particular blood levels of acetaminophen measured 4 to
12 hours after ingestion is shown in Figure 53-2.
d. Rate of disposition
e. Activity of the P-450 MFO system. The rate of production of the toxic
metabolite clearly affects the toxicity of acetaminophen when large doses
(10 mg) are ingested. The capacity of the liver to sulfate and glucuronidase the
drug is overwhelmed, and the absolute and relative amounts that are metabo-
lized by the P-450 MFO system to the toxic metabolite are increased. Also, pre-
vious induction of the P-450 MFO system by chronic alcohol ingestion or by
drugs known to stimulate the P-450 system such as barbiturates and phenytoin
increases the biotransformation of the acetaminophen to the toxic metabolite.
f. Adequacy of glutathione stores. Hepatic tissue levels of glutathione are
critical to the toxic effects of acetaminophen. Toxicity and cell necrosis ensue
when more than 70% of hepatic glutathione stores are used up by the toxic
metabolite or when the tissue glutathione levels are depleted by previous
fasting, malnutrition, or alcohol ingestion.
2. Hepatotoxicity in alcoholics. Serious hepatotoxicity has been reported with
therapeutic doses of acetaminophen in alcoholics. This is because chronic alco-
hol ingestion enhances the formation of toxic metabolite by the previously
induced P-450 MFO system, and malnutrition reduces the removal of the toxic
metabolite due to reduced levels of hepatic glutathione.
3. The location of hepatic injury is centraxonial and corresponds to the location
of the enzymes responsible for the metabolism of the drug. Sinusoids are often
congested and dilated centrally. There is extensive hemorrhagic hepatocellular
necrosis with minimal inflammatory infiltrate but without steatosis.
B. Diagnosis
1. Clinical presentation. A few hours after ingesting a large dose (10 g) of aceta-
minophen, the patient usually has nausea and vomiting. If sedating drugs were
also ingested, the patient may be obtunded. These symptoms usually disappear
within 24 hours, and the patient appears fully recovered. Liver injury becomes
apparent 48 to 72 hours after ingestion. The patient may complain of pain and
tenderness in the right upper quadrant.
2. Diagnostic studies. SGOT (AST) and SGPT (ALT) levels are usually elevated
into the thousands with lesser increases in serum alkaline phosphatase. In most
cases, there is an early and severe coagulation abnormality with elevation of the
prothrombin time. Values greater than twice normal forebode a grave progno-
sis. Usually bilirubin levels are mildly elevated.
3. The severity of the liver injury is variable. Progression to fulminant hepatic
failure and death may occur 4 to 18 days after drug ingestion.
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404 Part V: Specific Complaints and Disorders

Figure 53-2. Semilogarithmic plot of plasma acetaminophen levels versus time. (From Rumack
BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871. Reprinted with
permission.)

4. Damage to other organs. Other organs may be damaged by acetaminophen

toxicity. Renal failure with acute tubular necrosis and myocardial damage evi-
denced by electrocardiographic changes may occur.
5. Recovery. If the patient recovers from the acute episode, there is a return of the
hepatic architecture to normal within 3 months.
C. Treatment
1. Therapeutic approaches to acetaminophen overdose have included measures to
reduce the absorption of the drug from the gastrointestinal tract by adminis-
tration of activated charcoal or cholestyramine or to enhance its clearance from
plasma by hemoperfusion or hemodialysis. None of these techniques has been
found to be totally effective.
2. N-Acetylcysteine. Because glutathione is critical to detoxification of the toxic
metabolite, replenishing hepatic stores of glutathione by providing its precursor
cysteine in the form of N-acetylcysteine (NAC) (Mucomyst) has been shown to
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Chapter 53: Drug-Related Hepatic Injury 405

be an effective antidote if administered within 10 hours of ingestion of the

overdose of acetaminophen. Use of NAC within 24 hours of ingestion of aceta-
minophen overdose is recommended, but its usefulness beyond the first
10 hours is less dramatic. Oral NAC is well tolerated by most patients; it causes
mild nausea and occasional vomiting. The intravenous route may be used if
oral administration is not possible.
The protocol for treatment consists of identification of the patient and
determination of the time and amount of acetaminophen ingested. If the inges-
tion has occurred within 24 hours of presentation, the patient should be
intubated with a large-bore nasogastric tube, and gastric lavage should be per-
formed. A loading dose of NAC, 140 mg/kg body weight, should be given
orally and followed by 17 maintenance doses of 70 mg/kg each at 4-hour
intervals for a total treatment period of 72 hours. While therapy is being admin-
istered, the blood level of acetaminophen should be determined and plotted on
the nomogram shown in Figure 53-2. If the blood level of the drug falls in the
range likely to lead to hepatotoxicity, the full course of therapy should be com-
pleted. The therapy can be discontinued if the level is below the toxicity range.
If an oral dose of NAC is vomited within 1 hour of administration, that dose
should be repeated. An antiemetic can be given to patients who are intolerant
of oral NAC. In patients who persistently vomit the medication, NAC may be
administered through a nasogastric or jejunal tube. NAC may be diluted 3:1
with cola, fruit juice, or water to produce a more palatable solution.
3. Severely ill patients should be given full supportive care as for severe viral
hepatitis. Patients should be intensively monitored for maintenance of normal
vital signs and urine output and for cardiac, renal, and hematologic status. Any
abnormalities of fluid, electrolytes, or acid-base balance should be corrected
immediately.
4. The Rocky Mountain Poison Center in Denver, Colorado, may be contacted
day or night (telephone: 800-525-6115) to advise on any aspects of therapy.

VII. DRUG-INDUCED CHRONIC HEPATITIS. Drugs that have been documented to cause
chronic hepatitis (CH) include oxyphenisatin, alpha-methyldopa, nitrofurantoin,
dantrolene, isoniazid, propylthiouracil, sulfonamides, and halothane. The incidence of
CH with any one drug is low, and the total number of cases is small. However, a drug
history should be obtained from each patient suspected to have CH. In most cases,
if drug-induced CH has not developed into cirrhosis, it improves or resolves with
discontinuation of the drug.
A. Methyldopa (Aldomet). The incidence of hepatitis with methyldopa is very low;
however, if the hepatitis is not noted in early stages, the disease may progress to
chronic active hepatitis (CAH). Hepatitis occurs within weeks after starting the
drug, suggesting a role for hypersensitivity. If the lesion is recognized early on, the
injury and inflammation regress with discontinuation of the drug.
B. Oxyphenisatin. This laxative, although taken off the market in the United States,
is still in popular use, especially among women in Europe and South America.
Oxyphenisatin has been shown to cause acute and chronic hepatitis resembling
“lupoid hepatitis.” The disease may progress to cirrhosis if the drug is continued
after the onset of liver injury. In most instances, however, after the withdrawal of
the drug, the disease is halted and even reversed.
C. Isoniazid (INH). Isoniazid produces asymptomatic elevation of serum transami-
nases with mild liver injury in up to 20% of the patients within the first 2 to
3 months of therapy. However, approximately 1% of the individuals develop
severe hepatic injury, even fulminant hepatic failure, associated with a high mor-
tality. Chronic hepatitis generally does not develop if the drug is stopped within the
first few weeks of recognition of the hepatitis. However, severe CAH accompanied
by cirrhosis develops with persistent administration of INH.
1. Pathogenesis. INH-induced liver injury is thought to result from hepatotoxic
reactive intermediates of INH metabolism. INH is first acetylated and then con-
verted to acetylphenylhydrazine, which is a potent hepatotoxin. There are some
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406 Part V: Specific Complaints and Disorders

data to suggest that rapid acetylators (e.g., most East Asians) are more suscep-
tible to INH-induced liver injury.
2. Clinical presentation. The clinical features of hepatitis induced by INH are
nonspecific and resemble those of viral hepatitis. Fatigue, malaise, anorexia,
nausea, vomiting, and abdominal discomfort are commonly noted. Jaundice is
the presenting complaint in 10% of the patients. Signs and symptoms of hyper-
sensitivity, rash, lymphadenopathy, arthralgia, and arthritis are rare.
Older patients, especially older women, have a higher susceptibility to
INH-induced hepatitis. Hepatitis is rare in patients younger than 20 years of
age. The risk increases to 0.5% in patients 20 to 35, 1.5% for patients 35 to 50,
and 3% for those over 50 years old. Alcohol and drugs that induce the hepatic
P-450 enzyme system such as rifampin seem to increase susceptibility to INH
injury. Continuation of INH after the onset of prodromal symptoms increases
the severity of the hepatitis. Thus it is crucial to stop INH therapy in sympto-
matic patients immediately during the first 1 to 2 weeks.
3. Treatment. There is no specific therapy for INH hepatitis other than prompt
withdrawal of the drug. Patients should be given supportive care. There is no
role for corticosteroid therapy.

Selected Readings
Buckley NA, et al. Oral or intravenous N-acetylcysteine: Which is the treatment of choice
for acetaminophen (paracetamol) poisoning? Toxicol Clin Toxicol. 1999;37:759.
Hanje AJ, et al. Thalidomide-induced severe hepatotoxicity. Pharmacotherapy. 2006;26:
1018–1022.
Kafrouni MI. Hepatotoxicity associated with dietary supplements containing anabolic
steroids. Clin Gastroeterol Hepatol. 2007;5(7)809–812.
Lewis JH. Drug induced liver disease. Med Clin North Am. 2000;84:1275.
Lewis JH, et al. Drug and chemical induced cholestasis. Clin Liver Dis. 1999;3:433.
Marino G, et al. Management of drug induced liver disease. Curr Gastroenterol Rep.
2001;3:38.
Woo OF, et al. Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen
overdose. Ann Emerg Med. 2000;35:363.
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CHRONIC IMMUNE-MEDIATED 54
LIVER DISEASE

I. Chronic hepatitis (CH) refers to a condition of hepatic inflammation, necrosis, and

fibrosis that is present for at least 6 months. There are numerous causes of CH. The nat-
ural history and response to therapy depend on the etiology and the age and condition
of the patient. However, the end stage of all forms of chronic hepatitis, cirrhosis, and its
complications is the same for all causes.
A. Forms of CH. Histologically, CH has been subdivided into three forms:
1. Chronic mild hepatitis refers to mild disease in which the inflammation is
confined to the portal tracts. Serum transaminases may be near normal or mod-
erately elevated.
2. Chronic active hepatitis (CAH) refers to symptomatic CH in which the liver tests
and histology are compatible with active inflammation, necrosis, and fibrosis,
which may lead to cirrhosis. On histology, there is active inflammation spilling out
of the portal tracts into the parenchyma with piecemeal necrosis and fibrosis.
3. Chronic lobular hepatitis (CLH) refers to lobular inflammation with spotty
necrosis.
The histologic classification emphasizes the importance of liver biopsy in
the diagnosis, management, and prognosis of the disease. Any of the causes
described in section B can take any of these forms in histologic appearance;
hence histology alone is not sufficient for diagnosis and proper management of
these patients.
B. The causes of CH can be classified into several basic groups: viral, metabolic,
autoimmune, and drug-induced CH. It is also important to exclude Wilson’s dis-
ease,
1-antitrypsin deficiency, and hemochromatosis in these patients. Table 54-1
summarizes the causes of CH.
1. Autoimmune hepatitis (AH) is a progressive inflammatory liver disease of
unknown cause in which immune reactions against host antigens are believed
to be the major pathogenic mechanism. Exclusion of other liver diseases that
have similar features are very important before diagnosis of AH is made. These

TABLE 54-1 Causes of Chronic Hepatitis

Viruses Metabolic causes

Hepatitis B virus Primary biliary cirrhosis
Hepatitis C virus Sclerosing cholangitis
Hepatitis D virus Alpha1-antitrypsin deficiency
Drugs Wilson’s disease
Alpha-methyldopa Hemochromatosis
Oxyphenacetin Autoimmune hepatitis
Isoniazid Type I (antiactin)
Alcoholic liver disease Type II (anti-KLM)
Nonalcoholic steatohepatitis Type III (anti-SLA)
Cryptogenic

407
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408 Part V: Specific Complaints and Disorders

include Wilson’s disease, chronic viral hepatitis, alpha-1-antitrypsin deficiency,

hemochromatosis, alcoholic and nonalcoholic steatohepatitis, drug-induced
liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis.
a. Three types of AH have been recognized. These are Types I, II, and III.
i. Type I (or Lupoid) AH is the most common type in the United States and
affects all ages. The majority (78%) of patients are women of northern
European descent. Most patients also may have concurrent extrahepatic
autoimmune diseases including autoimmune thyroiditis, Graves disease,
ulcerative colitis, Crohn’s disease, rheumatoid arthritis, pernicious anemia,
progressive systemic sclerosis, systemic lupus erythematosus, Coombs pos-
itive hemolytic anemia, idiopathic thrombocytopenic purpura, leukoclastic
vasculitis, nephritis, erythema nodosum, and fibrosing alveolitis. HLA-DR3
and DR4 are independence risk factors of susceptibility.
Most patients (40%) present with an acute onset, and a subset of
patients present with fulminant hepatitis. Others (25%) may present with
cirrhosis indicating an indolent progressive subclinical disease.
a) Prevalence in Europe and the United States is approximately 17 per
100,0000. AH accounts for 11% to 23% of chronic hepatitis in the
United States.
b) Diagnosis
1) Clinical features. Most common symptoms are malaise and
easy fatigability. Hepatomegaly and jaundice are usually present.
2) Laboratory findings. Serum transaminases are usually elevated
up to 10 times normal. Hyperbilirubinemia is usually below 3
times normal. Serum alkaline phosphatase level is frequently
increased, but usually below 2 times normal. Patients also have
hypergammaglobulinemia in the range of 50 to 100 g /L with a
predominance of IgG fraction. Autoantibodies necessary for diag-
nosis included ANA, SMA, and anti-LKMI, but other antibodies
may also be present. These include antiactin, SLA/LP, ASGPR,
liver cytosol type I. Cryoglobulinemia may occur. The autoanti-
body and gamma globulin profiles are discussed in Table 54-2.
3) On pathologic examination of the liver biopsies there is mod-
erate to severe interface hepatitis and no biliary lesions, granu-
lomas, or prominent changes suggestive of another liver disease.
Plasma cells and rosettes may be seen.

Clinical and Immunologic Comparison of the

TABLE 54-2
Three Types of Autoimmune Chronic Hepatitis

Type I (lupoid) Type II Type III

Characteristic anti-SM (antiactin) anti-KLM-I anti-SLA

Age at presentation (y) 10–30 and 40–70 17 30–40

Other autoimmune disorders 10% 15%–20%
Autoantibodies (%)
Anti-SM 100 35%
ANA 30–90 1–5
AMA 10–20 1–5
LE cells 10–50
Gamma globulins (g/L) 30–100 20–30
IgG 20–50 20–30
IgA 3–5 1–3
IgM 1–2 2–5

SM, smooth muscle; KLM, kidney-liver-microsomal; SLA, soluble liver antigens; ANA, antinuclear
antibody; AMA, antimitochondrial antibody; LEZ, lupus erythematosus.
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Chapter 54: Chronic Immune-Mediated Liver Disease 409

ii. Type II: anti-KLM (kidney-liver-microsomal) antibody–positive. Type II

is less prevalent than type I and has been described most often in
Continental Europe. It tends to present predominantly in the pediatric age
group (ages 2–14); however, it may also occur in adults and is more often
associated with other autoimmune diseases, such as insulin-dependent
diabetes mellitus, autoimmune thyroid disease, and vitiligo. The presenta-
tion is often acute, even fulminant, and has a propensity to progress
rapidly to cirrhosis.
iii. Type III: Anti-SLE-LP (soluble liver antigen). These patients constitute
a small group of AH patients who are, in general, negative for antinuclear
antibody (ANA) and KLM antibodies. Type III AH may be a variant of
Type I AH rather than a separate entity.
However, up to 30% of these patients may have smooth muscle
antibody (SMA) and liver membrane antibody (LMA), rheumatoid
factor, antithyroid antibodies, or antimitochondrial antibody (AMA).
Nevertheless, there is no evidence that these patients differ in any signif-
icant respect from those with type I AH.
b. Other findings. Anti-liver specific protein (anti-LSP) and anti-asialoglycoprotein
receptor (anti-ASGP-R) are found in virtually all AH patients with positive
ANA or SMA and KLM-I. Anti-LSP is found in a number of chronic liver
disorders, primarily those with an underlying immunopathology and in which
periportal inflammation is a feature. Titers of anti-LSP and anti-ASGP-R corre-
late with histologically assessed disease severity and fluctuate in response to
immunosuppressive therapy.
The distinction between AH and primary biliary cirrhosis is not always
clearcut; histologic, clinical, and immunologic overlaps have been well
described. In some young patients, AH may progress to sclerosing cholangitis.
Viral hepatitis (A, B, C, D, and E) should be excluded initially. The
frequent finding of false-positive anti-HCV in patients with AH should be
confirmed with HCV viral titer determination by the polymerase chain
reaction (PCR).
AH runs a slow course in most patients. In some cases, however, a dra-
matic acute episode may develop, which may result in sudden death.
c. Treatment. In the past, patients with AH were diagnosed with histologic fea-
tures showing advanced liver disease, and the disease was noted to be progres-
sive and fatal within 4 to 5 years. In current practice, most patients come to
medical attention in the earlier stages of the disease before the development of
cirrhosis; thus, the life expectancy is improved. The mortality figures in the
placebo groups of the major controlled trials all showed that more than half of
the untreated patients died within 3 to 5 years. There is considerable evidence
that immunosuppressive therapy that includes corticosteroids leads to a decrease
in mortality. The goals of therapy are to diminish hepatic inflammation and
fibrosis and prevent the progression of the chronic hepatitis to cirrhosis.
Following assessment of alternative causes of chronic hepatitis and of
the extent of liver injury by liver biopsy, a therapeutic trial should be initi-
ated. A response should occur within 3 months or will not occur at all.
Soon after initiation of corticosteroid therapy, patients with AH feel better
with abatement of fatigue, malaise, anorexia, and fever. Serum AST, ALT,
and bilirubin levels fall, and there is a reduction in serum gamma globulin
levels.
i. Corticosteroids. There is general agreement that the treatment of ACH
should begin with a corticosteroid. Prednisone and prednisolone are
equally effective. An acceptable regimen is prednisone or prednisolone
30 to 40 mg per day for 2 to 4 weeks. If the patient has a good response,
the dose of the corticosteroid is reduced every 2 weeks according to
serum ALT and AST levels. Once remission is obtained, some patients do
remarkably well at low doses (2.5–7.5 mg per day) only to relapse if
the drug is discontinued. In most (about 75%) of the patients, lifelong
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410 Part V: Specific Complaints and Disorders

treatment is required. When a patient is in remission, a trial of drug

withdrawal may be reasonable. If relapse occurs, however, treatment
should be instituted promptly and continued indefinitely.
Patients who receive long-term corticosteroid therapy are at risk for
progressive osteoporosis and vertebral compression fractures. Regular
exercise, calcium 1.0 to 1.5 g daily and vitamin D 400 U daily and a bis-
phosphonate are indicated and recommended.
Corticosteroids have well-established, predictable dose-related side
effects including hypertension, cataracts, diabetes mellitus, osteoporosis,
and a predisposition to a variety of infections and weight gain. Most
of these side effects are manageable if the dose is kept at less than 10 to
15 mg per day.
ii. Azathioprine and 6-Mercaptopurine (6-MP). The use of azathioprine
has been of considerable value in permitting a lower dose of cortico-
steroids to be used to achieve remission.
It is recommended that azathioprine be started along with the cor-
ticosteroid at 2 mg/kg dose. Although azathioprine alone has not been
effective in achieving remission, in some patients its use alone has been
sufficient in maintaining remission. The dose is decreased to 75 to 50 mg
when patients reach remission.
6-MP is an active metabolite of azathioprine, but the drugs are not
equivalent in the treatment of AH. In small clinical trials, it was noted
that 6-MP initially at 50 mg daily and increased to 1.5 mg/kg daily can
salvage patients who have failed therapy with azathioprine.
Homozygous deficiency of thiopurine methyl transferase (TPMT)
(an enzyme in the metabolic pathway of azathioprine and 6-MP) occurs
in 0.3% of the population and heterozygous (intermediate deficiency) in
11% of the population. These deficiencies increase the potency of a given
dose and enhance toxicity such as neutropenia, bone marrow suppres-
sion. Thus, TPMT enzyme genetics should be determined prior to onset
of therapy with azathioprine and 6-MP.
Side effects of this therapy include nausea, vomiting, rash, pancreati-
tis, and cytopenia in less than 10% of patients. Side effects are reversible
with dose reduction or termination of therapy. Risk of extrahepatic malig-
nancy is about 1.4-fold in age- and sex-matched normal population.
iii. Alternative therapeutic approaches. Cyclosporine 5 to 6 mg/kg has
been reported to be effective in treating patients with ACH in whom
there has been no response to corticosteroids and in whom drug sensi-
tivity prevents the use of azathioprine.
Other drugs including tacrolimus (4 mg twice daily), mycopheno-
late mofetil (1 g twice daily), 6-thioguanine (0.3 mg daily), sirolimus
(1–3 mg daily), and budesonide (9 mg daily) have been tried in small
numbers patients with variable results.
iv. Treatment results. Remission is accomplished in 65% of patients
within 18 months and 80% of patients within 3 years. Histologic reso-
lution lags behind clinical resolution by 3 to 8 months.
Drug withdrawal may be tried in patients who satisfy remission cri-
teria; however, it is achievable in about 21% of patients. Relapse after
drug withdrawal occurs in 50% within 6 months and 70% to 86%
within 3 years. Reinstitution of original therapy usually induces another
remission, but relapse commonly occurs if therapy is stopped. Thus
maintenance therapy either with low-dose prednisolone or azathioprine
is recommended.
Treatment failure occurs in about 10% of patients. Higher doses of
prednisone (60 mg daily) or prednisolone (30 mg daily) in conjunction
with azathioprine (150 mg daily) results in improvement in 70% of these
patients. Therapy needs to be continued indefinitely. Dose decrease of
the drugs may be tried after remission is attained.
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Chapter 54: Chronic Immune-Mediated Liver Disease 411

Ten-year life expectancy for treated patients is about 90%.

Histologic cirrhosis does not alter treatment response and these patients
should be treated similarly as those without cirrhosis.
Hepatocellular carcinoma (HCC) occurs in 0.5% of patients with
AH, but only in patients with cirrhosis. Yearly abdominal ultrasound
may be used for surveillance.
v. Liver transplantation may be offered to patients who have advanced
liver disease and have failed medical therapy It is recommended that
patients with AH be considered for liver transplantation at early stages
of disease, before severe complications of cirrhosis develop. Survival
ranges from 83% to 92% and 10-year survival is 75%. Recurrent dis-
ease may be seen mainly in recipients who are inadequately immunosup-
pressed. De Novo AH occurs in 3% to 5% of recipients transplanted for
nonautoimmune disease, especially children receiving cyclosporin.

II. PRIMARY BILIARY CIRRHOSIS

A. Epidemiology. Primary biliary cirrhosis (PBC) is one of the more common forms of
chronic liver disease. Its cause is unknown; however, genetic and immunologic fac-
tors appear to play a role. The lack of concordance of PBC in identical twins sug-
gests that a triggering event is necessary to initiate PBC in a genetically susceptible
person. It is characterized by chronic inflammation and destruction of small intra-
hepatic bile ducts, leading to chronic cholestasis, cirrhosis, and portal hypertension.
PBC primarily (90%) is a disease of middle-aged women. The disease has
not been seen in children. The age of onset ranges from 30 to 70 years. It affects
all races and socioeconomic classes and seems to be associated with HLA-DR8
and DPQ1 gene.
PBC is associated with other autoimmune diseases including thyroiditis,
hypothyroidism, Sjögren’s syndrome, scleroderma, rheumatoid arthritis, and
CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly,
and telangiectasia).
Patients with PBC also have abnormalities of cellular immunity, impaired T-cell
regulation; negative delayed hypersensitivity skin tests, decreased numbers of circu-
lating T lymphocytes, and sequestration of T lymphocytic with hepatic portal triads.
B. Histopathology of PBC includes gradual destruction of interlobular bile ducts
with a lymphocytic and plasma cell rich inflammatory reaction, leading to pro-
gressive cholestasis, disappearance of bile ducts, portal fibrosis, and ultimately cir-
rhosis. The disease can be divided histologically into four stages of increasing
severity. However, because the inflammation is patchy throughout the liver and
the typical changes of all four stages sometimes can be found in a single liver
biopsy specimen, it is often difficult to follow the course of the disease or the effi-
cacy of a treatment program.
1. In Stage I, there is a florid destruction of small bile ducts with mononuclear
cell (mostly lymphocytic) infiltrate. The infiltrate is confined to the portal
tracts. Granulomas may be seen.
2. In Stage II, the lesion is more widespread with inflammation spilling into the
periportal parenchyma. There is loss of bile ducts with few remaining irregular-
appearing ones. Diffuse portal fibrosis may be present.
3. In Stage III, histology is similar to Stage II; however, fibrous septa extend
between triads and form fibrous bridges.
4. Stage IV represents the end stage with frank cirrhosis and absence of bile ducts
in portal tracts.
Hepatic copper accumulation occurs due to chronic cholestasis, and levels
of hepatic copper may be higher than those found in patients with Wilson’s
disease.
C. Diagnosis
1. Clinical presentation. In 50% to 60% of patients, the disease progresses insid-
iously and patients present with fatigue and pruritus. Usually, jaundice follows
months or years later. In 25% of patients, jaundice may be the presenting
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412 Part V: Specific Complaints and Disorders

symptom. Darkening of the skin, hirsutism, anorexia, diarrhea, and weight loss
may also be present. Less commonly, patients may present with a complication
of portal hypertension, such as variceal bleeding or ascites, or have the disease
identified during the workup of an accompanying connective tissue disease
such as Sjögren’s syndrome, scleroderma or CREST syndrome, systemic lupus
erythematosus (SLE), or thyroiditis, or during routine blood screening. In fact,
up to 50% of the patients are asymptomatic when initially diagnosed. Physical
findings are variable and depend on the extent of the disease. Hepatomegaly,
splenomegaly, spider angiomata, palmar erythema, hyperpigmentation, hirsutism,
and xanthomata may be present. Complications of malabsorption, especially of
fat-soluble vitamins and calcium, and those patients with Sjögren’s also may
have pancreatic insufficiency.
Renal tubular acidosis with defective urinary acidification after an
acid load occurs frequently in PBC, but it is usually subclinical. Deposition
of copper in the kidneys may cause the renal dysfunction. An increased sus-
ceptibility to urinary tract infection has been observed in women with PBC;
the cause of this susceptibility is unknown. Also, there appears to be an
increased prevalence of hepatocellular and breast cancer among patients
with PBC.
2. Laboratory studies
a. Serum tests. Serum alkaline phosphatase level is usually elevated
markedly (2–20 times normal). The values for 5-nucleotidase and
-glutamyltranspeptidase (GGTP) parallel those for alkaline phosphatase.
Serum transaminase levels are slightly elevated (1–5 times normal). The
degree of elevation of these chemistry tests does not have prognostic sig-
nificance. The serum bilirubin level usually rises with the progression of
the disease and is a prognostic indicator of the disease. Serum albumin
and the prothrombin time are normal early in the course of the disease. A
low serum albumin level and prolonged prothrombin time that are not
corrected by vitamin K therapy indicate advanced disease: Both findings
are poor prognostic signs. Serum lipid levels may be strikingly elevated.
Patients with early PBC tend to have slight elevations of low-density
lipoproteins (LDL) and very-low-density lipoproteins (VLDL) and strik-
ing elevations of high-density lipoproteins (HDL). Patients with advanced
disease have marked elevations of LDL and decreased HDL; lipoprotein
X is present in patients with chronic cholestasis. Serum ceruloplasmin is
normal or elevated in contrast to Wilson’s disease. Elevated thyroid stim-
ulating hormone (TSH) levels may be present.
b. Serology and immunologic abnormalities. Serum IgM levels are markedly
increased (4–5 times normal), whereas IgA and IgG levels are commonly
within normal limits. The hallmark of the disease is the presence of AMA,
which is present in more than 99% of the patients. It is usually present in
high titer and is predominantly IgG. AMA has no known inhibitory effect on
mitochondrial function and it does not affect the course of the disease. The
finding of a significant AMA titer (1:40) is strongly suggestive of PBC, even
in the absence of symptoms and the presence of normal levels of serum alka-
line phosphatase. The liver biopsy in these patients shows the characteristic
lesions of PBC. Demonstration of AMA by indirect immunofluorescence
lacks complete diagnostic specificity, however, because AMA may be found
in other disorders using this technique. Newer techniques now available are
more sensitive than immunofluorescence in detecting AMA. These include
radioimmunoassays (RIA), enzyme-linked immunosorbent assays (ELISA),
and immunoblotting technique. A PBC-specific mitochondrial antibody
termed M2 has been characterized. The M2 autoantibody reacts with four
antigens on the inner mitochondrial membrane. These are the E2 components
and protein X of the pyruvate dehydrogenase complex (PDC). PDC is one of
the three related multienzyme complexes (the 2-oxo-acid dehydrogenase com-
plexes) of the Krebs cycle. These complexes are loosely associated with the
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Chapter 54: Chronic Immune-Mediated Liver Disease 413

inner face of the inner mitochondrial membrane. Two other antimitochondrial

antibodies that are associated with PBC are anti-M4 and anti-M8, which
react with antigens on the outer mitochondrial membrane. Anti-M8 is found
only in patients who have anti-M2, and its presence may be associated with
a more rapidly progressive course. The presence of anti-M4 with anti-M2
identifies the CAH–PBC overlap syndrome, and anti-M9 may identify cases
with a benign clinical course. Other AMAs are found in syphilis (anti-M1),
drug-induced disorders (anti-M3 and -M6), collagen vascular diseases (anti-M5),
and some forms of myocarditis (anti-M7). Other autoantibodies such as
ANA, rheumatoid factor, antithyroid antibodies, antiacetylcholine antibod-
ies, antiplatelet antibodies, and antihistamine and anticentromere antibodies
may also be present in some patients.
The complement system appears to be in a chronically activated state
in patients with PBC due to activation of the classic complement pathway.
There are decreased numbers of circulating T lymphocytes (both T4 and T8)
and abnormalities of the regulation and function of these cells. Bile duct
cells in patients with PBC express increased amounts of the class I histo-
compatibility-complex antigens HLA-A, HLA-B, and HLA-C and class II
HLA-DR antigens on their cell membrane, in contrast to normal bile duct
cells. These bile duct cells in patients with PBC are good targets for attack
by activated cytotoxic T cells. Indeed, the bile duct lesion in PBC resembles
that found in graft-versus-host disease and in instances of rejection of
hepatic allografts—disorders that are known to be mediated by cytotoxic
lymphocytes.
3. Diagnosis of PBC is not difficult in a middle-aged woman presenting with
pruritus, an elevated alkaline phosphatase level, and the presence of AMA in
the serum. Pathopneumonic findings in the liver biopsy confirm the diagno-
sis. However, if atypical features are present, such as absence of the mito-
chondrial antibody, male gender, or young age, other possibilities need to be
excluded.
4. The differential diagnosis of PBC includes gallstones, tumor, cyst, postopera-
tive or other causes of extrahepatic bile duct obstruction, primary sclerosing
cholangitis, cholangiocarcinoma, sarcoidosis, drug-induced cholestatic liver
disease, autoimmune hepatitis, alcoholic hepatitis, chronic active hepatitis, and
cholestatic viral hepatitis.
The anatomy of the extra- and intrahepatic ducts may be satisfactorily
demonstrated with endoscopic retrograde cholangiography or MRCP to rule
out the first three of these possibilities.
D. The prognosis for asymptomatic patients with PBC is better than that for symp-
tomatic patients. Patients who are asymptomatic at the time of diagnosis may have
a normal life expectancy. Cases of prolonged survival with minimal progression of
the disease and symptoms are well described. In symptomatic patients, advanced
age, elevated serum bilirubin levels, decreased serum albumin levels, and cirrhosis
each correlate with shortened survival.
E. The treatment of PBC can be divided into three areas: (a) management of symp-
toms, (b) specific drug treatments to halt the progression of the disease, and
(c) hepatic transplantation.
1. Relief of symptoms
a. Pruritus is the most distressing symptom of PBC. The cause of pruritus is
not known. It may be related to the retention of bile salts or other chemicals
in the skin, or it may be immunologically mediated.
i. Cholestyramine. Oral cholestyramine is the treatment of choice. By
binding and removing bile salts in the intestine, it interrupts the entero-
hepatic circulation and thus decreases the blood levels of bile salts. The
usual dosage is 4 g before and 4 g after breakfast. Many patients
require another 8 g with the evening meal. Cholestyramine reduces vit-
amin A, D, E, and K absorption and may contribute to worsening of
osteoporosis, osteomalacia, and hypoprothrombinemia.
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414 Part V: Specific Complaints and Disorders

ii. Colestipol hydrochloride (5 g orally t.i.w.) is as affective as cholestyra-

mine with similar side effects; however, it may be more palatable.
iii. Rifampin, at 150 mg p.o. b.i.d., a potent inducer of hepatic drug metab-
olizing enzymes, also relieves itching. Naloxone, naltrexone, cimetidine,
phenobarbital, UVB light, and metronidazole have also been reported to
be of benefit in some patients.
iv. Plasmapheresis relieves itching in refractory cases.
b. Hyperlipidemia. Skin xanthomas and xanthelasmas are likely to occur when
the total serum lipids exceed 1800 mg/dL. Cholestyramine, 12 to 16 g per
day, is the treatment of choice. Treatment with corticosteroids, phenobarbi-
tal, and plasmapheresis also has been reported to result in regression of the
lipid deposits. Repeated plasmapheresis or plasma exchange may relieve
symptoms of xanthomatous neuropathy. Clofibrate therapy of hypercholes-
terolemia is contraindicated in PBC.
c. Gallstones. The incidence of gallstones is increased in PBC, occurring in
about 40% of the patients. Gallstone disease may complicate the course of
PBC and should be addressed appropriately by endoscopic sphincterotomy
or surgery.
d. Malabsorption and malnutrition. Steatorrhea is common and may reach
levels as high as 40 g of fat per day in patients with PBC. In such patients,
nocturnal diarrhea, weight loss, and muscle wasting may be prominent.
Malabsorption in PBC is multifactorial. The progressive bile duct lesion in
these patients reduces bile salt concentrations in the small intestine and
markedly decreases micelle formation and fat absorption.
The incidence of celiac sprue is increased in this patient population,
which in itself causes further malabsorption.
Pancreatic dysfunction may also be present. Since medium-chain
triglycerides (MCT) do not require micelle formation for absorption, 60%
of the dietary fat intake may be given as MCT to these patients.
Patients should be screened for fat-soluble vitamin deficiency. Oral vit-
amin A (25,000–50,000 units per day) should be given to patients with
advanced PBC to prevent night blindness, with monitoring of serum levels to
prevent toxicity. Some patients may require oral zinc supplementation
for improved dark adaptation. Vitamin E deficiency is also common in patients
with PBC, but routine supplementation is not indicated. Vitamin K deficiency
and hypoprothrombinemia may be monitored by following the prothrombin
time. Oral vitamin K supplementation usually corrects this deficiency.
e. Hepatic osteodystrophy is osteoporosis and osteomalacia with sec-
ondary hyperparathyroidism. In PBC, fat malabsorption and steatorrhea
interfere with calcium absorption both by malabsorption of vitamin D and
by loss of calcium with unabsorbed long-chain fatty acids. Vitamin D defi-
ciency in PBC may be corrected with oral doses of vitamin D, between 400
and 4,000 IU daily. Since the hepatic and renal hydroxylation of vitamin D
remains intact with PBC, the more expensive hydroxylated vitamin D prepa-
rations are not necessary. For the correction of osteoporosis, postmenopausal
patients with PBC should be given calcium supplements together with
vitamin D prophylaxis and bisphosphonates.
2. Specific drug treatment. Even though the etiology of PBC is unknown, it is
well accepted that it is an autoimmune disease. Defects of both cellular and
humoral immunity have been demonstrated. Also, with chronic cholestasis,
there is intraparenchymal copper deposition and progressive hepatic fibrosis.
Thus, drugs chosen to treat the hepatic lesion of PBC are those that stimulate
or suppress the immune response, chelate copper, or decrease collagen forma-
tion. Corticosteroids, cyclosporin, azathioprine, chlorambucil, D-penicillamine,
triethylene tetramine dihydrochloride, and zinc sulfate have been used in con-
trolled trials in the treatment of PBC and have been found to be ineffective.
a. Ursodeoxycholic acid at doses of 12 to 15 mg/kg of body weight per day
is now used as the initial therapy of PBC. It improves the serum alkaline
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Chapter 54: Chronic Immune-Mediated Liver Disease 415

phosphatase, aminotransferase, IgM, and bilirubin levels. Histologic

improvement is less impressive, but the rate of worsening may be slowed.
Also, the need for cholestyramine is decreased in patients with pruritus. It
appears that ursodeoxycholic acid is safe, effective, and well tolerated and
its efficacy is usually maintained for up to 10 years.
b. Colchicine, an antiinflammatory and anticollagen agent at doses of 0.6 mg
daily or twice daily, has been shown in some studies to slow the progression
PBC and to improve serum levels of bilirubin, albumin, alkaline phos-
phatase, aminotransferases, and cholesterol. After 2 to 4 years, however,
there is no improvement in histology, symptoms, or physical findings. Except
for diarrhea in a few patients, there is no toxicity. It seems likely that
colchicine is of some benefit to patients with PBC.
c. Methotrexate. Low-dose oral pulse methotrexate 0.25 mg/kg per week may
induce striking improvement in biochemical tests, fatigue, and pruritus in
some patients with PBC. Histologic improvement also has been seen. In one
study 15% of patients with PBC treated with methotrexate developed inter-
stitial pneumonitis. This high incidence has not been seen in other studies.
At this time, methotrexate is best reserved for patients with PBC who do not
respond to UDCA and/or colchicine and are noted to be clinically
worsening.
Most patients with PBC are initially treated with UDCA 12 to 15 mg /kg
body weight per day. In patients whose liver chemistry tests do not normal-
ize in 6 months and/or whose liver biopsies fail to improve or worsen after
1 year of treatment with UDCA, colchicine is added to the treatment regi-
men. Methotrexate is added if the liver biopsy does not improve or worsens
after one year of treatment with UDCA and colchicine. It is reported that
using this individualized approach of stepwise combination therapy more
than 80% of patients with precirrhotic PBC has responded by improvement
of their symptoms, normalization of the liver chemistry tests, and some
improvement of the liver histology.
3. Liver transplantation is an effective treatment for PBC, with 1- and 5-year
survival rates of 75% and 70% in most centers. Transplantation markedly
improves chances for survival, and results are better with earlier transplanta-
tion. Patients developing cirrhosis should be referred to transplant centers and
placed on waiting lists. Clinical variables have been determined at transplant
centers to help in assessing the timing of transplantation. Recurrence of PBC in
the grafted liver is rare.

III. PRIMARY SCLEROSING CHOLANGITIS

A. Definition. Primary sclerosing cholangitis (PSC) is a chronic, fibrosing inflamma-
tion of the biliary ductal system leading to cholestasis, bile duct obliteration, and
cirrhosis of the liver. Most patients are male (67%). PBC may present in two forms:
1. Large-duct PSC. Involvement of the larger bile ducts can be identified by
cholangiography. In the classic manifestation of the disease, large-duct PSC may
be accompanied by small-duct PSC.
2. Small-duct PSC (pericholangitis). Involvement of microscopically identifiable
bile ducts may be the major manifestation of PSC. Changes in large bile ducts
may accompany small-duct PSC.
B. Pathogenesis
1. The etiology of PSC remains unclear. Injury from infection of the bile ducts
due to portal bacteremia, viremia, toxins, or ischemia from hepatic arterial
damage has been proposed but not substantiated. There is a close relation
between PSC and inflammatory bowel disease (IBD). In the United States
approximately 75% of all patients with PSC have coexisting ulcerative colitis
(UC) or Crohn’s enterocolitis. PSC is the most common form of chronic liver
disease accompanying UC; about 5% to 10% of all patients with UC eventu-
ally have PSC. Immunologic injury may be the most likely cause of the
disease.
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416 Part V: Specific Complaints and Disorders

a. Genetic factors. A close association has been found between the HLA-B8
phenotype and PSC in 60% to 80% of patients with or without UC. Also,
HLA-DR3 has been found in 70% of patients with PSC. It appears that a
patient with UC who possesses HLA-B8, DR3 haplotype has a 10-fold
increase in the relative risk of development of PSC. Of patients who do not
possess HLA-B8, DR3, an association with HLA-DR2 has been found in
70%. HLA-B8, DR3 and HLA-DR2 are equally distributed in patients with
PSC, with or without UC. It appears that HLA-DR3, HLA-DR2, and UC are
separate, independent risk factors for the development of PSC.
b. Humoral immune abnormalities. As in primary biliary cirrhosis, adult
patients with PSC usually have hypergammaglobulinemia and increased lev-
els of IgM. High levels of IgG are found in all children with PSC, and 50%
of these children also have elevated IgM levels. Smooth muscle antibody
(SMA) and antinuclear antibody (ANA) may also be present in patients with
PSC. However, there is no correlation between the presence of circulating
autoantibodies and any clinical parameter of the disease.
Circulating anticolonic antibodies have been detected in 60% to 65%
of patients with PSC and UC. Antineutrophil cytoplasmic antibody (ANCA)
is present in 80% of patients.
Elevated levels of circulating immune complexes also have been found
in both sera and bile of patients with PSC. Whether this finding is primary
or an epiphenomenon is not clear. There is also activation of the complement
system via the classic pathway, supporting the involvement of humoral
immune mechanisms in PSC.
c. Cellular immune abnormalities. A significant reduction in the total number
of circulating T cells, especially in the suppressor-cytotoxic (T8) cells, has
been noted in PSC, leading to an increased ratio of helper suppressor (T4/T8)
cells. There is also an increase in the number and percentage of B cells.
In the liver, the portal T4/T8 ratio has been found to be higher in the
portal tract than around proliferating bile ductules. Cytotoxic (T8) cells
tended to localize in areas of bile duct proliferation and infiltrate the ductal
epithelium.
d. Bile duct expression of HLA-DR. Intra- and extrahepatic bile ducts in
normal subjects do not express HLA class II (HLA-DR) antigens. It has been
shown that most intrahepatic bile ducts in patients with PSC express HLA-
DR antigens on the surface cell membrane of the bile duct epithelial cells.
This aberrant expression may play a role in the pathogenesis of bile duct
damage in PSC.
e. Conclusion. There is strong evidence that genetic and immunologic factors
are important in the pathogenesis of PSC. The immunologic destruction of
bile ducts seems to be triggered in genetically predisposed individuals, possi-
bly by viruses, bacteria, or toxins. The association with IBD and UC may be
explained by the passage of these microorganisms or toxins across the dam-
aged colonic epithelial barrier into the portal circulation.
2. The prevalence of PSC in the United States is approximately 5 cases per
100,000 persons. It affects predominantly young males with an age range of
15 to 75 years. At the time of diagnosis, most patients are younger than
45 years. PSC has been reported in children 4 to 14 years old.
3. Associated disorders. PSC may be associated with a variety of autoimmune
disorders. These include Sjögren’s syndrome, retroperitoneal and mediastinal
fibrosis, thyroiditis, myasthenia gravis, Type 1 diabetes mellitus, celiac sprue,
sarcoidosis, cystic fibrosis, Peyronie’s disease, idiopathic chronic pancreatitis,
lupus, rheumatoid arthritis, systemic sclerosis, immune thrombocytopenic
purpura, and autoimmune hemolytic anemia.
4. Cholangiocarcinoma. Clinical experience and pathologic evidence strongly sup-
port an association between PSC and cholangiocarcinoma. Cholangiocarcinoma
arises in 5% to 10% of patients with preexisting PSC and can present in a syn-
chronous fashion with PSC. The most frequent location is the bifurcation of the
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Chapter 54: Chronic Immune-Mediated Liver Disease 417

common right and left hepatic ducts (Klatskin tumor); however, it can be multifo-
cal. It is usually heralded by rapid clinical deterioration with progressive jaundice,
weight loss, and abdominal discomfort. Regardless of therapy, including trans-
plantation, the prognosis for patients with cholangiocarcinoma complicating PSC
has been poor. Active smoking and alcohol abuse may increase the risk of devel-
oping cholangiocarcinoma in patients with PSC. PSC may also be an independent
risk for colorectal carcinoma.
C. Diagnosis. The diagnosis of PSC is based on clinical, biochemical, radiologic, and
histologic criteria. The disease is suspected in patients with a cholestatic biochem-
ical profile for longer than 3 to 6 months.
1. Clinical presentation
a. History. Most patients are initially asymptomatic but have a chronic indo-
lent form of the disease, which may remain quiescent for many years. When
fatigue, pruritus, and jaundice develop, patients typically have advanced dis-
ease. Weight loss, abdominal pain, and sometimes complications of cirrhosis
or portal hypertension such as variceal bleeding, ascites, or encephalopathy
may be the presenting findings.
Approximately 15% of patients with PSC present with an acute relaps-
ing type of disease with fever, chills, night sweats, recurrent upper quadrant
pain, and intermittent episodes of jaundice. This “cholangitic” group of
patients may have self-limited, recurrent episodes of bacterial cholangitis
caused by biliary sludge, which may intermittently obstruct strictured bile
ducts.
The distinction between these two presentations of PSC may merge
with progression of disease. In both types, intrahepatic bile duct obstruction
may develop with sludge or pigment stones and recurrent symptoms of bac-
terial cholangitis.
b. Physical examination. Many patients, especially asymptomatic ones, have
a normal physical examination. However, with advanced disease, patients
may have jaundice and hepatosplenomegaly, xanthomas, signs of portal
hypertension, and stigmata of chronic liver disease.
2. The differential diagnosis should include extrahepatic bile duct obstruction;
drug-induced cholestasis; primary biliary cirrhosis; chronic active hepatitis,
autoimmune hepatitis, and alcoholic hepatitis with a cholestatic profile; cholan-
giocarcinoma and secondary sclerosing cholangitis arising in patients with
choledocholithiasis; and congenital or postsurgical abnormalities of the biliary
tract such as Caroli’s disease, choledochal cyst, or strictures. In immunodefi-
cient patients, infections with HIV, cytomegalovirus, and Cryptosporidium
should be considered. Vascular damage to the hepatic arterial tree by cytotoxic
drugs, chemotherapy, and graft-versus-host disease after liver transplantation
may mimic PSC.
3. Diagnostic studies
a. Laboratory tests. All patients with PSC have an elevated serum alkaline
phosphatase level (2 times normal). Serum transaminases are also usually
elevated (2–5 times normal). Serum bilirubin level is variable. Serum albu-
min and prothrombin time are dependent on the severity of the liver dys-
function. CA-19-9 levels greater than 100 U/mL may raise the suspicion for
the presence of cholangiocarcinoma.
Hepatic copper concentration is elevated in most of these patients due
to cholestasis; however, serum ceruloplasmin levels are also elevated. Serum
gamma globulin and IgM levels are elevated in half of the patients with PSC.
b. Radiologic visualization of the biliary tree is necessary for the diagnosis of
PSC. Endoscopic retrograde cholangiopancreatography (ERCP) is the preferred
technique over percutaneous endoscopic cholangiography (PTC) since the
intrahepatic ducts are not dilated. Cholangiography typically shows the pres-
ence of multifocal stricturing and irregularity of intra- or extrahepatic biliary
ducts, or both, giving a “beaded” appearance. There are bandlike short stric-
tures and diverticulumlike outpouchings in the biliary tree in one fifth of
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418 Part V: Specific Complaints and Disorders

patients. Up to 20% of patients have an abnormal pancreatic duct resembling

that seen in chronic pancreatitis. The cystic duct and the gallbladder are usually
spared but are involved in 5% of the patients. ERCP, in addition to defining the
extent of ductal disease, allows for brushings to be obtained for cytologic exam-
ination to rule out malignancy. It also allows therapeutic dilatation and stent-
ing of the abnormal bile ducts when indicated.
c. Magnetic resonance cholangiography (MRC) and positron emission
tomography (PET) are noninvasive radiologic techniques that may be used
in the diagnosis of PSC. However, not enough experience has accumulated
with these techniques at the present time. Further experience and advances
in MRC and PET may allow these modalities to be useful adjuncts in dis-
criminating benign from malignant disease.
d. Ultrasound. In many patients, an initial ultrasound of the biliary tree may
help rule out choledocholithiasis and ductal dilatation as well as pancreatic
pathology.
e. A liver biopsy is recommended for diagnosis and staging of PSC. As in
PBC, four arbitrary stages have been assigned to describe the severity of
PSC. In the initial stages, the abnormal findings of fibrosis and oblitera-
tive cholangitis are confined to the portal tracts. Later, scar formation,
ductal obliteration, and parenchymal liver involvement with fibrous
piecemeal necrosis and septum formation are seen, leading eventually to
cirrhosis.
4. Complications
a. Progressive cholestasis may eventually lead to fat malabsorption, steat-
orrhea, and fat-soluble vitamin (A, D, E, K) deficiencies. Hepatic osteodys-
trophy, visual abnormalities, and coagulation defects may occur but are
uncommon in these patients.
b. When cirrhosis and portal hypertension develop, patients may present
with ascites, hemorrhage from esophageal varices, or encephalopathy.
c. The prevalence of cholelithiasis, choledocholithiasis, and cholangiocar-
cinoma is increased in patients with PSC. Ascending cholangitis may com-
plicate each of these disease entities. Cholangitis may also occur in patients
with PSC without biliary stones. However, it is much more common and
recurrent in patients with previous biliary surgery.
d. Intra- or extrahepatic cholangiocarcinoma in patients with preestab-
lished PSC is usually multicentric and may be found as carcinoma in situ in
areas of fibrous cholangitis. Thus PSC seems to be a premalignant lesion of
the bile ducts.
D. Treatment
1. Medical therapy. The medical management of patients with PSC may be
divided into two categories:
a. Management of complications of chronic cholestasis and bile duct obstruc-
tion, such as malabsorption, itching, and recurrent cholangitis.
i. Malabsorption. Fat-soluble vitamin deficiency should be established
with measurement of serum levels of vitamin A and 25-OH vitamin D,
and prothrombin time. Vitamin A replacement therapy consists of
15,000 units per day. Vitamin D replacement may be done using doses
similar to those used in PBC (see section II.E.1.e). The value of calcium
supplementation in PSC is unknown. Steatorrhea may be diminished
with the use of medium-chain triglycerides instead of long-chain triglyc-
erides, as recommended for PBC (see section II.E.1.d).
ii. Pruritus. Itching appears to present later in the course of PSC than in PBC.
It is worse at night and may result in insomnia and excoriation. The main-
stay of therapy is cholestyramine as long as there is adequate bile flow into
the intestine. The dose is 4 to 8 g before breakfast and 4 to 8 g after break-
fast. If stools are acholic, there is insufficient bile flow for cholestyramine
to work. It usually takes 2 to 4 days for the itching to diminish. Once the
itching has resolved, the dose may be adjusted downward. However, if
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Chapter 54: Chronic Immune-Mediated Liver Disease 419

itching does not diminish after 2 to 4 days, the dosage may be increased to
8 g three times daily. Additional increases in dosage have not been shown
to be effective.
In patients who cannot tolerate cholestyramine, colestipol hydrochlo-
ride may be substituted. If constipation occurs with either drug, laxatives
and fiber supplements may be added. Activated charcoal capsules also have
been used for pruritus. Phenobarbital 60 to 90 mg at bedtime may increase
bile flow and act as a sedative. Ultraviolet B light and large-volume plasma-
pheresis may be helpful in intractable cases. The use of ursodeoxycholic
acid is discussed in the next section. Intractable pruritus suggests intensive
bile duct scarring and obstruction and is an indication for liver transplan-
tation. Also see the recommendation mentioned for PBC-related pruritus in
section II.E.1.a.
iii. Recurrent cholangitis. Antibiotics may be used to treat episodes of
ascending cholangitis. Prophylactic antibiotics such as daily doses of
ciprofloxacin hydrochloride, amoxicillin, or double-strength trimetho-
prim/sulfamethoxazole may decrease the frequency and severity of such
episodes.
b. Treatment of the underlying disease process. A variety of immunosup-
pressive, antifibrotic, and antiinflammatory drugs have been tried in the
treatment of PSC. The slow progression of PSC and spontaneous fluctuation
in bilirubin levels make it difficult to evaluate treatment. However, no drug
has been shown to improve its natural history.
i. Cyclosporin, azathioprine, penicillamine, colchicine, and pred-
nisone have been studied and found ineffective.
ii. Ursodeoxycholic acid (UDCA) at 20 mg/kg of body weight per day has
given promising results in the long-term treatment of PSC in several stud-
ies. UDCA is postulated to decrease serum aminotransferase by stabiliz-
ing hepatocyte membranes rather than by decreasing levels of other bile
acids. It also alkalinizes bile and increases the bile flow. Theoretically,
the result should be a decrease in the formation of pigment stones in the
biliary tract.
iii. Methotrexate. In a small number of patients with PSC, methotrexate
15 mg/kg of body weight per week has resulted in dramatic improvement in
symptoms and biochemistry. In several patients, cholangiographic
improvement also has been noted with no worsening of liver histologic
findings. However, it is not certain that methotrexate is effective in most
patients with PSC.
iv. Tacrolimus decreased the serum bilirubin by 75%, alkaline phosphatase
by 70%, and aminotransferase by 83% after 1 year when given to 10
patients with PSC. The dose of tacrolimus was that which kept trough
levels between 0.6 and 1.0 mg/mL. There are no data on liver biopsy or
ERCP findings.
v. Combination therapy with prednisolone, 1 mg/kg of body weight per
day, azathioprine 1.0 to 1.5 mg/kg of body weight per day, and urso-
diol 500 to 750 mg per day in 15 patients has shown promising results
with significant improvement in liver enzyme levels and liver histology.
Studies using tumor necrosis factor (TNF) inhibitors (etanercept and
remicade) are under way.
vi. Summary. Because damaged or destroyed bile ducts either lack the
capacity to regenerate or do so slowly and ineffectively, diseases such as
PBC and PSC should be treated at early stages before the loss of much of
the biliary system and while there are still adequate numbers of func-
tioning bile ducts.
2. Surgical therapy
a. Biliary drainage procedures, either percutaneously, endoscopically, or surgi-
cally performed, provide only temporary benefit and are riddled with compli-
cations such as infection, obstruction, perforation, leakage, and hemorrhage.
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420 Part V: Specific Complaints and Disorders

b. Balloon dilatation and stenting. In patients with one or two dominant

strictures of the extrahepatic bile ducts or at their bifurcation, balloon
dilatation, either by percutaneous or endoscopic approach and stenting,
offers a less invasive alternative to surgery; however, a surgical backup is
necessary in such cases.
c. Liver transplantation offers an important, successful therapeutic option,
especially in young patients with advanced PSC in whom any of the follow-
ing indications exist: (a) clinically significant gastroesophageal varices, (b)
persistent bilirubin level greater than 10 mg/dL, (c) spontaneous bacterial
peritonitis, (d) repeated bouts of cholangitis, (e) loss of synthetic liver func-
tion, and (f) refractory pruritus. Colectomy does not ameliorate PSC in
patients who also have ulcerative colitis.
One-year survival rates after liver transplantation are in the range of
approximately 85% to 90%. Previously undiagnosed cholangiocarcinoma
has been noted in some of the patients who have undergone transplantation,
with a very high incidence of recurrence in the transplanted livers. Increased
risk of development of colonic malignancy with long-term immunosuppres-
sion in patients with chronic ulcerative colitis who have had a transplant is
highly suspected and warrants periodic colonoscopic surveillance. In 20%
of patients, PSC recurs in the new liver.

Selected Readings
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autoimmune hepatitis. J Hepatol. 1999;31:929.
Angulo P, et al. Primary biliary cirrhosis and primary sclerosing cholangitis. Clin Liver Dis. 1999;3:529.
Charatcharoenwitthaya, et al. Long-term survival and impact of ursodeoxycholic acid treatment for recurrent
PBC after liver transplantation. Liver Transpl. 2007;131:1236–1245.
Corpechot, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.
Hepatology. 2006;43:1118–1124.
Czaja AJ. Ursodeoxycholic acid in autoimmune hepatitis. Hepatology. 1999;30:138.
Czaja AJ. Autoantibodies in liver disease. Gastroenterology. 2001;120:239.
Donaldson PT, et al. HLA class II alleles, genotypes, haplotypes, and aminoacids in primary biliary cirrhosis:
A large scale study. Hepatology. 2006;44:667–674.
Ghali, P, Marotta PJ, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian
experience. Liver Transpl. 2005;11:1412–1416.
Gong T, et al. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review
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Graziadei IW, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing
cholangitis. Hepatology. 1999;30:1121
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INHERITED LIVER DISEASES 55

I. WILSON’S DISEASE
A. Pathogenesis. Wilson’s disease is a treatable, genetic disorder. The metabolic
defect leads to progressive accumulation of copper in the liver, brain (particularly
in the basal ganglia), cornea, and kidneys, causing severe functional impairment
leading to irreversible damage. If not treated, this disease is invariably fatal, but
with early diagnosis and treatment, the clinical manifestations can be prevented
and reversed.
Wilson’s disease is an autosomal recessive disorder. The abnormal gene is dis-
tributed worldwide with a prevalence of heterozygotes of 1 in 200 and homozy-
gotes of 1 in 30,000. The genetic defect is on chromosome 13 near the red-cell
esterase locus. In 95% of patients, there is also an absence or deficiency of serum
ceruloplasmin, the main copper-transporting protein in blood. This deficiency
is caused by a decrease in transcription of the ceruloplasmin gene located on
chromosome 3.
B. Copper metabolism
1. Copper concentration in the liver. The liver of a human newborn contains
six to eight times the copper concentration of an adult liver. Within the first
6 months of life, this diminishes to a concentration of 30 mg/g of dry tissue.
Thereafter, throughout life, the liver concentration of copper is maintained at
this steady state by careful regulation of intestinal absorption and transport and
of the liver stores through the synthesis of plasma and tissue copper proteins
and excretion of copper from the body in the bile.
2. Absorption and excretion. Approximately 50% of the average dietary intake
of 2 to 5 mg of copper is absorbed from the proximal small intestine and loosely
binds to albumin. It is promptly cleared by the liver, where it is incorporated
into specific copper proteins such as cytochrome oxidase and ceruloplasmin or
is taken up by lysosomes before being excreted in bile. There are two main
routes by which copper is mobilized from the liver.
a. Synthesis of copper-containing ceruloplasmin and its release into the
circulation.
b. Biliary excretion amounting to 1.5 mg of copper per day. This is the princi-
pal route of elimination of copper from the body.
3. Genetics. The copper excess seen in Wilson’s disease has been shown to be the
result of decreased biliary excretion and not an increase in the absorption of
copper. The defect is caused by mutations in the Wilson’s gene (ATP7B) on
chromosome 13 gene. The gene ATP7b encodes a cation-transporting P-type
adenosine triphosphatase that is expressed in the liver, kidney, and placenta.
Mutations in ATP7b result in disordered export of copper from the liver into
bile with resultant accumulation of copper cation in hepatocytes. The ATP7b
protein is present primarily in the trans-Golgi where it is critical for excretion
of copper into bile, as well as providing appropriate copper for binding to ceru-
loplasmin. Lack of functional ATP76 limits the availability of copper for
ultimate incorporation into ceruloplasmin. When copper is not available for
binding, an apoprotein is secreted from the hepatocytes that is rapidly degraded
in the plasma, resulting in the hallmark of Wilson’s disease, diminished
circulating ceruloplasmin levels.

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422 Part V: Specific Complaints and Disorders

4. Family screening. More than 200 mutations have been identified in the
Wilson’s gene. Once a proband has been identified as having Wilson’s disease,
it may be possible to screen siblings on the basis of genetic analysis. As an auto-
somal recessive disorder, 1 in 4 siblings may be expected to be homozygous for
the gene defect. Genetic testing of siblings requires the sequencing of both alle-
les of the ATP7b gene in the proband and then subsequent comparison of those
alleles to the ATP7b alleles in the siblings.
C. Copper toxicity
1. Acute toxicity. Ingestion of gram quantities of copper causes serious gastroin-
testinal and systemic injuries and occasionally hepatic necrosis. Generally, how-
ever, the vomiting and diarrhea that follow the ingestion of copper salts protect
the patient from serious toxic effects.
2. Chronic toxicity. Hepatic copper overload may occur in disorders other than
Wilson’s disease. These include primary biliary cirrhosis, extrahepatic biliary
artesian, Indian childhood cirrhosis, and other chronic cholestatic disorders.
The excess hepatic copper may aggravate the underlying pathologic process by
direct damage to the organelles or through promotion of fibrosis.
D. Diagnosis
1. Clinical presentation. Wilson’s disease has many modes of presentation. It
may simulate several different neurologic and psychiatric disorders. It may pre-
sent as asymptomatic elevation of the transaminases, chronic active hepatitis,
fulminant hepatitis, cirrhosis of the liver, acquired hemolytic anemia, renal
disease, or eye abnormalities such as sunflower cataracts and Kayser-Fleischer
(K-F) rings.
a. Liver disease is the most common presentation of Wilson’s disease in
childhood. About 40% of all patients with Wilson’s disease come to med-
ical attention with evidence of liver disease. Because an increase of 30 to
50 times the normal hepatic concentration of copper can occur without
any clinical manifestations, symptoms of liver disease do not appear
before 6 years of age. However, one half of the patients have symptoms
by 15 years of age. Thus, overt Wilson’s disease is encountered predomi-
nantly in older children, adolescents, young adults, and rarely in older
adults.
i. Forms. The hepatic disease may take several different forms.
a) Commonly it begins insidiously and runs a chronic course character-
ized by weakness, malaise, anorexia, mild jaundice, splenomegaly, and
abnormal liver chemistry tests. The disease may mimic acute viral
hepatitis, mononucleosis, or chronic active hepatitis.
b) Fulminant hepatitis may occur suddenly, characterized by progres-
sive jaundice, ascites, and hepatic failure. The outcome is usually
fatal, particularly when the disorder is accompanied by hemolytic
anemia.
c) Some patients present with the typical picture of postnecrotic cirrho-
sis with spider angiomata, splenomegaly, portal hypertension, ascites,
bleeding esophageal varices, or thrombocytopenia mimicking idio-
pathic thrombocytopenic purpura (ITP). The liver enzymes may be
normal. The diagnosis of Wilson’s disease should always be consid-
ered in patients younger than 30 years with negative serology for viral
hepatitis; with a history of chronic active hepatitis; or with juvenile,
cryptogenic, or familial cirrhosis. Although fewer than 5% of such
patients have Wilson’s disease, it is one of the few forms of liver dis-
ease for which specific and effective therapy is available.
ii. Histology. There is no one specific histologic profile to identify Wilson’s
disease in liver biopsy specimens. In the early stages of copper accumula-
tion, when copper is diffusely distributed in the cytoplasm, it is unde-
tectable by rhodanine or rubeanic acid stains. At this stage, lipid droplets
are seen in the hepatocytes with ballooned, vacuolated nuclei containing
glycogen. This initial steatosis progresses to fibrosis, then ultimately to
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Chapter 55: Inherited Liver Diseases 423

cirrhosis. With time and progression of the liver disease, the hepatocyte
lysosomes seem to sequester the excess copper, which is detectable
throughout some nodules by routine histochemical staining. Because of
the variable stainability and the irregular distribution of copper among
adjacent nodules, absence of a positive rhodanine or rubeanic acid stain
on a histologic slide does not exclude the diagnosis of Wilson’s disease.
The parenchyma usually is infiltrated with mononuclear cells. There may
be cholestasis, focal necrosis, and Mallory’s hyalin. In other cases, the
histology may resemble that of acute or chronic active hepatitis.
Once macronodular cirrhosis develops, the microscopic findings are
nonspecific. Hepatocytes may contain some cytoplasmic lipid, vacuolated
glycogen-containing nuclei, and cytoplasmic inclusions containing
copper-rich lipofuscin granules.
b. Neurologic disease is the most common presentation of Wilson’s disease.
The usual age of onset is 12 to 32 years. The most common symptoms are
as follows:
i. Incoordination particularly involving fine movements such as handwrit-
ing, typing, and piano playing.
ii. Tremor is usually at rest but intensifies with voluntary movement
and emotion. It ranges from a fine tremor of one hand to generalized
tremor of the arms, tongue, and head. It may be slow, coarse, or choreoa-
thetoid. Dystonia, ataxic gait, spasticity, and rigidity are late neurologic
manifestations.
iii. Dysarthria begins with difficulty in enunciating words and progresses to
slurring of speech, microphonia, and aphasia.
iv. Excessive salivation occurs early in the course of the disease.
v. Dysphagia is progressive and oropharyngeal; patients have difficulty ini-
tiating swallowing, leading to regurgitation and aspiration.
c. K-F rings are corneal copper deposits laid in the Descemet’s membrane in
layers appearing as granular brown pigment around the periphery of the iris.
They may be absent in early stages but are present in all patients in the neu-
rologic stage of Wilson’s disease. Most K-F rings can be visualized by the
naked eye, but some require slit-lamp examination.
d. Psychiatric disease. Almost all of the patients demonstrate some form of psy-
chiatric disturbance, which may appear as teenage adjustment behavior, anxi-
ety, hysteria, or a manic-depressive or schizoaffective disorder. Psychotropic
drugs may accentuate the neurologic manifestations of Wilson’s disease and
increase the patient’s problems.
e. Hematologic disease. In a few patients, Wilson’s disease presents as a
Coombs-negative hemolytic anemia with transient jaundice. It may be inter-
mittent and benign, or it may occur with fulminant hepatitis. The hemolysis
occurs during phases of hepatocellular necrosis with sudden release of cop-
per from necrotic hepatocytes into the circulation. This effect is indicated by
a marked rise in the concentration of nonceruloplasmin copper in the blood
and in the amount of copper excreted through the urine.
With portal hypertension and splenomegaly, hypersplenism may result
in thrombocytopenia and pancytopenia. Progressive liver disease also gives
rise to clotting factor deficiencies and bleeding.
f. Kidney disease. Renal abnormalities result from accumulation of copper
within the renal parenchyma. These abnormalities range from renal insuffi-
ciency with decreased glomerular filtration rate to proximal tubular defects
resembling Fanconi’s syndrome, renal tubular acidosis, proteinuria, and
microscopic hematuria.
g. In disorders involving “inflammation” and metabolic syndrome iron over-
loading may occur due to reduced iron egress. Iron is essential for many
bacterial and viral pathogens. Hepciden plays a key role in protecting the
body’s precious iron from these pathogens. In response to inflammatory
cytokins, hepcidin degrades ferroprotin, thus preventing iron from entering
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424 Part V: Specific Complaints and Disorders

the bloodstream where it could be used by the invading pathogens. This

leads to iron accumulation in the macrophages. With chronic inflammation
this may lead to iron restricted erythropolisis and anemia.
2. Diagnostic studies
a. Serum ceruloplasmin. Ninety-five percent of patients with Wilson’s dis-
ease have a serum ceruloplasmin concentration less than 20 mg/dL. Because
approximately 20% of heterozygotes also have diminished levels, deficiency
of ceruloplasmin is not sufficient for the diagnosis of Wilson’s disease.
Patients with fulminant hepatitis and 15% of patients with Wilson’s disease
presenting with only a hepatic disorder may have a ceruloplasmin concen-
tration of 20 to 30 mg /dL due to a slight increase of this acute-phase reac-
tant protein with inflammation. Hypoceruloplasminemia also may be found
in patients with nephrotic syndrome, protein-losing enteropathy, or malab-
sorption; these conditions can be distinguished easily from Wilson’s disease.
b. Serum copper. Because ceruloplasmin is the main copper-transporting pro-
tein in the blood, total serum copper levels are often decreased in patients
with Wilson’s disease, but free copper is elevated and is therefore responsi-
ble for excess copper deposition in various tissues. The determination of the
serum free copper concentration represents the most reliable finding for
the initial diagnosis of Wilson’s disease. This value is calculated as the dif-
ference between total serum copper concentration and the amount of copper
bound to ceruloplasmin (0.047 mmol of copper per mg of ceruloplasmin).
c. Urinary copper excretion. Serum free copper is readily filtered by the kid-
neys and accounts for the increased urinary copper excretion seen in
Wilson’s disease. Most patients have urinary copper excretion levels greater
than 1.6 mmol per day. However, urinary copper levels often are elevated
also in patients with cirrhosis, chronic active hepatitis, or cholestasis. This
measurement does not distinguish these entities from Wilson’s disease, there-
fore, despite the administration of D-penicillamine, an agent that increases
urinary copper excretion.
d. Liver biopsy should be obtained for histologic studies and quantitative
hepatic copper concentration in excess of 250
g /g. Edition of dry tissue is
compatible with the diagnosis of Wilson’s disease. To obtain a reliable result,
it is essential that contamination of the specimen with traces of copper be
avoided (a disposable biopsy needle minimizes this hazard) and that an ade-
quate sample (ideally 1 cm in length) be submitted for analysis. A trasjugu-
lar biopsy is inadequate for quantitative purposes. Other disorders such as
primary and secondary biliary cirrhosis and long-standing bile duct obstruc-
tion can also lead to a very elevated hepatic copper concentration by inter-
fering with hepatic excretion of copper into bile. These patients, however,
have elevated ceruloplasmin levels.
e. In the rare patient with a normal serum ceruloplasmin concentration in whom
a liver biopsy is contraindicated because of clotting abnormalities, a radio cop-
per loading test can be performed using 64Cu, with a half-life of 12.8 hours,
given to patients by mouth (p.o.) (2 mg) or intravenous (IV) (500 mg); the
serum concentration of radioactive copper is plotted with time in hours.
In individuals who do not have Wilson’s disease, radioactive copper
appears and disappears from the serum within 4 to 6 hours. A secondary
rise of radioactivity appears in the serum after the isotope is incorporated by
the liver into freshly synthesized ceruloplasmin. In patients with Wilson’s
disease, this secondary rise in radioactivity is absent, since the rate of hepatic
incorporation of radio copper into ceruloplasmin is diminished.
f. K-F rings are present in all patients with Wilson’s disease who have neuro-
logic manifestations, but they may be absent in patients presenting only
with hepatic disease. If they are not visible, they should be sought with slit-
lamp examination.
g. In Wilson’s disease presenting as fulminant hepatitis, the combination of a
disproportionately low serum alkaline phosphatase level and a comparatively
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Chapter 55: Inherited Liver Diseases 425

modest aminotransferase Mia with jaundice and clinical and histologic

evidence of hepatic necrosis suggests Wilson’s disease. The ratio of the serum
alkaline phosphatase to the total serum bilirubin also may be used.
h. All siblings of known patients should be screened for the possibility of Wilson’s
disease by physical examination, slit-lamp examination of the corneas, and
determinations of serum ceruloplasmin and aminotransferase concentrations.
E. Treatment. Untreated Wilson’s disease causes progressive damage of the liver,
brain, and kidneys. Until the late 1940s, patients usually died before reaching
30 years of age. The prognosis improved substantially after the introduction of the
copper-chelating agent D-penicillamine in the 1950s. It is important to establish a
firm diagnosis of Wilson’s disease, because the patient will be on lifelong therapy.
1. Diet. The dietary intake of copper should be less than 1.0 mg per day. Foods
rich in copper such as organ meats, shellfish, dried beans, peas, whole wheat,
and chocolate should be avoided.
2. D-Penicillamine was the first oral drug used for the treatment of any stage of
Wilson’s disease. Penicillamine chelates heavy metals, especially copper, and
facilitates their urinary excretion, thus shifting the equilibrium from tissues to
plasma. It is also antiinflammatory and may interfere with collagen synthesis
and fibrosis. Pyridoxine, 25 mg daily, is given to compensate for the weak
antipyridoxine effects of penicillamine.
The usual daily dose is 0.75 to 2.0 g p.o. The effectiveness of therapy can
be monitored using the calculated free serum copper concentration, which
should be less than 1.6 mmol/L. The earlier the therapy is instituted, the better
the results. The histologic abnormalities and many of the symptoms are
reversed; however, already established cirrhosis, portal hypertension, and some
neurologic abnormalities such as dystonia, rigidity, dysarthria, and dementia
may not be reversible.
Up to 20% of patients have sensitivity reactions within weeks of the insti-
tution of penicillamine therapy. These reactions include fever, rash, lym-
phadenopathy, polyneuropathy, leukopenia, and thrombocytopenia. Dose
reduction or short-term interruption of penicillamine therapy followed by
restarting treatment at slowly increasing doses is usually successful in overcom-
ing these side effects. For the 5% to 10% of patients who have serious penicil-
lamine toxicity (lupus, nephrotic syndrome, pemphigus, and elastosis of skin,
myasthenia gravis, thrombocytopenia, or severe arthralgias), another chelating
agent, and trientine dihydrochloride, may be used.
3. Trientine dihydrochloride is another chelating cupruretic agent used in the
treatment of Wilson’s disease. It has less of a cupruretic effect than penicillamine,
but its clinical effectiveness is comparable. Typical dosage for initial therapy in
adults is 750 to 1,500 mg per day in divided doses, and 750 to 1,000 mg per day
for typical maintenance therapy. Trientine dihydrochloride has a better safety
profile than penicillamine. No hypersensitivity reactions have been reported.
Reversible sideroblastic anemia and bone marrow toxicity have been observed in
patients who were overtreated with resultant copper deficiency. Due to its better
safety profile, trientine dihydrochloride is now the drug of choice in the treat-
ment of Wilson’s disease. Both D-penicillamine and trientine dihydrochloride
should be continued without interruption during pregnancy. Noncompliance
with or interruption of the penicillamine or trientine dihydrochloride regimen is
often followed by recurrence of symptoms or fulminant hepatitis.
4. Oral zinc. Orally administered zinc sulfate (200–300 mg t.i.d.) has been found
to be effective in the treatment of Wilson’s disease, especially in patients who
cannot tolerate cupruretic treatment. Orally administered zinc induces the syn-
thesis of intestinal metallothionein, thus increasing the capacity for copper
binding by the epithelial cells and trapping the metal in the intestinal mucosa,
thereby preventing its systemic absorption. In addition, zinc may exert a pro-
tective effect by inducing metallothionein in the hepatocytes, thus decreasing
the toxic effects of copper. In some patients, large doses of zinc are associated
with headaches, abdominal cramps, gastric irritation, and loss of appetite. Zinc
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426 Part V: Specific Complaints and Disorders

also interferes with absorption of iron, alters immune responses, and affects the
serum lipoprotein profile.
Oral zinc therapy may serve as an adjunct to standard chelation therapy
with D-penicillamine or trientine; however, there are reports that have raised con-
cerns regarding the formation of zinc-penicillamine complexes that may diminish
or abolish the therapeutic effectiveness of both drugs when used in combination.
Zinc is not recommended as the sole agent for initial therapy of sympto-
matic patients, but it is recommended as maintenance therapy at 150 mg per
day in three divided doses to keep patients at negative copper balance. Zinc
acetate is better tolerated than zinc chloride or sulfate.
5. Tetrathiomolybdate, an agent that appears to block the absorption of copper
by holding the metal in a tight, metabolically inert bond, has been used in some
patients intolerant to penicillamine. It is not commercially available for use in
North America. Although the drug is generally well tolerated, at least two cases
of bone marrow suppression have been documented. Further clinical trials are
needed before it may be used as a primary therapy for Wilson’s disease.
6. Monitoring. Periodic physical examinations, slit-lamp examinations of the
cornea for documentation of the disappearance of K-F rings, and measurements
of 24-hour urinary copper excretion and serum free copper should be per-
formed to assess the effectiveness of therapy.
7. Significant clinical improvement may occur only after 6 to 12 months of
uninterrupted treatment.
8. Fulminant hepatic failure may develop in a number of patients with Wilson’s
disease, either as an initial manifestation of the disease or as a consequence of non-
compliance with medical therapy. A smaller subset of patients will have cirrhosis
and hepatic decompression unresponsive to medical interventions outlined above.
9. Orthotopic liver transplantation (OLT) is a lifesaving procedure for patients with
fulminant hepatitis or irreversible hepatic insufficiency due to Wilson’s disease. The
metabolic abnormality is reversed and the disease is cured. One-year survival follow-
ing liver transplantation is now approximately 80%. The replacement of the affected
liver expressing the mutant A7P7b gene protein product with a donor organ that
expresses the normal gene protein product is expected to correct the defect in hepatic
copper metabolism. Thus, the allograft is not susceptible to copper accumulation.
However, the resolution of the extra hepatic manifestations of Wilson’s
disease after OLT has been less than universal. Thus, OLT in the absence of
decompensated liver disease and solely for the management of extrahepatic dis-
ease such as neurologic defects is not routinely recommended. Liver cell trans-
plantation is currently under study as an alternative to liver transplantation.

II. HEMOCHROMATOSIS. Hemochromatosis refers to a group of disorders in which

excessive iron absorption, either alone or in combination with parenteral iron load-
ing, leads to a progressive increase in total body iron stores. Iron is deposited in the
parenchymal cells of the liver, heart, pancreas, synovium, and skin, and the pituitary,
thyroid, and adrenal glands. Parenchymal deposition of iron results in cellular dam-
age and functional insufficiency of the involved organs.
A. Classification of hemochromatosis
1. Genetic.
a. Heredity hemochromatosis (HH) associated with HFE, TPR2, HJV, and
HAMP.
b. Ferroportin disease
c. Aceruloplasminemia
d. Hyporovatransferrinemia
e. Frederick’s ataxia
2. Acquired
a. Refractory anemias (e.g., thalassemia, spherocytosis, aplastic, sideroblastic
anemia).
b. Chronic liver injury (e.g., alcoholic cirrhosis, chronic viral hepatitis B and C,
post–portacaval shunt).
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Chapter 55: Inherited Liver Diseases 427

c. Dietary iron overload (e.g., Bantu, medicinal).

d. Porphyria cutanea tarda.
e. In thalassemia; sideroblastic, hypoproliferative, anemias with increased bone
marrow turnovers; and repeated transfusions combined with increased
intestinal iron absorption can lead to iron overload.
Each unit of transfused blood contains 200 mg of iron; thus a patient
receiving 4 units of blood per month over a period of 2 years will receive
about 20 g of iron, an amount that overwhelms the limited capacity of the retic-
uloendothelial system to excrete the element.
3. Parenteral iron overload
a. Multiple blood transfusions.
b. Excessive parenteral iron. Hemodialysis (rare since the introduction of
recombinant erythropoietin).
B. Iron metabolism
1. The total body iron in healthy, iron-replete individuals is approximately 4 to 5 g.
Hemoglobin iron constitutes about 60%, and myoglobin, cytochromes, cata-
lase, and peroxidase about 10% of the total body iron. Less than 1% is present
as circulating iron bound to transferrin. About 35% is in the storage form as
ferritin and hemosiderin, located mainly in the macrophages of the liver, spleen,
and bone marrow as well as the parenchymal cells of the liver, muscle, and
other organs. Approximately one third of the storage iron is found in the liver,
primarily as ferritin. This provides an internal reserve that can be mobilized
when needed.
2. Absorption. A normal adult on the average ingests about 10 to 15 mg of iron
per day. Only about 10% of this is absorbed into the circulation through the
mucosal cells of the duodenum and proximal jejunum. Heme iron (meats) is
absorbed four times more effectively than inorganic iron (vegetables and
grains). There is no physiologic mechanism for excretion of iron out of the
body in any appreciable quantity. Therefore, the intestinal absorption of iron is
finely regulated in the normal individual. This permits the entry of only the
amount necessary to replace the iron lost from exfoliated epithelial cells of the
gastrointestinal tract and skin, and menstrual blood loss in women, which
amounts to 1.0 mg per day in men and 1.5 mg per day in women.
C. Iron transport and storage proteins
1. Transferrin is a beta globulin found in the plasma that transports inorganic
ferric irons from the gastrointestinal tract to the reticulocyte and tissue stores
as well as from the tissue stores to the bone marrow. The rate of synthesis of
transferrin by the liver is regulated by the total body iron stores rather than
the hemoglobin level. Thus the decreased transferrin levels in hemochro-
matosis are due to increased total body iron stores. Low transferrin levels are
also seen in conditions such as inflammation, ineffective erythropoiesis,
and liver diseases. Normally transferrin is about 30% saturated with iron;
thus the total iron binding capacity (TIBC) of the serum is about 250 to
400 mg /dL.
2. Ferritin is an intracellular protein made up of 24 subunits that sequesters inor-
ganic iron within its core. When fully saturated, iron composes 23% of molecule.
It is found in the macrophages, reticulocytes, intestinal mucosa, testis, kidney,
heart, pancreas, skeletal muscle, and placenta. Serum and tissue ferritin are regu-
lated by total body iron stores, with each 1 mg/mL of ferritin in the serum corre-
sponding to 8 to 10 mg of stored tissue iron. The serum level of ferritin is a good
estimation of total body iron stores.
3. Hemosiderin. Multiple aggregates of ferritin make up this more stable form of
iron storage. Iron stored in ferritin, as well as hemosiderin, can be mobilized by
venisection.
D. Pathogenesis of HH.
1. Iron excess in the bloodstream due either to increased intestinal iron absorption or
parenteral iron administration will lead to the progressive accumulation of iron in
the parenchymal cells of key organs creating the risk of toxicity and disease.
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428 Part V: Specific Complaints and Disorders

2. The circulating forms of iron that lead to tissue iron overload are not tightly asso-
ciated with plasma transferring and are referred to as non-transferrin bound iron
(NTBI). NTBI increases whenever the capacity of transferring to incorporate incom-
ing iron from the gut or reticulo endothelian cells becomes a limiting factor. A frac-
tion of NTBI, called Labile plasma iron (LPI), is translocated across cell membranes
in a non-regulated manner and leads to excessive iron accumulation in various
organs. The extent of organ damage depends on the rate and magnitude of plasma
iron overload. In transfusion dependant iron overload and juvenile forms of
hemochromatosis early damage of the heart and endocrine glands predominate. In
milder forms of iron overload late onset liver disease is more common.
3. The control center that keeps blood levels of iron within the narrow physiolog-
ical range is in the hepatocyte. “Special sensors” respond to the iron and stimu-
late the synthesis and release of the iron-hormone hepcidin, which is encoded by
HAMP gene. Hepcidin circulates through the body and interacts with the iron-
exporter ferroprotin expressed in the surfaces of iron rich macrophages and
intestinal cells. As a result of this interaction, ferroportin is internalized and
degraded. The unneeded iron remain in the cells where it is saved for future use
in the form of ferritin. The diminished release of iron restores blood levels to the
non-toxic range, thus reinsuring the stimulus for further hepcidin synthesis and
ferroportin gradually resumes its iron-exporting activity.
4. The mechanisms underlying hepatocyte iron sensing are still being investigated.
However, as a result of their involvement in transferring and non-transferrin
mediated iron uptake, HFE (the hemochromatosis gene) and transferrin receptor 2
might play a role in conveying iron signals to the hepatocyte control center. The
details of this process are still unclear. However, both are important for hepcidin
expression. Their functional loss causes hepcidin insufficiency and iron overload.
5. Hepcidin production can be impaired by genetic as well as acquired factors.
Hepcidin deficiency has been associated with loss of HAMP, HJV, HFE, or
TFR2. Even though there is genetic heterogeneity of HH, all forms identified so
far originate from the presence of unneeded iron in the circulatory pool caused
by insufficient hepcidin.
Nongenetic factors which affect hepcidin output and lead to iron overload
include ethanol abuse, toxic and viral insults, e.g., hepatitis C virus, diminished
functional hepatic virus, e.g., in acute hepatic failure, end-stage liver disease or
immune mediated liver disease.
6. “Hepcidin resistance or insensitivity” may also result from genetic or acquired
factors that impair hepcidin-ferroprotein interaction. Mutations in ferroprotin
gene have been noted to cause disease similar to HFE-hemochromatosis.
7. All forms of iron overload above the same basic features. Iron overload initially
involves the plasma compartment signified biochemically by increased saturation
of the iron transporter, parenchymal cells of key organs is reflected by increasing
serum ferritin levels.
8. Expansion of the pool of non-transferrin-bound iron and its preferential uptake
by parenchymal cells as the iron level and transferrin saturation increase in
plasma. The result is total body iron overload with predominant deposition in
parenchymal liver cells, leading to hepatic fibrosis and cirrhosis. A growing body
of experimental evidence suggests that iron induces membrane lipid peroxidation,
possibly as a consequence of free radical formation. This process damages lysoso-
mal, microsomal, and other cellular membranes, resulting in cell death. Because
iron is a cofactor for proline and lysine hydroxylase, two critical enzymes involved
in the synthesis of collagen, some investigators have postulated that elevated tis-
sue iron levels may promote an increased deposition of collagen and hepatic fibro-
sis. In addition, iron overload may activate and enhance the expression of some
target genes in the liver, such as genes for ferritin and procollagen.
Parenchymal cell deposition of iron also occurs in other tissues and may
result in cardiac failure, diabetes mellitus, gonadal insufficiency, and arthritis.
E. Incidence. It has been estimated that the prevalence of homozygous and het-
erozygous HFE associated HH in populations of Northern European descent is
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Chapter 55: Inherited Liver Diseases 429

about one in 250 and 1 in 8 to 10, respectively. The HFE associated HH disease is
rarely identified in Africans or Asians. It is more common in men. The male-female
ratio is 5 to 10:1. Nearly 70% of the patients have their first symptoms between
the ages of 40 and 60 years. It is rarely clinically evident below the age of 20.
F. Genetics. In 1966 the HFE gene was identified in the short arm of chromosome 6.
HFE-linked HH is responsible for 85% to 90% of cases of HH. HFE-linked HH is
inherited as an autosomal recessive disorder. Its phenotypic expression is depen-
dent on diet, gender, and other factors. An affected individual is often the offspring
of two heterozygotes.
At least 30 missense mutations have been identified in HFE. One results in a
change of cysteine to tyrosine at amino acid (AA) position 282(C282Y); a second
mutation results in a change in histidine to aspartate at AA position 63(H63D); and a
third mutation results in a change of serine to cysteine at AA 65(S65C). Homozygosity
for the C282Y mutation has been identified in approximately 90% of individuals who
have typical phenotypic HH. The clinical impact of H63D and S65C mutations is
small. Approximately 83% of patients with HH are homozygous for C282Y muta-
tion; an additional 4% are compound heterozygotes (C282Y/H63D).
Heterozygosity for C2824 is approximately 1 in 10 in the United States.
Approximately one third of the males and one sixth of the females sharing one
haplotype (heterozygotes) exhibit partial biochemical expression; however, these
individuals rarely develop clinical manifestations of the disease.
Phenotypic expression of the inherited abnormality is modified by a variety of
factors, including dietary iron intake, iron supplementation, chronic hemodialysis,
alcohol consumption, menstrual blood loss, multiple pregnancies, and accelerated
erythropoiesis.
Ten percent to 15% of patients have a clinical syndrome similar to HH, but
do not have C282Y mutation.
The other inherited forms of iron overload, which do not involve mutations
of the HFE, include iron overload resulting from mutations in transferrin receptor-2.
Juvenile HH, which is caused by either mutation in hemojuvelin (HJV) or in the
hepcidin gene, or HAMP. Neonatal iron overload is a rare disorder that is
thought to be caused by an intrauterine hepatic viral infection resulting in an exces-
sive uptake of iron into the fetal liver.
Decreased cell iron efflux may also cause HH. Iron egress from mammalian
cells depends on the activity of a specialized membrane associated iron exporter,
ferroportin and a circulating protein, ceruloplasmin, which oxidizes Fe2+ to
Fe3+ and helps loading iron onto circulating transferring. Genetic or acquired fac-
tors that impair the function of these proteins lead to iron overload due to impaired
iron egress. In such disorders, the reduced ability to deliver iron into circulating
transferring causes low saturation of transferring with iron. Inefficient iron exit
out of the cells causes tissue iron overload and organ injury.
Ferroportin disease is associated with the A77D mutation of ferroportin as an
autosomal dominant disorder which causes progressive iron retention predominantly
in reticuloendothelial cells of the spleen and liver. It is characterized by steadily increas-
ing serum ferritin, marginal anemia and mild organ disease. The disorder appears to be
spread worldwide in the different ethnic groups. So far 32 pedigrees of ferroportin
mutations have been reported. Mutations of ferroportin cause impairment of iron recy-
cling, particularly by reticuloendothelial macrophages which normally process and
release a large quantity of iron derived from the lysis of senescent erythrocytes.
In hypo or aceruloplasminemia, an autosomal recessive neurodegenerative
disease characterized by iron accumulation with brain as well as visceral organs
such as the liver and pancreas is caused by mutations in the ceruloplasmin gene.
Cerulopasmin plays a role in brain iron traffic. Patients due to diminished exit of
iron from cells often present with iron deficiency anemia, neurologic disorder, reti-
nal degeneration and diabetes velitus.
G. Pathophysiology of HFE. Since the discovery of HFE as the gene responsible for
HH, its role in the dysregulated iron absorption seen in HH has been elucidated.
In addition to leading to diminished hepcidin expression, HFE protein is also found
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430 Part V: Specific Complaints and Disorders

in the crypt cells of the duodenum, associated with B2-microglobulin and transfer-
rin receptor. It is thought that HFE protein may facilitate transferrin receptor-
dependent iron uptake into crypt cells and that mutant HFE protein may lose this
ability, leading to a “relative” iron deficiency in the duodenal crypt cells. In turn,
this may result in an increase in the expression of an iron transport protein called
divalent metal ion transporter 1 (DMI-1) that is responsible for dietary iron
absorption in the villous cells of the duodenum.
H. Diagnosis
1. Clinical presentation. Early in the course of IHC, patients may have the fol-
lowing signs or symptoms: lethargy, weight loss, and change in skin color, con-
gestive heart failure, loss of libido, abdominal pain, joint pain, or symptoms
related to diabetes mellitus. Hepatomegaly, skin pigmentation, testicular atro-
phy, loss of body hair, and arthropathy are the most prominent physical signs.
Patients with hemochromatosis secondary to transfusion therapy for
chronic anemia present with clinical symptoms at a young age. The typical
patient with thalassemia, having received more than 100 blood transfusions,
experiences failure of normal growth and sexual development in adolescence
and hepatic fibrosis. Many patients die of cardiac disease by early adulthood.
a. Liver disease. The liver is the first organ affected in IHC, and
hepatomegaly is present in 95% of the symptomatic patients. Hepatomegaly
may exist in the absence of symptoms and abnormal liver tests. In fact, serum
aminotransferases are frequently normal or only slightly elevated in patients
with IHC, even in the presence of cirrhosis. This finding reflects the relative
preservation of the hepatocyte integrity, which usually persists throughout
the course of the disease.
Palmar erythema, spider angiomata, loss of body hair, and gynecomas-
tia are often seen. Manifestations of portal hypertension may occur but are
less common than in alcohol-related cirrhosis. Hepatocellular carcinoma
(HCC) develops in approximately 30% of the patients with cirrhosis. This
increased incidence of HCC may be due to chronic iron-overload-induced
damage to hepatic DNA.
b. Skin pigmentation, which may be absent early in the course of the disease, is
present in a large percentage of symptomatic patients. The dark metallic hue is
largely due to melanin deposition in the dermis. There is also some iron depo-
sition in the skin, especially around the sweat glands. Pigmentation is deeper
on the face, neck, exterior surfaces of the lower arms, dorsa of hands, lower
legs, and genital regions, and in scars. Ten percent to 15% of the patients have
pigmentation of the oral mucosa. Skin is usually atrophic and dry.
c. Endocrine disorders
i. Diabetes mellitus develops in 30% to 60% of the patients with
advanced disease. The presence of a family history of diabetes mellitus
and the presence of liver disease and direct damage to the beta cells of the
pancreas by deposition of iron all probably contribute to the develop-
ment of diabetes mellitus in IHC. Complications of diabetes mellitus
such as retinopathy, nephropathy, and neuropathy may occur. IHC spares
the exocrine pancreas.
ii. Loss of libido and testicular atrophy. Hypogonadism is common with
symptomatic IHC and is most likely due to hypothalamic or pituitary
failure with impairment of gonadotropin secretion. Liver damage, alco-
hol intake, and other factors may contribute to sexual hypofunction.
iii. Other endocrine disorders. Addison’s disease, hypothyroidism, and
hypoparathyroidism are less common in IHC.
d. Arthropathy is present in about one fifth of the patients with IHC. It is more
common in patients over 40 years of age and occasionally may be the pre-
senting symptom.
i. Osteoarthritis involving the metacarpophalangeal and proximal inter-
phalangeal joints of the hands, and later of the knees, hips, wrists, and
shoulders, is most commonly seen.
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Chapter 55: Inherited Liver Diseases 431

ii. Pseudogout (chondrocalcinosis) occurs in approximately 50% of the

patients with arthropathy. Knees are most commonly affected, but wrists
and metacarpophalangeal joints are also usually involved.
iii. The pathogenesis of arthritis is not known. However, iron deposition in
the synovial cells may predispose to calcium pyrophosphate deposition.
e. Cardiac involvement. Approximately 15% to 20% of the patients present
with cardiac disease, most commonly cardiomyopathy, leading to heart fail-
ure. The heart is diffusely enlarged. Because iron is also deposited in the con-
duction system, a great variety of arrhythmias, such as tachyarrhythmias,
conduction blocks, and low-voltage patterns, may also be present.
f. Infection. Patients with hemochromatosis seem to have an increased risk of devel-
opment of severe bacterial infections, particularly with Yersinia enterocolitica,
Yersinia pseudotuberculosis,Vibrio vulnificus, Neisseria species, enteric gram-negative
bacteria, Staphylococcus aureus, and Listeria monocytogenes. Sepsis, meningitis,
enterocolitis, peritonitis, and intraabdominal abscesses have been reported. The
ingestion of raw seafood appears to contribute to the risk of these infections and
should be avoided. It is hypothesized that the increased availability of iron height-
ens susceptibility to infection because most bacteria utilize iron in growth.
2. Diagnostic studies. Diagnostic criteria are based on demonstration of exces-
sive parenchymal iron stores in the absence of other causes of iron overload
such as refractory anemia, thalassemia, and alcoholic cirrhosis.
a. Serum iron and TIBC. The normal range for serum iron is 50 to 150 mg/dL.
If the level is greater than 180 mg/dL, the patient should be questioned with
regard to intake of iron-containing medicines. The serum iron should be
rechecked 1 month after these medicines are discontinued. The serum iron
and percentage of saturation of transferrin (TS) or TIBC are elevated
(45%), especially early in the course of the disease.
b. Serum ferritin reflects both hepatic and total body iron stores. The levels
are lower in women than in men. It is the most specific screening test for
increased iron stores. However, normal levels may be found occasionally in
patients with latent or precirrhotic HH. Ascorbic acid deficiency in patients
with iron overload results in inappropriately low serum ferritin concentra-
tion. Elevated serum ferritin levels in the absence of iron overload may be
attributable to infection, acute or chronic liver disease especially when asso-
ciated with hepatocellular necrosis (e.g., viral, drug-related, or steatohepati-
tis), lymphoma, lymphocytic leukemia and other malignancies, rheumatoid
arthritis, hyperthyroidism, and uremia.
c. Genetic testing is recommended in patients with an elevated fasting TS or
ferritin level. If individuals are C282Y-homozygotes or compound heterozy-
gotes (C282Y/ H630) younger than 40 years with normal liver enzyme (ala-
nine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels,
no further workup is necessary. In patients with abnormal liver tests or who
are older than 40 years, a liver biopsy is recommended to define the liver
disease and extent of fibrosis.
d. Liver biopsy. For patients older than 40 years with elevated liver chemistry
tests, liver biopsy should be performed. Liver biopsy permits the following:
i. Estimation of tissue iron by histochemical staining. The amount of
stainable parenchymal iron is graded from 0 to 4, but the relation
between histochemical grading and hepatic iron concentration is not lin-
ear. Grades 1 and 2 (slight-to-moderate siderosis) are quite common in
the normal liver. Grade 4 siderosis indicates heavy iron excess. Grade 3
(submaximal siderosis) is difficult to interpret in quantitative terms.
Early in HH, stainable iron is almost exclusively present in the hepa-
tocytes, whereas in early secondary iron overload, the iron is predomi-
nantly in the Kupffer’s cells. With progressive iron accumulation, the
histologic features and pattern of stainable iron in various etiologic types
of iron overload become indistinguishable, and iron is seen throughout
the lobule, biliary duct epithelium, Kupffer’s cells, and connective tissue.
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432 Part V: Specific Complaints and Disorders

ii. Measurement of hepatic iron concentration by dry weight by chem-

ical analysis is the most objective means of assessing total body iron
stores. The normal range is 7 to 100
g/100 mg of dry weight of liver tis-
sue. In IHC, values are greater than 1,000
g/100 mg of dry weight.
Patients with alcoholic cirrhosis and increased stainable iron usually
have a hepatic iron concentration less than twice normal. There is evi-
dence that alcoholic patients with gross iron overload carry the IHC gene.
The hepatic iron index, which is the hepatic iron concentration in
mol/g of dry weight per age, seems to discriminate homozygous from
heterozygous HH before the development of frank iron overload in
homozygotes.
iii. Histologic assessment of liver damage. In the early stages, the histo-
logic appearance of the liver may be normal despite increased iron in the
hepatocytes. Necrosis and inflammation are usually absent. Before cirrhosis
is fully established, there is fibrosis radiating from expanded portal tracts.
The hepatic iron concentration and the duration of exposure are critical
determinants of the extent of liver injury. In the absence of coexistent alco-
holic liver disease, fibrosis or cirrhosis usually does not occur in HH until
the hepatic iron concentration reaches 4,000 to 5,000 mm/g liver (wet
weight), or 2.2% dry weight. In patients with thalassemia major, the appar-
ent threshold concentration for the development of hepatic fibrosis is about
twice this level. Whether this difference is due to the initial location of iron
in the reticuloendothelial cells or a shorter duration of exposure of the hepa-
tocytes to high iron concentration is uncertain. As cirrhosis develops, the
histology may resemble cirrhosis from chronic biliary obstruction. Some
patients may have histology similar to that of alcoholic cirrhosis.

I. The treatment of IHC involves the removal of excess iron and therapy of func-
tional insufficiency of the organs involved, such as congestive heart failure, liver
failure, and diabetes mellitus.
1. Phlebotomy. Iron is best removed from the body by phlebotomy. There are
250 mg of iron in 500 mL of blood. Because the body burden of iron in IHC
may be in excess of 20 g, 2 to 3 years of weekly phlebotomy of 500 mL of
blood may be necessary to achieve hemoglobin of 11% and serum ferritin
level of 10 to 20 mg/L. Thereafter, the frequency of phlebotomy may be
decreased to 1 unit of blood every 3 months for the rest of the patient’s life.
2. Chelating agents such as deferoxamine remove only 10 to 20 mg of iron per
day. In patients with anemia, hypoproteinemia, or severe cardiac disease preclud-
ing phlebotomy, this technique may be used. However, it is difficult to achieve a
negative iron balance by this means. In patients with refractory anemia, if it is ini-
tiated early in the course of iron loading, this approach can lower the risk of
cardiac disease, promote sexual maturation, and generally improve the prognosis.
Nightly subcutaneous infusion of deferoxamine induces excretion of chelat-
able iron into urine and, probably via the bile, into stool. The recommended
dosage is approximately 40 to 80 mg/kg per day. At daily dosages of more than
50 mg/kg, the potential increases for hypersensitivity and ocular and otologic
complications, including night blindness, visual field changes, irreversible retinal
pigmentation, optic neuropathy, deafness, and other adverse reactions. In addi-
tion, the iron chelator deferoxamine can promote infections, including gram-
negative sepsis and abscesses, by functioning as a siderophore, delivering iron to
bacteria that use it in growth. Chelating compounds that can be taken orally,
most notably including
-hydroxypyridine, are being developed.
Despite the potential of vitamin C deficiency to exacerbate iron over-
load, vitamin C supplementation is contraindicated in patients with
hemochromatosis. Sudden cardiac deaths have occurred in patients receiving
chelation therapy and vitamin C supplements. The cause of these events may
involve sudden shifts of iron from reticuloendothelial to parenchymal cells of
the myocardium or increased cellular injury from increased lipid peroxidation.
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Chapter 55: Inherited Liver Diseases 433

3. Prognosis. In patients treated with phlebotomy, there is a decrease in the size

of the liver and spleen, skin pigmentation, cardiac failure, serum aminotrans-
ferases, and glucose intolerance. Removal of iron has no effect on hypogo-
nadism, arthropathy, or portal hypertension. Hepatic fibrosis may decrease, but
cirrhosis is irreversible. Hepatocellular carcinoma occurs in one third of the
patients with IHC and cirrhosis, despite iron removal. This complication does
not seem to develop if the disease is treated in the precirrhotic stage. Hepatomas
in IHC are usually multicentric and not amenable to surgical resection. Only
30% to 40% of the patients have elevated serum alpha-fetoprotein levels.
4. Liver transplantation is an option for patients in whom HH is diagnosed late
in the course of their disease (i.e., with decompensated cirrhosis). Patients
should be carefully evaluated for cardiac disease, arrhythmias, and left ventric-
ular function and hepatocellular carcinoma.
HH patients seem to have diminished posttransplant survival rates in com-
parison to patients with other forms of liver disease. This is most likely related
to unrecognized cardiac disease and increased propensity for infections. Patients
who are successfully “de-ironed” prior to transplant have more successful out-
comes. Recurrent HH disease does not appear to develop in the allograft.
J. Early diagnosis of IHC in family members. To prevent the development of per-
manent organ damage, cirrhosis, and hepatocellular carcinoma, it is very impor-
tant to diagnose and treat the disease in relatives at an early stage. The following
are guidelines for screening relatives of patients with HH:
Once a proband with HH is identified, genetic family screening is recommended
for all first-degree relatives. In young proband with children, it is useful to perform HFE
mutation analysis in the spouse to accurately predict the genotype in the children. If the
spouse has either mutation, then the children will also need to undergo HFE mutation
analysis. If C282Y homozygosity or compound heterozygosity (C282Y/H63D) is found
in adult relatives of the proband, serum iron studies should be obtained. If ferritin or TS
levels are increased, therapeutic phlebotomy should be considered. If ALT and AST lev-
els are normal and ferritin is 1,000
g/L, liver biopsy is probably not necessary.

III. 1-ANTITRYPSIN DEFICIENCY

A. 1-antitrypsin (AAT) is an acute-phase reacting -1 globulin found in serum, various
body fluids, and tissues. It is a potent protease inhibitor (PI) synthesized by hepato-
cytes, monocytes, and bronchoalveolar macrophages for protection against tissue
injury resulting from proteases such as trypsin, chymotrypsin, elastase, and collage-
nase as well as from proteases released from polymorphonuclear leukocytes and
macrophages. AAT is responsible for 90% of the serum protease-inhibiting capacity
and approximately 90% of the alpha-1 band on serum protein electrophoresis.
1. AAT is a glycoprotein consisting of a single polypeptide chain with four carbo-
hydrate side chains. Due to genetic mutations, at least 60 variants of AAT have
been identified by their mobility on acid starch gel electrophoresis followed by
crossed immunoelectrophoresis on agarose gel. Isoelectric focusing in polyacry-
lamide (PIEF) has replaced the starch gel techniques and offers increased reso-
lution of PI variants. These variant proteins (phenotypes) have been designated
by different letters of the alphabet. The faster moving proteins have been
assigned earlier letters of the alphabet: PIM is the most common protein with
medium mobility, PI S is slow, and PI Z is the slowest.
2. The inheritance of AAT is autosomal codominant. Each allele acts independently
of the other and contributes its own active protein. The PI locus is on chromo-
some 14. Phenotypes are usually expressed as two alleles. Common PI variants
associated with decreased plasma concentration of AAT are PI S at 60% and the
classic deficiency phenotype PI Z at 10% to 15% of normal levels. The rare alle-
les PI I, PI P, PI M malton, and PI M Duarte also have low plasma levels. PI null
(PI  or PI–) phenotypes result in no detectable circulating AAT. PI S is relatively
common in Spain, whereas PI Z is most common in Scandinavia.
3. The PI MM phenotype is associated with an average serum level of 220 mg of
AAT/dL. Serum levels of AAT may be increased by acute and chronic inflammation
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434 Part V: Specific Complaints and Disorders

as a response to tissue injury, estrogen or oral contraceptive ingestion, preg-

nancy, carcinoma, and typhoid inoculation in normal individuals. In severely
deficient individuals, the level rises only slightly with such stimuli.
4. When the livers of severely deficient subjects are examined histologically, accu-
mulation of an amorphous material within most hepatocytes has been demon-
strated. This material, like glycogen, takes the periodic acid–Schiff (PAS) stain
but, unlike glycogen, is resistant to digestion with diastase. This PAS-positive
material is a variant of AAT that has been excreted out of the hepatocytes. The
greatest accumulation of this material is in the smooth endoplasmic reticulum
(SER). The basic difference in the structure of this protein (PI Z) from that of
the normal (PI M) is the replacement of a glutamic acid by a lysine. This limits
its transport out of SER to the Golgi and thus its excretion from the hepato-
cytes, resulting in low serum levels of AAT. Other, less severe types of AAT defi-
ciency have other amino acid substitutions. PI M Duarte and M malton have
nearly normal electrophoretic mobilities but are associated with low plasma
levels, intracellular aggregates, and lung and liver disease. PI S has decreased
stability and does not accumulate in the liver cells. The non-PI M alleles are
rare in African Americans. PI Z has its greatest frequency in northern Europe.
In the United States, approximately 1 in 676 whites have severe AAT deficiency.
5. It is clear that subjects of phenotype PI ZZ and probably PI SZ and possible PI MZ
are much more susceptible to the development of emphysema or chronic bronchi-
tis or both than the general population. This tendency is potentiated by smoking.
The emphysema is usually of the panlobular type and affects the lower lobes first.
6. Whereas emphysema is inversely related to plasma AAT levels, liver disease cor-
relates with intracellular accumulation of AAT. Liver injury occurs in AAT phe-
notypes associated with intracellular protein accumulation (PI Z, PI M malton,
PI M Duarte, PI ZZ, and possibly PI MZ). In contrast, no liver disease is seen
in deficiency phenotypes due to intracellular protein degradation (PI S, PI null).
The pathogenesis of the liver injury is not clear.
B. Liver disease. The first genetic association of AAT deficiency with liver disease
and cirrhosis was made in children. Subsequently, its association with cirrhosis in
adults has been confirmed. There is also an increased incidence of hepatic cancer
in patients with cirrhosis.
1. In clinical studies involving PI ZZ infants, it has been found that 12% present
with cholestasis and another 7% present with other evidence of liver disease
during early infancy. By 6 months of age, these infants appear to recover clini-
cally from their liver disease but continue to have elevated liver enzymes. At
3 months of age, 47% of “normal” PI ZZ infants have elevated liver enzymes.
Only 34% of PI ZZ infants have no clinical or laboratory evidence of liver
injury. At 4 years of age, approximately one half of the PI ZZ children continue
to have elevated serum hepatic enzyme concentrations.
2. Roughly 75% of children with AAT deficiency and clinically apparent liver dis-
ease present with jaundice and cholestasis during infancy. The remainder pre-
sent with evidence of portal hypertension in later childhood. Only 25% of the
cholestatic infants recover without evidence of chronic liver disease.
3. The severe degree of cholestasis in some infants with AAT deficiency may sim-
ulate extrahepatic biliary obstruction with respect to both clinical evaluation
and liver pathology. Surgical exploration in these instances has revealed “phys-
iologic hypoplasia” of the extrahepatic biliary tract, secondary to decreased
bile flow. Atresia of the ducts has not been demonstrated.
4. Approximately 25% of the children with AAT deficiency who present with
cholestasis persist in having grossly abnormal liver function tests. These
patients develop cirrhosis and portal hypertension with ascites and
esophageal varices, and die from hepatic complications in the first 10 years of
life. Another 25% have evidence of persistently abnormal liver function tests
but are slower in developing clinical signs of cirrhosis and die of complica-
tions of their liver disease between 10 and 20 years of age. Another 25% have
minimal liver dysfunction, minimal organomegaly, and less severe liver fibrosis
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Chapter 55: Inherited Liver Diseases 435

and live to adulthood. The remaining 25% appear to recover from their initial
insult and return to normal liver function with minimal evidence of residual
liver fibrosis.
5. In adults, as in children, men are twice as likely to have liver disease as women.
In studies done with patients with PI ZZ phenotype from Sweden or of Northern
European ancestry, the relative risk for cirrhosis was noted to be 37% to 47%,
and of hepatoma, 15% to 29%. In studies done in heterozygotes of PI MZ or PI
SZ phenotypes, the relative risk for cirrhosis was noted to be 1.8 and for
hepatoma 5.7, compared with other patients investigated for liver disease.
6. Diagnosis
a. Diagnosis of AAT deficiency should be considered in any chronic liver disease
of uncertain cause in children and adults of white and particularly Northern
European populations. The probability of AAT deficiency as a cause of the
disease increases in patients with a family history of liver or obstructive lung
disease and in patients in whom alcohol or viral hepatitis may be excluded.
Children with neonatal hepatitis, giant cell hepatitis, juvenile cirrhosis, or
chronically elevated liver chemistry tests should be investigated for AAT phe-
notype. Adults with chronic active hepatitis lacking serologic markers, or with
cryptogenic cirrhosis, with or without hepatoma, also should be evaluated.
b. The initial discovery of AAT deficiency is usually made by the absence of the
alpha-1 peak on serum protein electrophoresis. This method is not very sen-
sitive, and quantitative determination of serum AAT level and PI typing is
usually necessary for accurate diagnosis. Liver biopsy further supports the
diagnosis and helps to stage the extent of liver damage.
c. Biochemical studies. Plasma AAT levels may be determined in most clini-
cal laboratories by electroimmunoassay. Plasma levels should be related to
the normal reference range for each laboratory. Functional analysis may also
be performed by determination of total trypsin inhibitory capacity, 90% of
which is due to AAT activity. Discrepancies may occur between immunologic
and functional analyses due to the presence of dysfunctional or inactive
species. Subnormal levels suggest a genetic AAT variant and are only rarely
secondary to a disease process. Low levels have been described, however, in
the infant respiratory distress syndrome, in protein-losing states, and in ter-
minal liver failure. Levels below 20% of normal suggest the homozygous
deficiencies PI Z, PI M malton, PI M Duarte, and PI null or heterozygous
combinations of these alleles. Levels in the range 40% to 70% are compati-
ble with heterozygous deficiency (PI MO, SZ, MZ, etc.). Heterozygotes with
liver disease or active inflammation may well exhibit normal levels.
d. Phenotype determination. Isoelectric focusing is the method of choice for
phenotyping. A monoclonal antibody specific for PI Z AAT has been developed
and is useful in detecting the presence of the PI Z allele. It has been used for
mass population screening in an enzyme-linked immunosorbent assay (ELISA).
Such antibodies also may be used for specific staining of histologic material.
Specific diagnosis of most phenotypes also may be performed at the DNA
level. Some genetic mutations may be identified by Southern blotting due to
their fortuitous localization at a restriction endonuclease site (restriction frag-
ment length polymorphism). This method may be performed on DNA purified
from very few cells and therefore is ideally suited to prenatal diagnosis.
e. Liver biopsy and histopathology. 1-antitrypsin globular inclusions are
localized predominantly in periportal hepatocytes, are weakly acidophilic,
and may be overlooked easily on routine hematoxylin-eosin sections. After
diastase treatment to remove glycogen, the remaining immature glycoprotein
is strongly PAS-positive, reflecting high mannose content. In general, the num-
ber and size of globules increase with age and disease activity. Globules may
be missed entirely in liver biopsies from heterozygotes due to sampling error.
Immunofluorescence and immunoperoxidase staining with nonspecific
antisera against AAT are more sensitive than PAS-D staining for the detection
of intrahepatocellular aggregates. These techniques can be applied to both
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436 Part V: Specific Complaints and Disorders

frozen and formalin-fixed tissue. Electron microscopy can reveal AAT, in the
endoplasmic reticulum (ER), with dilatation in other periportal hepatocytes
in which biosynthesis generally predominates, in both hereto- and homozy-
gotes. Adult liver disease in AAT deficiency is usually characterized by rela-
tively low-grade inflammation radiating from portal tracts. Inflammatory
cells (primarily lymphocytes) are distributed in close proximity to areas of
abundant PAS-D globules. There may be piecemeal necrosis. As the disease
progresses, the liver becomes more fibrotic with the development of macron-
odular cirrhosis. Hepatoma of a hepatocellular or cholangiocellular type may
accompany the cirrhosis.
C. Treatment
1. Prevention. As in all genetic disease, the diagnosis of 1-antitrypsin deficiency
in a patient, regardless of the mode of clinical presentation (lung, liver, or other
symptoms), should lead to investigations of the family. It is desirable to identify
homozygotes in an asymptomatic stage. Patients should be advised against
smoking. Genetic counseling should be provided to families with one or more
children affected by liver disease.
2. Medical therapy. No medical therapy is beneficial in patients with liver
disease.
3. Liver transplantation. Liver transplantation provides a new source of plasma
AAT. In these patients, the PI typing converts to that of the donor. The 1-year
survival is 90% and the 5-year survival of juvenile patients in most transplant
centers is 80% to 85%. The experience of liver transplantation for cirrhosis in
PI Z adults is limited. In the absence of serious pulmonary manifestations, indi-
cations for liver transplantation are essentially those for decompensation due to
chronic liver disease of any cause. Preoperative evaluation of pulmonary func-
tion and the exclusion of hepatoma are essential.

IV. CYSTIC FIBROSIS

A. Epidemiology. Cystic fibrosis (CF) is one of the most common, serious inherited
diseases in Caucasians. It predominantly affects the lungs and the pancreas and
causes early mortality in most patients. The overall prevalence of overt liver dis-
ease in patients with CF is 5% to 10%. However, as the general care of patients
with CF has continued to improve, the proportion of patients living to adulthood
has increased, thus the relative importance of liver disease has also increased.
The incidence of liver disease rises steadily with age and peaks in the adoles-
cence years. It is rare for liver disease to have its onset after 20 years of age. It is
more common in males compared to females with a ratio of 3:1.
B. Pathogenesis of the liver disease in CF is not fully understood. It is thought that
there is altered bile ductular secretion resulting in concentrated viscous bile caus-
ing plugging and inflammation.
Several forms of hepatobiliary disease are seen in patients with CF. Neonatal
cholestasis occurs in 2% to 20% of affected infants and may persist for several
months. Hepatic steatosis is commonly seen. Micronodular cirrhosis occurs in 2%
to 5% of patients.
Patient with CF have a high incidence of biliary tract disease including hyper-
plastic gallbladders, gallstones, common bile duct (CBD) strictures and CBD
obstruction form severe pancreatic fibrosis, and a cholangiopathy indistinguish-
able from primary sclerosing cholangitis.
C. Treatment. Ursodeoxycholic acid has been shown to be helpful in the manage-
ment of patients with hepatobiliary disease in the setting of CF. Special attention
should be given to pulmonary function, infection, dosage of medications in the set-
ting of malabsorption and blood sugar control due to high incidence of diabetes
mellitus in patients with CF.
Liver transplantation has been used in children and adults with end-stage liver
disease associated with CF. Survival rates were approximately 75%. For CF patients
with severe pulmonary and liver disease, combined lung/liver or heart/lung/liver
transplantation may be offered.
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Chapter 55: Inherited Liver Diseases 437

Selected Readings

Wilson’s Disease

Brewer GI, et al. Treatment of Wilson’s disease with zinc, XVII: Treatment during
pregnancy. Hepatology. 2000;31:304.
Eghtesad B, et al. Liver transplantation for Wilson’s disease: A single center experience.
Liver Transplant Surg. 1999;5:467.
Ferenci P, et al. Late onset Wilson’s disease. Gastroenterol. 2007;132:1294–1298.
Mufti AR, et al. Is a copperbinding protein deregulated in Wilson’s disease and other
copper toxic disorders? Mol Cell. 2006;21:775–785.
Schilsky ML. Treatment of Wilson’s disease: What are the roles of penicillamine, trientine,
and zinc supplementation? Curr Gastroenterol Rep. 2001;3:54.
Sternlieb I. Wilson’s disease and pregnancy. Hepatology. 2000;31:304.
Taly AB, et al. Wilson’s disease: description of 282 patients evaluated over 3 decades.
Medicine (Baltimore). 2007;86:112–121.

Hemochromatosis

Brunt EM, et al. Histologic evaluation of iron in liver biopsies: Relationship of HFE
mutations. Am J Gastroenterol. 2000;95:1788.
Harrison-Findik DD, et al. Alcohol metabolism mediated oxidative stress down porter
expression. J Biol Chem. 2006;281:22974–22982.
Papanikolanon G, et al. Mutations in HFE2 cause iron overload in chromosome 1g-linked
juvenile hemochromatosis. Nat Genet. 2004;36:77–82.
Pietrangelo A. Hereditary hemochromasis—a new look at an old disease. N Eng J Med.
2004;350:2382–2397.
Pietrangelo A. Hereditary hemochromatosis: Biochemia and biophysician. Acta. 2006;
1763:700–710.

1-Antitrypsin Deficiency

Arroyo M, et al. Hepatic inherited Metabolic disorders. Semin Diag Pathol. 2006;
23:182–189.
Perlmutter DH. The cellular basis of liver injury in alpha-1-antitrypsin deficiency.
Hepatology. 1990;13:172.
Perlmutter DH, et al. Molecular pathogenesis of alpha-1-antitrypsin deficiency associated
liver disease. A meeting review. Hepatology. 2007;45:1313–1323.
Pietrangelo A. The ferroportin disease. Blood Cells Mol D13. 2004;32:131–138.
Pietrangelo A, et al. Genetics in liver diseases. J Hepot. 2007;46:1143–1146.
Powell PF, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterol.
2005;129:1932–1943.
Sveger T, et al. The liver in adolescents with a1-antitrypsin deficiency. Hepatology.
1995;22:514.
Whiting PF. Fetal and infantile hemochromatosis. Hepatology. 2006;43:654–660.
Wong K, et al. The diversity of liver disease associated with an elevated ferratin. Con J
Gastro. 2007;20:467–470.
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56 CIRRHOSIS AND ITS COMPLICATIONS

I. Cirrhosis is a disease state that is the consequence of a wide variety of chronic, pro-
gressive liver diseases. These result in diffuse destruction of hepatic parenchyma and
its replacement with collagenous scar tissue and regenerating nodules with disruption
of the normal hepatic lobular and vascular architecture. Regardless of etiology, the
triad of parenchymal necrosis, regeneration, and scarring is present in all cirrhotic
patients.
A. Classification
1. Morphologic. The pattern of scarring and gross appearance of the liver can be
used to classify cirrhosis into three groups:
a. Micronodular (Laënnec’s)
b. Macronodular
c. Mixed
Morphologic classification seldom permits the determination of the spe-
cific etiology. However, micronodular cirrhosis is most commonly seen as the
consequence of alcoholic liver disease, and macronodular and mixed cirrhosis
are the result of most other inflammatory or infiltrative diseases of the liver.
2. Etiologic
a. Alcohol
b. Viral hepatitis B, C, and D—most common causes of cirrhosis in the United
States
c. Drug- or toxin-induced
d. Hemochromatosis
e. Wilson’s disease
f.
1-Antitrypsin deficiency
g. Autoimmune hepatitis
h. Nonalcoholic steatohepatitis (NASH)
i.Biliary obstruction
i. Primary biliary cirrhosis (without extrahepatic bile duct obstruction)
ii. Secondary biliary cirrhosis (with extrahepatic bile duct obstruction)
j. Venous outflow obstruction
i. Budd-Chiari syndrome
ii. Venoocclusive disease
k. Cardiac failure
i. Chronic right-sided failure
ii. Tricuspid insufficiency
l. Malnutrition
i. Jejunoileal bypass surgery
ii. Gastroplasty
m. Miscellaneous
i. Schistosomiasis
ii. Congenital syphilis
iii. Cystic fibrosis
iv. Glycogen storage disease (type IV)
n. Idiopathic
B. Diagnosis. A specific diagnosis generally requires a combination of history, physical
findings, laboratory tests, and the identification of characteristic histologic features.

438
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Chapter 56: Cirrhosis and Its Complications 439

1. History. Most symptoms found in patients with cirrhosis are nonspecific.

Fatigue, malaise, and loss of vigor are common. There may be other symptoms
caused by a complication of the disease leading to cirrhosis or of cirrhosis itself.
These are discussed in the corresponding chapters or sections.
2. Physical examination. No physical abnormality establishes the diagnosis of
cirrhosis.
a. Characteristic findings include palmar erythema, spider angiomata,
gynecomastia, testicular atrophy, Dupuytren’s contractures, and findings due
to portal hypertension such as splenomegaly, ascites, esophageal varices, and
prominent superficial veins of the abdominal wall (caput medusae).
b. The liver in most patients with cirrhosis is enlarged and palpable below
the costal margin. The left lobe often extends to the left upper quadrant
below the xiphoid process. A small, hard, shrunken liver is a sign of very
advanced cirrhosis. The liver edge in most patients with cirrhosis feels firm.
Occasionally, regenerating nodules may be palpable in macronodular cirrho-
sis. Micronodules are not palpable.
C. Pathophysiologic consequences of cirrhosis
1. Alteration of hepatic blood flow: portal hypertension
2. Reduction in functional cell mass
a. Decreased synthesis: albumin, coagulation proteins, other proteins
b. Decreased detoxification: bilirubin, ammonia, drugs

II. PORTAL HYPERTENSION

A. Pathogenesis. The normal adult liver is perfused by about 1,500 mL of blood per
minute. Two thirds of this blood flow and one half of the oxygen supply are pro-
vided by the portal vein, the rest by the hepatic artery. Normally, the pressure in
the portal vein is low because the vascular resistance in the hepatic sinusoids is also
low. A sustained elevation of portal venous pressure above the normal of 6 to 10
mmHg is called portal hypertension. There are many causes of portal hyperten-
sion, but cirrhosis is the most common cause in the United States. Portal venous
pressure is primarily a function of volume of and resistance to the blood flow.
Factors contributing to distortion of the portal venous bed resulting in increased
resistance to blood flow in cirrhosis include the following:
1. Deposition of collagen in the space of Disse with consequent narrowing of the
sinusoids.
2. Distortion of sinusoids and the hepatic venous system by regenerating nodules.
3. The distortion of the hepatic parenchyma results in not only the development
of portal hypertension but also intrahepatic intravascular shunts between
portal venules through sinusoids to hepatic venules. Up to one third of the
hepatic blood flow may bypass the functioning liver tissue because of these
shunts.
B. Classification. The current classification (Table 56-1) of portal hypertension is
based on the major location of increased vascular resistance. Anatomically, the
obstruction to portal blood flow can occur at three levels:
1. Portal vein (prehepatic)
2. Intrahepatic (presinusoidal, sinusoidal, postsinusoidal)
3. Hepatic veins (posthepatic)
C. Complications resulting from portal hypertension and cirrhosis
1. Collateral circulation and varices
2. Ascites
3. Congestive splenomegaly
4. Encephalopathy

III. COLLATERAL CIRCULATION (VARICES). Extensive portosystemic venous collaterals

develop as a direct consequence of portal hypertension. These vessels form through
the dilatation of preexisting venous channels to decompress the high-pressure portal
venous system. Maintenance of portal hypertension, once collaterals are formed, is
attributed to a resultant increase in splanchnic blood flow.
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440 Part V: Specific Complaints and Disorders

TABLE 56-1 Classification of Portal Hypertension (A Partial Listing)

Intrahepatic

Prehepatic Presinusoidal Sinusoidal Postsinusoidal Posthepatic

Portal vein Schistosomiasis Cirrhosis Alcoholic Inferior vena

thrombosis hepatitis cava web
Splenic Sarcoidosis Primary Venoocclusive Tricuspid
arteriovenous biliary disease insufficiency
fistula cirrhosis
Constrictive Metastatic Cryptogenic; Hepatic vein Pericarditis
carcinoma alcohol- thrombosis
induced
cirrhosis

Major sites of collateral flow include the following:

A. The left gastric vein and short gastric veins join with intercostal, diaphragm
esophageal, and azygos veins of the caval system. This results in the formation of
esophageal and gastric varices.
B. The hemorrhoidal vein of the portal system joins hemorrhoidal veins of the caval
system. This results in the formation of large hemorrhoidal veins.
C. Remnants of the umbilical circulation of the fetus present in the falciform ligament
may form a large paraumbilical vein (caput medusae).
D. Others. Retroperitoneal veins, lumbar veins, omental veins.

IV. VARICES. The thin-walled varices in the lower esophagus and upper stomach may
bleed extensively and constitute the major complication of portal hypertension.
Variceal bleeding occurs without an obvious precipitating cause and presents usually
as a painless massive hematemesis or melena.
Variceal bleeding primarily reflects portal hypertension. The role of acid reflux
and its contribution to initiation of variceal bleeding is not clear. Even though there is
no clear agreement as to whether bleeding correlates with the severity of portal hyper-
tension, it is generally accepted that hemorrhage usually is seen with a portal pressure
above 12 mm Hg and is more likely in patients with large varices.
A. Diagnosis. The presence of varices may be detected by barium swallow and upper
gastrointestinal (GI) series (40% sensitivity), angiography, and endoscopy. Upper
GI endoscopy is preferred; it not only shows the presence and size of the varices
but also reveals whether they are the sites of bleeding. Forty percent of the bleed-
ing in patients with cirrhosis with known varices has a nonvariceal source.
Congestive or portal hypertensive gastropathy is a major source of bleeding in
these patients.
B. Prognosis. Once esophageal varices are diagnosed, the risk of bleeding ranges
from 25% to 35% within 1 year of diagnosis of large varices. Risk factors for
variceal bleeding include size of varices, severity of liver disease, and presence of
active alcohol consumption. The overall mortality of variceal bleeding is 70% to
80% in patients with cirrhosis. The prognosis is dependent on the patient’s nutri-
tional status, presence or absence of ascites; encephalopathy, bilirubin level, albu-
min level, and prothrombin time (see modified Child’s criteria in Table 56-2).
C. Treatment. Prompt care of the patient with massive hematemesis or melena from
bleeding esophageal or gastric varices requires coordinated medical and surgical
efforts.
1. Transfusion. The first step is to ensure adequate circulation with transfusion
of blood, fresh-frozen plasma, and, if necessary, platelets. Because patients with
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Chapter 56: Cirrhosis and Its Complications 441

TABLE 56-2 Modified Child’s Classification

Scorea

Variable 1 2 3

Encephalopathy (degree) Nil Slight–moderate Moderate–severe

Ascites (degree) Nil Slight Moderate–severe
Bilirubinb (mg/dL) 2 2–3 3
Albumin (g/dL) 3.5 2.8–3.4 2.8
Prothrombin index (%) 70 40–70 40
Prothrombin time(s) 14 15–17 18
(our modification)
aScores are summed to determine Child’s class: class A, 5–7; class B, 7–10; class C, 10–15.
bFor primary biliary cirrhosis, the bilirubin score is adjusted: 1  4; 2  410; 3  10 mg/dL.
From DiMagno EP, et al. Influence of hepatic reserve and cause of esophageal varices on survival and
rebleeding before and after the introduction of sclerotherapy: A retrospective analysis. Mayo Clin Proc.
1985;60:149. Reprinted with permission.

liver disease often have deficiency of clotting factors, the infusion of fresh blood
or fresh-frozen plasma is important.
2. Endoscopy or angiography. After the vital signs are stabilized, the site
and cause of the bleeding should be established by endoscopy. If bleeding is
too brisk and endoscopic diagnosis is not possible, angiography may be per-
formed to determine the site of bleeding and the vascular anatomy of the portal
circulation.
3. Choice of therapeutic method. Once the diagnosis of active variceal bleeding
is made, there are several therapeutic options. The treatment of choice is endo-
scopic sclerotherapy or endoscopic variceal banding.
If these methods are not immediately available, medical drug therapy, bal-
loon tamponade, or transhepatic variceal obliteration may be used. Surgical
therapy with a portosystemic shunt (PSS) carries a very high mortality but may
be lifesaving. Transjugular introduction of an expandable stent (transjugular
intrahepatic portosystemic shunt [TIPS]) into the liver may create a PSS with
much less morbidity or mortality.
4. Endoscopic sclerotherapy, the direct injection of a sclerosing agent into the
esophageal varices, is effective in the immediate control of variceal bleeding.
This technique is preferentially used as an initial therapy before the infusion of
vasopressin or balloon tamponade. The sclerosants most commonly used are
tetradecyl, sodium morrhuate, and ethanolamine oleate. The sclerosing agent is
injected directly into the variceal wall or into the mucosa between the varices.
It causes clotting of the varices and a severe necrotizing inflammation of the
esophageal wall followed by a marked fibrotic reaction.
After control of the bleeding, the endoscopic sclerotherapy is repeated at
weekly or monthly intervals until the varices are totally obliterated, leaving a
scarred esophagus. Sclerotherapy of gastric varices has not been shown conclu-
sively to be effective and may result in gastric ulceration. The complications of
endoscopic sclerotherapy of esophageal varices include ulceration, hemorrhage,
perforation, stricture, and pleural effusion. Sclerotherapy controls acute variceal
hemorrhage in 80% to 90% of patients. Chronic sclerotherapy that obliterates
the esophagus and varices decreases the risk of rebleeding.
5. Endoscopic banding of esophageal varices has been shown to be as effec-
tive as or slightly more effective than injection sclerotherapy in the initial treat-
ment of bleeding esophageal varices. The technique requires expertise and a
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442 Part V: Specific Complaints and Disorders

cooperative patient. Tracheal intubation and sedation of the patient may be

necessary.
6. Drug therapy. Although endoscopic banding or sclerotherapy is widely
accepted as the treatment of choice for acutely bleeding esophageal varices,
drug therapy may be a useful adjunctive treatment, particularly in severe hem-
orrhage and when bleeding is present from sites inaccessible to sclerotherapy
(e.g., portal hypertensive gastropathy, gastric fundal varices, and varices in the
more distal gastrointestinal tract). Several agents have been evaluated in the set-
ting of acute portal hypertensive bleeding: vasopressin and its analogs with or
without short-acting nitrates and somatostatin and its analog octreotide.
a. Vasopressin (Pitressin). Parenteral vasopressin results in constriction of
the splanchnic blood flow and subsequent decrease in portal venous pres-
sure. There is no clear evidence that direct infusion of vasopressin into the
superior mesenteric artery is more effective or less toxic than intravenous
(IV) administration of the drug. The IV route is preferred initially.
A continuous infusion of 0.4 unit per minute (or up to 0.9 U/min if nec-
essary) is given for 4 to 12 hours with subsequent gradual decrease in the
dose for duration up to 36 to 48 hours. The complications of vasopressin
therapy are generalized vasoconstriction leading to myocardial and periph-
eral ischemia, lactic acidosis, cardiac arrhythmias, and hyponatremia (anti-
diuretic hormone effect).
b. Short-acting nitrates. The addition of nitroglycerin administered via
transdermal, sublingual, or IV routes reduces the peripheral vasospastic
effects of vasopressin and lowers the portal pressure further via direct vasodi-
lation of portosystemic collaterals. The dosages are as follows: transder-
mal: 10 mg applied to skin q12h; sublingual: 0.6 mg every 30 minutes; IV:
40 g/min increasing to 400 g/min, adjusting doses to keep systolic blood
pressure greater than 90 mmHg.
c. Somatostatin. Somatostatin appears to be highly selective in its ability to
reduce splanchnic blood flow and hence reduce portal pressure. It has been
shown to be as effective as vasopressin with considerably fewer hemodynamic
effects. It can be administered for prolonged periods. The possible side effects
are nausea, abdominal pain, and minor disturbances in glucose tolerance with
prolonged use. Octreotide, the synthetic somatostatin analog, appears to be
as effective as somatostatin. The dosages are as follows: somatostatin:
250-g IV bolus followed by 250 g per hour IV continuous infusion up to
5 days; octreotide: 50-mg IV bolus followed by 50 mg per hour IV. In cases
of severe bleeding, the bolus dose may be repeated and the dose of somatostatin
or octreotide in the continuous infusion may be doubled.
Octreotide has replaced vasopressin in the treatment of bleeding
esophageal varices.
7. Balloon tamponade. The Sengstaken-Blakemore (SB) and the
Minnesota tube consist of two balloons, an elongated esophageal and a
round gastric balloon, with orifices in the tube to suction the stomach and
upper esophagus of collecting secretions. Variceal tamponade with the SB
tube stops the bleeding, at least temporarily, in more than 90% of patients.
Many difficulties that have been associated with the procedure can be
avoided if the patient is monitored in an intensive care unit. The proper pro-
cedure requires inserting the tube through either the mouth or the nose,
inflating the gastric balloon with 250 to 300 mL of air, and positioning the
balloon tightly against the gastroesophageal junction. In most patients, this
procedure alone stops the bleeding. If the bleeding persists, the esophageal
balloon must be inflated to a pressure of 30 to 40 mmHg. The main compli-
cations of the SB tube are esophageal or gastric ischemia, rupture, and aspi-
ration. Because the chance for complications from the SB tube increases with
the length of time the balloon is kept inflated, the balloon should be deflated
after 24 hours. If bleeding has stopped, the SB tube may be removed in
another 24 hours.
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Chapter 56: Cirrhosis and Its Complications 443

8. Percutaneous transhepatic obliteration of the varices with either a scler-

osant or embolization controls active variceal bleeding 70% of the time.
However, bleeding usually recurs. It should be used only as a secondary
approach after other therapy has failed or for bleeding gastric varices in
patients who are poor surgical risks.
9. Portosystemic shunts (PSSs). Recurrent or continued bleeding may indi-
cate a need for a PSS with surgical decompression of the portal venous pres-
sure. This major surgery, when performed on an emergency basis, carries a
mortality of 40%. If the surgery can be performed electively, mortality
declines substantially. PSS procedures do not appear to prolong survival, but
they do prevent subsequent bleeding. Because PSS diverts much of the blood
away from the liver into the vena cava, the underperfusion of the liver results
in liver failure and intractable hepatic encephalopathy in most of the patients.
A variation of the PSS, the distal splenorenal shunt with concomitant gastro-
esophageal devascularization, selectively decompresses esophageal varices
while maintaining mesenteric blood flow to the liver. In many studies, the use
of the distal splenorenal shunt has been shown to reduce the incidence of
severe encephalopathy as a late complication following surgery compared to
other PSSs. This procedure is technically difficult, however, and is not advised
in the presence of significant nonresponsive ascites, which it tends to worsen.
Emergency PSSs have been compared with endoscopic sclerotherapy
in the treatment of patients with severely decompensated alcoholic liver dis-
ease and active variceal bleeding. Subsequent recurrence of bleeding may be
less frequent in the shunted patients, but liver failure and encephalopathy
were greater in this group. The survival was comparable in the two groups.
Insertion of a prophylactic PSS prior to bleeding is not recommended for
patients with cirrhosis and varices. The resultant overall survival is not
improved. There is evidence to suggest that prophylactic endoscopic scle-
rotherapy and obliteration of large esophageal varices prevents bleeding.
10. Transjugular intrahepatic portosystemic shunts. Partial portal decom-
pression may be achieved by creating a channel between the hepatic vein and
the portal vein via a percutaneous transjugular approach.
Elastic recoil of the liver parenchyma occluding the shunt lumen is pre-
vented by the use of an expandable metallic endoprosthesis. With use of TIPS,
portal pressure has been reduced from 34 to 22 mmHg, with effective control
of variceal bleeding. Shunt patency is 90% up to 6 months afterward and may
be restored by shunt dilatation or restenting. Late complications of TIPS are
encephalopathy and ascites in about 10% to 20% of the patients.
11. Other surgical therapy. Surgical transection of the esophagus, devascular-
ization of the distal esophagus and proximal stomach, and splenectomy has
been used in patients with acute refractory variceal bleeding. These operations
carry a very high mortality and are not routinely recommended.
12. Liver transplantation is curative for portal hypertension, but it is impractical
in the acute setting of variceal bleeding. It is not necessary in patients with
only moderate liver disease and should be reserved for patients with irre-
versible advanced liver disease.
13. Prevention of first variceal bleeding and rebleeding in cirrhosis.
Nonselective beta-adrenergic receptor blockers (e.g., propranolol 20–180 mg
b.i.d.—a dose that reduces the resting heart rate by 25%) have been shown to
reduce portal hypertension and prevent the first variceal bleeding in patients
with large varices or gastropathic hemorrhage and to decrease rebleeding;
these drugs probably improve survival in patients with cirrhosis. Long-acting
nitrates (e.g., isosorbide-5-mononitrate) have been shown to be at least as
effective as propranolol in the prevention of first bleeding in cirrhosis. It has
fewer side effects than propranolol and may be used as an alternative.
Beta-blockers are minimally effective in patients with decompensated cir-
rhosis. Propranolol also has been shown to prevent bleeding from portal
hypertensive gastropathy. Beta-blocker therapy should not replace sclerotherapy
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444 Part V: Specific Complaints and Disorders

or variceal band ligation in the early management of variceal bleeding. It

should be considered as adjunctive therapy in the long-term management of
portal hypertension.

V. Ascites refers to the accumulation of excessive volumes of fluid within the peritoneal
cavity. Cirrhosis is the most common cause of ascites. The other main causes are infec-
tion (acute and chronic, including tuberculosis), malignancy, pancreatitis, heart fail-
ure, hepatic venous obstruction, nephrotic syndrome, and myxedema.
A. Pathogenesis. Ascites forms because of an imbalance between the formation and
resorption of peritoneal fluid. Distribution of fluid between vascular and tissue
spaces is determined by the equilibrium of hydrostatic and oncotic pressures in the
two compartments. The accumulation of fluid in the peritoneal cavity of patients
with cirrhosis results from an interaction of a number of factors:
1. Portal hypertension with increased total splanchnic plasma volume.
2. Renal changes favoring increased sodium and water resorption and retention
include the following:
a. Stimulation of the renin-aldosterone system
b. Increased antidiuretic hormone release
c. Decreased release of “natriuretic” hormone or third factor
3. Imbalance in the formation and removal of hepatic and gut lymph.
Lymphatic drainage (removal) fails to compensate for the increased lymph leak-
age, mainly due to elevated hepatic sinusoidal pressure, leading to formation of
ascites.
4. Hypoalbuminemia from decreased hepatic synthesis, which results in decreased
intravascular oncotic pressure. The leakage of albumin through lymph into the
peritoneal cavity increases the intraperitoneal oncotic pressure, favoring ascites
formation.
5. Elevated plasma vasopressin and epinephrine levels. These hormonal responses
to a volume-depleted state further accentuate renal and vascular factors.
B. Diagnosis
1. Clinical presentation. The physical findings of ascites include the puddle sign,
bulging flanks, flank and shifting dullness, and fluid wave. Abdominal or umbil-
ical herniation, penile or scrotal edema, or right-sided pleural effusion may be
present.
Detection of more than 2 L of ascites is not difficult, but less than this
amount is not always ascertained by physical examination. The percussion
maneuvers require the presence of at least 500 mL of fluid. The diagnostic accu-
racy of all the maneuvers described is only about 50%. The maneuver to deter-
mine flank and shifting dullness is probably the most reliable.
2. Radiologic studies
a. Plain abdominal x-ray films may reveal general haziness of the abdomen
with loss of the psoas shadow. Usually, there is centralization and separation
of bowel loops.
b. Ultrasonography can detect as little as 30 mL of ascitic fluid with the
patient in the right lateral decubitus position. Free and loculated collections
can be identified.
c. Computed tomography (CT) scans of the abdomen may detect small
amounts of ascites and at the same time evaluate intraabdominal anatomy,
giving important information on the size and state of the liver and spleen
and on the presence or absence of varices and tumors.
3. Characterization of ascitic fluid
a. Paracentesis. A diagnostic paracentesis should be performed for new onset
ascites or when a complication is suspected. The procedure is performed
under sterile conditions using a 20- to 23-gauge angiocatheter. The most
frequent site of puncture is on the linea alba slightly below the umbilicus.
The iliac fossa also may be used. Paracentesis rarely leads to serious compli-
cations (1%), which include bowel perforation, hemorrhage, and persis-
tent ascitic fluid leakage. It is much safer to perform the paracentesis under
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Chapter 56: Cirrhosis and Its Complications 445

ultrasound guidance with proper localization of ascitic fluid away from

bowel loops.
b. Laboratory studies
i. Approximately 50 mL of ascitic fluid is withdrawn for diagnostic pur-
poses. The ascitic fluid is analyzed for appearance, color, red and white
blood cell counts, and percentage of neutrophils, total protein, albumin,
glucose, triglycerides, and amylase determination. The fluid should be
inoculated into blood culture bottles at the bedside for aerobic and
anaerobic organisms. Samples should be sent for Gram’s and acid-fast
bacillus (AFB) stains, tuberculin and fungal cultures, and cytologic study
to look for malignant cells. Gram’s stain is helpful only in the setting of
gut perforation. A concomitant serum sample is also analyzed for the
preceding chemical parameters.
ii. A serum ascites albumin gradient equal to or greater than 1.1 g/dL is
consistent with ascites secondary to portal hypertension and cirrhosis.
The cell count in cirrhotic ascites is usually less than 500 white cells/L
with less than 25% neutrophils (polymorphonuclear [PMN] cells). PMN
counts greater than 250/l/L strongly suggest bacterial infection either
from spontaneous bacterial peritonitis or from perforation of a viscus.
Patients with bloody ascites should have a corrected PMN count calcu-
lated, as one PMN is subtracted from the total absolute PMN count for
every 250 red blood cells. Ascitic fluid, lactate, and pH values are not
helpful in diagnosing infection.
iii. The presence of blood in the ascitic fluid suggests infection with tuber-
culosis, fungi, or, more commonly, malignancy. Pancreatic ascites has
a high protein concentration, increased number of neutrophils, and ele-
vated amylase levels. Increased triglycerides in the ascitic fluid indicate
chylous ascites and suggest the presence of lymphatic obstruction and
disruption by trauma, lymphoma, tumor, or infection.
C. Spontaneous bacterial peritonitis
1. Spontaneous bacterial peritonitis (SBP) seems to occur in 8% to 10% of
patients with alcoholic cirrhosis. The patient may be totally asymptomatic or
present with signs and symptoms of peritonitis or increased liver failure and
encephalopathy or both. When SBP is suspected, ascitic fluid and blood cultures
should be obtained, and the patient should be treated promptly with broad-
spectrum antibiotics (e.g., a third-generation cephalosporin). Because untreated
SBP results in high mortality, overtreatment rather than delayed treatment is
recommended. The antibiotic coverage may be altered following culture results.
Five days of IV antibiotic therapy is sufficient even for patients with bacteremia.
2. The organisms most commonly found in the infected ascitic fluid belong to the
gut flora such as Escherichia coli, pneumococcus, and Klebsiella organisms.
Anaerobic infection is rare. In 70% of patients, the blood cultures are also pos-
itive for bacteria. The pathogenesis of SBP is multifactorial. The decreased
hepatic reticuloendothelial filtration of gut bacteria and the decreased antimi-
crobial activity of ascitic fluid with low opsonic activity due to low complement
and antibody levels and neutrophil dysfunction are thought to play a large role.
Possible routes of entry for the bacteria are transmurally from the gastrointesti-
nal tract, from the lymphatics, or, in women, from the genital tract and fallop-
ian tubes. Recurrent SBP may be seen in a high percentage of patients. An ascitic
fluid protein concentration less than 1.0 g/dL is the best predictor of recurrence.
Oral quinolone therapy (e.g., norfloxacin) has been shown to be effective in
decreasing the rate of recurrence of infection. Diuresis also may help in SBP by
increasing ascitic fluid opsonic and total protein concentrations.
3. SBP is sometimes difficult to distinguish from secondary peritonitis result-
ing from rupture of an abscess or bowel perforation. The number and type of
infecting organisms may be helpful in distinguishing spontaneous from
secondary peritonitis. Unlike secondary peritonitis, in which there are always
multiple organisms, a single organism is cultured in 78% to 88% of SBP cases.
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446 Part V: Specific Complaints and Disorders

If present, pneumoperitoneum strongly suggests secondary bacterial peritonitis.

The treatment of secondary peritonitis is surgical. However, all patients require
proper broad-spectrum antibiotic coverage.
D. Complications of ascites. Most of the complications of ascites result from
increased intraabdominal pressure and are proportional to the volume and rate of
fluid accumulation. The most common complications are dyspnea, decreased car-
diac input, anorexia, reflux esophagitis, vomiting, ventral hernia, and escape of the
ascitic fluid along tissue planes to the chest (hydrothorax) and the scrotum. By
increasing the portal hypertension, the risk of upper gastrointestinal bleeding may
also be increased.
E. Treatment of ascites. The treatment of uncomplicated ascites should start with
attempts to improve the hepatic function. Patients should abstain from alcohol
and other hepatotoxic drugs and should receive good nutrition to promote hepatic
regeneration. When drug therapy may be helpful in decreasing hepatic inflamma-
tion, patients should be treated appropriately. Hepatic healing and regeneration
have resulted in decrease of ascites.
Most patients, especially those with urine sodium concentrations less than
10 mEq/L, respond to moderate periods of bed rest and restriction of dietary
sodium to 0.5 to 1.0 g per day and fluid intake to less than 1 L per day with spon-
taneous diuresis.
1. Diuretics. If the preceding measures do not induce spontaneous diuresis, diuret-
ics may be used. Optimally, diuresis should result in loss of 1 L or 1 to 2 lb
(0.4–0.9 kg) per day. Peripheral edema is more easily mobilized by diuretics
than ascites and serves as a safety valve for fluid loss. Excessive diuresis may
result in azotemia, hyponatremia, hepatorenal syndrome, and encephalopathy.
a. Spironolactone (Aldactone) is usually the diuretic of choice at 100 to 200 mg
per day given in a single dose. If the urinary sodium concentration remains
less than 10 mEq/L and the diuresis is suboptimal, doses up to 600 mg per
day may be used. The effect of the drug (inhibition of the effect of aldos-
terone at the distal tube) is slow, and initial diuresis begins after 2 to 3 days.
The possible side effects are gynecomastia, lactation, and hyperkalemia.
b. Furosemide. In patients in whom diuresis is not successful with spirono-
lactone, furosemide (Lasix) may be added, starting at 40 mg per day. The
dosage may be increased to 240 mg per day, especially in patients with
peripheral edema.
c. Combination therapy. Although single-agent spironolactone has been
shown to be superior to single-agent furosemide, it is usually preferable to
start spironolactone and furosemide together, beginning with 100 mg and
40 mg, respectively, given as a single dose.
Single daily doses of medications are most appropriate and enhance
compliance. Amiloride hydrochloride 10 mg per day can be substituted for
spironolactone; amiloride hydrochloride is less available and more expensive
than spironolactone, but it is more rapidly effective and does not cause
gynecomastia. If the combination of 100 mg per day of spironolactone (or
10 mg of amiloride hydrochloride) and 40 mg per day of furosemide is inef-
fective in increasing urinary sodium or decreasing body weight, the dosages
of both drugs should be simultaneously increased as needed (e.g., 200 plus
80, then 300 plus 120, and finally 400 mg per day of spironolactone [or 40 mg
per day of amiloride hydrochloride] plus 160 mg per day of furosemide).
Doses higher than 400 mg per day plus 160 mg per day can be given, but
additional increments in urine sodium are marginal. Addition of a third
diuretic such as hydrochlorothiazide can lead to a natriuresis in such a
patient but may result in hyponatremia. Although the preceding ratios of
spironolactone and furosemide usually maintain normokalemia, the doses of
these two drugs can be adjusted to correct serum potassium imbalance.
F. Treatment of refractory ascites. In 10% to 20% of patients with ascites, the
standard medical therapy is ineffective or causes serious side effects. Ascites that is
resistant to mobilization with the usual therapy is not always the result of refractory
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Chapter 56: Cirrhosis and Its Complications 447

hepatorenal failure. The conditions that may contribute to refractory ascites

include worsening of the primary liver disease, such as active inflammation, portal
or hepatic vein thrombosis, gastrointestinal bleeding, infection, SBP, malnutrition,
hepatocellular carcinoma, superimposed cardiac or renal disease, and hepatotoxic
(e.g., alcohol and acetaminophen) and nephrotoxic substances. Nonsteroidal
antiinflammatory drugs (NSAIDs) reduce renal blood flow by reducing renal
vasodilating prostaglandins, glomerular filtration rate, and response to diuretics.
Angiotensin-converting enzyme (ACE) inhibitors and some calcium channel block-
ers decrease peripheral vascular resistance, effective vascular volume, and renal
perfusion. Aminoglycoside nephrotoxicity is more prevalent in patients with cir-
rhosis and may result in renal failure.
Current options for the 10% of patients whose condition is refractory to
routine medical therapy include therapeutic paracentesis, PV shunt, and liver
transplantation. Side-to-side portacaval shunts have been used in the treatment of
refractory ascites, but operative hemorrhagic complications and portosystemic
encephalopathy have led to the abandonment of this approach. Whether TIPS will be
of value in the treatment of patients with diuretic resistant ascites remains to be seen.
1. Therapeutic paracentesis. The safety and efficacy of large-volume paracen-
tesis have been confirmed. The procedure involves the daily removal of 4 to 6 L
of ascitic fluid until the abdomen is completely evacuated. After paracentesis,
adjunctive therapy with diuretics and dietary sodium restriction should be con-
tinued to prevent rapid reaccumulation of ascitic fluid. The procedure may be
repeated at intervals of 2 to 4 weeks.
In view of the ease and efficacy of diuretic therapy in more than 90% of
patients, therapeutic paracentesis should be reserved for treatment of tense ascites
and ascites that is refractory to diuretic therapy. In addition to being time-
consuming for both the physician and the patient, the procedure leads to protein
and opsonin depletion; diuresis, on the other hand, conserves proteins and opsonins.
Depletion of opsonins could predispose to spontaneous bacterial peritonitis.
Colloid replacement after large-volume paracentesis remains controversial.
The cost of albumin infusion ranges from $120 to $1,250 per tap. The changes
noted in plasma renin and serum electrolytes and creatinine in patients who
receive no colloid replacement do not seem to be clinically significant and have
not resulted in increases in morbidity or mortality.
2. Shunts. In about 5% of patients, ascites does not respond to the usual dosages
of diuretics, and increases in diuretic dosages result in the deterioration of renal
function. In these patients, a shunting procedure may be considered. A side-to-
side portosystemic shunt has been used in some patients, but the procedure is
associated with high mortality.
3. Peritoneovenous shunts. The reinfusion of ascitic fluid by a peritoneovenous
(PV) shunt (e.g., LeVeen or Denver shunt) may be therapeutic in selected
patients. The PV shunt routes the ascitic fluid subcutaneously from the peri-
toneal cavity into the internal jugular vein through a pressure activated one-way
valve. Most patients still require diuretics but at reduced doses. There is also a
concomitant improvement in renal blood flow. Serious complications of the PV
shunt occur in more than 10% of the patients and may lead to death. The com-
plications include peritoneal infection and sepsis, disseminated intravascular
coagulation (DIC), congestive heart failure, and ruptured esophageal varices.
The shunt may clot in about 30% of the recipients and require replacement.
The procedure is contraindicated in patients with sepsis, heart failure, malig-
nancy, and history of variceal bleeding. The morbidity and survival rates of
patients with cirrhosis treated with PV shunts correlate with the degree of
impairment of liver and renal functions. The best results are obtained in the few
patients with diuretic-resistant ascites and relatively preserved hepatic function.
At the present time, PV shunting is reserved for a very small group of
patients who fail to improve with both diuretic and paracentesis therapy or
patients in whom diuretic therapy has failed, or who live too far from medical
care to receive large-volume paracentesis every other week.
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448 Part V: Specific Complaints and Disorders

4. Liver transplantation. Orthotopic liver transplantation should be considered

among the treatment options of a patient with refractory ascites who is other-
wise a transplant candidate. The 12-month survival of patients with ascites
refractory to medical therapy is only 25%. With liver transplantation, however,
the 12-month survival is 70% to 75%.

VI. Hepatorenal syndrome is a progressive, functional renal failure that occurs in

patients with severe liver disease. Most of these patients have decompensated cirrho-
sis and tense ascites. Similar syndromes may be seen in metastatic liver disease and
fulminant hepatitis from viral, alcoholic, or toxic causes.
The kidneys are anatomically and histologically normal and capable of normal
function. The functional integrity of the renal tubules is maintained during the renal
failure, as manifested by relatively normal capacity for both sodium resorption and
urine concentration. When transplanted into patients without liver disease, these kid-
neys have been shown to function normally. Conversely, normal function has returned
when liver transplantation is carried out successfully.
A. Pathogenesis. The exact pathogenesis of hepatorenal syndrome is unclear. Most
evidence suggests that the primary abnormality in the kidneys is altered blood
flow. Hepatorenal syndrome is presently viewed as a perturbation of renal hemo-
dynamics characterized by vasoconstriction of arterioles of the outer renal cortex
with shunting of blood to the renal medulla, which results in decreased glomeru-
lar filtration rate and urine flow.
The renal hemodynamic alterations in hepatorenal syndrome are thought to
be a consequence of decreased “effective” blood volume and increased sympa-
thetic tone, increased intraabdominal and renal venous pressure, and alteration of
the normal balance of vasoactive humoral agents such as renin-angiotensin,
prostaglandins, thromboxanes, kinins, endotoxins, and renal kallikrein. Newer
studies suggest the involvement of endothelin-1 and endothelin-3 in hepatorenal
syndrome. Other studies focus on the florid systemic hemodynamic disturbances
that accompany this syndrome. These include a hyperdynamic circulation,
increased heart rate and cardiac output, and decreased blood pressure and sys-
temic vascular resistance. The identity of the “excess” vasodilator has not been
elucidated. Nitric oxide, a vasodilator synthesized from L-arginine and released
from vascular endothelium, has been proposed as the mediator for both the hyper-
dynamic circulation and renal failure. Nitric oxide synthetase can be induced by
bacterial lipopolysaccharide endotoxin and leads to peripheral vasodilatation,
tachycardia, and a decline in blood pressure.
B. Diagnosis. Hepatorenal syndrome is characterized by progressive azotemia (serum
creatinine 2.5 mg/dL) oliguria (urine volume 500 mL per day), a concentrated
urine with a urine-plasma osmolality ratio greater than 1.0, urinary sodium con-
centration less than 10 mEq/L, and normal urine analysis. The urine may contain
small amounts of protein, hyaline, and granular casts. The oliguria may occur
spontaneously but usually follows diuretic-therapy diarrhea, paracentesis, gas-
trointestinal hemorrhage, or sepsis. Hyponatremia, hyperkalemia, hepatic
encephalopathy, and coma may precede or accompany the renal functional deteri-
oration. A modest decrease in systemic blood pressure is present, but profound
hypotension is not part of the syndrome.
C. Differential diagnosis. Hepatorenal syndrome must be differentiated from other
types of renal failure that can occur in patients with liver disease. These include
renal failure from exposure to toxins such as acetaminophen, NSAIDs, and carbon
tetrachloride; infections; acute tubular necrosis due to hypotension or exposure to
aminoglycoside or angiographic dyes; and obstructive uropathy.
D. The prognosis of hepatorenal syndrome is very poor with an associated mortality
greater than 90%.
E. Treatment
1. Factors precipitating renal failure. The management of these patients should
include the identification, removal, and treatment of any factors known to pre-
cipitate renal failure. Diuretics should be stopped, blood volume lost due to
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Chapter 56: Cirrhosis and Its Complications 449

hemorrhage or dehydration should be replaced, serum electrolyte abnormalities

(hyponatremia and hypokalemia) corrected, and infections promptly treated.
Drugs that inhibit prostaglandin synthesis such as aspirin and NSAIDs should
not be given to patients with severe liver disease, because these drugs may pre-
cipitate renal failure.
2. Fluid challenge. All patients should undergo a trial of fluid challenge to
increase the “effective” plasma volume, using saline with salt-poor albumin or
plasma. Administration of fluid should be closely monitored, preferably with
measurement of the central venous pressure to document adequacy of the fluid
replacement as well as to prevent congestive heart failure. If diuresis does not
occur, the fluid challenge should be stopped.
3. Drugs. There is no effective treatment for hepatorenal syndrome. Numerous
agents have been tried in a limited number of patients to reverse the renal vaso-
constriction, including phentolamine, papaverine, aminophylline, metaraminol,
dopamine, phenoxybenzamine hydrochloride, and prostaglandin E1. No consis-
tent benefit has been observed with any of these agents. The current treatment
of hepatorenal syndrome remains conservative with supportive measures.
4. Dialysis. It is advisable to use dialysis for patients with potentially reversible
liver disease, such as fulminant hepatitis, to allow the liver to heal with the hope
that renal function will benefit. Spontaneous reversion of the syndrome,
although infrequent, occurs when the liver disease begins to improve.
5. Surgery. There are a few reports of recovery from hepatorenal syndrome fol-
lowing portacaval shunt or liver transplantation. However, these major sur-
gical interventions are inapplicable to most patients with this disorder.
Reversal of the hepatorenal syndrome after insertion of a PV shunt has been
reported.
6. Liver transplantation is a frequently successful therapy for the hepatorenal
syndrome. It is currently the only definitive treatment; the improvement in liver
function that follows liver transplantation is associated with complete recovery
from the hepatorenal syndrome.

VII. HYPERSPLENISM. Portal hypertension and obstruction to portal flow may cause
enlargement and engorgement of the spleen. The resulting hypersplenism causes
sequestration and destruction of all or some of the blood cells, leading to decreased
red cell survival, neutropenia, and thrombocytopenia. These hematologic abnormali-
ties are usually not severe and do not require specific therapy.
In patients with thrombocytopenia who require a surgical procedure, a normal
bleeding time is a good index of adequacy of hemostasis. If it is abnormal, cryopre-
cipitate and platelet transfusions should be administered prior to surgery.
Splenectomy is not routinely recommended for patients with hypersplenism. The
effect of surgical portal decompression on hypersplenism is unpredictable.

VIII. Hepatic encephalopathy is a neuropsychiatric syndrome occurring in patients with

acute or chronic liver failure. The acute disorder seen in fulminant hepatic failure is
discussed in Chapter 17. Patients with chronic liver disease develop a more indolent
encephalopathy, called portosystemic encephalopathy (PSE). It accompanies the
development of portal systemic collaterals that arise from portal hypertension, most
often due to cirrhosis. PSE involves the alteration of mental state and behavior. PSE
may be subclinical, recurrent with overt episodes, or chronic, and may lead to hepato-
cerebral degeneration. In most instances, PSE is precipitated by a specific cause such as
gastrointestinal bleeding, acid-base disorders, electrolyte abnormalities, hypoxia, car-
bon dioxide retention, azotemia, infection, or use of sedatives or other medications.
A. The pathogenesis of hepatic encephalopathy is incompletely understood. Using
sensitive CT scan and magnetic resonance imaging (MRI), significant frontoparietal
atrophy of the cortical brain has been found in patients with PSE including those
with subclinical PSE. The findings were dramatic in alcoholic cirrhotics.
Histopathologic evaluation of brain tissue from patients with PSE reveals astro-
cytic changes (Alzheimer type II astrocytosis). The degree of astrocytic damage
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450 Part V: Specific Complaints and Disorders

was directly related to the severity and duration of PSE. It is thought to be a meta-
bolic disorder, and in most patients the cerebral dysfunction is reversible.
However, in patients with hepatocerebral degeneration and spastic paraparesis, it
may be progressive. Reduced neuronal activity and brain energy metabolism and
decreased brain glucose utilization in PSE is due to neurotransmission failure,
rather than primary energy failure.
The shunting of blood from the gut directly to the systemic circulation,
bypassing the liver, due to portal hypertension and the poor function of the dis-
eased liver, allows the accumulation of various “toxins,” leading to deranged cere-
bral function. The various toxins and states implicated in the pathogenesis of
hepatic encephalopathy include ammonia, -aminobutyric acid (GABA), mercap-
tan, short-chain fatty acids, false neurotransmitters, an imbalance of excitatory
and inhibitory neurotransmitters, and the reversed ratio of serum aromatic amino
acids to branched-chain amino acids.
Several pathogenetic mechanisms involving neurotransmitter systems have
been proposed to explain hepatic encephalopathy, including the following:
1. Ammonia neurotoxicity (most commonly accepted theory)
a. Direct effects of ammonia on inhibitory and excitatory synaptic transmission
b. Glutamate synaptic dysregulation due to astrocytic changes
c. Increased serotonin turnover (especially in preclinical PSE)
2. The GABA-benzodiazepine system
a. Increased brain GABA uptake
b. Increased GABA-ergic tone
c. Presence of “endogenous” benzodiazepines
3. Other neurotransmitter systems (acetylcholine, histamine, taurine, opioid system,
other peptides).
Moreover, in these patients, other metabolic disturbances such as
azotemia, electrolyte abnormalities, acid-base disorders, such as hypokalemic
alkalosis, and infections may also contribute to the cerebral dysfunction. In
addition, in patients with cirrhosis and PSE, the central nervous system (CNS)
appears to be very sensitive to the sedative effects of drugs. Decreased hepatic
drug metabolism with subsequent accumulation of the drug, decreased binding
of the drug to decreased plasma proteins (making more free drug available to
penetrate the altered, “more porous” blood-brain barrier), and enhanced cere-
bral receptor sensitivity to sedative drugs such as benzodiazepines and barbitu-
rates probably combine to increase susceptibility of the patient to development
of encephalopathy and coma.
B. Diagnosis
1. Clinical presentation. The diagnosis of hepatic encephalopathy is clinical and
depends on documentation of the presence of mental status changes, fetor
hepaticus, and asterixis in a patient with parenchymal liver disease. Fetor
hepaticus refers to the feculent-fruity odor of the breath in these patients.
Asterixis is a flapping motion of the hands caused by intermittent loss of exten-
sor tone. It is best elicited by asking the patient to outstretch his or her arms,
with hands extended at the wrist and fingers separated. The flap is maximal
with sustained posture. The motor disturbance can also be detected in tightly
closed eyelids, pursed lips, and protruded tongue. Asterixis is not specific for
hepatic encephalopathy. It can also occur in patients with uremia, severe pul-
monary disease, and sedative overdose.
a. Stages. Hepatic encephalopathy can be subclinical or overt; the overt form
can be classified roughly into four stages of increasing severity as follows:
i. Stage I. Patients exhibit inappropriate behavior, altered sleep pattern,
loss of affect, depression, or euphoria. There is usually asterixis and dif-
ficulty with writing and other fine motor skills.
ii. Stage II. Patients are moderately obtunded, confused, and disoriented.
There is accompanying fetor hepaticus and asterixis.
iii. Stage III. Patients are stuporous with marked confusion. They are
barely responsive to painful stimuli. If it can be elicited, asterixis should
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Chapter 56: Cirrhosis and Its Complications 451

be present. There is usually hyperreflexia, clonus, and rigidity of limbs,

extensor response, grasping, and sucking responses.
iv. Stage IV. Patients are in deep coma, usually with no response to stimuli.
Muscle tone may be totally absent, limbs flaccid, and reflexes depressed.
b. The neurologic signs in hepatic encephalopathy are caused by metabolic
abnormalities and in most instances are transient, changing, and potentially
reversible.
2. Diagnostic studies
a. Laboratory abnormalities found in patients with hepatic encephalopathy
may include abnormal liver chemistry tests, which reflect the state of the
underlying parenchymal liver disease. Respiratory alkalosis with central
hyperventilation is usually present. In 90% of the patients with hepatic
encephalopathy, the arterial ammonia concentration is increased. The arter-
ial ammonia level does not correlate linearly with the depth of the coma.
However, serial measurements are helpful in following the course of the
hepatic encephalopathy in individual patients. Since the brain does not have
a urea cycle, the removal of ammonia depends on glutamine synthesis. Thus
the spinal fluid glutamine is a more sensitive test than arterial ammonia and
correlates closely with the depth of the coma.
In patients with PSE, blood levels of free fatty acids are elevated. There
is also an increase in the aromatic amino acids and methionine in the blood,
whereas branched-chain amino acid levels are decreased.
b. The electroencephalogram (EEG) and evoked potentials (visual, auditory,
somatosensory) offer little additional useful information to the clinician
except in atypical cases. The EEG shows characteristic slowing or flattening
of the waves with 3:1 high-voltage waves. Similar EEG changes may be seen
in patients with other metabolic encephalopathies.
Focal abnormalities should not be present. Some investigators believe
visual evoked potential recording is a useful tool in the diagnosis of
hepatic encephalopathy. It has been demonstrated that latency of the N3
component of the flash visual evoked response (VER) is useful for the diag-
nosis of preclinical PSE and the assessment of patients with clinically overt
PSE. VER may replace the tedious psychometric testing of patients sus-
pected to have preclinical PSE.
C. The treatment of PSE includes the following:
1. Improvement of the hepatic function, if possible, by treatment of the underly-
ing parenchymal liver disease.
2. Identification and removal or correction of the precipitating causes.
3. Removal of any sedative drugs.
4. Reduction of the “influx” of the putative cerebral “toxins.” Most of the
putative toxins implicated in PSE such as ammonia, GABA, and mercaptans
are protein breakdown products from the gut. Due to portal hypertension and
PSS, these toxins are more available to the “sensitive” CNS in these patients.
The reduction of the formation and influx of these toxins into the CNS is
accomplished by the following:
a. Supportive care is crucial in these patients. Catabolism of patients’ own
endogenous protein should be prevented by providing adequate calories
(1,800–2,400 per day) in the form of glucose or carbohydrates. Vitamins
and minerals such as magnesium, calcium, phosphorus, and zinc may be
deficient and should be replenished. Electrolytes, acid-base imbalances, and
prerenal azotemia should be corrected. Gastrointestinal bleeding and infec-
tions should be meticulously searched for and treated.
b. Restriction of dietary protein. The degree of restriction of dietary protein
depends on the severity of the mental status changes. Dairy and vegetable
proteins are much better tolerated than animal protein. In most patients
who can eat, the dietary protein is initially restricted to 40 g per day. Since
these patients require protein for hepatic regeneration and protein synthesis
(anabolism), complete withdrawal of protein should be brief. As the mental
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452 Part V: Specific Complaints and Disorders

status improves, protein should be reintroduced, preferably in the form of

vegetable protein, and advanced to 60 to 110 g as tolerated. Amino acid
mixtures, rich in branched-chain amino acids and low in aromatic amino
acids and methionine, such as HepatAmine or Hepatic-Aid may be used as
protein source or supplement.
c. Intestinal cleansing, especially if there is gastrointestinal bleeding. Bowel
cleansing is initially accomplished by enemas or intestinal lavage solutions
such as GoLYTELY or Colyte. However, these patients require prolonged
bowel cleansing to eliminate the contents as well as the organisms that break
down proteins and “convert” them to the putative toxins. This is accom-
plished by the use of antibiotics or nonabsorbable sugars.
d. Antibiotics
i. Neomycin is a nonabsorbable aminoglycoside given orally in doses of
2 to 6 g per day or as a 1% enema if the patient has ileus. Its effect is
thought to be by the inactivation of gut bacteria. About 1% to 3% of
the drug is absorbed and excreted by the kidneys. Prolonged use of the
drug may lead to renal failure as well as eighth cranial nerve damage.
ii. Vancomycin has been shown to be effective in the management of resis-
tant hepatic encephalopathy, but its high cost is prohibitive.
iii. Metronidazole has become the oral antibiotic of choice for acute man-
agement of hepatic encephalopathy when lactulose alone does not
achieve adequate results. It must be used with caution in this setting
because the drug is cleared by the liver and thus is likely to accumulate
in patients with chronic liver disease. The recommended dosage is 250
mg by mouth three or four times daily. Use of metronidazole beyond 7
to 10 days is not advisable.
iv. Rifaximin (Xifaxan) has recently shown to be effective in the treatment
of PSE in the dose range of 400 mg 2–3 times daily. It is a nonab-
sorbable, gut-specific antibiotic that alters the intestinal flora with any
systemic side effects.
e. Nonabsorbable sugars
i. Lactulose is a nonabsorbable disaccharide (galactoside fructose). It is
given orally in dosages of 60 to 120 mg of syrup per day. The goal is ini-
tially to achieve diarrhea, then to produce two to three soft bowel move-
ments per day. The mechanism of action of lactulose is multifactorial:
a) It causes an osmotic diarrhea, providing for a rapid evacuation of
nitrogenous toxins from the bowel.
b) It is broken down in the colon by gut bacteria to short-chain fatty acids,
which lower the pH of stool. The low pH promotes ammonia (NH3) to
ammonium (NH+4) well as the –NH2 group of other amines, thus mak-
ing them less lipid soluble and less apt to cross cell membranes of ente-
rocytes to be absorbed into the circulation. Also, the low pH promotes
the growth of low-ammonia producing gut bacteria.
c) It serves as a substrate for bacteria in utilizing ammonia.
ii. Lactitol is similar to lactulose but has a less sweet taste (hence is less
likely to cause aversion and noncompliance). It is as effective as lactu-
lose but is not yet available in the United States.
f. Lactulose and neomycin or metronidazole. Since lactulose has no toxi-
city, it is usually preferred over neomycin or metronidazole. In some
patients, the two types of drugs may be used concomitantly for further ther-
apeutic benefit. As long as the stool pH remains less than 5, the antibiotic
is not interfering with the action of lactulose. Thus the stool pH should be
checked periodically to ensure that the addition of neomycin does not pre-
vent bacterial action required to reduce lactulose to the active organic acids.
g. Branched-chain amino acid (BCAA)-enriched formulas. No consensus has
been reached on whether the use of IV BCAA-enriched formulas leads to
more rapid resolution of hepatic encephalopathy. The results of oral BCAA
regimens have strongly suggested that this dietary strategy may be useful.
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Chapter 56: Cirrhosis and Its Complications 453

Since the cost of these formulations is very high, they may be reserved for
patients in whom other measures have failed.
h. Zinc. Zinc deficiency has been suggested to play a role in hepatic encephalopa-
thy, but few data are available to support this hypothesis. Zinc sulfate and zinc
acetate supplementation have been studied in limited trials. Zinc histidine holds
promise as a superior oral preparation to use in future trials.
i. Benzodiazepine receptor antagonists such as flumazenil (Romazicon)
have been used in several trials. Sixty to seventy percent of patients improved
after IV flumazenil administration. Larger trials are under way at this time.
j. Surgical considerations
i. Portosystemic shunts. Distal splenorenal shunts, portacaval H-graft
shunts, mesocaval calibrated shunts, and TIPS have been successful in
decompressing portal hypertension and ameliorating PSE. All of these
special shunt procedures do not completely decompress the preexisting
portal hypertension and allow hepatic perfusion.
ii. Liver transplantation. Intractable hepatic encephalopathy unmanage-
able by medical treatment is a clear indication for liver transplantation.
Nontransplant surgical procedures, with the exception of TIPS, should be
considered only for patients who are not transplant candidates.
iii. Other procedures. Patients with demonstrated large, spontaneous, or
surgically created PSSs and intractable hepatic encephalopathy some-
times benefit from the closure of the shunt. This operation should be
accompanied by additional procedures to prevent variceal bleeding.
Shunt occlusion by radiologic techniques has been described. Duplex
ultrasound may be used instead of angiography to identify patients
with large spontaneous PSSs. Portosystemic shunts, especially end-to-
side shunts and sometimes side-to-side shunts, can induce hepatic
encephalopathy. Colonic exclusion has been used in selected patients for
the management of severe post–PSS hepatic encephalopathy.

Selected Readings

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Liver Dis. 2006;10:499–512.
Tripodi A, et al. Abnormalities of hemostasitis in chronic liver disease. Reappraisal of their
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Variceal Bleeding

Bosch J, et al. Prevention of variceal rebleeding. Lancet. 2003;361:952–954.

Corley DA, et al. Octreotide for acute esophageal variceal bleeding: A meta-analysis.
Gastroenterology. 2001;120:946.
Fernandez J, et al. Norfloxactlin versus ceftriaxone in the prophylasix of infections in patients
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Sarin SK, et al. Comparison of endoscopic ligation and propranolol for the primary
prevention of variceal bleeding. N Engl J Med. 1999;340:988.

Hepatorenal Syndrome

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hepatorenal syndrome. J Hepatol. 2007;46(5):935–946.
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Hepatic Encephalopathy

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Ascites and Spontaneous Bacterial Peritonitis

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syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133:818–824.
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Nutrition

Als-Nielsen B, et al. Branched-chain aminoacids for hepatic encephalopathy Cochrane

Database. Syst Rev. 2003;(2)CD 001939.
Als-Nielsen B, et al. Non-absorbable disaceharides for hepatic encephalopathy: systematic
review of randomized trials. Brit Med J. 2004;324:1046.

Hepatocellular Carcinoma

Bruix J, et al. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236.

Bruix J, et al. Diagnosis of small HCC. Gastroenterology. 2005;129:1364.
Colli A, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance and alphatoprotein
in diagnosing a systematic review. Am J Gastroenterol. 2006;101(3):513–523.
Ioannou GN, et al. Incidence and predictors of hepatocellular carcinoma in patients with
cirrhosis. Clin Gastroenterol Hepatol. 2007;5(8):938–945.
Llover JM, et al. Resection and liver transplantation for hepatocellular carcinoma. Semin
Liver Dis. 2005;25:181–200.
Lopez PM, et al. Systematic review: evidence based management of hepatocellular
carcinoma—an updated analysis of randomized controlled trials. Aliment Parmacol
Ther. 2006;23:1537–1547.
79466_CH57.qxd 1/2/08 1:36 PM Page 455

TUMORS OF THE LIVER 57

AND BILIARY SYSTEM

I. LIVER TUMORS. The liver filters both arterial and portal venous blood and thus is a
major site for the spread of metastatic cancers, particularly those that originate in the
abdomen. Metastatic liver tumors can develop after the primary tumor has been iden-
tified, or patients can present initially with the signs and symptoms of metastatic liver
disease. Common primary tumors that metastasize to the liver are colon, pancreas,
stomach, breast, lung, gallbladder, and bile duct tumors, and lymphoma.
The most common primary liver cancer is hepatoma, or hepatocellular carci-
noma (HCC). HCC often is a consequence of cirrhosis. Worldwide, chronic hepatitis
B and C are major causes of HCC. Other primary liver malignancies are fibrolamellar
carcinoma and cholangiohepatocellular carcinoma and sarcoma, including angiosar-
coma, leiomyosarcoma, fibrosarcoma, and mesenchymal sarcoma.
Benign tumors of the liver include hepatic hemangioma, adenoma, focal nodular
hyperplasia, and focal regenerative hyperplasia.
A. Clinical presentation
1. History. Primary hepatoma often occurs in the setting of established cirrhosis
of any cause. In fact, abrupt deterioration of a patient with known cirrhosis is
a signal to consider the possibility of HCC. Other pathogenic antecedents of
HCC include hepatitis C virus, chronic hepatitis B virus infection (HBV) with
or without cirrhosis, exposure to aflatoxins in food (implicated in parts of
Africa and Asia), and exposure in the distant past to thorium dioxide, a radi-
ologic contrast material, nonalcoholic steatohepatitis (NASH) associated with
obesity and diabetes mellitus. Uncommon consequences of HCC include fever
of unknown origin, portal vein thrombosis, hypoglycemia, polycythemia,
hypercalcemia, porphyria, and dysglobulinemia.
The incidence of HCC has doubled in the United States for the past
20 years and continues to increase due to HCV- and HBV-related complications
and NASH-related cirrhosis.
The mean age at the time of diagnosis of HCC in the United States is
65 years. Seventy-four percent of cases occur in men. In patients younger than
40 years of age who present with liver cancer, only a third are HCC; others
include fibrolamellar carcinoma, which has a much better prognosis, and
metastatic cancer.
In patients with metastatic liver cancer, the primary lesion may not be
known. Thus the initial presentation may be due to the metastatic disease to the
liver. About half of the patients who die from malignant disease have metas-
tases in the liver at postmortem examination.
Abdominal pain is a common complaint of patients with primary HCC or
metastatic liver disease. Some patients have nonspecific complaints, such as
anorexia, weight loss, and malaise.
2. Physical examination. The liver typically is enlarged and nodular and may be
tender. Ascites often has developed. A friction rub heard over the liver with respi-
ration indicates involvement of the liver capsule. Rarely, a bruit is heard, reflecting
the vascular nature of most HCC and some metastatic tumors. Jaundice usually
develops later in the course of both HCC and metastatic liver disease. If jaundice
is present initially, it means that preexisting liver disease is present, the tumor
involves much of the liver parenchyma, or a large bile duct is obstructed.

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456 Part V: Specific Complaints and Disorders

B. Diagnostic studies
1. Laboratory studies. Anemia is common in patients with liver cancer. It may be
the nonspecific anemia of chronic disease or the macrocytic anemia associated
with a chronic liver disorder. Bilirubin is elevated for the same reasons that the
patient may be jaundiced (see section I.A.2). Elevation of alkaline phosphatase
is common simply because obstruction of even the small biliary radicals causes
generation and release of this enzyme. If the source of an elevated alkaline
phosphatase level is in question, a 59-nucleotidase elevation will confirm its
origin in the liver. Often mild elevations of aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) occur.
The serum alpha-fetoprotein concentration is elevated in about half of the
patients with hepatoma in the United States; thus, the measurement is useful in
helping make the diagnosis. However, some patients with gonadal malignancies
and metastatic disease to the liver also have elevated serum alpha-fetoprotein.
2. Radiologic studies include ultrasound, computed tomography (CT), magnetic
resonance imaging (MRI), dimethylphenylcarbamylmethyliminiodiacetic acid
(HIDA) scan, and sulfur colloid liver scan.
Many physicians proceed immediately to CT in the evaluation of liver
tumors after the initial blood chemistry studies have been done. The CT scan
has the advantage of not only providing accurate information about the liver
but also identifying enlarged lymph nodes and other abnormalities of the
abdominal organs. Furthermore, a CT-guided needle biopsy of a liver lesion or
other abdominal mass may provide important diagnostic information.
3. Liver biopsy. Percutaneous liver biopsy is diagnostic of liver cancer in about
80% of patients in whom alkaline phosphatase is elevated due to intrahepatic
cancer. Biopsy of the liver under direct laparoscopic vision is an alternative to
percutaneous liver biopsy. Laparoscopy also can assess the spread of tumor to
the peritoneum, lymph nodes, and other abdominal organs.
4. Angiography. Celiac axis angiography can determine operability in a patient
with a HCC or with a solitary metastatic lesion to the liver. If the CT scan sug-
gests tumor in both lobes of the liver, arteriography is not indicated. An arteri-
ogram is helpful in differentiating a benign hemangioma from a malignant
tumor when the CT scan suggests a vascular lesion.
C. Natural history and treatment. Survival of patients diagnosed with HCC remains
very poor. Survival is related to tumor size, liver function, and the receipt of effec-
tive and potentially curative treatment (resection or orthotopic liver transplanta-
tion [OLT]). In recent years, living-donor partial liver transplantation (LT) has
made transplantation more available for this indication. Five-year survival rates
after OLT may be as high as 70% for a Child class A patient with one tumor less
than 2 to 5 cm in diameter. Patients with intermediate to advanced HCC tend to
have uniformly poor prognosis.
1. Surgical resection is possible only for a small number of patients. Tumor
spread, poor liver function, and the presence of portal hypertension preclude
patients for surgery. Even with resectable tumors, there is a high recurrence
rate. This increases with large tumors, those with vascular invasion, and those
with poor differentiation. Well-differentiated and encapsulated HCC especially
less than 3 cm in size has been associated with lower recurrence rates after
resection.
2. Liver transplantation (OLT or living-donor partial LF) may be offered to
patients with HCC. The eligibility criteria include solitary tumors less than 5
cm or up to three tumors each less than 3 cm. Recurrence is much lower than
that of resection if these criteria are used.
3. Local ablation using US- or CT-guided percutaneous ethanol injection (PEI) or
radiofrequency ablation have become established modes of therapy for patients with
HCC with no significant coagulopathy or ascites. For patients with a single tumor
less than 3 cm, HCC recurrence-free survival is similar to that surgical resection.
4. Palliative therapy is used for patients not suitable for potentially curative
therapy. Unfortunately, several studies have confirmed no survival benefit with
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Chapter 57: Tumors of the Liver and Biliary System 457

treatments of 5-fluorouracil, tamoxifen, or PEI. Transarterial chemoembolization

(TACE) was found to have a small, but significant benefit in prolonging survival.

II. BILIARY TUMORS. Biliary tumors include those that arise in the gallbladder and in the
intra- and extrahepatic biliary system. Benign tumors are rare and include papilloma,
leiomyoma, lipoma, myxoma, and fibroma. On the other hand, adenocarcinomas of the
gallbladder and bile ducts (cholangiocarcinomas) are not rare, accounting for about
5% of all malignancies.
A. Carcinoma of the gallbladder (CG)
1. Epidemiology. CG is extremely rare in the United States. However, CG is the
most common gastrointestinal malignancy in the Native Americans living in the
Southwest and in Mexican Americans. The incidence is highest in Chile and
Bolivia. The risk is higher in women and in the elderly. If it is diagnosed early or
incidentally on routine cholecystectomy for gallstone disease, the prognosis is
very good. Incidental CG is noted in 1% to 3% of cholecystectomy specimens.
2. Risk factors for CG include gallstones, chronic cholecystitis, and porcelain
gallbladder. Adenomatous polyps of the gallbladder may progress to cancer.
Polyps smaller than 1 cm seldom undergo malignant change. Other risk factors
for CG include congenital biliary cysts, anomalous drainage of the pancreatic
duct to the common bile duct (CBD), and chronic infection of the gallbladder
with Salmonella.
CG associated with gallstones are most commonly seen with large gall-
stones (
2.5 cm) and in patients with long duration of gallstone disease. Use of
certain drugs (i.e. isoniazid, methyldopa, and oral contraceptive) may also be
associated with CG.
3. Clinical picture. Most patients with CG may present with symptoms of gallstone
disease (i.e., right upper quadrant pain, malaise, anorexia, nausea, vomiting, weight
loss, and jaundice). Unfortunately, most patients at the time of diagnosis have tumors
that have invaded adjacent organs and lymph nodes and may even have distant
metastases. The 5-year survival for such patients is usually less than 5%.
4. Diagnosis is usually obtained by imaging techniques including abdominal US,
CT, MRI (magnetic resonance imaging), and MRCP (magnetic resonance
cholangiopancreatography). Tumor markers such as CEA and CA-19-9 are not
helpful.
5. Prognosis and treatment. Prognosis depends on the stage of CG. If the CG is
thought to be a T1 lesion, surgical resection (i.e., simple cholecystectomy) may
be sufficient. Advanced cases may require radical resection. Postoperative radi-
ation and chemotherapy may reduce rates of recurrence.
B. Cholangiocarcinoma (CGC)
1. Epidemiology. CGC arises from the epithelium of the intra- or extrahepatic
biliary ductular system. It is less common than HCC and tends to occur at an
older age than HCC. The incidence is similar in both men and women.
2. Risk factors of CGC include primary sclerosing cholangitis (PSC), ulcerative
colitis, inflammatory bowel disease (IBD), choledochal cysts, biliary ductal
ectasia (Caroli’s disease), intrahepatic gallstones, biliary duct infections (chronic
cholangitis), infections with Clonorchis sinensis and Opisthorchis viverrini,
multiple biliary papillomatosis, bile duct adenoma, and exposure to thorotrast
(contrast agent used in the past for radiologic imaging).
3. Clinical features depend on whether CGC is central or peripheral.
a. Central CGC arises in major bile ducts and is often associated with chronic
inflammation of the bile ducts ( i.e., with PSC). Klatskin tumor arises in the
bifurcation of the CBC. Central CGC is often present with obstructive jaundice.
b. Peripheral CGC is rarely associated with PSC or cirrhosis. It often presents
with weight loss and abdominal pain.
c. Mixed HCC and CGC may be found in association with cirrhosis.
4. Diagnosis. Abnormal laboratory tests include elevated levels of alkaline phos-
phatase, bilirubin, 5nucleotidase, -glutamyltransferase, and serum CA19-9
above 100 mm /mL.
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458 Part V: Specific Complaints and Disorders

Central tumors may be more difficult to diagnose. Cytologic and histologic

examination of tissue obtained from endoscopic brushing and biopsy during
ERCP as well as direct cholangioscopy may help make the diagnosis.
Peripheral tumors may be amenable to needle biopsy during CT or MRCP.
5. Treatment. Peripheral and central CGC may be resectable when the tumor is
small; however, the recurrence rate after surgical resection is high and survival
is poor. Liver transplantation is not a viable alternative for treatment of HCC
due to high posttransplant recurrence rates. Radiation and chemotherapy may
provide symptomatic relief. Placement of stents in the obstructive ducts during
ERCP may be palliative.

Selected Readings
Bruix J, et al. Management of hepatocellular carcinoma. Hepatology. 2006;42:1202–1236.
Case Records of the Massachusetts General Hospital (Case 13-2006). A man with bone
mass and lesions in the liver. N Engl J Med. 2006;354:1828–1837.
Colli A, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance and alfa-etoprotein
diagnosing hepatocellular carcinoma. A systematic review. Am J Gastroenterol. 2006;
101:513–523.
deGroen PC. Cholangiocarcinoma: Making the diagnosis. Clin Perspect Gastroenterol.
2001;4:77–89.
DeVreede T, et al. Prolonged disease five-year survival after orthotopic liver transplantation
plus adjuvant chemo-irradiation for cholangiocarcinoma. Liver Transplant. 2000;6:399.
DiBisceylia AM. Liver tumors. Clin Liver Dis. 2001;5:1–286.
Geahigan TA. Primary hepatic lymphoma: A case report and discussion. Pract Gastroenterol.
2001;25:58.
Heimbach JK, et al. Liver transplantation for perihilar cholangiocarcinoma after aggressive
neoadjuvant therapy: a new paradigm for liver and biliary malignancies? Surgery.
2006;140:331–334.
Koslin DB. Hepatocellular carcinoma. Rev Gastroenterol Disord. 2001;1:58.
Larsson SC. Coffee consumption and risk of liver cancer: A metaanalysis. Gastroenterology.
2007 May;132:1740–1745.
Llover JM, et al. Resection and liver transplantation for hepatocellular carcinoma. Seminar
Liver Dis. 2005;25:181–200.
Llovert JM, et al. Hepatocellular carcinoma. Lancet. 2003;362:1907–1917.
Lopez PM, et al. Systematic review: evidence based management of hepatocelluar
carcinoma—an updated analysis of randomized controlled trials. Ailment Pharmacol
Ther. 2006;23:1537–1547.
Rea DJ, et al. Liver transplantation with neoadjuvant chemoradiation is more effective
than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242:451–461.
Sheth S, et al. Primary gallbladder cancer: Recognition of risk factors and the role of
prophylactic cholecystectomy. Am J Gastroenterol. 2000;95(6):1402–1409.
79466_CH58.qxd 1/2/08 1:36 PM Page 459

LIVER TRANSPLANTATION 58

L iver transplantation is an effective and accepted therapy for a variety of chronic,

irreversible liver diseases for which no other therapy has proved to be satisfactory. The
liver can be transplanted as an extra (auxiliary) organ at another site (Fig. 58-1) or in the
orthotopic location after the removal of the host liver (Figs. 58-2 and 58-3). The discus-
sions of this chapter mainly concern the orthotopic liver transplantation (OLT).
Split liver and living-donor liver transplantation has become available and successful.
Although the number of patients requiring OLT continues to grow steadily, the number of
available donors remains unchanged. Fifteen percent to 20% of patients awaiting liver
transplantation die prior to receiving an organ. Currently the majority of patients wait 6
to 24 months for OLT. Although the number of patients requiring OLT continues to grow
steadily the number of available organ donors remains unchanged. The referring physician
faces three important questions regarding liver transplantation: first, candidacy (patient
selection); second, appropriate timing for referral; and third, follow-up care of patients
returning from a successful operation.

I. GENERAL INFORMATION. The American Liver Foundation estimates that in the

United States at any one time as many as 5,000 people with end-stage liver disease
could benefit from liver transplantation. The two major factors limiting the number
of liver transplantations performed are the availability of suitable donor organs
and the fact that donor livers are recovered from only about 25% of potential donors.

Figure 58-1. Anastomoses in auxiliary partial liver transplantation. VC, inferior vena cava; PV,
portal vein; AO, aorta; CJ, choledochojejunostomy. (From Terpstra OT, et al. Auxiliary partial liver
transplantation for end-stage chronic liver disease. N Engl J Med. 1988;319:1507. Reprinted with
permission. Copyright © 1988 Massachusetts Medical Society. All rights reserved.)

459
79466_CH58.qxd 1/2/08 1:36 PM Page 460

Figure 58-2. Orthotopic liver transplantation. Biliary reconstruction can be accomplished through
choledochojejunostomy or duct-to-duct anastomosis (inset). (From Starzl TE. Liver transplantation, II.
N Engl J Med. 1989;321:1092. Reprinted with permission. Copyright © 1989 Massachusetts Medical
Society. All rights reserved.)

Figure 58-3. Diagram of appearance after orthotopic liver transplantation. Sequence of anasto-
moses is as follows: upper vena caval anastomosis above the liver (1), lower vena caval anastomosis
beneath the liver (3), end-to-side hepatic artery anastomosis (4), portal vein anastomosis (2), and com-
mon bile duct anastomosis over a T tube (5). (From Krom RAF. Liver transplantation at the Mayo Clinic.
Mayo Clin Proc. 1986;61:278–282. Reprinted with permission.)

460
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Chapter 58: Liver Transplantation 461

The second factor is due partly to inadequate identification of potential organ donors
by physicians. Members of the medical community, especially physicians dealing with
patients who may require transplantation (internists, nephrologists, gastroenterolo-
gists, cardiologists), must begin to increase their own and their patients’ awareness of
the need for donor organs.
In an attempt to increase the number of organ donors, 27 states have passed leg-
islation for required request. This legislation obligates hospitals to have policies in place
to offer organ donation as an option to families of patients dying in that hospital.
These laws are designed to relieve the attending physician of the burden of requesting
organ donation from grieving families by making the request for organ donation part
of the routine hospital policy.
Many patients do not receive a liver transplant because they are never referred to
a transplantation center. Other patients are referred only after their liver disease has
reached its terminal stage, and they often die before a suitable donor organ can be
found. To allow all appropriate patients the opportunity to undergo liver transplanta-
tion and survive the procedure, physicians must be aware of the criteria for candidacy
and for timing of the referral.
There are more than 30 active centers in which liver transplant operations are
performed in the United States. For the success of this procedure, centers must main-
tain high standards and achieve and maintain acceptable 1- and 5-year survival rates.
Centers performing fewer than 10 liver transplantations each year are unlikely to
maintain the necessary expertise for optimal management of patients with this
extremely complex disease. Currently 1-year survival rates range from 80% to 95%
and 5-year survival rates are 80% to 85%. The dramatic increase in the survival rates
results from the following factors:
A. Advances in standardization and refinement of the transplantation procedure.
B. Expertise of anesthesiologists in the prevention and treatment of the metabolic
abnormalities that occur in patients with end-stage liver disease during the trans-
plantation procedure.
C. Use of the venovenous bypass system, which ensures venous return to the heart
from both the portal and systemic venous systems during the hepatic phase of the
transplantation procedure, reduces blood loss, decreases the incidence of postop-
erative renal failure, and generally results in less hemodynamic instability during
the procedure.
D. Improved techniques for the identification and support of potential organ donors.
E. Refinement of operative techniques for the recovery and preservation of the donor
livers.
F. Use of more effective and less toxic immunosuppressive regimens. It is important to
remember that successful liver transplantation does not return a patient to normal.
Rather, a new disease, a “transplanted liver,” replaces the former disease. However,
this new state allows patients a chance for both long-term survival and a more nor-
mal lifestyle than were possible during the late stages of their liver disease. After
liver transplantation, patients must take immunosuppressive medications for the
remainder of their lives. Discontinuation of the prescribed medications may lead to
rejection and rapid deterioration in the patient’s condition.

II. CANDIDACY (PATIENT SELECTION). In the past, patients were referred for liver
transplantation only after their disease had reached its end stage. For best results,
however, earlier referral to a transplantation center is desirable for all appropriate
patients. Because of the variable course of many liver diseases, the determination of
the most appropriate time for referral of any patient for transplantation is difficult.
A. Criteria. There are three general criteria used in most transplantation centers.
These are as follows:
1. The unavailability of other surgical or medical therapies that offer the patient
an opportunity for long-term survival.
2. Absence of complications of chronic liver disease that may significantly increase
the patient’s operative risk or lead to the development of absolute or relative
contraindications to transplantation.
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462 Part V: Specific Complaints and Disorders

3. Understanding by the patient and family of the physical and psychological

consequences of the transplantation procedure including the risks, potential
benefits, and costs.
B. Indications. The indications for liver transplantation have been expanding. Currently
the indications can best be grouped into four major categories of liver disease:
1. Chronic irreversible advanced liver disease of any cause
2. Nonmetastatic hepatic malignancies
3. Fulminant hepatic failure
4. Inborn errors of metabolism
Table 58-1 summarizes the indications for liver transplantation used in
most transplant centers. More than 60 distinct diseases have been treated with
liver transplantation. In adults, the most common diagnoses have been fulmi-
nant hepatic failure, chronic active hepatitis, cryptogenic cirrhosis, primary
biliary cirrhosis, alcoholic cirrhosis, and inborn errors of metabolism. In pedi-
atric patients, biliary atresia and inborn errors of metabolism are the most
common indications (Table 58-2).
C. OLT for specific disease indications
1. Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for
OLT in adults, accounting for 40% to 60% of OLTs in some centers. The over-
all 3- to 5-year survival rate after OLT for HCV cirrhosis is 80% to 85%.

TABLE 58-1 Indications for Liver Transplantation

Adults Children

Primary biliary cirrhosis Biliary atresia

Sclerosing cholangitis Inborn errors of metabolism (see Table 58-2)
Fulminant liver failure Acute liver failure (viral, toxic, metabolic)
Hepatitis (viral, drug, or toxin induced) Reye’s syndrome
Metabolic liver diseases Neonatal hepatitis
Alcoholic liver disease Chronic hepatitis
Postnecrotic cirrhosis Cryptogenic cirrhosis
Secondary biliary cirrhosis Familial cholestasis
Autoimmune liver disease Arterial thrombosis
Hepatic traumas Benign or malignant hepatic tumors
Polycystic liver Rejection
Budd-Chiari syndrome
Venoocclusive disease
Liver tumors (benign, malignant, metastatic)
Primary nonfunction
Rejection

Inborn Errors of Metabolism Treated with

TABLE 58-2
Liver Transplantation

Cystic fibrosis Erythropoietic protoporphyria

Alpha-1 antitrypsin deficiency Crigler-Najjar syndrome type I
Wilson’s disease Urea-cycle enzyme deficiencies
Type I and type IV glycogen Type I hyperoxaluria
storage disease Hemophilia A and B
Niemann-Pick disease Homozygous type II hyperlipoproteinemia
Tyrosinemia Protein C deficiency
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Chapter 58: Liver Transplantation 463

Prognosis after OLT may be affected by comorbid conditions including renal

insufficiency, cryoglobulinemia, and hepatocellular carcinoma (HCC).
There is no effective antiviral regimen to prevent recurrence of HCV in
allograft. Fortunately, reinfection rarely (5%–10% of patients) leads to graft
failure within the first 3 to 5 years after OLT, but survival rates are lower than
in patients with OLT for other causes of cirrhosis in seven or more years after
OLT. Cirrhosis occurs in 10% to 30% of patients post-OLT. HCV recurrence in
the allograft may be treated by reduction of immunosuppression antiviral ther-
apy or both. Retransplantation for patients with graft failure due to HCV recur-
rence is controversial and is associated with poor survival (40% 1-year survival).
2. Hepatitis B virus (HBV)-induced cirrhosis is also a common indication for
OLT; however, HBV also recurs in the allograft.
3. Alcoholic cirrhosis/liver disease. Strict selection of criteria is necessary to
identify appropriate patients for OLT. A period of
6 months of sobriety is
usually required, but this factor alone is not sufficient for post-OLT recidivism.
Many of these patients present with multiple organ systems’ dysfunction and
severe malnutrition that requires aggressive preoperative management. Also,
other coexistent liver diseases need to be identified (i.e., hemochromatosis,
alpha-1-antitrypsin deficiency, viral hepatitis [B, D, C], and ACC). The 5-year
survival of patients with alcoholic cirrhosis post-OLT is similar to other patients
who undergo OLT for other indications.
4. Liver tumors. OLT may be indicated for patients with liver tumors who are
unable to undergo surgical resection either due to the anatomic location of the
tumor or due to the severity of the underlying liver disease (cirrhosis).
Tumors of the liver for which OLT should be considered are HCC, fibro-
lamellar HCC, epithelioid hemangioendothelioma, hepatoblastoma, and
metastatic neuroendocrine tumors.
For HCC, OLT may be offered if the tumor is confined to the liver, docu-
mented by imaging (CT or MRI); if the tumor is single (5 cm) and/or there are
fewer than three tumors, each 3 cm in diameter; there is no invasion or throm-
bosis of the portal vein; and there is no lymph node involvement. For patients
fulfilling these criteria, the 5-year survival may approach that of patients who
undergo OLT for other causes.
5. Cholestatic liver diseases. In children, OLT is performed for patients with
biliary atresia and Alagille syndrome. In adults, OLT is performed for primary
biliary cirrhosis (PBC) and primary sclerotic cholangitis (PSC). A risk score for
PBC has been formulated based on patients’ serum bilirubin, albumin, pro-
thrombintre, presence of edema, and variceal bleeding. Patients should be
referred for OLT when the lirubin is
10 mg/dL. Posttransplant recurrence of
PBC is rare. Patients’ 5-year survival is 80% to 85%.
For PSC, a similar criteria as for PBC has been formulated for OLT and
provides more accurate prognostic information. Patients with PSC should be
referred for OLT when serum bilirubin is
10 mg/dL. In a small number of
patients, PSC may recur in the allograft.
6. Fulminant hepatic failure (FHF). OLT may be lifesaving in patients with FHF
(see Chapter 17). Early referral to a transplant center is necessary to ensure a
good outcome. Death of patients with FHF is usually due to late referral and/or
inability to find an appropriate donor within the necessary timeframe. Five-year
survival of patients with FHF is in the range of 70% to 80%.
D. Contraindications. Absolute and relative contraindications to liver transplantation
include the conditions listed in Table 58-3. The absolute contraindications are condi-
tions that would result in a prohibitively high mortality risk after transplant surgery.
A number of diseases for which transplantation might have been precluded
5 or 10 years ago are no longer absolute contraindications to the procedure.
An upper age limit has been eliminated because recipients over 50 years of age
have a 5-year survival after transplantation similar to that of younger adults. Also,
liver transplantation in very young infants and even newborns has become com-
mon, although the results are better with older children.
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464 Part V: Specific Complaints and Disorders

TABLE 58-3 Contraindications to Liver Transplantation

Absolute contraindications
Extrahepatic malignancy
Advanced cardiopulmonary disease
Acquired immunodeficiency syndrome (AIDS)
Active substance abuse
Other organ system failure not curable with hepatic transplantation
Relative contraindications
Active sepsis outside the hepatobiliary tract
Renal insufficiency/failure
Advanced protein-calorie malnutrition
Portal vein thrombosis
Operative procedures, such as end-to-side portacaval shunt or complex hepatobiliary surgery
Previous extrahepatic malignancies

Preoperative diagnosis by advanced imaging techniques and intrasurgical use

of vein grafts have made it possible for patients with extensive thromboses of
the portal, mesenteric, or splenic veins to be candidates for liver transplantation.
The routine use of imaging techniques to measure the size of the liver and deter-
mine the state of the host vessels helps identify these patients in advance so that
appropriate plans can be made.
Previous upper abdominal surgery, especially splenectomy and portosystemic
shunts, that may affect the portal vein reconstruction during transplantation previ-
ously were considered absolute contraindications. With the advanced surgical tech-
niques used today, however, many of these patients, especially those with mesocaval
and distal splenorenal shunts, have had successful transplantations.
Primary liver malignancy is still a relative contraindication for liver trans-
plantation. Hepatocellular carcinoma other than fibrolamellar hepatoma has a
recurrence rate of approximately 80% at 1 year after transplantation. Because of
this high recurrence rate, most centers do not recommend liver transplantation for
patients with large or advanced hepatocellular malignancy.
Transplantation in patients with fulminant hepatic failure secondary to drugs
or viral hepatitis provides good results if the patient receives the transplant before
the onset of major systemic complications. Stage IV hepatic coma in adult patients is
a relative contraindication to transplantation. Referral before development of this
level of coma and other complications (see Chapter 56) is the key to successful trans-
plantation in this group of critically ill patients. Most patients with fulminant hepatic
failure should be transferred to a transplantation center once the diagnosis is estab-
lished. With worsening of the patient’s condition (increasing coagulopathy and
encephalopathy), the patient should be placed on the center’s active transplantation
list at the highest possible status.
Before the availability of HIV antibody testing, a group of patients who
received liver transplants were subsequently found to be HIV positive. The AIDS-
related mortality in this group was 37% in a 6-year follow-up period. The most
commonly accepted policy in the United States is to screen all recipients for HIV,
but not to exclude transplantation because of a positive test.

III. EVALUATION
A. Goals. Once the attending physician identifies a patient as a potential candidate
for liver transplantation, he or she refers the patient to a transplant center where
the patient undergoes a thorough evaluation to satisfy four specific goals:
1. The establishment of a specific diagnosis
2. Documentation of the severity of the disease
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Chapter 58: Liver Transplantation 465

3. Identification of all complications of the disease or concomitant diseases that

might adversely affect the patient’s survival
4. Estimation of the long-term prognosis of the disease with or without orthotopic
liver transplantation
B. Criteria for organ donation include confirmation of
1. Consent signed by family
2. Brain death of the donor
3. Absence of systemic diseases, including HIV, HBV, HCV, bacterial and fungal
infection, and neoplasia
4. Presence of normal or near-normal liver tests
5. Absence of incorrectable coagulopathy and disseminated intravascular coagu-
lopathy (DIC)
6. Liver size and blood-type compatibility
The donor factors associated with poor graft function include steatosis
(
30% fat), prolonged cold preservation time (
12 hours), and initial poor
function of graft after transplantation.
C. Criteria for OLT recipient. The following criteria (score) are used to determine a
patient’s candidacy for OLT: Model for end-stage liver disease (MELD) and
pediatric end-stage liver disease (PELD).
MELD uses readily available tests to predict mortality risk: 3.8 log (bilirubin) 
11.2 log (INR)  9.6 log (Creative)  6.4. MELD scores range from 6 to 40. MELD
has been validated as a predictor of mortality in adult patients with end-stage liver
disease.
D. Testing. The routine evaluation process involves a number of laboratory tests and
imaging studies. Additional studies are tailored to the individual patient after a
thorough review of the patient’s records from the referring physician. All patients
undergo Doppler ultrasonography of the portal venous system to measure portal
vein flow and to confirm its patency. Adult patients also undergo pulmonary func-
tion testing and electrocardiography. In patients suspected of having coronary
artery or valvular disease, a stress test or coronary angiography may be required.
In addition, patients with significant nutritional deficiencies are identified and
treated with an intensive program of nutritional support while they are awaiting a
donor liver.
Patients are also evaluated by a psychiatrist, a social worker, and a hospital
finance officer. The social worker ensures that all appropriate arrangements have
been made to allow the patient to return to the transplantation center when a suit-
able donor liver is located.
After completion of the evaluation process, each patient’s situation is
discussed by a transplantation committee, and he or she is placed into one of four
categories:
1. Active candidate
2. Active candidate pending additional evaluation
3. Inactive candidate (liver disease not far enough advanced for transplantation)
4. Unacceptable candidate for transplantation. In addition, a decision is made
regarding the urgency of the need for transplantation.
Once accepted as an active candidate for liver transplantation, the patient
is placed on the active transplantation list. The waiting period varies widely
among transplantation centers. When a potential liver donor is identified and
located, all suitable candidates on the active list are reviewed by the transplan-
tation committee and priority is given to the patient with the most urgent need.
The chosen recipient is admitted to the transplant hospital on an emergency
basis and is surgically prepared to receive the donor organ. The recipient
operation is precisely timed with the donor liver procurement procedure, and
the donor and recipient operating teams maintain close communication regard-
ing the progress of the two operative procedures. If the two procedures are
performed at different sites, the donor liver is preserved and transported to the
recipient team under cold ischemia conditions within 6 to 20 hours of
procurement.
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466 Part V: Specific Complaints and Disorders

IV. OPERATIVE PROCEDURE

A. Technical (procedure-related) complications. The abdominal wall incision
used by most transplant surgeons is a bilateral subcostal incision that is extended
in the upper midline. The xiphoid process is excised. Complications of these inci-
sions include infections, hernias, and granulomas of the fascial sutures, which may
occur as late as several years after transplantation. In addition to the abdominal
incisions, adult patients also have cutdowns performed in the groin and axilla to
accommodate the venovenous bypass system (placed in the axillary and saphenous
veins) (Fig. 58-4). In addition to wound infections, lymphoceles are a frequent
complication in these sites. Lymphoceles may require repeated aspirations or the
placement of drains to allow complete resolution.
The four vascular anastomoses established in the transplantation procedure
involve the suprahepatic inferior vena cava, infrahepatic inferior vena cava, portal
vein, and hepatic artery. Complications related to these anastomoses usually pre-
sent in the early postoperative period but may occur as late as several months to
years after transplantation. These complications include bleeding, thrombosis,
stenosis, infection, and pseudoaneurysm formation. Postoperative anasto-
motic bleeding requires reoperation in the immediately postoperative period and
has been associated with a higher early mortality. Arterial thrombosis is the most
frequent vascular complication in the early postoperative period and usually
requires immediate retransplantation. Thrombosis of the portal vein or inferior
vena cava is rare.
The biliary system of the recipient is reconstructed in one of two ways (see
Fig. 58-4). If the patient has no intrinsic disease of the bile duct, a duct-to-duct

Figure 58-4. Venovenous bypass system in place during the anhepatic phase of the transplant
procedure. Venous blood from the femoral and portal veins is returned to the heart via the axillary
vein. (From Griffith BP, et al. Venovenous bypass without systemic anticoagulation for transplantation
of the human liver. Surg Gynecol Obstet. 1985;160:270. Reprinted with permission.)
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Chapter 58: Liver Transplantation 467

anastomosis (choledochocholedochostomy) is performed over a T tube usually

brought out through the recipient’s native bile duct. The T tube is left on depen-
dent drainage until the patient’s total bilirubin level falls below 4 mg/dL. The tube
is then clamped; it is usually removed as an outpatient procedure approximately
3 months later. Even after this prolonged period of clamping, T-tube removal may
result in either bile peritonitis or a localized bile collection.
In the recent years, T tubes are not being used in OLT. Primary areas to miosis
are being constructed to avoid possible bile ductular complications.
In patients in whom the native bile duct is diseased or judged too small to
accommodate a T tube, the donor bile duct is anastomosed end-to-side to a
Roux-en-Y limb of jejunum (choledochojejunostomy). The Roux-en-Y recon-
struction drains all bile internally. A localized bile collection is usually amenable
to percutaneous drainage, but bile peritonitis requires operative repair of the
leaking common bile duct.
The biliary reconstruction is a frequent cause of early and late postopera-
tive complications. Complications related to either type of biliary reconstruction
are leak, stricture, infection, and formation of gallstones or sludge. Any
patient who is noted to have laboratory evidence of liver dysfunction unrelated to
a rejection episode or who has episodes of cholangitis during the first several
months to years after liver transplantation should be evaluated radiologically or
endoscopically (e.g., ERCP) to ascertain biliary patency and function. If the prob-
lem cannot be resolved percutaneously or endoscopically, operative reconstruction
of the biliary tract may be required, often including the conversion of a choledo-
chocholedochostomy to a Roux-en-Y choledochojejunostomy.
B. Perioperative graft failure. If a transplanted liver fails to function, the only
recourse is retransplantation to prevent complications of fulminant hepatic failure
before cerebral edema and brainstem herniation occur. Graft injury can allow
short-term survival, but retransplantation or death remains the end point.
Currently, the rate of retransplantation in the first 3 postoperative months is 10%
to 20%. There are four general reasons for graft failure:
1. A technically imperfect operation
2. Unrecognized liver disease in the donor liver
3. An ischemic injury to the graft
4. Accelerated rejection
Obvious technical complications account for less than 10% of the primary
graft failures in adults but 30% of those in infants and children. The risk in infants
is inversely related to the patient’s size, and complications are mainly attributable
to vascular thromboses.
Portal vein thrombosis is rare and usually occurs only when the recipient’s
splanchnic venous bed has been altered by a portosystemic shunt, a splenectomy,
or another operation. Early portal vein thrombosis usually requires retransplanta-
tion, but a few patients have been saved by immediate or delayed secondary recon-
struction of the portal vein.
Thrombosis of the hepatic artery may be asymptomatic in 20% to 30% of
instances, and the diagnosis can be made only with the routine use of Doppler
ultrasonography. The complications that can result are serious; they include failure
of the primary graft to function, hepatic infarction, bacteremia, abscess, rupture of
the dearterialized ducts resulting in bile peritonitis orbile leakage and the forma-
tion of biloma within the graft parenchyma.
Later, these biliary duct lesions may form multiple intrahepatic biliary stric-
tures that resemble sclerosing cholangitis. Although secondary rearterialization has
been attempted, retransplantation is usually the only alternative.
The most common cause of postoperative graft dysfunction is ischemic
injury to the donor liver, which may occur during the death of the donor, the pro-
curement operation, or the period of refrigeration. The preservation solution,
which is infused through the portal vein or hepatic artery, allows the safe cold
storage of donor livers for at least 24 hours. The restoration of clotting function
and the absence of lactic acidosis are also important predictors of success of the
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468 Part V: Specific Complaints and Disorders

transplanted liver. Measurements of blood amino acid clearance and other prod-
ucts of intermediary metabolism have been used to distinguish between patients in
whom the new liver is expected to recover and those in whom it is not.
Host immune factors and hyperacute rejection may result in primary failure of
the liver graft. Compared to other transplanted organs such as kidney and heart, the
human liver seems to be more resistant to antibody-mediated injury. Because of this
resistance, liver transplantation is often performed in spite of major blood-group
incompatibilities. However, a progressive and severe coagulopathy that develops
shortly after hepatic revascularization should arouse suspicion of an accelerated
rejection.
C. Nontechnical complications
1. Hypertension is almost universally present in a transplant recipient, especially
in the early postoperative period, and requires aggressive treatment. The cause
of the hypertension is probably multifactorial and includes the use of
cyclosporine. Blood pressure control often requires at least two antihyperten-
sive medications, usually a vasodilator and a beta-blocker. In addition, patients
need diuretics both for blood pressure control and to relieve the ascites that
usually develops after transplantation. Hypertension is usually less severe after
the first 6 months after transplantation, and many patients require no antihy-
pertensive medications by 1 year after the procedure.
2. Infection. Serious bacterial, viral, and fungal infections may occur in “routine”
liver transplantation patients up to several years after the transplant operation.
However, infectious complications are much more common in patients who
require multiple reoperations or who have poor initial function of the trans-
planted liver. Therefore, fever in any posttransplant patient requires a thor-
ough investigation to rule out infection. The initial workup of fever should
begin with a detailed history and physical examination and appropriate cultures
of blood, urine, and sputum. Suspected bacterial infections should be treated
aggressively with broad-spectrum antibiotics, which are modified when culture
results become available.
Fever may be one of the earliest signs of rejection of the transplanted liver,
and patients experiencing an acute rejection episode may complain of flulike
symptoms. Therefore, the workup of any fever must include a close examina-
tion of the patient’s most recent liver function tests.
Liver transplantation patients do not appear to be more susceptible to
common viral illnesses than other people. However, if the physical examination
reveals oral or cutaneous lesions compatible with either herpes simplex or
herpes zoster, the lesions should be cultured and acyclovir therapy instituted
for at least 2 weeks. When the cause of the fever cannot be identified or the
patient fails to respond to initial treatment, repeat cultures and serum titers for
cytomegalovirus and Epstein-Barr virus should be obtained and compared
to those obtained before transplantation to identify patients with acute viral
infections. Biopsy specimens, especially of liver, skin, and lung, should be cul-
tured and histologically examined for evidence of virus. Any patient with evi-
dence of a severe viral infection should return to the transplantation center for
treatment. Appropriate management includes careful reduction in the patient’s
immunosuppression and treatment with antiviral agents.
Opportunistic infections may occur in the posttransplant patient and
require prompt diagnosis and treatment. Pneumocystis carinii pneumonitis,
rare in the early posttransplantation period, most commonly presents between 3
and 6 months after surgery. In most patients, the presenting symptom is tachyp-
nea. Physical examination and chest x-ray are usually normal initially, but
arterial blood gases reveal moderate-to-severe hypoxemia. All patients with
suspected pneumocystic pneumonia should be started on intravenous trimetho-
prim/sulfamethoxazole and undergo immediate bronchoscopy with bron-
choalveolar lavage to confirm the diagnosis. A dramatic worsening of the
pulmonary status commonly occurs after treatment is initiated, and the patient
may require intubation and mechanical ventilation. Early diagnosis and treatment
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Chapter 58: Liver Transplantation 469

usually result in a relatively brief, limited illness, whereas failure to make the
diagnosis expediently may prove fatal.
Other opportunistic infections include Cryptococcal meningitis, coc-
cidiomycosis, Listeria meningitis, and tuberculosis.
Because a reduction in the dosage of immunosuppressive medications is
essential, a transplant patient with a serious infection should return to the
transplantation center for treatment of the infection. Too rapid or aggressive a
reduction in the immunosuppressive regimen may put the patient at risk for
acute rejection. Full immunosuppressive therapy should be reinstituted as soon
as possible. If full immunosuppression is reinstituted before complete recovery,
however, the infection may recur; on the other hand, failure to resume full
immunosuppressive therapy at the appropriate time may lead to an acute rejec-
tion episode, which could result in loss of the transplanted liver.
3. Rejection. Despite advances in immunosuppression, rejection of the grafted
liver is one of the most common indications for retransplantation. Acute rejec-
tion episodes may occur at any time after transplantation but become less
frequent with time. Severe rejection episodes should be treated at the liver
transplant center, but mild rejection episodes usually can be handled by the
patient’s physician in consultation with the transplant surgeons.
After transplantation, the follow-up of the patient may continue at the
transplantation center or may be done by the patient’s physician. Initially, rou-
tine blood work is performed three times per week, including a complete blood
count with platelet count, electrolytes, blood urea nitrogen, creatinine, aspar-
tate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl
transpeptidase (GGTP), alkaline phosphatase, total and direct bilirubin, and a
cyclosporine trough level. If the patient remains stable, the frequency of routine
blood work may be decreased to once or twice a month by 6 months after
transplantation.
Most acute rejection episodes that occur in the late postoperative period are
due to either too rapid a reduction in immunosuppressive drugs or a decreased
cyclosporine level. The cyclosporine level depends on absorption from the small
intestine and is affected by vomiting, diarrhea, and interaction with other drugs
taken by the patient (e.g., phenytoin [Dilantin], ketoconazole, and rifampin).
Gastroenteritis and diarrheal illnesses may be associated with a rapid fall in the
patient’s cyclosporine level and may result in a severe rejection episode. Therefore,
these patients may require hospitalization for the administration of intravenous
cyclosporine and corticosteroids until the gastrointestinal function returns to nor-
mal. Drug interactions that may affect cyclosporine levels also should be closely
monitored. Patients with mild rejection episodes may be entirely asymptomatic or
may have flulike symptoms. Such episodes are generally diagnosed by a slight ele-
vation in any of the liver chemistry tests; after consultation with the transplant
surgeons, they are usually treated with a single 500- to 1,000-mg bolus of methyl-
prednisolone or with a short course (usually 5 days) of an increased dosage of oral
prednisone. If the liver chemistry tests improve, nothing else may be required
except a temporary increase in the frequency of laboratory tests.
Patients who fail to respond to steroid therapy or respond only tem-
porarily should be returned to the transplant center for additional investiga-
tion and treatment of the suspected rejection episode. The workup includes a
liver biopsy and an ultrasound study of the biliary tract to rule out obstruc-
tion, and Doppler ultrasound to ascertain the patency of the hepatic artery
and portal vein. The liver biopsy may differentiate rejection from cholangitis,
hepatitis, and ischemic injury, all of which may clinically mimic rejection.
Because therapy for most of these disorders is vastly different from treatment
of acute rejection, making an accurate and prompt diagnosis is essential.
Treatment of biopsy-confirmed rejection is initiated with a short course of
high-dose steroids. Patients who fail to respond to this therapy are usually given
a 10- to 14-day course of either antilymphocyte globulin or the monoclonal
antibody OKT3. Repeat liver biopsy to confirm continued rejection and to rule
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470 Part V: Specific Complaints and Disorders

out the other diagnoses should be performed if liver chemistry tests do not
improve after a course of either of these drugs. Patients in whom rejection is
confirmed should be treated with whichever therapy they have not yet received.
Cytomegalovirus hepatitis may develop during the antirejection therapy. A liver
biopsy is necessary to make this diagnosis so that appropriate antiviral therapy
may be initiated.
If repeat biopsy reveals a severely damaged liver secondary to rejection,
additional antirejection therapy is not administered, and the patient is considered
at high priority for retransplantation. Retransplantation should be considered for
any patient who continues to demonstrate severe liver dysfunction despite
adequate therapy for rejection.
Chronic rejection, in contrast to acute rejection, often fails to respond to
any form of antirejection therapy. It is a more indolent process, characterized
by a gradual, progressive, and unrelenting rise in the patient’s liver chemistry
tests. This form of rejection may occur at any time after transplantation, and
most of these patients eventually require retransplantation. Approximately
20% of all liver transplantation patients require retransplantation. The 1-year
survival rate after retransplantation is approximately 50%.
D. Immunosuppression. Most transplant centers use similar immunosuppression
protocols. The primary immunosuppressive agents currently used are cyclosporine
and corticosteroids.
1. Corticosteroids. Adults receive 1,000 mg of methylprednisolone intravenously
after revascularization of the donor liver. The dosage of methylprednisolone is
tapered rapidly over the first 6 days by 40 mg/day until a baseline of 20 mg/day
is reached. By day 6, most patients are able to tolerate oral medications, and
prednisone 20 mg/day is begun. Most adult patients are discharged with this
dosage of prednisone; depending on the frequency and severity of rejection
episodes, the dosage is reduced in 2.5 mg increments in the first year until a
baseline of 5 to 10 mg is reached in adult patients.
2. Cyclosporine and tacrolimus are the two agents used in combination with
prednisone.
a. Cyclosporine is given as a single dose (2 mg / kg IV) before the start of the
transplantation procedure, and the next dose is given immediately postop-
eratively when the patient is in the intensive care unit. If urinary output is
adequate, a dose of 2 mg / kg is administered q8h. The frequency of the
cyclosporine dose of 2 mg / kg may be reduced to twice daily in patients with
marginal urinary output or with prior evidence of renal dysfunction. Oral
cyclosporine is initiated at a dosage of 10 mg / kg twice daily as soon as ade-
quate gastrointestinal function has returned. When oral cyclosporine ther-
apy is begun, the intravenous dose of cyclosporine is gradually reduced and
eventually eliminated. All additional adjustments in dosage are based on
daily cyclosporine trough levels. A cyclosporine level of 1,000 ng /dL by
radioimmunoassay (RIA) is accepted as ideal. The intestinal absorption of
cyclosporine tends to be erratic, and the maintenance of stable blood levels
is sometimes difficult. The cyclosporine level is maintained at a level that is
proportionately lower than 1,000 ng/dL if toxicity develops.
In patients in whom cyclosporine is not well tolerated, it may be nec-
essary to add azathioprine 1.5 to 2.5 mg / kg daily to ensure adequate
immunosuppression. After a stable course of several months, the dosage of
cyclosporine may be reduced gradually to obtain a blood level of 500 to 800
ng /dL by 1 year after transplantation. During the late postoperative period,
it is difficult to predict how much the dosages of immunosuppressive med-
ications can be lowered without causing an acute rejection episode.
However, doses should be maintained at as low a level as possible because
most side effects of immunosuppressive drugs are dose related. Except for
the immunosuppressive regimen, which is usually managed indefinitely by
the transplant surgeon, care is resumed by the referring physician when the
patient returns home.
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Chapter 58: Liver Transplantation 471

b. Side effects. The most common side effects directly related to cyclosporine
are hypertension, nephrotoxicity, hepatotoxicity, hirsutism, gum hyperpla-
sia, and a fine motor tremor.
i. Hypertension. The hypertension may be quite severe initially but
becomes less severe during the first year after transplantation. Often the
referring physician is left with the task of gradually reducing the patient’s
antihypertensive medications during the first year after transplantation.
ii. Nephrotoxicity. Some degree of nephrotoxicity is experienced by most
patients taking cyclosporine, but in most cases it is not clinically signifi-
cant. During the early postoperative period, some degree of nephrotoxi-
city is tolerated because the patient is most vulnerable to severe rejection
episodes during this time. This nephrotoxicity is usually reversible when
the dosage of cyclosporine is reduced. However, patients who require
continued high dosages of cyclosporine because of repeated rejection
episodes might have a significant deterioration in renal function after an
otherwise successful liver transplantation. Azathioprine may be added as
a third immunosuppressive drug in patients in whom severe nephrotoxi-
city develops so that the dosage of cyclosporine may be reduced. In most
liver transplant patients, however, close monitoring of the patient’s renal
function and cyclosporine trough levels allows the cyclosporine dosage
to be adjusted appropriately both to prevent rejection and to avoid sig-
nificant toxicity without the addition of a third drug.
iii. Hepatotoxicity is common when the patient’s cyclosporine level is
greater than 1,200 ng/dL; therefore, it is rarely seen in patients who take
a lower dosage of cyclosporine.
iv. Hirsutism, tremor, and gum hyperplasia. These side effects are less
serious but may be indicative of overimmunosuppression. If clinically
possible, the transplant surgeon may reduce the dose of the immunosup-
pressants. To prevent serious gum disease, all liver transplant patients
should receive frequent dental examinations. Excessive hair growth may
require the use of a depilatory, especially in young female patients with
body and facial hair.
Tacrolimus has similar pharmacologic properties as cyclosporine
and gives similar patient and graft survival rates. It is available as 0.5 mg,
1 mg, and 5 mg capsules for oral use and as a solution 5 mg/mL for par-
enteral use. The principal side effects include nephrotoxicity and neuro-
toxicity, hypertension, hyperbulemia, hyperglycemia, and nausea, vomit-
ing, and diarrhea.
Patients receiving cyclosporine and tacrolimus may develop lym-
phoprolerative disorders.
3. Carcinogenesis. The incidence of cancer is significantly increased in immuno-
suppressed patients. The most common cancers are carcinoma of the cervix,
vulva, perineum, shin, and lip; Kaposi’s sarcoma; and non-Hodgkin’s lym-
phoma. Most lymphomas appear to be related to infection with or reactivation
of the Epstein-Barr virus. In most patients, the presenting problem is fever,
lymphadenopathy, gastrointestinal perforation, obstruction, or hemorrhage.
The treatment of these lymphomas is controversial. Some authorities believe
that reduction of immunosuppression is sufficient, and others recommend
chemotherapy or radiation therapy or both. All physicians involved in the long-
term care of transplantation patients must be aware that these patients are at
increased risk of the development of some cancers (especially lymphomas). Any
patient suspected of having a lymphoma should be evaluated promptly and
referred back to the transplant center.
E. Long-term management of the liver transplant patient. Adult patients’ hospi-
tal stay for OLT is 7 to 14 days and children’s 10 to 20 days. After discharge,
patients are asked to remain near the transplant center for 2 to 6 weeks for inten-
sive monitoring of liver function and immunosuppression. They are also monitored
for the need for nutritional support, antibiotics, and/or antiviral therapy. Initially,
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472 Part V: Specific Complaints and Disorders

outpatient visits occur twice weekly, then weekly for the first month, then less
frequently. Laboratory tests are initially performed weekly, then monthly indefi-
nitely. In the outpatient setting, patient’s primary caregivers need to follow patient’s
symptoms, assess and encourage strict compliance with medications, perform
physical exams and appropriate laboratory testing, including a chemistry panel,
complete blood count, trough levels for cyclosporine, and tacrolimus at the indi-
cated intervals. Patients should be referred to the transplant center if at any time
rejection is suspected.

V. QUALITY OF LIFE. Even though a successful liver transplantation does not return a
patient to “normal” but to a life of indefinite immunosuppression, the operation
allows patients a chance for long-term survival and a much more productive lifestyle
than they experienced during the late stages of their liver disease. Most patients are
able to return to work in 3 to 6 months after OLT. Active physical fitness programs
and psychotherapeutic support facilitate patients’ return to normal daily activities.

Selected Readings
Alexander JW, et al. The influence of immunomodulatory diets on transplant success and
complications. Transplantation. 2005;79:460–465.
Clavien PA, et al. Strategies for safer liver surgery and partial liver transplantation. N Eng
J Med. 2007;356:1545–1550.
Di Bisceglie A. Pretransplant treatments for hepatocellular carcinoma: Do they improve
outcomes? Liver Transplantation. 2005;11:510–513.
Fausto N, et al. Liver regeneration. Hepatology. 2006;43(suppl 1):S45–S53.
Lee J, et al. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol.
2007;5(11):1313–1315.
Levy M, et al. The elderly liver transplant recipient: A call for caution. Ann Surg. 2001;
233:107.
Mantel HT, Heimbach JK, et al. Vascular complications after orthotopic liver transplantation
following neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl. 2006;82.
Middleton PF, et al. Living donor liver transplantation—adjust donor outcomes: a
systematic review. Liver Transpl. 2006;12:24–30.
Pomfret EA, et al. Liver and intestine transplantation in the United States. Am J Transpl.
2007;7:1376–1389.
Tan HP, et al. Adult living donor liver transplantation: Who are the ideal donor and
recipient: J Hepatol. 2005;43:13–17.
Tillman HL. Successful orthotopic liver transplantation. Gastroenterology. 2001;120:1561.
VanThiel D, et al. Liver transplantation: What the non-hepatologist should know. Pract
Gastroenterol. 2001;25(4):46.
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ANOREXIA NERVOSA AND 59

BULIMIA NERVOSA

A norexia nervosa and bulimia nervosa are eating disorders that are distinct but
related syndromes that have in common an intense preoccupation with food. Patients with
anorexia nervosa are characterized by a fear of becoming obese, disturbance in body
image, anorexia, extreme weight loss, and amenorrhea. On the other hand, bulimia is
characterized by periods of binge eating, alternating with fasting; self-induced vomiting;
and the use of diuretics and cathartics. Bulimic behavior is seen in some patients with
anorexia.

I. EPIDEMIOLOGY. Eating disorders affect an estimated 5 million Americans every year.

It is estimated that about 6% to 10% of all young women have an eating disorder.
Eating disorders typically run in adolescent girls or young women; however, 5% to
15% of cases of anorexia and bulimia nervosa occur in young boys and men. The age
of onset most commonly is the teenage years, but these diseases also occur in young
children and in older adults (e.g., after age 40).

II. ETIOLOGY. The cause of these disorders has been attributed in part to the great
emphasis our society places on thinness. However, the disorders are caused by a com-
bination of genetic, neurochemical, psychological, and sociocultural factors.
Despite profound weight loss, patients with anorexia nervosa usually regard
themselves as being too fat. They may be reluctant to admit this and, in fact, often
agree to increase their food intake when prompted by relatives and friends. However,
they typically continue to avoid food, indulge in excessive physical exercise, and con-
sume medications to inhibit appetite and promote diuresis and catharsis.
Emotionally, the anorectic patient tends to be isolated and shuns relationships,
whereas the bulimic patient is likely to be outgoing and sociable. Weight may
fluctuate in bulimics because of the alternate food binging and purging, but the low
points in weight usually do not reach the point of dangerous weight loss that some-
times occurs in anorectics.

III. COMPLICATIONS AND CONSEQUENCES. Starvation is the most serious complica-

tion of anorexia nervosa. Mortality in excess of 5% has been estimated, but this fig-
ure may reflect the experience in large referral centers that deal with the most severe
cases. Amenorrhea is common, and other organ system abnormalities may develop
(Table 59-1). Particularly worrisome are the cardiac arrhythmias, diuretic-induced
changes in electrolytes, and complications of vomiting, such as gastric and esophageal
rupture and aspiration pneumonia.

IV. CLINICAL PRESENTATION. The diagnosis of anorexia nervosa or bulimia should be

considered when a young woman has had severe weight loss but denies that anything
is wrong. A preoccupation with weight and food, distortion of body image, or any of
the characteristics mentioned previously strengthens the suspicion.
The physical examination often is normal, unless a serious complication, such as
cardiac arrhythmia or aspiration pneumonia, has developed. Patients with anorexia
nervosa characteristically are thin or even emaciated, whereas bulimics range from
underweight to overweight.

473
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474 Part V: Specific Complaints and Disorders

Medical Complications of Anorexia Nervosa

TABLE 59-1
and Bulimia Nervosa

Organ system Complication

General Dry skin and hair, hair loss, altered temperature regulations
Cardiovascular Hypotension, abnormal electrocardiogram: bradycardia,
low voltage, prolonged Q interval, arrhythmias, mitral
valve prolapse, cardiomyopathy
Renal Edema, decreased glomerular filtration rate, increased
blood urea nitrogen level, renal calculi
Endocrine/Metabolic Electrolyte abnormalities, hypoglycemia, hypomagnesemia,
hyperphosphatemia, euthyroid sick syndrome, delay in
puberty, menorrhea, infertility, decreased estradiol and
testosterone, lipid abnormalities, osteoporosis
Gastrointestinal Constipation, rectal prolapse, decreased intestinal motility,
esophagitis, Mallory-Weiss tear, gastric dilatation,
delayed emptying, elevated liver enzymes, elevated
amylase level
Hematologic Anemia, leukopenia, thrombocytopenia, elevated
prothrombin time
Pulmonary Aspiration pneumonia
Neurologic Peripheral neuropathy

V. DIFFERENTIAL DIAGNOSIS. Clearly, other disorders that cause anorexia, weight loss,
or vomiting must be considered. Crohn’s disease, which typically begins in adolescence
or young adulthood, can present with many of the signs and symptoms of anorexia
nervosa. Malabsorption syndromes (see Chapter 31) also can cause profound weight
loss and diarrhea (steatorrhea). Neoplasia, unusual in the age group under considera-
tion, may also be considered. Finally, metabolic, endocrinologic, cardiovascular, renal,
pulmonary, and hematologic disorders must be considered when appropriate. The
complications of anorexia nervosa or bulimia may mimic those conditions.

VI. Diagnostic studies are performed in patients suspected of having anorexia nervosa
or bulimia for two reasons: to document the severity and complications of the disease
and to exclude other disorders. Thus a complete blood count, serum electrolytes,
serum proteins, liver tests, and renal function tests should be obtained. Examination
of the entire gastrointestinal tract by sigmoidoscopy, barium enema or colonoscopy,
and barium swallow–upper gastrointestinal– small-bowel x-ray series may be done. If
vomiting persists, upper gastrointestinal endoscopy and esophageal motility testing
are appropriate in most patients because of the high frequency of Crohn’s disease, gas-
trointestinal motility disorders, and other conditions in patients originally thought to
have anorexia nervosa. Studies for the evaluation of diarrhea or malabsorption may
be indicated in some patients.

VII. TREATMENT. Typically, anorectic patients deny the severity of their illness and evade
adequate psychiatric and medical care or fail to comply with the treatment regimen.
Bulimic patients are more motivated to seek treatment but do not tolerate therapeutic
regimens that fail to give immediate relief of symptoms.
Treatment includes improvement of medical and nutritional status, reestablish-
ment of healthful patterns of eating, and identification and resolution of psychosocial
precipitants of the disorder. Most patients are treated on an outpatient basis; however,
some patients may require inpatient medical and psychiatric care. Rapid weight loss,
intractable purging, severe electrolyte imbalances, cardiac disturbances, and a high
suicide risk are some of the indications for inpatient care.
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Chapter 59: Anorexia Nervosa and Bulimia Nervosa 475

A. Restoring adequate nutrition is essential to effective treatment. This may be

accomplished on an outpatient basis in some instances, but hospitalization may
be necessary. Some patients respond to a system of goals and rewards, that is, set-
ting goals in terms of food intake each day and rewarding success with privileges.
Malnutrition and protein deficiency may be associated with impairment of pan-
creatic exocrine function and mucosal lactase deficiency. Thus, initial oral feed-
ings may result in diarrhea and failure to respond unless lactose is omitted and
food is administered in small amounts. Severely malnourished patients may
require enteral or parenteral nutrition, with special attention to correction of elec-
trolyte and metabolic disorders. Vitamin supplementation should be provided as
well as calcium 1,000 to 1,500 mg and vitamin D 400 IU per day to prevent
osteopenia and osteoporosis.
B. Psychiatric therapy and pharmacotherapy. Several psychiatric methods have
been used, including individual psychotherapy, group therapy, and family therapy.
Psychodynamic psychotherapy with concomitant use of behavioral strategies to
control symptoms has been found to be effective. Education of the patient’s family
and enlisting their support in the treatment increases the chances of success.
Psychopharmacologic therapy is moderately effective in treating bulimia nervosa,
less so anorexia nervosa. The most effective and studied drugs are the serotonin
reuptake inhibitors (SSRIs), such as fluoxetine hydrochloride (Prozac) 20 to 80 mg
per day, and sertraline hydrochloride (Zoloft) 20 to 80 mg per day. Desipramine
hydrochloride 50 to 300 mg per day has also been beneficial; however, it is con-
traindicated for patients with Q-T interval prolongation and for those taking other
tricyclic antidepressants.

Selected Readings
Becker AE, et al. Eating disorders. N Engl J Med. 1999;340:1092.
Gard ME, et al. The dismantling of a myth: A review of eating disorder and socioeconomic
status. Int J Eat Disord. 1996;20:1.
Kohn MR, et al. Cardiac arrest and delirium: Presentations of the refeeding syndrome in
severely malnourished adolescents with anorexia nervosa. J Adolesc Health. 1998;22:239.
Pike KM, et al. Ethnicity and eating disorders. Psychopharmacol Bull. 1996;32:265.
Vitiello B, et al. Research on eating disorders: Current status and future of prospects. Biol
Psychiatry. 2000;47:777.
Walsh BT, et al. Medication and psychotherapy in the treatment of bulimia nervosa. Am J
Psychiatry. 1997;154:523.
79466_CH60.qxd 1/2/08 6:15 PM Page 476

60 OBESITY

I. EPIDEMIOLOGY. Obesity has become an epidemic throughout the world, even in the
Third World countries. In the United States it is estimated that three of five American
adults are overweight or obese and the cost of obesity is in excess of $100 billion
annually. In the last 35 years, the prevalence of obesity has more than doubled in the
United States. The prevalence of obesity is particularly high in many ethnic minority
women (e.g., African American, Mexican American, Native American, Pacific Islander
American, Puerto Rican, and Cuban American). Obesity, in fact, is equal to tobacco
use as a public health hazard, contributing to more than 500,000 premature deaths
annually and is associated with a twofold increase in mortality. Obesity is a major
health problem in young adults and children. In minority populations, up to 30% to
40% of the children and adolescents are overweight.

II. DEFINITION. Obesity is defined as a complex multifactorial chronic disease that

develops from an interaction of genotype and environment. The type of fat accumu-
lated and the site where the fat is deposited has different health implications and
require different approaches to management. The precise amount of body fat mass
that causes medical complications depends on patient’s gender, body fat distribution,
and weight (fat) gain since early adulthood, level of fitness and genetic factors.
A. Body mass index. Table 60-1 represents the relationship between weight and
height. Body mass index (BMI) is calculated as weight in kilograms divided by
height in square meters or as weight in pounds multiplied by 704.5 and divided
by height in square inches. The National Institutes of Health has issued guidelines
for the classification of weight status by BMI that separates patients by risk:
Those with a BMI of 25.0 to 29.9 kg /m2 are considered overweight; those with a
BMI more than 30 kg /m2 are considered obese. Extreme obesity is defined as
a BMI more than 40 kg /m2 and carries a much higher risk for morbidity and
mortality. The optimal BMI to minimize the consequences of obesity-related dis-
eases is probably in the range of 19 to 21 kg /m2 for women and 20 to 22 kg /m2
for men. It is reported that American adults, especially women, who weigh 15%
less than their age-matched, normal-weight peers have a significant reduction in
projected mortality. Additional factors such as fat distribution and recent weight
gain also modify the risk within each BMI category. Persons with increased
abdominal fat have increased risk for hypertension, ischemic heart disease, dys-
lipidemia, diabetes mellitus, and insulin resistance syndrome over those with
increased gluteal and femoral fat.
Weight gain during adulthood is an additional risk factor for medical com-
plications. Weight gain of 75 kg in body weight since the age of 12 to 20 years
increases the relative risk for cholelithiasis, diabetes mellitus, hypertension, and
ischemic heart disease.
B. Waist circumference correlates adequately with abdominal fat distribution.
Deposition of fat in the abdomen, particularly if it is out of proportion to fat
distribution elsewhere in the body, represents a health risk for morbidity and
mortality that is independent of being overweight or obese. Measuring waist
circumference, best taken at the level of the umbilicus with the patient in the supine
position, is a reasonable method for assessing a patient’s health risk and monitor-
ing weight-reduction interventions (Table 60-2).

476
 TABLE 60-1 Body Mass Index
79466_CH60.qxd

BMI
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
1/2/08

Height Body Weight

(in.) (lb)

58 91 96 100 105 110 115 119 124 129 134 138 143 148 153 158 162 167
59 94 99 104 109 114 119 124 128 133 138 143 148 153 158 163 168 173
6:15 PM

60 97 102 107 112 118 123 128 133 138 143 148 153 158 163 168 174 179
61 100 106 111 116 122 127 132 137 143 148 153 158 164 169 174 180 185
62 104 109 115 120 126 131 136 142 147 153 158 164 169 175 180 186 191
63 107 113 118 124 130 135 141 146 152 158 163 169 175 180 186 191 197
64 110 116 122 128 134 140 145 151 157 163 169 174 180 186 192 197 204
Page 477

65 114 120 126 132 138 144 150 156 162 168 174 180 186 192 198 204 210
66 118 124 130 136 142 148 155 161 167 173 179 186 192 198 204 210 216
67 121 127 134 140 146 153 159 166 172 178 185 191 198 204 211 217 223
68 125 131 138 144 151 158 164 170 177 184 190 197 203 210 216 223 230
69 128 135 142 149 155 162 169 176 182 189 196 203 209 216 223 230 236
70 132 139 146 153 160 167 174 181 188 195 202 209 216 222 229 236 243
71 136 143 150 157 165 169 179 186 193 200 208 215 222 229 236 243 250
72 140 147 154 162 169 174 184 191 199 206 213 221 228 235 242 250 258
73 144 151 159 166 174 179 189 197 204 212 219 227 235 242 250 257 265
74 148 155 163 171 179 184 194 202 210 218 225 233 241 249 256 264 272
75 152 160 168 176 184 189 200 208 216 224 232 240 248 256 264 272 279
76 156 164 172 180 189 193 205 213 221 230 238 246 254 263 271 279 287
77 160 168 177 185 193 202 210 219 227 235 244 252 261 269 278 286 294
78 164 173 181 190 198 207 216 224 233 232 250 259 268 276 285 293 302

To obtain the BMI, locate height on the left, then move across the line to the weight; the BMI will be on the top.
BMI, body mass index.

477
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478 Part V: Specific Complaints and Disorders

TABLE 60-2 Weight-Associated Disease Risk

Waist circumference
women 88 cm or
Body mass 35 in. Men 102 cm
Weight class index (kg/m2) or 40 in.

Extreme obesity
40 Extremely high risk

Obesity II
35.0–39.9 Very high risk
Obesity I
30.0–34.9 High risk
Overweight
25.0–29.9 Increased risk
Normal 18.0–24.9 Increased risk
Underweight 18.5 Increased risk

C. Waist-to-hip ratio (WHR) is another measurement that may be helpful in assess-

ing the risk of morbidity and mortality in relation to excess weight. The waist cir-
cumference is measured at the level of the umbilicus with the patient in the supine
position and the hip circumference should be measured at the maximal girth
around the buttocks. The WHR is calculated as:
WHR
waist circumference (cm or in)/hip circumference (cm or in)
A WHR of more than 0.95 for males and more than 0.80 for females is asso-
ciated with an increased risk of morbidity and mortality.

III. PATHOGENESIS. Both genetic and environmental factors contribute to body size.
Genetic background can explain up to 40% of the variance in body mass in humans.
However, the marked increase in the prevalence of obesity in the last 20 years cannot
be attributed to genetic change and may be caused by alterations in the environment,
such as sleep deprivation, increased stress at work and home, lack of regular meal times,
and choices of foods, i.e., fast food versus mediterranian-type diet.
Simplistically, obesity originates from ingesting more energy and calories than is
expended over a long period of time. The excess ingested calories are stored as fat. Even
small, but persistent differences between energy intake and energy expenditure can lead
to large increases in body fat. For example, ingestion of only 5% more calories than
expended could result in the accumulation of about 5 kg of adipose tissue in one year.
Ingestion of 7 kcal/day more than expended over 30 years can lead to an increase of 10
kg body weight, which is the average amount of weight gained by American adults from
25 to 55 years of age.
Technological advances have led to changes in lifestyle that favor a positive
energy balance due to an increased availability and palatability of inexpensive energy-
dense foods, decreased daily physical activity because of labor-saving devices, changes
in job-work patterns, and accessibility to mechanical transportation. Persons with
certain genetic backgrounds are particularly predisposed to weight gain when they are
exposed to this “modern” lifestyle. For example, Pima Indians living in reservations
in Arizona have a much greater prevalence of obesity and diabetes mellitus than their
genetic counterparts who live in rural areas of Mexico.
The modern American diet of fast food and beverages are high in fat and calo-
ries and low in nutritional value. An estimated 60% to 90% of Americans are under-
nourished meaning that despite excessive caloric intake, they do not meet their daily
recommended dietary allowances (RDAs) in one or more food groups. In addition to
increased caloric intake, only about 9% of men and 3% of women exercise vigorously
on a regular basis as part of their leisure time activities.

IV. MEDICAL COMPLICATIONS ASSOCIATED WITH OBESITY. Obesity is a significant

risk factor for many medical diseases, impaired quality of life, and premature
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Chapter 60: Obesity 479

TABLE 60-3 Obesity-Associated Medical Complications

Cardiovascular Hypertension, congestive heart failure, pulmonary hypertension,

coronary artery disease, arrhythmia, ischemic stroke, venous
stasis, deep vein thrombosis, pulmonary embolism
Pulmonary Pulmonary hypertension, sleep apnea, obesity-hypoventilation
syndrome
Gastrointestinal Ventral hernia, gastroesophageal reflux, gallstone, steatohepatitis
Musculoskeletal Osteoarthritis, lower-back problem, gout
Endocrine-metabolic Diabetes mellitus, insulin resistance, dyslipoproteinemia
(hypertriglyceridemia, hypercholesterolemia)
Genitourinary Menstrual dysfunction, infertility, complication of pregnancy,
urinary stress incontinence
Postoperative risk Deep vein thrombosis, pulmonary embolism, atelectasis,
and pneumonia
Cancer Breast, uterus, prostate, colon, gallbladder, cervix
Psychiatric Social stigmatization, psychoemotional disorder

death (Table 60-3). In addition, obese individuals experience depression, frustration,

insecurity, and other negative feelings because of the way society reacts to them and
the way they feel about themselves.

V. THERAPY
A. General principles. Table 60-4 lists the key principles involved in the therapy of
obesity. Americans spend in excess of $70 billion a year on commercial weight-loss
products. Most persons lose weight on these diets, but unfortunately within 1 to
5 years the weight is gained back with extra pounds.
Obesity is a chronic illness and requires long-term management for long-
term success. Behavior modification is necessary for long-term lifestyle changes.
Dietary and nutritional education is also very important. Patients should be
encouraged to lose weight in a systemic and modest way through increased insulin
sensitivity, decreased blood pressure and blood lipid levels, and reduction of fatty
infiltration of the liver.
Caloric reduction needs to be individualized based on the individual’s age and
comorbid risk factors. A useful formula for losing about a pound a week is as follows:
Current weight in pounds  13 kcal  500 kcal  daily caloric requirement
Reduction of fat intake is essential in a successful weight-reduction pro-
gram. Many patients will do well by reducing their total dietary fat intake to 10%
to 20% of their total caloric intake (about 20–30 g of total dietary fat daily). Most
commercial weight loss programs limit caloric intake to 800 to 1,200 calories a
day. When followed carefully, these programs will induce a weight loss of 0.5 to
2.0 lbs a week for up to 30 weeks.

TABLE 60-4 Principles of Weight Reduction and Maintenance

1. Long-term weight loss and management 4. Behavior modification

2. Gradual and modest weight loss 5. Physical activity
in increments 6. Pharmacotherapy
3. Nutrition education 7. Surgery
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480 Part V: Specific Complaints and Disorders

Many “fad diets” have little merit. Some of these diets may be actually harm-
ful. For example, avoiding carbohydrates will induce ketosis; excessively high pro-
tein intake may adversely affect the kidneys and accelerate calcium loss from
bones, thereby promoting or enhancing osteoporosis. In addition, reduced caloric
intake may lead to micronutrient deficiencies that impair metabolic fitness.
The assistance of a dietitian is very important. The National Registry of
Dietitians may be contacted for recommendations of a dietitian in patients’ living
areas (telephone: 1-800-366-1655). Diet advice should include encouraging
patients to eat three meals a day, avoid snacking between meals, avoid energy-
dense and high-fat foods, and increase the intake of fruits and vegetables.
Physical activity is important for long-term weight management and
improved health. Physical activity should be increased slowly over time. Studies
suggest that about 80 minutes per day of moderate-intensity exercise (e.g.,
brisk walking or 35 minutes per day of vigorous activity such as fast bicycling
or aerobic exercise) is needed for long-term weight maintenance after initial
weight loss has been achieved. Physical activity does not necessarily have to be
part of a structured exercise program. Increasing daily lifestyle activities is just
as effective in maintaining weight loss as participating in an aerobic program
exercise.
Recent data indicate that weight-resistance training appears to be the most
beneficial form of exercise for successful weight management. By improving
the integrity of existing muscle or by developing muscle mass, this type of exercise
increases overall metabolism and enhances the oxidation of fat as fuel. These
effects make long-term weight control far more likely.
B. Very-low-calorie diets (VLCDs) or protein-sparing diets are proven, safe
alternatives to starvation for significant sustained and progressive weight loss.
These diets deliver a total daily caloric intake of 400 to 800 calories. Successful
and safe programs include a daily intake of 0.8 to 1.0 g of protein per kilogram of
desirable body weight or about 70 to 100 g of protein and at least 45 to 50 g of
carbohydrate to minimize nitrogen losses and ketosis, respectively. All VLCDs
require careful physician supervision and close patient monitoring. Generally,
weight loss is rapid and progressive for several weeks to months. After about
6 months, weight loss slows and plateaus and further weight loss becomes difficult
to achieve. Unfortunately, once the VLCD is discontinued, initial weight-loss main-
tenance is also difficult to sustain. Incorporation of regular exercise and lifestyle
changes improve the likelihood of sustaining the weight loss. Intermittent use of
VLCD products or meal substitutions along with restrained eating patterns offers
considerable promise.
C. Pharmacotherapy. It is extremely difficult to achieve and sustain significant
reductions in weight and body fat in obese patients without pharmacotherapy or
VLCDs. Pharmacotherapy can help selected patients maintain long-term weight
loss, but it should not be considered a short-term treatment approach. Obesity is a
chronic disease and patients who respond to drug therapy usually regain weight
when the drug therapy is stopped. Also, the effectiveness of pharmacotherapy may
diminish with time. It is of paramount importance that pharmacotherapy be cou-
pled with dietary, lifestyle, and behavioral changes.
1. Sibutramine hydrochloride maleate (Meridia) is a relatively new drug that
was approved by the U.S. Food and Drug Administration (FDA) for long-term
use in 1997. It is a monoamine reuptake inhibitor that was initially developed as
an antidepressant to prevent the reuptake of serotonin, dopamine, and norepi-
nephrine; thus, it synergistically promotes enhanced satiety and a reduction in
food intake. In most patients, it induces a dose-dependent reduction in weight.
The drug is available in capsule form in once-daily doses of 5, 10, and 15 mg. In
one study, at 1 year, 39% of patients randomized to sibutramine hydrochloride
maleate (15 mg per day) lost 70% of their initial body weight compared to 9%
of those randomized to receive placebo. Based on clinical trials, it appears to be
safe. With long-term use, parallel to the weight loss, successful reduction in obe-
sity associated comorbid conditions has also been observed.
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Chapter 60: Obesity 481

The most common side effects associated with sibutramine hydrochloride

maleate therapy are dry mouth, headache, constipation, and insomnia. These
were usually mild and transient. Small increases in systolic rate (1–3 mmHg)
and heart rate (4–5 beats per minute) occur in some patients. However, in a very
small percentage of patients, greater increases in blood pressure and pulse may
occur and reduction of dose or discontinuation of the drug may be necessary.
2. Orlistat (Xenical) was approved by the FDA in 1999 for control of obesity.
Orlistat inhibits gastric and pancreatic lipases and impedes the hydrolysis of
dietary triglycerides into fatty acids; consequently, a significant portion of
dietary fat is not absorbed and passes undigested through the small intestine to
the colon for elimination in stool. In clinical trials of Orlistat given in dosages
of 120 mg t.i.d. with meals, at 1 year, 40% of the patients had lost more than
10% of their initial body weight compared with 20% of patients receiving
placebo. Thus, Orlistat was noted to be effective in inducing weight loss and
reducing abdominal adiposity regardless of meal composition. The drug does
not ameliorate hunger or enhance satiety. The side effects include abdominal
cramping, loose stools, and flatulence; however, with a high dietary fat intake,
reducing fat intake to less than 60 g a day eliminates most of these gastroin-
testinal (GI) side effects. A slight decrease in plasma concentration of fat-soluble
vitamins A and D and B-carotene was observed, but their levels remained in the
normal range. Orlistat is contraindicated in patients with chronic malabsorp-
tion or cholestasis. Orlistat is currently available as an over-the-counter medi-
cine (Alli) as 60 mg tablets to be taken per 2 tablets t.i.d.
3. Olestra is a fat substitute that consists of six to eight fatty acids esterified to a
sucrose molecule. Olestra resembles fat (butter) in texture and taste, but it is not
hydrolyzed by the lipolytic enzymes of the GI tract and is excreted unchanged
with stool. It is commercially used in the production of potato chips and is also
marketed as a butter substitute; thus, the drug may help patients reduce their fat
intake by satisfying the taste for butter or fat.
D. Surgery (bariatric surgery) is the most effective approach for achieving weight
loss in extremely obese patients (BMI
40 kg/m2) or patients with a BMI of 35 to
40 kg/m2 and obesity-related diseases who are unlikely to lose weight with non-
surgical therapy. Patients need to be well enough to have acceptable surgical risks
and are able to comply with long-term follow-up treatment.
The goal of bariatric surgery is to either reduce the size or bypass the stom-
ach and part of the small intestine (SI) to enhance satiety and create malabsorption.
1. Surgical procedures. There are three main categories of bariatric surgery:
a. Restrictive surgery involves changing the GI anatomy to limit food intake
with no interference to the absorptive process (i.e., gastric stapling, verti-
cal banded gastroplasty ( VBG), Silastic ring gastroplasty, horizontal
gastroplasty, gastric banding, and adjustable silicone gastric band).
b. Malabsorptive surgery involves changes in GI anatomy to impair the
absorption of calories and nutrients (i.e., biliopancreatic diversion with or
without duodenal switch (BPC) and jejunoileal bypass [no longer per-
formed due to causing cirrhosis of the liver]).
c. Combined restrictive and malabsorptive surgery involves changes in GI
anatomy to limit food intake as well as impair absorption of calories and
nutrients (i.e., Roux-en-Y gastric bypass, transected vertical gastric
bypass, distal Roux-en-Y gastric bypass, and intestinal bypass).
The most commonly used bariatric surgery types are gastric banding
and gastric bypass operation. Laparoscopic approach has become the pre-
ferred method.
2. Surgery types
a. Gastric bypass involves the stapling of the upper stomach into a vertical or
horizontal 15- to 25-mL pouch and creating an outlet to the SI. Surgery is
reversible and can be performed laparoscopically or with the open approach.
The gastric outlet joins with the limb of the SI containing bile and pancreatic
juice. The standard SI Roux limb is 75 cm long, the SI limb is 150 cm, and
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482 Part V: Specific Complaints and Disorders

distal gastric bypass is
150 cm. Weight loss occurs due to early satiety
from the small gastric size and induction of mild malabsorption. If weight
loss is not satisfactory the standard Roux gastric bypass can be revised to a
very long limb Roux-en-Y procedure.
b. Laparoscopic mini-gastric bypass (LMGB) is a modification of gastric
bypass with a longer lesser curvature tube.
c. Gastric banding or laparoscopic adjustable gastric banding (LABG) is usu-
ally performed laparoscopically. It involves placement of a “band” high on the
stomach creating a small pouch of 15-mL capacity without cutting the stomach.
Adjustments are made up to six times per year to limit gastric capacity.
LABG is reversible by the removal of the band, tubing and port or it
can be revised by removal of the device and performance of a restrictive-
malabsorptive or malabsorptive procedure.
d. Vertical banded gastroplasty ( VBG) is usually performed using an open
surgical approach and involves the creation of a small 15-to 25-mL linear
gastric pouch along the lesser curve of the stomach with an outlet of 0.75
to 1.25 cm in diameter. This procedure may be revised by the removal of
the ring or the band allowing the outlet to dilate. In patients with inade-
quate weight loss, VGB may be revised by conversion to gastric bypass or
duodenal switch.
3. Results
a. Benefits. Weight loss is greater with gastric bypass (about 70 kg vs. 30 kg
in 12 months) than with gastroplasty or gastric banding procedures.
Postoperatively, patients experience prolonged satiety and have improved
well-being, attractiveness, self-regard, and social or physical activity. There
is a significant reduction in the incidence of diabetes, hyperlipidemia, hype-
ruricemia, sleep apnea, hypertension, and mortality rate. In addition, there
are significant risk reductions for developing cardiovascular, malignant,
endocrine, infectious, psychiatric, and mental disorders.
b. Complications. Short-term complications are those expected as in any
postoperative period.
Long-term complications may include anastomotic ulceration, bleed-
ing, stenosis, and possible increase in certain GI symptoms such as diarrhea.
Deficiencies in certain vitamins and nutrients and neurologic and psychiatric
complications may occur. Patients should be monitored for vitamin and nutri-
ent deficiencies and should be placed on replacement therapies as needed.

Selected Readings
Balasekasan R, et al. Positive results in tests for steatorrhea in person consuming olestra
potato chips. Am Intern Med. 2000;132:279.
Bardia A, et al. Diagnosis of obesity by primary care physicians and impact on obesity
management. Mayo Clin Prac. 2007;82(8):927–932.
Bloomberg RD, et al. Nutritional deficiencies following bariatric surgery: What have we
learned? Obes Surg. 2005;15(2):145–154.
Buchwald H, et al. Bariatric surgery: A systematic review and meta-analysis. JAMA. 2004;
292(14):1724–1737.
Choban PS, Dickerson RN. Morbid obesity and nutrition support: is bigger different?
Nutr Clin Pract. 2005;20:480–487.
Christou NV, et al. Surgery decreases long-term mortality, morbidity and health care use in
morbidly obese patients. Ann Surg. 2004;240(3):416–423.
DeMaria EJ. Bariatric surgery for morbid obesity. N Eng J Med. 2007;356:2176–2183.
Dixon AF, et al. Laparoscopic adjustable gastric banding induces prolonged satiety:
A randomized blind crossover study. J Clin Endocrinol Metab. 2005;90(2):813–819.
Flum DR, et al. Impact of gastric bypass on survival: A population-based analysis. J Am
Coll Surg. 2004;199(4):543–551.
Inabnet WB, et al. Laparoscopic Roux-en-Y gastric bypass in patients with BMI 50:
A prospective randomized trial comparing short and long limb lengths. Obes Surg.
2005;15(1):51–57.
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Chapter 60: Obesity 483

Koffman BM, et al. Neurologic complications after surgery for obesity. Muscle Nerve. June
22, 2005 (Epub ahead of print).
Kruger J, et al. Attempting to lose weight: specific practices among adults. Am J Prev Med.
2004;26:402–406.
Lee WJ, et al. Laparoscopic vertical banded gastroplasty and laparoscopic gastric bypass:
A comparison. Obes Surg. 2004;14(5):626–634.
Lujan JA, et al. Laparoscopic versus open gastric bypass in the treatment of morbid
obesity: A randomized study. Ann Surg. 2004;239(4):433–437.
Madan A. Laparoscopic bariatric surgery. US Gastroneterol Rev. 2007;1:29–331.
Maggard MA, et al. Meta-analysis: Surgical treatment of obesity. Ann Intern Med.
2005;142(7):547–559.
Malone AM. Permissive underfeeding: Its appropriateness in patients with obesity, patients
on parenateral nutrition, and non-obese patients receiving enteral nutrition. Curr
Gastroenterol Rep. 2007;9(4):317–322.
Padwal RS, et al. Drug treatments for obesity: orlistat, sibutramine, and rimonabant.
Lancet. 2007:369:71–77.
Perrin EM. Preventing and treating obesity: pediatricians’ self-efficacy, barriers, resources,
and advocacy. Ambul Pediatr. 2005;5:150–156.
Redinges RN. The pathophysiology of obesity and its clinical manifestations. Gastroenteric
Hepatol. 2007;3(11):856–874.
Sjostrom L, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric
surgery. N Engl J Med. 2004;351(26):2683–2693.
Slater GH, et al. Serum fat-soluble vitamin deficiency and abnormal calcium metabolism
after malabsorptive bariatric surgery. J Gastrointest Surg. 2004;8(1):48–55.
Wang W, et al. Short-term results of laparoscopic mini-gastric bypass. Obes Surg. 2005;
15(5):648–654.
Yan LL, et al. Midlife body mass index and hospitalization and mortality in older age.
JAMA. 2006;295:190–1989.
79466_Index.qxd 1/2/08 6:16 PM Page 484

INDEX

Page numbers followed by “f” indicate figures; those followed by “t” indicate tables.

A Abdominal tenderness
AAs. See Amino acids in acute abdomen, 81
AAT (
1-antitrypsin deficiency) examination for, 8
Abdomen Abetalipoproteinemia, and malabsorption,
acute. See Acute abdomen 219–220
areas of, 6, 7f Abscesses
auscultation of, 6–7 anorectal, 284
percussion and palpation of, 708 pancreatic, 321
Abdominal angina, 264–265 Absorbents in diarrhea treatment, 193
Abdominal blunt trauma, in pancreatitis, Acalculous cholecystitis, 301–302
308 Acetaldehyde, 389
Abdominal examination, 6–8, 7f Acetaminophen, in alcoholic liver
Abdominal films, 29, 39 disease, 391
of acute abdomen, 82t Acetaminophen hepatoxicity, 401–405
of acute pancreatitis, 312 Acetylcysteine, in fulminant hepatic
of ascites, 443 failure, 109
of diverticulitis, 238 Achalasia, 144, 151, 152f
of inflammatory bowel disease, 248, treatment of, 153
250f Acid clearance in GERD, 129
of jaundice, 345 Acid ingestion, 100t, 101
of malabsorption, 210, 210f AcipHex (rabeprazole sodium), 136
of small-intestinal neoplasms, 222 Acquired deficiency of glucuronyl
of toxic megacolon, 259 transferase, 342
Abdominal pain, 79–83 Acquired immunodeficiency syndrome
and bloating, 234 (AIDS). See also Hepatobiliary
clinical presentation of, disease in AIDS; Human
79–81 immunodeficiency virus
differential diagnosis of, 79, 80t and cytomegalovirus (CMV), 361–362
in diverticular disease, 239 cytomegalovirus esophagitis (CMV) in,
evaluation of, 81–83, 82t 124
indication for laparoscopy, 27 HSV esophagitis in, 123
in inflammatory bowel disease, 246 idiopathic esophageal ulcer (IEU) in, 125
and intestinal gas, 234 sexually transmitted enteric disorders,
in irritable bowel syndrome, 246 288
in pancreatic cancer, 327 Acticall (ursodeoxycholic acid), 114
in pancreatitis Actos (pioglitazone), 398
acute, 79 Acute abdomen, 79–83
chronic, 318–319 clinical presentation, 79, 81
referred, 79 history, 79, 81
somatic, 79 known disorders, 79, 81
treatment of, 83 pain, 79
in vascular disorders, 264 vomiting, 79
visceral, 79 physical examination, 81

484
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Index 485

differential diagnosis, 79, 80t pathophysiology, 309–310

evaluation and management of the prognostic factors in, 310–311, 310t, 311t
patient, 81–83 treatment of, 313–315
diagnostic paracentesis, 83 Acute respiratory distress syndrome
laboratory studies, 81–82, 82t (ARDS), in fulminant hepatic
radiologic studies, 82–83, 82t failure, 108
treatment, 83 Acute thiamine deficiency, and parenteral
Acute acalculous cholecystitis, 355. nutrition, 73
See also Gallstones Acute toxic hepatitis, 104
Acute calculous cholecystitis, 353–355. Acyclovir (Zovirax), 124, 294
See also Gallstones Adalimumab (Humira), for inflammatory
Acute diarrhea, 187–191. See also disease, 256
Diarrhea Additives to parenteral nutrition solutions,
Acute edematous or interstitial 69–71
pancreatitis, 306 Adefovir dipivoxil, for HBV infection, 374
Acute fatty infiltration of the liver, and Adenocarcinoma, 270–272, 271f, 271t.
parenteral nutrition, 73 See also Colonic polyps;
Acute fatty liver of pregnancy Colorectal cancer; Pancreatic
(AFLP), 114 cancer
Acute gastrointestinal bleeding. See Adenodarcinoma of the esophagus,
Bleeding, gastrointestinal 142, 154
Acute liver failure, 104. See also radiation therapy for, 156
Fulminant hepatic failure Adenomatous polyps, 269. See also
Acute pancreatitis, 306–316. See also Colonic polyps
Chronic pancreatitis ADH. See Alcohol dehydrogenase
complications of, 306–307, 314t Adolph’s Meat Tenderizer, 97
defined, 306 Adult respiratory distress syndrome, 306
acute edematous or interstitial Advanced gastric adenocarcinoma, 176
pancreatitis, 306 Aeromonas hydrophilia, 207
hemorragic or necrotizing Afferent loop syndrome, 182–183
pancreatitis, 306 AFLP. See Acute fatty liver of pregnancy
diagnosis, 311–313 AH. See Autoimmune hepatitis
clinical presentation, 311 Air embolism, in central
diagnostic studies, 311–313 catheterization, 64
differential diagnosis, 313, 313t Alanine aminotransferase (ALT), 335
hyperamylasemia, 311, 312t Albumin, in parenteral nutrition, 71
etiology, 307–309, 307t, 308t Alcohol abuse, and acute abdomen, 81
alcoholism and biliary tract disease, Alcohol consumption, and chronic
307–308, 307t calcifying pancreatitis (CCP), 318
blunt abdominal trauma, 308 Alcohol dehydrogenase (ADH), 387–388
connective tissue diseases, 309 Alcoholic hepatitis (AH), 390, 392. See
drugs, 308t, 309 also Alcoholic liver disease
endoscopic retrograde pancreatography Alcoholic liver disease (ALD), 386–394
(ERCP), 308, 313 clinical course of, 392
hereditary, 309 diagnosis of, 390–392
infections, 309 epidemiology of, 386
metabolic disorders, 308 ethanol metabolism, 386–389
miscellaneous causes, 309 absorption, distribution, and
organ transplantation, 309 elimination, 386–387
postoperative pancreatitis, 308 chemical metabolism, 387–388f, 389
pregnancy, 309 laboratory studies in, 344, 390–391
vasculitis, 309 nutritional factors in, 390
necrotizing pancreatitis, 313 pathogenesis of, 389–390
pancreatic pseudocysts, 315–316 acetaldehyde, 389
complications and treatment, hepatic fibrogenesis, 389–390
315–316 hepatocyte injury, 389
diagnostic studies, 315 relation to alcohol consumption,
pathogenesis, 315 386, 387t
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486 Index

Alcoholic liver disease (contd.) Angiography, 42

treatment of, 392–394 for angiodysplasia, 267
alcohol withdrawal, 392–393 for jaundice, 347
controversial therapies, 393–394 for liver tumors, 456
diet, 392 for pancreatic cancer, 329
liver transplantation, 394 for pancreatitis, 320
strict abstinence from alcohol, 392 for varices, 440
supportive therapy, 392 Annular pancreas, 317
Alcoholism and biliary tract disease, Anorectal disorders, 283–287
307–308, 307t anal fissures, 284
Alcohol withdrawal, 392–393 fistulas and abscesses, 284
ALD. See Alcoholic liver disease hemorrhoids, 283–284
Aldactone (spironolactone), for ascites, proctalgia fugax, 285–286
446 proctitis, 285
Aldehyde dehydrogenase (ALDH), pruritus ani, 286
387–388 rectal prolapse, 285
ALDH. See Aldehyde dehydrogenase sexually transmitted, 286, 288–291
Aldomet (methyldopa), 405 tumors, 286
Alkali ingestion, 99–100, 99t Anorectal examination, 8–9
Alkaline phosphatase level, in gastric Anorectal manometry, 37
adenocarcinoma, 177 in constipation, 241
Alkalosis, in fulminant hepatic failure, 108 Anorectal sexually transmitted disorders,

1-antitrypsin deficiency (AAT), 289, 291
433–436 Anorectal syphilis, 289
background and definition of, 433–436 Anorexia nervosa, 473–475
biochemical studies in, 435 background and definition of, 473
diagnosis of, 435 clinical presentation of, 473
liver biopsy and histopathology in, complications and consequences of,
435–436 473, 474t
liver disease, 435–436 diagnostic studies for, 474
liver transplantation for, 436 differential diagnosis of, 474
phenotype determination, 435 epidemiology of, 473
treatment for, 436 etiology of, 473
ALT. See Alanine aminotransferase and irritable bowel syndrome, 228
Amiloride hydrochloride, for ascites, 446 psychological and emotional aspects in, 10
Amino acids (AA) treatment of, 474–475
branched-chain (BCAAs), 66 psychiatric therapy and
essential, 55 pharmacotherapy, 475
in parenteral nutrition, 64, 66 restoring adequate nutrition, 475
Amiodarone hepatotoxicity, 400–401 Anoscopy, for anal fissures, 284
Amitiza (lubiprostone) Antacids
for constipation, 242 in GERD, 135
for diverticular disease, 238 in peptic ulcer disease, 165
for irritable bowel syndrome, 231 Anthropometric measurements, 49–51,
Amoxicillin 50t, 51t, 52t
for Helicobacter pylori, 173 Antibiotics
in peptic ulcer disease, 161 for diverticulitis, 238–239
Amphotericin B, 122 for hepatic encephalopathy, 110, 451
Ampulla of Vater, 20 for inflammatory bowel disease,
Ampullary carcinoma, 331. See also 254–255
Pancreatic cancer for pancreatitis, 314–315
Anabolic steroids, for alcoholic liver for sexually transmitted enteric
disease, 393–394 disorders, 290t, 291
Anal fissures, 284 for toxic megacolon, 259
Anascopy, in hemorrhoids, 283 Anticholinergic agents, in diarrhea
Angina pectoris, differentiation from treatment, 193
noncardiac chest pain, 152–153 Anticytokine therapy, for alcoholic liver
Angiodysplasia, 267 disease, 393
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Index 487

Antidepressants, for irritable bowel Axillary liver transplantation, 111

syndrome, 231 Azathioprine (Imuran)
Antidiarrheal medications, for inflammatory for autoimmune hepatitis, 410
bowel disease, 257 for inflammatory bowel disease, 254,
Antimicrobial therapy 255, 257
for diarrhea treatment, 193, 194t, 204t Azoles, 121
for enteric infections, 296t Azotemia, and parenteral nutrition, 73
Antioxidants, for alcoholic liver disease, 393 Azotorrhea, 322
Antireflux mechanisms, in AZT (zidovudine), 293
gastroesophageal reflux disease, Azulfidine (sulfasalazine), for inflammatory
126–127 bowel disease, 253, 253t
Antisecretory agents, in diarrhea
treatment, 193 B
Antispasmodics, for irritable bowel Bacillus cereus, 200
syndrome, 230 Bacterial and mycobacterial infections
Antral G-cell hyperplasia, in peptic ulcer in hepatobiliary disease in acquired
disease, 168 immunodeficiency syndrome
Anusol-HC, for hemorrhoids, 283 (AIDS), 298–299
Aortoenteric fistula, 94 in liver transplantation, 468
Appendiceal carcinoid tumors, 225 Bacterial esophagitis, 125
ARDS. See Acute respiratory distress Bacterial gastroenteritis, 199–208. See also
syndrome Gastroenteritis
Arteriae rectae, 26 “enteric” infections, 202–208, 202t
Arterial NH3, 107 Aeromonas hydrophilia, 207
Arterial puncture, in central Campylobacter jejuni and
catheterization, 64 Campylobacter fetus, 202–203
Arteriography, 42 Clostridium difficile, 207–208
for gastrointestinal bleeding, 91 Escherichia coli, 205–206
and noncardiac chest pain, 150 Plesiomonas shigelloides, 207
for small-intestinal neoplasms, 223 Salmonella, 203–204
Arthropathy, in hemochromatosis, 429 Shigella, 204–205
Asacol treatment of, 204t
for inflammatory bowel disease, 253 Yersinia enterocolitica, 206–207
for proctitis, 285 toxigenic bacteria, 199–202, 199t
Ascites, 443–447 Bacillus cereus, 200
causes of, 27 Clostridium botulinum, 201–202
detection in abdominal examination, 8 Clostridium perfringens, 201
Aspartate aminotransferase (AST), 335 enterotoxigenic Escherichia coli
Aspirin (ETEC), 200–201
in occult bleeding, 303 Staphylococcus aureus, 199–200
in peptic ulcer disease (PUD), 161 Vibrio cholerae, 200
Aspirin hepatotoxicity, 401 Vibrio parahaemolyticus, 201
AST. See Aspartate aminotransferase Balloon tamponade, for varices, 441–442
Astrovirus, 199 Balsalazide disodium (Colazal), for
Atabrine (quinacrine hydrochloride), 208 inflammatory bowel disease, 254
Auerbach’s plexus, 140 Bariatric surgery, for weight reduction,
Auscultation 481–482
in abdominal examination, 6–7 Barium-contrast studies
in acute abdomen, 81 for caustic ingestion, 101
Autoimmune hepatitis (AH), 407–411, for gastrointestinal bleeding, 91
408t for malabsorption, 210
Automatic biopsy needles, 31 in small-intestinal neoplasms, 222, 223f
Avandia (rosiglitazone), 398 Barium enema, 40
Avastin (bevacizumab), in metastatic for colonic polyps, 270, 270f
carcinoid tumors, 226 for colorectal cancer, 275, 277
Aventin, 217 for constipation, 241
Axid (nizatidin), in peptic ulcer for diverticulitis, 238
disease, 165 for diverticulosis, 237, 237f
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488 Index

Barium enema (contd.) Biliary tumors, 457–458

for hemorrhoids, 283 carcinoma of the gallbladder (CG), 457
for inflammatory bowel disease, 250, cholangiocarcinoma (CGC), 457–458
251f, 252f Billroth I and Billroth II, for peptic ulcer
for ischemic colitis, 267 disease, 167–168, 180
for occult bleeding, 304 Biochemical data, for nutritional status,
for proctitis, 285 51–52, 52t
for rectal prolapse, 285 Biotin deficiency, and parenteral nutrition,
for toxic megacolon, 259 74
Barium swallow, 39–40 Bismuth subsalicylate (Pepto-Bismol), 193
for dysphasia, 146–147 Bleeding, gastrointestinal, 84–95
for esophageal cancer, 155 in angiodysplasia, 267
for GERD, 131 diagnostic and therapeutic studies, 84,
for HIV, 294 84t, 88–91, 88f, 89f
for HSV esophagitis, 123 barium-contrast radiographic studies,
for noncardiac chest pain, 150 91
Barrett’s epithelium, 134 endoscopy, 88–90
Barrett’s esophagus, 134–135. See also radionuclide scanning, 90–91
Gastroesophageal reflux disease selective arteriography, 91
and esophageal cancer, 157 diverticular bleeding, 239
BCAAs. See Branched-chain amino acids esophageal varices, 91–94, 92f
B-cell lymphomas, and Helicobacter fluid, electrolyte, and blood
pylori, 171, 172 replacement, 86
Belching. See Intestinal gas and bloating in fulminant hepatic failure, 109
Benign tumors, 179 gastric and antisecretory agents, 91
and dysphagia, 142 history of, 84–85
Bentiromide test age of patient, 85
in malabsorption, 211 associated medical conditions, 85
in pancreatitis, 321 ingestion of gastric mucosal
Benzodiazepine receptor antagonists, for irritants, 85
hepatic encephalopathy, 452 vomiting or blood passage per
Bernstein test rectum, 84–85
in GERD, 131 initial management of, 84–88, 85t
in noncardiac chest pain, 149–153 laboratory studies for, 86–87
Bevacizumab (Avastin), in metastatic lower, 84, 84t, 89f, 90
carcinoid tumors, 226 nasogastric (NG) intubation and gastric
Biaxin (clarithromycin), in peptic ulcer lavage, 87–88
disease, 161 in peptic ulcer disease, 161
Bicarbonate, in peptic ulcer disease, 160 physical examination in, 86
Bile acid breath test, for malabsorption, 213 upper, 84, 84t, 88f, 88–90
Bile acid insufficiency, in malabsorption, in vascular-enteric fistulas, 267–268
216–217 Blenderized feedings in enteral
Bile duct stones, 16 nutrition, 56
Bile flow, 349 Bloating. See Intestinal gas and bloating
Biliary colic, 351–352 Blood replacement, in gastrointestinal
Biliary ductal system, 20, 21f bleeding, 86
Biliary obstruction, and pancreatic Blood studies
cancer, 330 in acute abdomen, 81, 82t
Biliary scintigraphy in diverticulitis, 238
for acute calculous cholecystitis, 354 in malabsorption, 209–210
in choledocholithiasis, 356 in small-intestinal neoplasms, 222
Biliary studies, 40–41 Blood urea nitrogen (BUN), 73
Biliary tract, 349 in fulminant hepatic failure, 109
Biliary tract disease (gallstones) in gastrointestinal bleeding, 86–87
in hepatobiliary disease in acquired Bloody diarrhea, 202t. See also Diarrhea
immunodeficiency syndrome Blunt abdominal trauma, in acute
(AIDS), 301–302 pancreatitis, 308
and pancreatitis, 307 BMI. See Body mass index
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Index 489

Body mass index (BMI), 476, 477t Carcinoid tumors, 224–226

Bowel, distribution of air in, 39 appendiceal, 225
Bowel infarction, 83 bronchial, 224
Brachial plexus injury, in central gastric, 224–225
catheterization, 64 metatastic, 225–226
Branched-chain amino acids rectal, 225
(BCAAs), 66 small-intestinal, 225
for hepatic encephalopathy, 451 Carcinoma
Bravo device (wireless pH monitoring), of the gallbladder (CG), 457
37, 132 in the gastric remnant, 183
Breath tests, for Helicobacter pylori, 172 in situ, 271
Bronchial carcinoid tumors, 224 Cardiac disease, and noncardiac chest
Budesonide (Entecort), for inflammatory pain, 149–150
bowel disease, 254 Cardiovascular disorders, in fulminant
Bulimia nervosa, 10, 473, 474, 474t. See hepatic failure, 108
also Anorexia nervosa Carnitine deficiency, and parenteral
BUN. See Blood urea nitrogen nutrition, 73–74
Burns, esophageal dysphasia due to, 142 Catheter care, in parenteral nutrition, 64–65
Catheter embolism, in central
C catheterization, 64
Calcemia, and parenteral nutrition, 73 Catheter infection, in parenteral nutrition,
Calcii viruses, 198 65, 74
Calcium salts (soaps), 306 Caustic ingestion, 99–103, 99t, 100t
Calculus retrieval, 20 acid ingestion, 100t, 101
Calorie requirements, 53–55 alkali ingestion, 99–100, 99t
Calories, in parenteral nutrition, 65 clinical evaluation, 101
Calorie sources, 55 diagnosis of tissue injury, 101–102
Campylobacter fetus, 202–203 therapy, 102–103
Campylobacter jejuni, 202–203, 247–248 CBC. See Complete blood count
Canasa, for proctitis, 285 CCP. See Chronic calcifying pancreatitis
Canasa rectal suppositories, for inflamma- CDCA. See Chenodeoxycholic acid
tory bowel disease, 254 Celebrex (celecoxib), in peptic ulcer
Cancer. See Carcinoid tumors; disease, 161
Carcinoma; Colorectal cancer; Celecoxib (Celebrex), in peptic ulcer
Esophageal cancer; Gastric ade- disease, 161
nocarcinoma; Gastric neoplasms; Celiac disease/gluten-sensitive enteropathy,
Hepatocellular carcinoma (HCC); 217–218, 218t
Tumors; Pancreatic cancer Celiac sprue (CS)
Cancer surveillance and irritable bowel syndrome, 228
in colonic polyps and colorectal cancer, and malabsorption, 217–218, 218t
276–278 in primary biliary cirrhosis, 414
in inflammatory bowel disease (IBD), Central (CPN) or total (TPN) parenteral
260–261 nutrition. See Parenteral nutrition
Candida albicans, 65, 119, 120, 302 Central venous catheter, placement of, 64
gastrointestinal pathogen in HIV- Central venous pressure, 86
infected patients, 292, 293t Central venous pressure catheter, in
in hepatobiliary disease, 300 gastrointestinal bleeding, 86
Candidacy (patient selection) for liver Cerebral edema assessment
transplantation, 461–464, in fulminant hepatic failure, 110–111
462t, 464t in hepatic encephalopathy, 108
Candidiasis, 113 Certolizumab pegol (Cimzia), for
in HIV-infected patients, 119, 292 inflammatory disease, 256
in oral thrush, 119, 120 CGC. See Cholangiocarcinoma
Capsule endoscopy, 21 Chagas’ disease, and esophageal smooth
in occult bleeding, 304 muscle dysfunction, 145
Carafate (sucralfate), 137 Chalamydis trachomatis, 289
in peptic ulcer disease, 166 Chelating agents, 431
Carbohydrates, 47 Chemoprevention of colorectal cancer, 277
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Chemoprophylaxis of traveler’s diarrhea, 195 primary biliary cirrhosis, 411–415

Chemotherapy diagnosis of, 411–413
for colorectal cancer, 275 epidemiology of, 411
for gastric adenocarcinoma, 178 histophathology of, 411
for metastatic carcinoid tumors, 226 prognosis for, 413
for pancreatic cancer, 330 treatment of, 413–415
for small-intestinal neoplasms, 224 primary sclerosing cholangitis, 415–420
Chenodeoxycholic acid (CDCA), 353 definition of, 415
Chest films, 39 diagnosis of, 417–418
in acute abdomen, 82, 82t pathogenesis for, 415–417
in dysphasia, 146 treatment of, 418–420
and noncardiac chest pain, 149–150 Chronic mucoutaneous candidiasis
Chest pain (CMC), 120
in GERD, 130 Chronic pancreatitis, 317–325. See also
noncardiac, 149–153 Acute pancreatitis
defined, 149 background and definition, 317
diagnosis of, 149–152, 150t chronic calcifying pancreatitis (CCP),
differential diagnosis of, 149, 150t, 317–318
152–153 morphology, 317
treatment of, 152–153 pathophysiology, 318
CHI. See Creatinine height index role of alcohol consumption and
Child’s classification in varices, 440t diet, 318
Cholangiocarcinoma (CGC), 416–417, classification, 317–318
457–458 diagnosis, 318–321
Cholangitis, 302 clinical presentation, 318–319
Cholecystitis, 353–356 diagnostic studies, 320–321
and parenteral nutrition, 73 local complications, 321
Choledocholithiasis, 351, 356–357 obstructive chronic pancreatitis, 317
Cholescintigraphy (HIDA scan), for treatment, 321–324
jaundice, 346 adjuvant acid-suppressant therapy, 323
Cholestasis, 342–345, 343t, 345t, 400 bacterial overgrowth, 324
Cholestasis tests, in liver disease, commercial pancreatic enzyme
337–340, 338t preparations, 322, 323t
Cholesterol gallstones, 350–353 diabetes mellitus, 324
Cholestyramine malabsorption, 322–324
for primary biliary cirrhosis, 413 nutritional support, 3224
for terminal ileal disorders, 216 pain management, 321–322
Cholestyramine resin (Questran), 114 pancreatic enzyme supplements,
CHOs. See Concentrated solutions 322–323, 323t
of carbohydrates Chylothorax, in central catheterization, 64
Chromogranin A (CGA) levels, in Cidofovir, 124, 294
metastatic carcinoid tumors, Cimzia (certolizumab pegol), for
225 inflammatory disease, 256
Chronic and recurrent diarrhea, 187, Circulatory shock, 307
190–191. See also Diarrhea Cirrhosis, 386, 391, 392, 437–454. See
Chronic calcifying pancreatitis (CCP), also Alcoholic liver disease;
317–318 Nonalcoholic fatty liver disease
Chronic gastritis, 183 ascites, 443–447
Chronic idiopathic intestinal pseudoob- complications of, 445
struction, and dysphasia, 146 diagnosis of, 443–444
Chronic immune-mediated liver disease, pathogenesis of, 443
407–420 spontaneous bacterial peritonitis
autoimmune hepatitis (AH), 407–411 (SBP), 444–445
treatment of, 409–411 treatment of, 445
types of, 408–409, 408t treatment of refractory ascites, 446–447
chronic hepatitis (CM), 407 background and definition of, 437
causes of, 407, 407t classification of, 437
forms of, 407 collateral circulation (varices) in, 438–439
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Index 491

diagnosis of, 438 Colon

etiology of, 437 foreign bodies in, 98
hepatic encephalopathy, 448–452 and HIV, 293t, 295–297
diagnosis of, 449–450 Colonic diverticulosis. See Diverticular
diagnostic studies for, 450 disease
pathogenesis of, 448–449 Colonic obstruction, in constipation, 240
treatment of, 450–452 Colonic polyps, 269–272. See also
hepatorenal syndrome, 447–448 Colorectal cancer
diagnosis of, 447 adenocarcinoma, 270–272, 271f, 271t
differential diagnosis of, 447 clinical presentation of, 269–270
pathogenesis of, 447 defined, 269
prognosis for, 447 diagnostic studies and screening for, 270
treatment of, 448 familial adenomatous polyposis (FAP),
hypersplenism in, 448 272
pathophysiologic consequences of, 438 Gardner’s syndrome, 272
portal hypertension in, 438, 439t histologic examination of resected
primary biliary cirrhosis, 411–415 polyps, 270
varices, 439–443 pathogenesis for, 269
diagnosis of, 439 Peutz-Jeghers syndrome, 272
prevention of first variceal bleeding polypectomy for, 270
and rebleeding, 442–443 polyposis syndromes, 272, 273t
prognosis for, 439, 440t size of, 269, 269t
treatment of, 439–443 treatment of, 270–272
Cisapride, 137 Turcot’s syndrome, 272
Clarithromycin (Biaxin), in peptic ulcer types of, 269
disease, 161 Colonoscopy. See also Endoscopy, lower
Clarithromycin, for Helicobacter gastrointestinal tract
pylori, 173 for angiodysplasia, 267
Clevudine, for HBV infection, 375 for colonic polyps, 270
Clinical coma scale, 107, 107t for colorectal cancer, 275, 277
Clostridium botulinum, 201–202 for diarrhea, 192
Clostridium difficile, 207–208 for diverticulitis, 238
in colitis, 245, 246t, 248 for hemorrhoids, 283
Clostridium perfringens, 201 for inflammatory bowel disease, 248
CLO test, for Helicobacter pylori, 172 for irritable bowel syndrome, 229
Clotrimazole troches, 121 for occult bleeding, 304
CMC. See Chronic mucoutaneous for proctitis, 285
candidiasis for rectal prolapse, 285
CMV. See Cytomegalovirus for toxic megacolon, 259
Coagulation disorders, in fulminant Colorectal cancer, 272, 274–279. See also
hepatic failure, 108 Colonic polyps
Coccidioidomycosis, in hepatobiliary chemoprevention of, 277
disease, 300 clinical presentation of, 274
Colazal (balsalazide disodium), for conditions predisposing to, 274, 274t
inflammatory bowel disease, diagnostic studies for, 274–275
254 differential diagnosis of, 274
Colazal, for proctitis, 285 digital rectal examination in, 276
Colchicine Dukes’ classification of, 275, 276t
for alcoholic liver disease, 394 hereditary nonpolyposis colorectal
in primary biliary cirrhosis, 415 cancer syndrome (HNPCC),
Colestipol hydrochloride, in primary 274, 275–276
biliary cirrhosis, 414 pathogenesis of, 272, 274
Colitis, indeterminate, 245. See also postoperative colonoscopic follow-up, 277
Irritable bowel syndrome; rationale for screening, 276
Ischemic colitis surveillance and follow-up of polyps
Collagenous colitis, 260–261. See also and cancer, 276–278
Inflammatory bowel disease test for occult blood in the stool,
Collateral circulation (varices), 438–439 276–277, 277t
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492 Index

Colorectal cancer (contd.) Continuous drip infusion in enteral

tests for general population, 278f nutrition, 61
tests for patients with colonic Copper metabolism, 422–423
polyps, 278f Coronaviruses, 199
tests for people with family history of, 277 Corrugated esophagus, 143
tests for screening, 276–277 Corticosteroid enema preparations, for
treatment and prognosis of, 274 inflammatory bowel disease, 254
Colostomies, 280. See also Ostomy care Corticosteroids
Colyte, 22, 110 for alcoholic liver disease, 393
Coma scale, 107, 107t for autoimmune hepatitis, 409–410
Complete blood count (CBC) for fulminant hepatic failure, 110
in acute abdomen, 81 for immunosuppression, 470
in colorectal cancer, 274–275 for inflammatory bowel disease, 254
in gastrointestinal bleeding, 86–87 for toxic megacolon, 259
in inflammatory bowel disease, 247 Cotazym, 322
Computed tomography (CT) scans, 41–42 COX II inhibitors, in peptic ulcer disease, 161
for acute abdomen, 82, 82t CPN. See Parenteral nutrition
for ascites, 445 Creatinine height index (CHI), 49
for choledocholithiasis, 356 Creatinine total arm-length ratio, 49
for colonic polyps, 270 Creon, 322
for colorectal cancer, 275, 277 Crigler-Najjar types I and II syndromes,
for diverticulitis, 238 342
for diverticulosis, 237 Criticare HN, 58t
for esophageal cancer, 155 Crohn’s disease. See also Inflammatory
for gastric neoplasms, 177 bowel disease
for inflammatiory bowel disease, 248, 259 diarrhea in, 190
for irritable bowel syndrome, 229 and irritable bowel syndrome, 228
for jaundice, 346 and ulcerative colitis (UC), 244–245,
for malabsorption, 210, 210f 244t, 245t
for metastatic carcinoid tumors, 225 Cryptococcus neoformans, in hepatobiliary
for pancreatic cancer, 328 disease, 299–300
for pancreatitis, 230, 312–313 Cryptosporidium, 208–209, 302
for small-intestinal neoplasms, 223 in hepatobiliary disease in AIDS, 300
for toxic megacolon, 259 CT scans. See Computed tomography (CT)
Computed tomography colography, scans
41–42 Cullen’s sign, 81, 306, 311
Computed tomography enterography, 42 Cyclic method of drip infusion in enteral
Concentrated solutions of carbohydrates nutrition, 61
(CHOs), in parenteral Cyclosporine
nutrition, 64 for immunosuppression, 470–471
Condylomata acuminata (anal warts), 291 for inflammatory bowel disease,
Congenital esophageal stenosis, 143 255–256
Conscious sedation, 18 for toxic megacolon, 259
Constipation, 240–243 Cystadenocarcinoma, 331
colonic obstruction in, 240 Cystic fibrosis, 317, 436
definition of, 240 epidemiology of, 436
diagnosis of, 240–241 liver transplantation for, 436
diagnostic studies for, 241 pathogenesis of, 436
diet for, 240, 242 treatment of, 436
etiology and differential diagnosis of, Cystic tumors of the pancreas, 331–332.
240, 241t See also Pancreatic cancer
exercise for, 240 Cytologic diagnosis, for pancreatic
fecal impaction in, 241t, 243 cancer, 329
in Hirschsprung’s disease, 241 Cytomegalovirus, 104, 122, 298, 302,
laxatives for, 240, 242 293t, 294, 361–362
treatment for, 242–243 in liver transplantation, 468
Constipation predominant irritable bowel Cytomegalovirus esophagitis, 124, 292,
syndrome (IBS-C), 227 293t
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Cytomegalovirus infection, in AIDS, 298 Dicyclomine hydrochloride

Cytoprotection, in peptic ulcer disease, for diverticular disease, 238
158–159 for irritable bowel syndrome, 230
Diet. See also Obesity
D in alcoholic liver disease (ALD), 392
DAEC. See Diffuse adherence E. coli and chronic calcifying pancreatitis
ddC (zalcitabine), 293 (CCP), 318
Demerol (meperidine), 18, 22 in constipation, 240, 242
for pancreatitis, 314 in GERD, 135
Dermatitis herpetiformis (DH), and celiac high fiber, 238, 283, 284
sprue (CS), 217 in inflammatory bowel disease
DES. See Diffuse esophageal spasm (IBD), 252
Dexamethasone, 114 in irritable bowel syndrome, 230
Dextrose solutions for parenteral low fiber, 283
nutrition, 67 in ostomy care, 281
Diabetes mellitus in peptic ulcer disease (PUD), 164
and chronic pancreatitis, 319, 324 very-low-calories diets (VLCDs) or
formulations for enteral nutrition, 60 protein-sparing diets, 480
and hemochromatosis, 429 in Wilson’s disease, 425
and nonalcoholic fatty liver disease, 395 Dietitians, 480
in pancreatic cancer, 327 Diffuse adherence E. coli (DAEC), 206
Diagnostic and therapeutic procedures, Diffuse esophageal spasm (DES), 144,
13–44 151, 152f
Diagnostic categories and tests, 4 Digestive disorders. See Gastroenterologic
Diagnostic paracentesis, in acute abdomen, disorders
82t, 83 Digital rectal examination, for colorectal
Diarrhea, 184–196 cancer, 276
acute diarrhea, 187–191 Dilantin (phenytoin), 400
causes/characteristics/organisms of, Diloxanide furoate (Furamide), 209
188t–189t Dipentum (olsalazine), for inflammatory
treatment of, 192–195, 195t bowel disease, 253
bloody, 202t Diphenoxylate hydrochloride (Lomotil),
chronic and recurrent diarrhea, 187, 205, 297
190–191 for inflammatory bowel disease, 257
causes of, 189t for irritable bowel syndrome, 231
treatment of, 195 Diquinol (iodoquinol), 209
diagnosis of, 191–192, 295–296 Direct percutaneous fine-needle aspiration,
exudative diarrhea, 185, 187 for pancreatic cancer, 329
in HIV-infected patients, 293t, Disaccharidase deficiency, diarrhea in, 190
295–297, 296t Disease-specific formulas in enteral
clinical presentation of, 295 nutrition, 59–60
diagnostic studies for, 295 Disseminated intravascular coagulation
etiologic agents in, 293t, 295 (DIC), 307
treatment of, 296–297 in fulminant hepatic failure, 108
in human immunodeficiency virus Diverticula, 236
(HIV), 295–297 Diverticular disease, 236–239
infectious diarrheal conditions, 289 definitions of, 236
motility disturbances in, 185, 187 differential diagnosis of, 238
normal intestinal fluid balance in, diverticular bleeding, 239
184–185, 184t diverticulitis, 238–239
osmotic diarrhea, 185–186, 185t pathogenesis of, 236
secretory diarrhea, 186, 186t, 185 symptomatic diverticulosis, 237–238, 237f
treatment of, 192–195, 194t, 195t terminology of, 236, 236t
watery, 202t Diverticulitis, 238–239
Diarrhea predominant irritable bowel Diverticulosis, 236, 237–238, 237f
syndrome (IBS-D), 227 Diverticulum, 236
DIC. See Disseminated intravascular Dobbhoff feeding tube, 60
coagulation Domperidone, 137
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494 Index

Donor organs, in liver transplantation, Ecchymosis in the flanks or around the

459, 461 umbilicus, 81
Double balloon enteroscopy, in occult Echoviruses, 199
bleeding, 304 Eclampsia in pregnancy, 115
Drug-induced chronic hepatitis, 300–301, Ectopic pregnancy, 81
405–406 EGC. See Early gastric cancer
Drug-induced jaundice, 343–344 EGD. See Endoscopy, upper
Drug-related hepatic injury, 399–406 gastrointestinal endoscopy
acetaminophen hepatoxicity, 401–405 EHEC. See Enterohemorrhagic
diagnosis of, 403–404 E. coli
pathogenesis of, 402–403, 402f, 404f EICI. See Enteroinvasive E. coli
treatment of, 404–405 Electrocardiogram
amiodarone hepatotoxicity, 400–401 in acute abdomen, 82, 82t
aspirin hepatotoxicity, 401 in noncardiac chest pain, 149
background and drug list for, 399, 399t Electrocautery, 16
cholestasis, 400 Electrocoagulation, 19
drug-induced chronic hepatitis, 405–406 Electroencephalogram (EEG), in hepatic
hepatocellular necrosis, 399–400 encephalopathy, 108, 450
mixed-pattern liver injury, 400 Electrolyte abnormalities, in fulminant
Drugs, and nonalcoholic fatty liver hepatic failure, 108
disease, 396 Electrolyte replacement, in gastrointestinal
DTO (deordorized tincture of opium), 61 bleeding, 86
Dubin-Johnson syndrome, 342–343 Electrolytes, 55
Ductal ectasia, 331 in parenteral nutrition, 69–70, 69t
Ductal ectatic mucinous cystadenoma, 331 Elemental formulas, 59
Dukes’ classification in colorectal cancer, Elemental Vivonex TEN, 58t
275, 276t Encephalopathy, hepatic (HE), 106–108,
Dumping syndrome, 180–181 107t, 110, 448–452
Duodenal ulcers, 127 and fulminant hepatic failure, 106–108,
Duodenogastric reflux, 128 107t, 110
DuVal procedure, 322 neurologic assessment,
Dysphagia, 140–148 107–108
definitions, 141 cerebral edema assessment, 108
dysphagia, 141 clinical coma scale, 107, 107t
globus hystericus, 141 electroencephalogram (EEG), 108
odynophagia, 141 visual-evoked potentials, 108
diagnostic approach for, 146–147 pathogenesis of, 106–107
in esophageal candidiasis, 120 arterial NH3, 107
esophageal dysphagia, 142–146 “false neurotransmitters,” 106
gastroesophageal reflux, 143, 146 multifactorial causes, 106–107
neuromuscular or motility disorders, “neurotoxic” substances, 106
143–146 treatment of, 110
structural disorders, 142–143, 148 gastrointestinal tract cleansing, 110
treatment of, 147–148 oral antibiotics, 110
esophagus, 140–141 Endocrine disorders, 429
anatomy of, 140 diarrhea in, 190–191
physiology of, 140–141 Endometriosis, and irritable bowel
in GERD, 130 syndrome, 228
preesophageal or oroesophageal Endoscopic balloon dilators, 133
dysphagia, 141–142 Endoscopic banding, 19
causes of, 141–142 of varices, 92, 94, 441
signs and symptoms of, 141 Endoscopic biopsies, 23
treatment of, 147–148 Endoscopic interventional therapy,
in gastroesophageal
E reflux disease (GERD), 19,
EAGGEC. See Enteroaggregating E. coli 137–138
Early gastric cancer (EGC), 175, 176–177 Endoscopic or transgastric surgery, 25
EBV. See Epstein-Barr virus Endoscopic plicators, 138
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Index 495

Endoscopic retrograde cholangiopancre- biopsy interpretation, 21f, 23–25, 24f

atography (ERCP), 16, 20–21, diagnostic value, 25
357, 358 indications and contraindications, 23
for cholesterol gallstones, 352 methods of obtaining mucosal
for jaundice, 347 biopsies, 23
for malabsorption, 211, 213 for small-intestinal neoplasms, 223
for pancreatic cancer, 328 therapeutic endoscopic techniques, 16,
for pancreatitis, 308, 313, 320 19, 22, 90, 90t
Endoscopic scierotherapy, in varices, 440 upper gastrointestinal endoscopy
Endoscopic suturing devices, 138 (EGD), 16, 18–20, 147
Endoscopic ultrasonography (EUS), 15f, complications of, 19–20, 20t
16, 16f, 17f, 42 contraindications for, 18, 19t
in esophageal cancer, 155 indications for, 18, 19t
in gastric neoplasms, 177 patient preparation for, 18–19
in pancreatic cancer, 329 therapeutic uses for, 19
Endoscopy, 15–26 in varices, 440
capsule endoscopy or pillcam video monitoring systems, 15
endoscopy, 21 Energy needs
for caustic ingestion, 102 normal, 47
for cytomegalovirus esophagitis, 124 in starvation, 48–49
for diarrhea in HIV-infected Enrich, 57t, 59
patients, 296 Ensure, 57t
endoscopic or transgastric surgery, 25 Entamoeba histolytica, 209
endoscopic retrograde cholangiopancre- Entecavir, for HBV infection, 375
atography (ERCP), 16, 20–21 Entecort (budesonide), for inflammatory
evaluation of pancreatic and biliary bowel disease, 254
ductal system, 20, 21f, 320 Enteral anabolic requirement, 60
sphincterotomy and calculus Enteral maintenance requirement, 60
retrieval, 20 Enteral nutrition, 56–63
stent insertion, 21 administration methods in, 60–61
endoscopic ultrasonography (EUS), 15f, caloric requirements in, 60–61
16, 16f, 17f complications of, 61–62
for eosinophilic esophagitis, 143 formulas for, 56–60, 57–58t
for esophageal cancer, 155 monitoring in, 62, 62t
for esophageal tuberculosis, 125 patient selection for, 56, 56t
for foreign bodies, 97, 98 Enteric adenovirus, 198
for fungal esophagitis, 120 “Enteric” infections, 202–208, 202t
for gastric neoplasms, 177 Enteroaggregating E. coli
for gastrointestinal bleeding, 88–90 (EAGGEC), 206
for GERD, 131 Enteroclysis or small-bowel enema, 40
for Helicobacter pylori, 172 Enterohemorrhagic E. coli (EHEC), 206
for HIV, 294 Enteroinvasive E. coli (EIEC), 205
for HSV esophagitis, 123 Enteropathogenic E. coli (EPEC),
indications for EUS, 18t 205–206
for irritable bowel syndrome, 229 Enteroscopy, in occult bleeding, 304
lower gastrointestinal tract, 16, 21–23 Enterotoxigenic Escherichia coli (ETEC),
biopsy and therapeutic procedures, 22 200–201
colonoscopy, 22–23 Enteroviruses, 199
complications, 22–23 Enteryx, 138
indications and contraindications, Entolase, 322
21, 19t Eosinophilic esophagitis, 142–143
proctosigmoidoscopy, 21–22 EPEC. See Enteropathogenic E. coli
modern fiberoptic endoscope, 15, 15f Epidermal growth factor (EGF), in peptic
in noncardiac chest pain, 150 ulcer disease, 160
in occult bleeding, 304 Epithelial regeneration
percutaneous endoscopic gastrostomy in GERD, 129–130
(PEG), 16 in peptic ulcer disease, 160
small-intestinal biopsy, 23–25 Epithelium, 24
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496 Index

Epstein-Barr virus (EBV), 359, 361 Ethanol metabolism, 386–389

and AIDS, 298 EUS. See Endoscopic ultrasonography
in esophageal infections, 123, 124 Examination of the patient, 6–9
in liver transplantation, 468 abdominal examination, 6–8, 7f
ERCP. See Endoscopic retrograde ascites detection, 8
cholangiopancreatography auscultation, 6–7
(ERCP) inspection, 6
Escherichia coli, 205–206, 247, 248 patient position, 6
Esomeprazole magnesium (Nexium), 136 percussion and palpation, 7–8
in peptic ulcer disease, 161, 166 puddle sign, 8
Esophageal cancer, 154–157 anorectal examination, 8–9
clinical features of, 155 general physical examination, 6
diagnosis of, 155–156 Exercise, and constipation, 240
epidemiology of, 154 Exocrine pancreatic cancer, 326. See also
predisposing factors for, 154 Pancreatic cancer
prevention and surveillance of, 157 Exploratory surgery, 4
prognosis for, 155 Extracorporeal shock-wave lithotripsy
treatment of, 156–157 (ESWL), 342
Esophageal clearance, in GERD, Extrahepatic billiary obstruction, jaundice
128–129, 137 in, 344
Esophageal dilatation, 153 Extrinsic compression, 143
Esophageal dysphagia. See Dysphagia Exudative diarrhea, 185, 187. See also
Esophageal infections, 119–125 Diarrhea, 185, 187
background of, 119
bacterial esophagitis, 125 F
esophageal tuberculosis, 125 Fad diets, 480
fungal esophagitis, 119–122 “False neurotransmitters,” 106
diagnosis of, 120–121, 121f Famiciclovir, 124
predisposing factors in, 119–120 Familial adenomatous polyposis (FAP), 272
treatment of, 121–122, 122t Familial conjugated hyperbilirubinemia,
idiopathic esophageal ulcer (IEU), 125 342–343
viral esophagitis, 122–124 Famotidine (Pepcid), in peptic ulcer
cytomegalovirus esophagitis, 124 disease, 165
HSV esophagitis, 123–124 FAP. See Familial adenomatous polyposis
Esophageal motility disorders, and Fat necrosis, 306
noncardiac chest pain, 151, 152 Fatty liver, 386. See also Alcoholic
Esophageal motility studies, 34–36 liver disease; Nonalcoholic fatty
in noncardiac chest pain, 150 liver disease
Esophageal mucosa, 140 Fecal fat determination, in malabsorption,
Esophageal mucosal biopsy, in noncardiac 210–211, 212t
chest pain, 150 Fecal impaction, in constipation, 243
Esophageal studies, in noncardiac chest Feeding modules for enteral nutrition, 60
pain, 150 Feeding tubes, 60–61
Esophageal submucosa, 140 Fentanyl, 18, 22
Esophageal tuberculosis, 125 Fever of unknown origin, 27
Esophageal varices. See Varices Fiberoptic endoscope, 15, 15f. See also
Esophagectomy, 135 Endoscopy
Esophagitis, pill-induced, 293 Fiberoptic sigmoidoscope, 21
Esophagogastroduodenoscopy (EGD). Fistulas, 258, 284
See Endoscopy, upper 5´-nucleotidase, 338–339
gastrointestinal endoscopy Flagyl (metronidazole), 208, 209
Esophagus, 140–141 for Helicobacter pylori, 173
anatomy of, 140 for inflammable bowel disease, 254–255
foreign bodies in, 96–97 for peptic ulcer disease, 161
human immunodeficiency virus (HIV) Flat plate or supine film, 39
in, 292–294, 293t Flatulence. See Intestinal gas and bloating
physiology of, 140–141 Fleet phospho-soda, 22
ETEC. See Enterotoxigenic Escherichia coli Fluconazole, 121–122, 294
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Index 497

Fluid replacement, in gastrointestinal G

bleeding, 86 Gallbladder, 349. See also Biliary
Fluid requirements, 55 tumors
Flumazenil (Romazicon), for hepatic Gallbladder and biliary studies, 40–41
encephalopathy, 453 Gallbladder carcinoma (CG), 457
Foregut carcinoids, 224 Gallstone disease, in acute abdomen, 81
Foreign bodies in the gastrointestinal tract, Gallstone dissolution, 353
96–98 Gallstone formation, 351
background, 96 Gallstone ileus, 355
colon and rectum, 98 Gallstones, 349–358
esophagus, 96–97, 142 anatomy and physiology, 349
small bowel, 98 bile flow, 349
stomach, 97–98 biliary tract, 349
Foscavir (Foscarnet), 124 gallbladder, 349
Fulminant hepatic failure (FHF), background and definition, 349
104–112 cholecystitis, 353–356
clinical syndrome, 106–109 choledocholithiasis, 351, 356–357
cardiovascular disorders, 108 cholesterol gallstones, 350–353
coagulation disorders, 108 clinical presentation of, 351
gastrointestinal and other diagnostic studies of, 352
bleeding, 109 differential diagnosis of, 352
hepatic encephalopathy (HE), gallstone formation, 351
106–108, 107t, 110 maintenance of therapy, 353
hypoglycemia, 109 management of, 352–353
renal-, electrolyte-, and acid-base risk factors of, 350–351
abnormalities, 108 side effects of, 353
respiratory disorders, 108 extracorporeal shock-wave lithotripsy
sepsis, 109 (ESWL), 342
defined, 104 gallstone dissolution, 353
diagnosis of, 105–106 obstructive cholangitis, 357–358
etiology of, 104–105m 195t and pancreatitis, 307
management, 109–111 pigment stones (black and brown),
acetylcysteine, 109 349–350
cerebral edema treatment, 110–111 epidemiology of, 349
corticosteroids, 110 pathogenesis of, 350
general measures, 109–110 in primary biliary cirrhosis, 414
hepatic encephalopathy treatment, 110 Ganiciclovir sodium, 294
liver transplantation, 111 Gardner’s syndrome, 272
nutritional support, 110 Gas, intestinal. See Intestinal gas and
penicillin and silibinin, 110 bloating
temporary hepatic support, 111 Gastrectomy, 180. See also Postgastrectomy
prognosis of, 106 disorders; Surgery
in Wilson’s disease, 424–425 Gastric acid hypersecretory states, in
Fulminant pancreatitis, 315 malabsorption, 220
Fungal esophagitis, 119–122 Gastric acid in GERD, 127–128
diagnosis of, 120–121, 121f Gastric adenocarcinoma, 175–178.
predisposing factors for, See also Gastric neoplasms
119–120 advanced, 176
treatment of, 121–122, 122t classification of, 175f
Fungal infections diagnosis of, 176–177
in hepatobiliary disease in AIDS, early gastric cancer (EGC), 175
299–300 incidence of, 175, 176
in human immunodeficiency virus pathogenesis of, 175–176
(HIV), 292 prognosis for, 177–178
Furamide (diloxanide furoate), 209 risk factors in, 176, 176t
Furazolidone (Furoxone), 208 treatment for, 177–178
Furosemide (Lasix), for ascites, 447 Gastric banding, 481, 482. See also
Furoxone (furazolidone), 208 Obesity
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498 Index

Gastric bypass, 481–482. See also Obesity pulmonary manifestations, 134

Gastric carcinoid tumors, 224–225 strictures, 132–134
Gastric factors, in GERD, 127–128 definitions of, 126
Gastric feeding tubes, percutaneous diagnosis, 130–132
endoscopic gastrostomy (PEG), 16 clinical presentation (symptoms), 130
Gastric mucosal barrier, in peptic ulcer diagnostic studies, 131–132
disease, 158 nighttime GER, 130
Gastric neoplasms, 175–179. See also pathogenesis, 126–130
Gastric adenocarcinoma; antireflux mechanisms, 126–127
Tumors epithelial regeneration, 129–130
malignant tumors, 178 esophageal clearance, 128–129, 137
MALT lymphoma, 178 gastric factors, 127–128
polypoid lesions and benign tumors, 179 tissue resistance of the esophageal
Gastrinomas, 332 mucosa, 120
in peptic ulcer disease, 168 as predisposing factor to cancer, 154, 157
Gastrinoma triangle, 332 in pregnancy, 113
Gastroenteritis, 197–210 treatment of, 135–137
bacterial, 199–208. See also Bacterial endoscopic interventional and/or
gastroenteritis surgical therapy, 19, 137–138
in immunocompetent patients, 197–210 medical therapy, 135
opportunistic infections in Gastrointestinal bleeding. See Bleeding,
immunocompromised gastrointestinal
patients, 197 Gastrointestinal complications in enteral
parasitic infections of the bowel, nutrition, 61
108–209 Gastrointestinal diseases and HIV. See
Cryptosporidium, 208–209 Human immunodeficiency virus
Entamoeba histolytica, 209 Gastrointestinal tract cleansing, for hepatic
Giardia lamblia, 208 encephalopathy, 110
viral, 197–199 Gastrostomies, 280. See also Ostomy care
astrovirus, 199 Gelfoam, 91
calcii viruses, 198 Genetic conditions, and nonalcoholic fatty
coronaviruses, 199 liver disease, 396
echoviruses, 199 Genetics, of hemochromatosis, 429
enteric adenovisus, 198 Genetic testing, for hemochromatosis, 429
enteroviruses, 199 GE scintiscan, in GERD, 131
Norwalk virus and Norwalk-like Giardia lamblia, 208
viruses, 198 Giardia organisms, 23
rotavirus, 197–198 Gilbert syndrome, 341
Gastroenterologic disorders Globus hystericus, 141
diagnostic categories and tests, 4 Glucagonomas, 332
examination of the patient, 6–9 Glucose, 47
patient’s complaints, 4–5 Glutamine, 55
patients with, 1–11 Glycogen, 47
psychological and emotional aspects of, GlycoLax, for constipation, 242
10–11 GoLYTELY, 22, 110
social impact of, 3 Gonococcal perihepatitis, 291
statistics on, 3 Gonococcal pharynigitis, 289
Gastroenterologic emergencies, 77–116 Gonococcal proctitis, 285, 289
acute abdomen, 79–83 Grey Turner’s sign, 81
Gastroesophageal reflux (GER), 129 Groshong-Broviac soft catheter, 64
in dysphasia, 143, 146
treatment of, 153 H
Gastroesophageal reflux disease (GERD), HAART. See Highly active antiretroviral
126–139 therapy
complications of, 132–135 HalfLytely, 22
Barrett’s esophagus, 134–135 Harris-Benedict equation, 60, 65, 66
esophageal ulcers and and basic energy expenditure (BEE),
bleeding, 134 52, 53t
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Index 499

HAV. See Hepatitis A virus Hepatic artery embolization, in metastatic

HBV. See Hepatitis B virus carcinoid tumors, 226
HCV. See Hepatitis C virus Hepatic encephalopathy. See
HDV. See Hepatitis D virus Encephalopathy, hepatic
Heartburn (pyrosis), in GERD, 130 Hepatic failure, parenteral nutrition in, 68
Height, 49 Hepatic fibrogenesis, 389–390
Helicobacter pylori, 171–174, 294 Hepatic formultions for enteral
diagnosis of, 172–173 nutrition, 60
epidemiology of, 171 Hepatic ischemia, 104
and gastric neoplasms, 176 Hepatic neoplasms, in hepatobiliary
infection in, 171–172 disease in AIDS, 301
and peptic ulcer disease, 158, Hepatic osteodystrophy, in primary biliary
160–161, 167 cirrhosis, 414
therapy for, 173 Hepatic redox state, 388, 388f
virulence factors in, 171 Hepatic rupture, in pregnancy, 115
HELLP syndrome, in pregnancy, 114–115 Hepatic steatosis, and parenteral
Hematocrit levels, in gastric nutrition, 73
adenocarcinoma, 177 Hepatitis, 104
Hematologic parameters, in alcoholic liver alcoholic hepatitis (AH), 390, 392
disease, 391 autoimmune hepatitis, 407–411,
Hematolymphoid malignancies, 105 408t
Hemochromatosis, 426–432 chronic hepatitis (CM), 407
classification of, 426–427 drug-induced hepatitis, 300–301,
diagnosis of, 429–431 405–406
arthropathy, 429 sexually transmitted hepatitis viruses
cardiac involvement, 430 and cytomegalovirus, 291
clinical presentation, 429 syphilitic hepatitis, 291
endocrine disorders, 429 viral, 359–385
infection, 430 acute, 359, 369t
liver disease, 429 causes of, 359
skin pigmentation, 429 cytomegalovirus (CMV), 361–362
diagnostic studies for, 430–431 definition and classification of,
early diagnosis of, 432 359, 360t
genetics of, 428 Epstein-Barr virus (EBV), 359, 361
incidence of, 428 jaundice in, 344
iron metabolism, 427 serologic diagnosis of, 360t
iron transport and storage proteins, 427 Hepatitis A virus (HAV), 104, 360t,
pathogenesis of, 427–428 362–364
pathophysiology of, 428 and AIDS, 297
prognosis for, 432 clinical presentation of, 362
treatment of, 431–432 complications from, 362–363
chelating agents, 431 diagnosis of, 362–363, 363f
liver transplantation, 432 pathogenesis of, 362
phlebotomy, 431 prophylaxis for, 363–364
Hemoglobin level, in gastric superinfection in, 371
adenocarcinoma, 177 treatment of, 363, 372
Hemorragic or necrotizing pancreatitis, 306 Hepatitis B virus (HBV), 104, 360t,
Hemorrhage, in GERD, 130 364–378
Hemorrhagic gastritis, 89 acute, 367–369, 368f
Hemorrhoids, 283–284 clinical presentation of, 367
clinical presentation of, 283 laboratory tests for, 367–368
diagnostic studies for, 283 prognosis of, 368–369
pathogenesis of, 283 and AIDS, 297–298
treatment if, 283–284 background and definition of,
Hemothorax, in central catheterization, 64 364–366
Heparin chronic, 369–372, 369f
in occult bleeding, 303 clinical characteristics of three phases
in parenteral nutrition, 71 of, 372–373, 372t
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500 Index

Hepatitis B virus (HBV) (contd.) diagnostic workup, 302

clinical course and serology of, 369–370 drug-induced hepatitis, 300–301
diagnosis of, 372 fungal infections, 299–300
differential diagnosis of, 371, 371t Candida albicans, 300
pathogenesis of, 372 coccidioidomycosis, 300
superinfection in, 371 Cryptococcus neoformans,
treatment of, 372–375 299–300
clinical states of, 366 Histoplasma capsulatum, 300
pathogenesis of, 366 sporotrichosis, 300
primary hepatocellular carcinoma hepatic neoplasms, 301
(PHC) in, 371 Kaposi’s sarcoma (KS), 301
risk factors for, 364 lymphoma, 301
serology in, 366, 367f protozoan infections, 300
structure of, 364f, 365f Cryptosporidium, 300
vaccine and prophylaxis for, Microsporidia, 300
375–378, 377t Pneumocystis carinii, 300
Hepatitis C virus (HCV), 104, 360t, 381–385 viral infections, 297–298
acute, 382, 383f CMV (Cytomegalovirus) infection,
and AIDS, 298 298
in alcoholic liver disease, 391 delta hepatitis (HDV), 298
chronic, 382–383 Eptstein-Barr virus, 298
clinical presentation in, 382–383 hepatitis A virus (HAV), 297
diagnosis of, 383 hepatitis B virus (HBV), 297–298
histopathologic examination of liver hepatitis C virus (HCV), 298
biopsy specimens, 383 herpes simplex virus, 298
serologic tests, 383 Hepatocellular carcinoma (HCC), 411
virologic tests, 383 Hepatocellular disease, jaundice in, 344
differential diagnosis of, 381t Hepatocellular necrosis, 399–400
epidemiology in, 381–382 Hepatocyte injury, 389
genotypes, 382 Hepatorenal syndrome, 447–448
and hepatocellular carcinoma, 383 Hereditary nonpolyposis colorectal
superinfection in, 371 cancer syndrome (HNPCC),
treatment of chronic HCV, 383–385 274, 275–276
Hepatitis D (HDV), 104, 360t, 378–381 Herpes, 291
acute coinfection in, 379, 379f Herpes esophagitis. See HSV esophagitis
in AIDS, 298 Herpes pharyngitis, 289
chronic hepatitis D, 380, 380f Herpes simplex virus (HSV), 104,
epidemiology in, 378 113, 292
pathogenesis for, 378–379, 378f and AIDS, 298
superinfection in, 379–380 Herpes viruses
treatment of, 381 in liver transplantation, 468
Hepatitis E virus (HEV), 104, 360t, 385 in viral esophagitis, 122–123
clinical course in, 385 HEV. See Hepatitis E virus
diagnosis of, 385 Hickman and/or Groshong-Broviac soft
Hepatobiliary disease in acquired catheters, 64
immunodeficiency syndrome HIDA scan, 42–43
(AIDS), 297t, 297–302 for acute abdomen, 82, 82t
bacterial and mycobacterial infections, for jaundice, 346
298–299 High-grade dysplasia, 271
Mycobacterium avium-intracellulare Highly active antiretroviral therapy
(MAI), 298–299 (HAART), 120
Mycobacterium kansasii, 299 for human immunodeficiency virus
Mycobacterium tuberculosis, 299 (HIV), 292
Mycobacterium xenopi, 299 High-resolution manometry (HRM), 37
Salmonella, 299 in GERD, 131
biliary tract diseases, 301–302 Hindgut carcinoids, 224
acalculous cholecystitis, 301–302 Hirschsprung’s disease, in
cholangitis, 302 constipation, 241
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Histamine-2 blockers, in GERD, 136 Hydrochlorothiazide, for ascites, 445

Histamine antagonists, in peptic ulcer Hydrophobic layer, in peptic ulcer
disease, 165 disease, 160
Histologic examination of resected polyps, Hydrothorax, in central
270 catheterization, 64
Histology, in GERD, 132 Hyperacute liver failure, 104. See also
Histoplasma capsulatum, in hepatobiliary Fulminant hepatic failure
disease, 300 Hyperamylasemia, 311, 312t
HIV. See Human immunodeficiency virus Hyperbilirubinemia, and jaundice,
HNPCC. See Hereditary nonpolyposis 340–345, 341t
colorectal cancer syndrome Hypercalcemia, and pancreatitis, 308
Hodgkin’s disease and non-Hodgkin’s Hyperemesis gravidarum, in
lymphoma, 27 pregnancy, 113
HRM. See High-resolution manometry Hyperglycemia, 71
HSV. See Herpes simplex virus and parenteral nutrition, 73
HSV esophagitis, 123–124 Hyperkalemia, and parenteral
Human immunodeficiency virus (HIV), nutrition, 73
292–302. See also Acquired Hyperlipidemia, in primary biliary
immunodeficiency syndrome cirrhosis, 414
antimicrobial therapy for enteric Hyperlipidemias, and nonalcoholic fatty
infections, 296t liver disease, 395
candidiasis in, 119 Hypermetabolic patients, 54
in esophageal infections, 123, 124 Hyperplastic polyps, 269. See also Colonic
esophagus, 292–294, 293t polyps
barium swallow for, 294 Hypersplenism, 448
clinical presentation of, 293 Hypertonic solutions, 59
empiric therapy for, 294 Hypertriglyceridemia, 308
endoscopy for, 294 Hyperuricemia, in acute fatty liver
fungi, 292 of pregnancy (AFLP), 114
gastroesophageal reflux disease Hypoalbuminemia, in ascites, 443
(GRD), 293 Hypoglycemia
idiopathic esophageal ulcers in fulminant hepatic failure, 109
(IEUs), 293 and parenteral nutrition, 73
laboratory tests for, 294 Hypokalemia, and parenteral
pill-induced esophagitis, 293 nutrition, 73
treatment for, 294
viruses, 292 I
highly active antiviral therapy Idiopathic esophageal ulcers (IEUs), 125
(HAART), 292 in HIV, 293
opportunistic infections in IEU. See Idiopathic esophageal ulcer
immunocompromised patients, Ileal loop urostomies, 280. See also
197, 292 Ostomy care
oral thrush in, 119, 120 Ileorectal pull-through, 280. See also
pathogens/diseases listed by Ostomy care
location, 293t Ileostomies, 280. See also Ostomy care
sexually transmitted enteric disorders, Ilozyme, 322
288, 288t IM. See Infectious mononucleosis
small intestine and colon, 293t, 295–297 Imaging studies, 39–44
diarrhea in, 295–297 in ascites, 443
stomach, 294 background of, 39
endoscopy with biopsies for, 294 for cholestasis, 400
gastric lesions in, 294 magnetic resonance imaging
treatment of, 294 (MRI), 43
treatment and management of, 292 in nonalcoholic fatty liver disease, 396
Humira (adalimumab), for inflammatory positron emission tomography
disease, 256 (PET), 43
Humoral immunity, 119 in primary sclerosing cholangitis,
Hurst dilators, 133 417–418
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502 Index

Imaging studies (contd.) surgery for, 257–258

radiologic and ultrasound studies, 39–42 toxic megacolon due to, 258–261
angiography, 42 treatment for, 252–258
barium enema, 40 ulcerative colitis (UC) versus Crohn’s
barium swallow, 39–40 disease, 244–245, 244t, 245t
computed tomography (CT) scans, Inflammatory polyps, 269. See also
41–42 Colonic polyps
gallbladder and billiary studies, 40–41 Infliximab (Remicade), for inflammatory
intravenous pyelogram (IVP), 41 disease, 256
plain chest and abdominal films, 39 Infusion types in enteral nutrition, 61
small-bowel series, 40 Inherited liver diseases, 421–436. See also
ultrasonography, 42 AAT
1-antitrypsin deficiency;
upper gastrointestinal series, 40 Cystic fibrosis; Hemochromatosis;
radionuclide studies, 42–43 Wilson’s disease
HIDA scan, 42–43 Injection sclerosis, 92
live-spleen scan, 42 Injection sclerotherapy, 19
scans using radiolabeled blood cells Inseparable entities of psyche (mind) and
and blood components, 43 soma (body), 10
Immune defects, 119 Inspection
Immune reactive phase of chronic HIV in abdominal examination, 6
infection, 372–373, 372t in acute abdomen, 81
Immune tolerant phase of chronic HIV Insulin, in parenteral nutrition, 71
infection, 372, 372t Insulinomas, 332
Immunocompetent patients, gastroenteritis Intact nutrients in enteral nutrition, 56, 59
in, 197–210 Interferon therapy
Immunocompromised patients. See also for HBV, 373–374
Human immunodeficiency virus for metastatic carcinoid tumors, 226
opportunistic infections in, 197, 292 Internet, 4
Immunomodulators, for inflammatory Interoperative enteroscopy, in occult
bowel disease, 255–256 bleeding, 304
Imodium (loperamide hydrochloride), Intestinal circulation, 263
205, 297 Intestinal cleansing, for hepatic
for inflammatory bowel disease, 257 encephalopathy, 452
for irritable bowel syndrome, 231 Intestinal gas and bloating, 232–235
Imuran. See Azathioprine composition and sources of, 232–233,
Inactive carrier phase of chronic HIV 232t, 233f
infection, 372t, 373 diagnosis of, 234
Indeterminate colitis, 245 pathogenesis of, 233–234
Indirect calorimetry and the respiratory treatment of, 234
quotient (RQ), 52–53 Intraductal papillary mucinous neoplasm
Infectious mononucleosis (IM), 359 (IPMN), 331
Inflammatory bowel disease (IBD), 244–262 Intrahepatic cholestasis, of pregnancy,
background and definition of, 244 113–114
cancer surveillance in, 260–261 Intravenous cholangiography, 41
clinical presentation of, 246–247 Intravenous pyelogram (IVP), 41
diagnostic studies for, 247–252 in acute abdomen, 82, 82t
diarrhea in, 190 Invasive surgery, 4
diet and nutrition for, 252 Iodoquinol (Diquinol), 209
differential diagnosis of, 245–246, 246t IPMN. See Intraductal papillary mucinous
drug therapy for, 252–257 neoplasm
etiology of, 245 Iron metabolism, in hemochromatosis, 429
extraintestinal manifestations of, 245t Irritable bowel syndrome (IBS), 227–231
laboratory studies for, 247 clinical presentation of, 228
pregnant patients with, 260 diagnosis of, 228–229, 228t
psychotherapy for, 257 diagnostic studies for, 229, 229t
radiography for, 248–252, 250f, differential diagnosis for, 228
251f, 252f and intestinal gas and bloating, 233
stool examination for, 247–248 pathogenesis of, 227–228
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Index 503

psychological and emotional aspects in, for alcoholic liver disease (ALD), 344,
10, 229–230 390–391
synonyms for, 227, 227t for ascites, 444
treatment for, 229–231, 230t for autoimmune hepatitis, 408–409
Ischemic colitis, 246, 246t, 265–267 for choledocholithiasis, 356
clinical presentation of, 265 for gastrointestinal bleeding, 86–87
diagnostic studies and differential for hemochromatosis, 430
diagnosis of, 265, 266f for hepatic encephalopathy, 450
pathophysiology of, 265 for hepatitis B virus (HBV),
treatment of, 265, 267 367–368
Islet cell tumors of the pancreas, 326. for hepatocellular necrosis, 399
See also Pancreatic cancer for human immunodeficiency virus
Isoniazid (INH), 405–406 (HIV), 294
Itraconazole, 122, 294 for liver disease, 335–340, 344, 345t
IVP. See Intravenous pyelogram for liver tumors, 456
for nonalcoholic fatty liver disease, 396
J for pancreatic cancer, 327–328
Jaundice, 335–348 for pancreatitis, 311–312
and cancer, 344–345 for peptic ulcer disease, 163
diagnostic studies, 345–348, 348f for primary biliary cirrhosis, 412–413
invasive techniques, 346–347 for toxic megacolon, 258
noninvasive techniques, 345–346 for Wilson’s disease, 424
drug-induced, 343–344 Lactase deficiency, in malabsorption, 219
extrahepatic billiary obstruction, 344 Lactic acidosis, in fulminant hepatic
and hepatocellular disease, 344 failure, 108
hyperbilirubinemia, 340–345, 341t Lactic dehydrogenase (LDH), 336
conjugated, 340, 342–345, 343t, Lactose absorption tests, in malabsorption,
345t 213–214, 213f
hereditary unconjugated, 341–342 Lactose-free formulas with intact nutrients
unconjugated, 340–341 in enteral nutrition, 59, 57t
laboratory studies for liver disease, Lactose intolerance, and irritable bowel
335–340, 344, 345t syndrome, 228
cholestasis tests, 337–340, 338t Lactose tolerance test, for irritable bowel
liver cell injury and necrosis, syndrome, 229
335–336 Lactulose, for constipation, 242
synthetic function, 336–337, 336f Laënnec’s cirrhosis, 392, 437
postoperative, 344 Lamina propria, 24–25
in pregnancy, 343 Lamivudine, for HBV infection, 374
and sepsis, 344 Lanreotide, in metastatic carcinoid
Jejunostomies, 280. See also Ostomy care tumors, 226
Jevity, 57t, 59 Lansoprazole (Prevacid), 136
in peptic ulcer disease, 161, 166
Laparascopy (peritoneoscopy), for
K jaundice, 346–347
Kaopectate, 193 Laparoscopic adjustable gastric
Kaposi’s sarcoma, 289, 291, 301 banding (LAGB), 482. See also
and dysphagia, 142 Obesity
Keofeed feeding tube, 60 Laparoscopic cholecystectomy, 28–29
Ketoconazole, 121 Laparoscopic mini gastric bypass (LMGB),
Klatskin tumors, 457 482. See also Obesity
Klebsiella pneumoniae, 65 Laparoscopic Nissen fundoplication, 138
Kock pouches, 280. See also Ostomy care Laparoscopic surgery, 28–29
KUB (kidney, ureter, and bladder) film, 39 laparoscopic cholecystectomy, 28–29
indications and contraindications,
L 28, 28t
Laboratory studies results, 29
in acute abdomen, 81–82 technique, 28–29
for acute calculous cholecystitis, 354 other operations, 29
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504 Index

Laparoscopy, 27–28 Liver transplantation, 111, 362, 459–472

background, 27 in alcoholic cirrhosis/liver disease, 463
contraindications, 27 in alcoholic liver disease (ALD), 394
indications, 27 in
1-antitrypsin deficiency (AAT), 435
ascites causes, 27 in autoimmune hepatitis, 411
chronic or intermittent abdominal axillary, 111
pain, 27 background, 459–461
fever of unknown origin, 27 donor organs, 459, 461
Hodgkin’s disease and orthotopic liver transplantation
non-Hodgkin’s lymphoma, 27 (OLT), 459–461, 460f
liver biopsy, 27. See also partial liver transplantation, 459, 459f
Percutaneous liver biopsy candidacy (patient selection), 461–464,
for pancreatic cancer, 329 462t, 464t
techniques, 27–28 contraindications, 463–464, 464t
therapeutic, 28 criteria for, 461–462
Laser photocoagulation, 19 indications for, 462, 462t
Lasix (furosemide), for ascites, 446 OLT for specific disease indications,
Laxatives 462–463
for constipation, 240, 242 in cholestatic liver disease, 463
for diverticular disease, 238 in cyctic fibrosis, 436
for irritable bowel syndrome, 230 evaluation, 464–465
LDH. See Lactic dehydrogenase criteria for OLT recipient, 465
LES. See Lower esophageal sphincter criteria for organ donation, 465
Leucine aminopeptidase, 339 goals, 464–465
Leukocytosis, in gastrointestinal testing, 465
bleeding, 87 in fulminant hepatic failure, 111, 463
Lifestyle in HBV and HCV-induced cirrhosis,
and constipation, 242 462–463
and GERD, 135 in hemochromatosis, 430
and peptic ulcer disease (PUD), 164 in hepatic encephalopathy, 453
Lipid emulsions for parenteral in hepatorenal syndrome, 449
nutrition, 67 in liver tumors, 463
Lipid infusion adverse reactions, and long-term management of transplant
parenteral nutrition, 73 patient, 471–472
Lipids, 47–48 in metastatic carcinoid tumors, 226
Lipid substitution, 53 operative procedure, 466–472, 466f
Lipumul, 60 immunosuppression, 470–471
Liver, 7. See also Alcoholic liver disease; carcinogenesis, 471
Chronic immune-mediated liver corticosteroids, 470
disease; Hepatitis; Jaundice; cyclosporine and tacrolimus,
Nonalcoholic fatty liver disease 470–471
Liver biopsy, 27, 362. See also nontechnical complications, 468–470
Percutaneous liver biopsy hypertension, 468
for alcoholic liver disease, 391–392 infection, 468–469
for
1-antitrypsin deficiency rejection, 469–470
(AAT), 435 perioperative graft failure, 467–468
for autoimmune hepatitis, technical (procedure-related)
408–409 complications, 466–467
for cholestasis, 400 in primary biliary cirrhosis, 415
for hemochromatosis, 430 in primary sclerosing cholangitis, 420
for hepatitis C virus (HCV), 383 quality of life, 472
for hepatocellular necrosis, 399–400 in refractory ascites, 446–447
for jaundice, 346–347 in varices, 442
for liver tumors, 456 in Wilson’s disease, 426
for nonalcoholic fatty liver disease, Liver tumors, 455–457
396–397 clinical presentation, 455
for primary sclerosing cholangitis, 418 history, 455
for Wilson’s disease, 424 physical examination, 455
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Index 505

diagnostic studies for, 456 blood tests for, 209–210

natural history and treatment, celiac sprue (CS) or celiac
456–457 disease/gluten-sensitive
liver transplantation, 456 enteropathy, 217–218, 218t
local ablation, 456 and chronic pancreatitis, 322–324
palliative therapy, 456–457 defined, 209
surgical resection, 456 diarrhea in, 190
Live-spleen scan, 42 diagnostic studies for, 209–214, 212t
Lomotil (diphenoxylate hydrochloride), disorders causing, 209, 209t, 212t
205, 297 fecal fat determination in, 210–211, 212t
for inflammatory bowel disease, 257 gastric acid hypersecretory states
for irritable bowel syndrome, 231 and, 220
Loperamide hydrochloride (Imodium), lactase deficiency and, 219
205, 297 lactose absorption tests for, 213–214, 213f
for inflammatory bowel disease, 257 lymphatic disorders, 220
for irritable bowel syndrome, 231 mixed defects in absorption, 220
Lower esophageal sphincter (LES), 34, mucosal disorders, 217–219
126–127, 140, 141 pancreatic exocrine insufficiency,
Lower esophageal sphincter pressure 215–216
(LESP), 127, 128t pancreatic function tests, 211, 213,
Lower gastrointestinal bleeding, 84, 84t, 320–321
89f, 90 in pancreatitis, 319
Lower gastrointestinal tract endoscopy. in postgastrectomy, 181–182, 220
See Endoscopy in primary biliary cirrhosis, 414
Lubiprostone (Amitiza) in primary sclerosing cholangitis, 418
for constipation, 242 radiographic studies for, 210, 210f,
for diverticular disease, 238 211f, 211, 217
for irritable bowel syndrome, 231 Schilling test for, 214, 216
Lundh test meal, in pancreatitis, 320 small-bowel biopsy in, 214–215, 214f,
Lupus, and esophageal smooth muscle 215f, 217
dysfunction, 145 small-bowel disease and, 217–220,
Lymphatic disorders, and 218t
malabsorption, 220 Whipple’s disease, 218–219
Lymphocytic colitis, 260–261. See also xylose tolerance test for, 213
Inflammatory bowel disease Malignant tumors, 178
Lymphogranuloma venereum (LGV) Mallory-Weiss gastroesophageal tear,
serotype, 289 89–90, 94
Lymphoma, 246, 246t Malnourished patients, 53
Malnutrition, 56
M in primary biliary cirrhosis, 414
Magnacal, 57t Maloney dilators, 133
Magnesemia, and parenteral MALT lymphoma, 160, 178
nutrition, 73 and Helicobacter pylori, 171, 172
Magnetic resonance cholangiography Mannitol, 111
(MRC), in primary sclerosing Manometric studies, 34–38
cholangitis, 418 anorectal manometry, 37, 241
Magnetic resonance cholangiopancreatog- esophageal motility studies,
raphy (MRCP), 328, 352, 357 34–36, 147
for jaundice, 346 indications and contraindications,
Magnetic resonance imaging (MRI), 43 34, 35t
for esophageal cancer, 155 interpretation, 36
of the liver for colorectal cancer, 275 manometry tube, 34–35, 35f
for pancreatic cancer, 328 method of performing, 34–35, 36f
Malabsorption, 209–221 in GERD, 131
abetalipoproteinemia, 219–220 in noncardiac chest pain, 150–151, 152f
bentiromide test for, 211 pH testing, 36–37
bile acid breath test, 213 after standard motility studies, 36
bile acid insufficiency, 216–217 ambulatory measurements, 36–37
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506 Index

Manometric studies (contd.) Minnesota balloon tamponade, for varices,

high-resolution manometry (HRM), 37 441–442
multichannel intraluminal impedance MiraLax, for constipation, 242
(MII), 37 Mirizzi syndrome, 355. See also Gallstones
wireless pH monitoring (Bravo) Misoprostol, in peptic ulcer disease, 166
device, 37 Mivrosomal ethanol oxidizing system
of the stomach, small intestine, and (MEOS), 388
colon, 37 Mixed defects in absorption, 220
Manometry tube, 34–35, 35f Modular Casec, 58t
Mass lesions, 81 Motility disorders, 185, 187. See also
MCT, 58t. See also Medium-chain Diarrhea
triglycerides in esophageal dysphagia, 143–146
MCT Oil, 60 MoviPrep, 22
MCV. See Mean cell volume MRI. See Magnetic resonance imaging
Mean cell volume (MCV), in Mucinous cystadenomas, 331
malabsorption, 209 Mucinous ductal ectasia, 331
Meckel’s diverticulum, 305 Mucosal ablation therapy, 135
Medium-chain triglycerides (MCTs), 59, 324 Mucosal biopsy
MEOS. See Mivrosomal ethanol oxidizing in GERD, 131
system for inflammatiory bowel disease, 248,
Meperidine (Demerol), 18, 22 249f
for pancreatitis, 314 Mucosal blood flow, in peptic ulcer
Meridia (siburtramine hydrochloride disease, 160
maleate), 480–481 Mucosal disorders, in malabsorption,
Meritine, 57t 217–219
Mesalamine enemas, 285 Mucosal protection, in peptic ulcer
Mesalamine preparations, for disease, 159–160
inflammatory bowel disease, Multichannel intraluminal impedance
253–254, 253t (MII), 37
Mesenteric vascular insufficiency, 263–267 for GERD, 132
Metabolic complications in enteral Multiple endocrine neoplasia type I
nutrition, 62 (MEN I), 332
Metabolism, 47–49 Muscularis mucosae, 25
Metamucil, for diverticular disease, 238 Mushroom poisoning (Amanta
Metatastic carcinoid tumors, 225–226 phalloides), 110
Methotrexate Mycobacterium avium-intracellulare
in primary biliary cirrhosis, 415 (MAI), in hepatobiliary disease,
in primary sclerosing cholangitis, 419 298–299
Methyldopa (Aldomet), 405 Mycobacterium kansasii, in hepatobiliary
Metoclopramide hydorchloride, 137 disease, 299
Metronidazole (Flagyl), 110, 208 Mycobacterium tuberculosis, in
for Helicobacter pylori, 173 hepatobiliary disease, 299
for inflammable bowel disease, 254–255 Mycobacterium xenopi, in hepatobiliary
for peptic ulcer disease, 161 disease, 299
Metronidazole, for small-bowel bacterial Mycostatin (nystatin), 121
overgrowth, 216 Myenteric plexus, 140
Microscopic (lymphocytic and collage- Myoneural junction, and dysphagia, 141
nous) colitis, cancer surveillance Myotomy, 153
for, 260–266. See also
Inflammatory bowel disease N
Microsporidia, in hepatobiliary disease N-acetylcysteine (Mucomyst), 404–405
in AIDS, 300 NAFLD. See Nonalcoholic fatty liver
Midazolam (Versed), 18, 20, 22 disease
Midgut carcinoids, 224 Nasoduodenal feeding tubes, 60
MII. See Multichannel intraluminal Nasogastric (NG) intubation and gastric
impedance lavage, in gastrointestinal
Mind and body as inseparable entities, 10 bleeding, 87–88
Mineral oil, for constipation, 242 Nasogastric feeding tubes, 60
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Index 507

Necrolytic migratory erythema, 332 Nutrients, 52, 54t

Necrotizing pancreatitis, 313 Nutritional and metabolic sequelae, in
NEMD. See Nonspecific esophageal motor postgastrectomy, 181–182
disorders Nutritional depletion rate, 52
Neomycin, 110 Nutritional factors, in alcoholic liver
Neoplasms, gastric, 175–179. See also disease (ALD), 390
Small-intestinal neoplasms; Nutritionally complete formulas in enteral
Tumors nutrition, 59
Nephramine, 68 Nutritionally depleted patients, 54
Neurologic assessment, in hepatic Nutritional requirements and assessment,
encephalopathy, 107–108 47–55. See also Diet
Neuromuscular or motility disorders, assessment of nutritional status, 49–52
in dysphagia, 143–146 anthhropometric measurements,
“Neurotoxic” substances, 106 49–51, 50t, 51t, 52t
Nexium (esomeprazole magnesium), biochemical data, 51–52, 52t
91, 136 rate of nutritional depletion, 52
in peptic ulcer disease, 166 metabolism, 47–49
Nicotine, for inflammatory disease, 256 carbohydrates, 47
Nighttime GER, 130. See also energy in starvation, 48–49
Gastroesophageal reflux disease lipids, 47–48
Nissen fundoplication, 133–134, 138 nitrogen balances, 48
Nitrates, for varices, 441 normal energy, 47
Nitrogen balances, 48 protein, 48
Nitrogen requirements, in parenteral nutritional requirements, 52–53, 54t
nutrition, 65 groups of nutrients, 52, 54t
Nitrogen sources, 55 Harris-Benedict equation and basic
Nizatidine (Axid), in peptic ulcer disease, 165 energy expenditure (BEE), 52, 53t
Nonabsorbable sugars, for hepatic indirect calorimetry and the
encephalopathy, 451 respiratory quotient (RQ),
Nonalcoholic fatty liver disease, 395–398 52–53
associated conditions of, 395–396 lipid substitution, 53
definition of, 395 nutritional support guidelines, 53–55, 54t
diagnosis of, 396–397 calorie and protein requirements,
histology, 397 53–55
natural history and prognosis of, fluid and electrolytes, 55
397–398 vitamins and trace elements, 55, 54t
pathogenesis of, 397 Nutritional support. See also Diet; Enteral
treatment of, 398 nutrition; Parenteral nutrition
Nonalcoholic steatohepatitis (NASH), in chronic pancreatitis, 322
395. See also Nonalcoholic fatty guidelines for, 53–55, 54t
liver disease in pancreatitis, 315
Noncardiac chest pain, 149–153 for small-intestinal neoplasms, 224
Non-Hodgkin’s lymphoma, 27 Nystatin (Mycostatin), 121
Nonmotility esophageal disorders, 153
Nonocclusive vascular disease, 264–267 O
Nonspecific esophageal motor disorders Obesity, 476–482
(NEMD), 145, 151, 152f definition of, 476–478
Normal intestinal fluid balance, 184–185, body mass index (BMI), 476, 477t
184t. See also Diarrhea waist circumference, 476, 478
Norwalk virus and Norwalk-like waist-to-hip ratio (WHR), 478
viruses, 198 epidemiology of, 476
NSAIDs, in peptic ulcer disease (PUD), 161 medical complications associated with,
Nucleoside and nucleotide therapy, for 478–479, 479t
HBV, 374–375 pathogenesis of, 478
NuLytely, 110 surgery (bariatric surgery) for, 481–482
Nutcracker esophagus, 145, 151, 152f benefits and complications, 482
Nutrient dense formulas in enteral surgical procedures, 481
nutrition, 59 surgical types, 481–482
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508 Index

Obesity (contd.) Organ enlargement, 81

therapy, 479–482 Orlistat (Xenical), 481
general principles of weight Oroesophageal dysphagia, 141–142
reduction, 479–48, 479t Oropharyngeal sexually transmitted
pharmacotherapy, 480–481 disorders, 289
physical activity, 480 Orthotopic liver transplantation (OLT),
very-low-calories diets (VLCDs) or 459–461, 460f. See also Liver
protein-sparing diets, 480 transplantation
weight-associated disease risks, 478t Osmolite, 57t
Obscure GI bleeding. See Occult Osmo-prep, 22
gastrointestinal bleeding Osmotic diarrhea, 185–186, 185t. See also
Obstruction, in peptic ulcer disease, 162 Diarrhea
Obstructive cholangitis, 357–358 Ostomy care, 280–282
Obstructive chronic pancreatitis, 317 consequences and complications of
Occlusive vascular disease, 263–264 ostomies, 280
Occult gastrointestinal bleeding, 303–305 dysfunction in, 281
background of, 303 fluids, salt, and diet, 281
detection of, 303–304 formation of ostomies, 280
frequency of testing, 303 ileorectal pull-through, 280
method of obtaining stool for testing, Kock pouches, 280
303–304 management of the patient with an
diagnosis, 304–305 ostomy, 280–281
clinical presentation, 304 odors in, 281
diagnostic studies, 304–305 preoperative considerations in, 280–281
occult blood in the stool, 276–277, 277t skin care in, 281
treatment of, 305 Overweight. See Obesity
Octreotide, 92–93 Oxyphenisatin, 405
in metastatic carcinoid tumors, 226
for varices, 441 P
Odynophagia, 141 Pain. See also Abdominal pain
in esophageal candidiasis, 120 in acute abdomen, 79
in GERD, 130 from excess intestinal gas and
Olestra, 481 bloating, 234
Oligosaccharides (glucose polymers), 69 Palpation
Olsalazine (Dipentum), for inflammatory in abdominal examination, 7–8
bowel disease, 253 in acute abdomen, 81
Omeprazole (Prilosec), 136 Pancreas divisum, 317
in peptic ulcer disease, 161, 166 Pancrease, 322
Omeprazole sodium bicarbonate Pancreatic abscesses, 306
(Zegerid), 136 Pancreatic and biliary ductal system,
in peptic ulcer disease, 166 20, 21f
Ondansetron (Zofran), 113 Pancreatic ascites, 306
Opiate derivatives, in diarrhea Pancreatic cancer, 326–331
treatment, 193 chemotherapy for, 330
Opportunistic infections clinical presentation of, 327
in immunocompromised patients, 197, diagnosis of, 327–329
292. See also Human immuno- differential diagnosis of, 327
deficiency virus epidemiology of, 326
in liver transplantation, 468 pathophysiology of, 326–327
Oral cholangiogram, for jaundice, 346 radiation therapy for, 330–331
Oral cholecystogram, 40–41 staging system for, 329
Oral rehydration therapy surgery for, 329–330
in diarrhea, 192–193 tumor markers, 328
solution preparations, 192–193 Pancreatic digestive enzymes and bile
Oral thrush salts, 128
in esophageal candidiasis, 120 Pancreatic endocrine tumors, 332–333
in HIV-infected patients, 119, 120 Pancreatic enzyme supplements,
Oral zinc, in Wilson’s disease, 425–426 322–323, 323t
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Index 509

Pancreatic exocrine insufficiency, and Parvovirus B19, 104

malabsorption, 215–216 Patients
Pancreatic function tests, 211, 213, examination of, 6–9
230–321 with gastroenterologic disorders, 1–11
Pancreatic lithogenesis, 318 Pedialyte, 198
Pancreatic pseudocysts, 315–316 Pedunculated polyps, 269. See also
Pancreatic stone protein (PSP), 318 Colonic polyps
Pancreatitis PEG. See Percutaneous endoscopic
in acute abdomen, 81, 83. See also gastrostomy
Acute pancreatitis; Chronic Pelvic examination, in acute abdomen, 81
pancreatitis Pencillamine, in Wilson’s disease, 425
and gallstones, 307 Penetration, in peptic ulcer disease, 162
Panlobular hepatic necrosis, 104 Penicillin, in fulminant hepatic failure, 110
Pantoprazole (Protonix), 136 Penicillin allergy, 173, 285
in peptic ulcer disease, 161 Pentasa, for inflammatory bowel disease,
Papillary cystic neoplasm (solid and 253–254
cystic tumor), 332. See also Pepcid (famotidine), in peptic ulcer
Pancreatic cancer disease, 165
Paraaminobenzoic acid (PABA), 211 Pepsin, 128
Paracentesis, in ascites, 444–446 Peptic ulcer disease (PUD), 158–168
Paracetamol, 401 complications of, 161–162
Parasitic infections of the bowel, 108–209 defined, 158
Parenteral nutrition, 64–76 diagnosis of, 162–164, 163t
additives, 69–71 pathogenesis, 158–161, 159f
albumin, 71 injurious factors, 158
electrolytes, 69–70, 69t protective factors, 158–160, 160t
heparin, 71 relation of aspirin and other
regular insulin, 71 NSAIDs, 161
trace elements, 71 relation of Helicobacter pylori to
vitamins, 71 peptic disease, 158, 160–161,
central (CPN) or total (TPN), 64–67 167
administration of, 64 treatment of, 164–168
calculations of nutrient values for diet and lifestyle in, 164
TPN, 67–68 drug therapy in, 165–167
caloric requirements, 65 hypersecretory states, 168
catheter care, 64–65 long-term, 167
example, 68–69 smoking control in, 164
initiating, tapering, and discontinuing surgery for, 167–168
TPN solution, 71–72 Pepto-Bismol (bismuth subsalicylate),
mechanical complications, 64 193
nutrient sources, 66–67 Percussion
placement of central venous in abdominal examination, 7–8
catheter, 64 in acute abdomen, 81
protein and nitrogen requirements, 65 Percutaneous endoscopic gastrostomy
solutions for, 67 (PEG), 16, 60–61, 357, 358
complications of TPN, 73–74 Percutaneous liver biopsy, 27, 30–33
definition of, 64 automatic biopsy needles, 31
indications for, 64, 65t background of, 30
monitoring of patient on TPN, 72–73 complications from, 31, 31t
peripheral parenteral nutrition (PPN), indications and contraindications in,
64, 74–76 30, 30t
administration methods, 75–76 interpretation of, 31–32, 32f, 33f
advantages and disadvantages of, 74 traditional method of performing,
example, 75 30–31
indictions for, 74 postbiopsy care, 31
solutions, 74–75 prebiopsy care, 30
Partial liver transplantation, 459, 459f. site choice, 30–31
See also Liver transplantation technique, 31
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510 Index

Percutaneous subclavian or internal Pleural effusion, 307

jugular catheter, 64 Plummer-Vinson syndrome, 142
Percutaneous transhepatic Pneumocystis carinii
cholangiography (PTC), 41, 347 in hepatobiliary disease in AIDS, 300
Percutaneous transhepatic obliteration, for in liver transplantation, 468
varices, 442 Pneumothorax, in central
Percutanious transhepatic cholangiogram, catheterization, 64
for pancreatic cancer, 329 Polycose, 58t, 60
Perforation, in peptic ulcer disease, 162 Polyethylene glycol (PEG) lavage, 22
Perianal area, examination of, 8 for constipation, 242
Pericardial effusion with tamponade, Polymyositis, and esophageal smooth
in central catheterization, 64 muscle dysfunction, 145
Peripheral parenteral nutrition (PPN), 64, Polypectomy, 16, 22, 270
74–76 Polypoid lesions, 179
Peristalsis Polyposis syndromes, 272, 273t. See also
in GERD, 128–129 Colonic polyps
in the upper exophagus, 140–141 Polysaccharides (complex
Peritoneovenous (PV) shunts, for ascites, carbohydrates), 59
446–447 Polyserositis, 306–307
Percussion in acute abdomen, 81 Portal hypertension, in cirrhosis, 438, 439t
PET. See Positron emission tomography Portosystemic encephalopathy (PSE), 448
Peutz-Jeghers syndrome, 272 Portosystemic shunts (PSSs), for varices, 442
Pharmacologic therapy, in GERD, Positron emission tomography (PET)
135–137 scan, 43
Pharyngeal irritation in enteral in esophageal cancer, 155
nutrition, 61 in primary sclerosing cholangitis, 418
Phenytoin (Dilantin), 400 Postgastrectomy disorders, 180–183, 180t
Phlebotomy, for hemochromatosis, 431 afferent loop syndrome, 182–183
pH monitoring chronic gastritis and carcinoma in the
in GERD, 131–132 gastric remnant, 183
in noncardiac chest pain, 151–152 dumping syndrome, 180–181
Phosphatemia, and parenteral nutrition, 73 and malabsorption, 181–182, 220
pH testing, 36–37 nutritional and metabolic sequelae,
Physical examination 181–182
in caustic ingestion, 101 malabsorption, 181–182
in colorectal cancer, 274 weight loss, 181
in constipation, 241 recurrent ulcers, 181
in diarrhea, 191 Postoperative pancreatitis, 308
in dysphasia, 146 Postural signs, in gastrointestinal
in gastric neoplasms, 177 bleeding, 86
in gastrointestinal bleeding, 86 PPIs. See Proton-pump inhibitors
in hemorrhoids, 283 PPN. See Peripheral parenteral nutrition
in inflammatory bowel disease, 247 Pradefovir, for HBV infection, 375
in irritable bowel syndrome, 229 Prebiotics and probiotics, for inflammatory
in pancreatic cancer, 327 disease, 256–257
in pancreatitis, 311, 319 Precision, 57t
in peptic ulcer disease, 162 Predigested formulas (elemental diets) in
in primary sclerosing cholangitis, 417 enteral nutrition, 59–60
in toxic megacolon, 258 Prednisone, 294
Pigment stones (black and brown), for autoimmune hepatitis, 409–410
349–350 in primary sclerosing cholangitis, 419
Pillcam endoscopy, 21 Preeclampsia and eclampsia in
Pill-induced esophagitis, 293 pregnancy, 115
Pioglitazone (Actos), 398 Preesophageal or oroesophageal
Plain abdominal films. See Abdominal films dysphagia, 141–142
Plasmapheresis, in primary biliary Pregnancy, 113–116
cirrhosis, 414 acute fatty liver of pregnancy (AFLP), 114
Plesiomonas shigelloides, 207 acute pancreatitis in, 309
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Index 511

ectopic, 81 Pruritus ani, 286

gastroesophageal reflux disease in, 113 in pregnancy, 114
HELLP syndrome, 114–115 Pseudocysts, 306
hepatic rupture, 115 PSP. See Pancreatic stone protein
hyperemesis gravidarum in, 113 Psychological and emotional aspects
and inflammatory bowel disease of gastroenterologic disorders, 10–11
(IBD), 260 of inflammatory bowel disease, 257
intrahepatic cholestasis of, 113–114 of irritable bowel syndrome (IBS), 10,
jaundice in, 343 229–230
preeclampsia and eclampsia, 115 PTC. See Percutaneous transhepatic
pruritus treatment, 114 cholangiography
recurring jaundice of, 343 PUD. See Peptic ulcer disease
Preoperative laparoscopy, in esophageal Puddle sign, 8
cancer, 155 Puestow procedure, 321–322
Preoperative thoracoscopy and Pulmonary symptoms, in GERD, 130
laparoscopy, in esophageal Pyloric channel ulcers, 127
cancer, 155 PyloriTek test, for Helicobacter
Prevacid (lansoprazole), 91, 136 pylori, 172
in peptic ulcer disease, 161, 166 Pyloroplasty, for peptic ulcer disease, 167
Prilosec (omeprazole), 136
in peptic ulcer disease, 161, 166 Q
Primary biliary cirrhosis, 411–415 Quadruple therapy, for Helicobacter
Primary hepatocellular carcinoma (PHC) pylori, 173
in, 371 Questran (cholestyramine resin), 114
Primary sclerosing cholangitis, 415–420 Quinacrine hydrochloride (Atabrine), 208
Proctalgia fugax, 285–286 Quinton tube, 23
Proctitis, 285
Proctocolectomies, 280 R
Proctosigmoidoscopy, 21–22 Rabeprazole sodium (AcipHex), 136
Pro-Mix, 60 Radiation bowel injury, 246
Propack, 58t Radiation therapy
Propofol IV, 19, 22 for esophageal cancer, 156
Propylthiouracil (PTU), for alcoholic liver for pancreatic cancer, 330–331
disease, 394 for small-intestinal neoplasms, 224
Prostaglandin analogs, 137 Radiofrequency ablation and cryoablation, in
Prostaglandins, in peptic ulcer disease, metastatic carcinoid tumors, 226
160, 165–166 Radiolabeled blood cells and blood
Protein, 48 components, 43
Protein-calorie malnutrition, 392 Radiologic studies, 39–42
Protein-calorie mismatch, parenteral for acute abdomen, 82–83, 82t
nutrition in, 74 for anal fissures, 284
Protein requirements, 53–55 for diarrhea, 192
in parenteral nutrition, 65 for diarrhea in HIV-infected
Protein solutions for parenteral nutrition, 67 patients, 295
Prothrombin time (PT), 337 for dysphasia, 146–147
Protonix (pantoprazole), 91, 136 for esophageal tuberculosis, 125
in peptic ulcer disease, 166 for foreign bodies, 96–97, 98
Proton-pump inhibitors (PPIs), 91 for fungal esophagitis, 120
in GERD, 136 for gastrointestinal bleeding, 91
in peptic ulcer disease, 166 for inflammatory bowel disease (IBD)
Protozoan infections, in hepatobiliary for jaundice, 345–346
disease in acquired for liver tumors, 456
immunodeficiency syndrome for malabsorption, 211, 217
(AIDS), 300 for pancreatitis, 312–313, 320
Pruritus for small-intestinal neoplasms, 222–223
in primary biliary cirrhosis, 413–414 Radionuclide scan, 41, 42–43
in primary sclerosing cholangitis, for gastrointestinal bleeding, 90–91
418–419 for jaundice, 346
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512 Index

Radiotherapy S
for colorectal cancer, 275 Saliva in esophageal clearance, 129
in gastric adenocarcinoma, 178 Salmonella, 203–204
Ranitidine (Zantac), in peptic ulcer in hepatobiliary disease, 299
disease, 165 SAMe, for alcoholic liver disease, 393
Raynoud’s phenomenon, and reflux Savory dilators, 133
esophagitis, 145 Schilling test, for malabsorption, 214, 216
Rectal carcinoid tumors, 225 Scleroderma, and reflux esophagitis, 145
Rectal examination Sclerotherapy (banding), 19
in acute abdomen, 81 Secretin stimulation test
in gastrointestinal bleeding, 86 in pancreatitis, 320
Rectal prolapse, 285 in peptic ulcer disease, 163–164
Rectum, foreign bodies in, 98 Secretory diarrhea, 185, 186, 186t.
Recurrent alcoholic pancreatitis, 318 See also Diarrhea
Red blood cells, radiolabeled for scans, 43 Sedation, conscious, 18
REE. See Resting energy expenditure Selenium deficiency, and parenteral
Refeeding syndrome, 53–54 nutrition, 74
Referred pain in acute abdomen, 79 Sengstaken-Blakemore (SB) balloon
Reflux esophagitis, 126, 127–128. See also tamponade, 93
Gastroesophageal reflux disease for varices, 442
Regurgitation, in GERD, 130 Sepsis
Rehydralylate, 198 in fulminant hepatic failure, 109
Remicade (infliximab), for inflammatory parenteral nutrition in, 68
disease, 254, 256 Serous cyctadenomas, 331
Renal abnormalities, in fulminant hepatic Serum alkaline phosphatase level,
failure, 108 337–338, 338t
Renal failure, parenteral nutrition in, 68 in alcoholic liver disease, 390
Renal formulations for enteral nutrition, 59 Serum amylase levels
Respiratory disorders, in fulminant hepatic in irritable bowel syndrome, 229
failure, 108 in pancreatitis, 311–312, 320
Respiratory failure, parenteral nutrition Serum bilirubin, 339–340
in, 68, 74 Serum carcinoembryonic antigen (CEN),
Respiratory formulations for enteral in gastric neoplasms, 177
nutrition, 60 Serum enzymes as marker of
Respiratory quotient (RQ), 52–53 hepatocellular injury and
Resting energy expenditure (REE), 65 necrosis, 335–336
Restitution, in peptic ulcer disease, 160 Serum gastrin, in peptic ulcer disease,
Retained antrum syndrome, in peptic ulcer 163, 163t
disease, 168 Serum globulins, in alcoholic liver disease, 391
Rifampin, in primary biliary cirrhosis, 414 Serum glutamic-oxaloacetic transaminase
Rifaximin (Xifaxan), 110, 193, 195 (SGOT), 335
for small-bowel bacterial overgrowth, 216 Serum glutamic-pyruvic transaminase
Rigid sigmoidoscope, 21 (SGPT), 335
Ringed esophagus, 143 Serum iron studies, for colorectal cancer,
Rings and webs, in esophageal dysphagia, 142 274–275
Riopan, 135 Serum lipase levels, in pancreatitis, 312
Romazicon (flumazenil), for hepatic Serum proteins, 336–337, 336f
encephalopathy, 453 Serum tests, for primary biliary cirrhosis, 412
Rosiglitazone (Avandia), 398 Sessile polyps, 269. See also Colonic
Rosol, 198 polyps
Rotavirus, 197–198 Sexually transmitted enteric disorders,
Rotor’s syndrome, 343 286, 288–291
Rowasa enema anorectal disorders, 289, 291
for inflammatory bowel disease, 254 anorectal syphilis, 289
for proctitis, 285 Chalamydis trachomatis, 289
RQ. See Respiratory quotient condylomata acuminata (anal
Rubber-band ligation, for hemorrhoids, 283 warts), 291
Rubine tube, 23 gonococcal proctitis, 289
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herpes, 291 clinical presentation of, 222

traumatic injury, 291 diagnostic studies of, 222–223
diagnosis of, 288–291 treatment of, 223–224
gastric disorders, 289 Small intestine, and human immunodefi-
infectious diarrheal conditions, 289 ciency virus (HIV), 293t,
liver disorders, 291 295–297
gonococcal perihepatitis, 291 Social impact of gastroenterologic
hepatitis viruses and disorders, 3
cytomegalovirus, 291 Solid and papillary neoplams of the
syphilitic hepatitis, 291 pancreas, 332. See also
oropharyngeal disorders, 289 Pancreatic cancer
gonococcal pharynigitis, 289 Somatic pain in acute abdomen, 79
herpes pharyngitis, 289 Somatostatin, for varices, 441
syphilis, 289 Somatostatin analogs, in metastatic carci-
pathogenesis of, 288, 288t noid tumors, 226
treatment of, 290t, 291 Somatostatinomas, 333
SGOT. See Serum glutamic-oxaloacetic Somatostatin receptor scintography, for
transaminase metastatic carcinoid tumors, 225
SGPT. See Serum glutamic-pyruvic Sound enteroscopy, in occult
transaminase bleeding, 304
Shatzki’s rings, 142 Sphincteroplasty of the sphincter of
Shigella, 204–205 Oddi, 322
Siburtramine hydrochloride maleate Sphincterotomy and calculus retrieval, 20
(Meridia), 480–481 Sphincterotomy of the sphincter of Oddi, 16
Sigmoidoscopy, 40 Spironolactone (Aldactone), for ascites, 445
for anal fissures, 284 Spleen, 7
for colonic polyps, 270 Spontaneous bacterial peritonitis (SBP),
for colorectal cancer, 275, 277 and ascites, 444–445
for diarrhea, 192 Sporotrichosis, in hepatobiliary disease, 300
for diverticulitis, 238 Sputum cultures, for esophageal
for hemorrhoids, 283 tuberculosis, 125
for inflammatiory bowel disease, 248 Squamous carcinoma of the esophagus, 154
for proctalgia fugax, 286 and dysphagia, 142
for proctitis, 285 radiation therapy for, 156
for pruritus ani, 286 SRH. See Stigmata of recent hemorrhage
for rectal prolapse, 285 Staging and prognosis, in esophageal
for toxic megacolon, 259 cancer, 155
Silibinin, for fulminant hepatic Staging system, for pancreatic cancer, 329
failure, 110 Staphylococcus aureus, 65, 199–200
Silymarin, for alcoholic liver disease, 393 Staphylococcus epidermidis, 65
Six-mercaptopurine (6-MP), for Starvation, energy needs in, 48–49
autoimmune hepatitis, 410 Steatorrhea, in primary biliary cirrhosis, 414
Sjögren’s syndrome, 129 Stent insertion, 21
Skin pigmentation, in hemochromatosis, 429 Stigmata of recent hemorrhage (SRH), 90
SLD, 58t Stomach
Small bowel, foreign bodies in, 98 foreign bodies in, 97–98
Small-bowel bacterial overgrowth, 216 and human immunodeficiency virus
Small-bowel biopsy (HIV), 294
for irritable bowel syndrome, 229 Stool, 9
in malabsorption, 217 occult blood in the stool, 276–277, 277t
Small-bowel disease, and malabsorption, Stool antigen test, for Helicobacter
217–220, 218t pylori, 172
Small-bowel enema or enteroclysis, 40 Stool examination
in occult bleeding, 304 in diarrhea, 191–192
Small-bowel radiologic series, 40 in inflammatory bowel disease (IBD),
Small-intestinal biopsy, 23–25 247–248
Small-intestinal carcinoid tumors, 225 in pancreatitis, 320
Small-intestinal neoplasms, 222–224, 222t in toxic megacolon, 258
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514 Index

Stool studies, for diarrhea in HIV-infected pancreaticoduodenectomy, 329

patients, 295 for pancreatitis, 315
Stress ulcers, 169–170 for peptic ulcer disease, 167–168
Stretta procedure, 138 for peptic ulcer disease (PUD), 167–168
Strictures for placement of feeding tubes, 60
in esophageal dysphagia, 142, 148 for postgastrectomy disorders,
in gastroesophageal reflux disease, 132–134 180–183, 180t
Structural disorders, in dysphagia, for primary sclerosing cholangitis,
142–143, 148 419–420
Subacute liver failure, 104. See also Puestow procedure, 321–322
Fulminant hepatic failure for small-intestinal neoplasms, 223–224
Submucosal polyps, 269. See also Colonic sphincteroplasty of the sphincter of
polyps Oddi, 322
Sucralfate (Carafate), 137 for strictures in GERD, 133–134
in peptic ulcer disease, 166 for toxic megacolon, 259, 259–260
Suction biopsies, 23 for ulcerative colitis, 257
Sudan stain for fecal fat, 210 for vascular-enteric fistulas, 268
Sulfasalazine (Azulfidine), for Sustacal, 57t
inflammatory bowel disease, Sutent (sunitinib), in metastatic carcinoid
253, 253t tumors, 226
Sunitinib (Sutent), in metastatic carcinoid Swallowing, 140–141
tumors, 226 Swan-Ganz catheters, 86
Supine film or flat plate, 39 in gastrointestinal bleeding, 86
Surgery. See also Postgastrectomy Sylose tolerance test, for malabsorption, 213
disorders; Liver transplantation Syphilis, 289
for acute calculous cholecystitis, 354–355 Syphilitic hepatitis, 291
for angiodysplasia, 267
bariatric, 481–482 T
Billroth I and Billroth II, 167–168, 180 Tacrolimus
cholecystectomy and cholecystostomy, for immunosuppression, 471
354–355 in primary sclerosing cholangitis, 419
for cholesterol gallstones, 352 Tagamet, in peptic ulcer disease, 165
for chronic pancreatitis, 321–322 Taurine deficiency, and parenteral
for colorectal cancer, 275 nutrition, 73
for Crohn’s disease, 257–258 Tegaserod (Zelnorm)
for diverticulitis, 238–239 for constipation, 242
DuVal procedure, 322 for irritable bowel syndrome, 230
endoscopic or transgastric surgery, 25 Telbivudine, for HBV infection, 374
for esophageal cancer, 156 Tenofovir, for HBV infection, 375
for gastric adenocarcinoma, 178 Terminal ileal disorders, 216–217
for GERD, 19, 137–138 Tetracycline, for small-bowel bacterial
for hemorrhoids, 284 overgrowth, 216
for hepatic encephalopathy, 452 Tetrathiomolybdate, in Wilson’s disease, 426
for inflammatory bowel disease (IBD), Thalidomide, 294
257–258 for inflammatory disease, 256
for ischemic colitis, 267 Therapeutic endodsopic techniques, 16,
laparascopy (peritoneoscopy) for 19, 22
jaundice, 346–347 Thiazolidinediones (TZDs), 398
laparoscopic, 28–29 Thiopental, 111
laparoscopic cholecystectomy, 352 THM system, in esophageal cancer, 155–156
laparoscopic Nissen fundoplication, 138 Thrombophlebitis, in central
for liver tumors, 456 catheterization, 64
for metastatic carcinoid tumors, 226 TIPS. See Transjugular intrahepatic
myotomy, 153 portosystemic shunt
Nissen fundoplication, 133–134, 138 Tissue injury, in caustic ingestion, 102
for obesity (bariatric surgery), 481–482 Tissue resistance of the esophageal
for occlusive vascular disease, 263 mucosa, in GERD, 120
pancreatectomy, 330 TLESR. See Transient LES relaxation
for pancreatic cancer, 329–330 TNF. See Tumor necrosis factor
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Index 515

Total parenteral nutrition, 64–67. See also Ulcers

Parenteral nutrition bleeding, 89, 90, 90t
in Crohn’s disease, 252 peptic. See Peptic ulcer disease
in inflammatory bowel disease, 252 recurrent in postgastrectomy, 181
Toxic megacolon due to inflammatory stress and, 169–170
bowel disease (IBD), 258–261 Ultrasonography, 42
Toxigenic bacteria, 199–202, 199t for acute abdomen, 82, 82t
TPN. See Total parenteral nutrition for acute calculous cholecystitis,
Trace element requirements, 55, 54t 354, 355
Trace elements, in parenteral for alcoholic liver disease, 391
nutrition, 71 for ascites, 443
Tracheoesophageal fistulas in enteral for choledocholithiasis, 356
nutrition, 61 for diverticulitis, 238
Tranquilizers, for irritable bowel for jaundice, 345–346
syndrome, 231 for pancreatic cancer, 328
Transgastric surgery, 25 for pancreatitis, 312, 320
Transient LES relaxation (TLESR), 127 for primary sclerosing cholangitis, 418
Transjugular intrahepatic portosystemic for small-intestinal neoplasms, 223
shunts (TIPS), 93–94 Ultrasound tranducers, 16
for varices, 442 Upper exophageal sphincter (UES),
Transplantation. See Liver transplantation 34, 140
Travasorb HN, 58t motility disorders causing dysphagia,
Triceps skinfold thickness, 49 141–142
Trientine dihydrochloride, in Wilson’s Upper gastrointestinal bleeding, 84, 84t,
disease, 425 88f, 88–90
Triglycerides, medium-chain, 59 Upper gastrointestinal endoscopy.
Tropheryma Whippelii, 218 See Endoscopy, upper
Trousseau’s sign, in pancreatic cancer, 327 gastrointestianl endoscopy
Tube clogging in enteral nutrition, 61 Upper gastrointestinal radiologic series, 40
Tuberculin skin test, for esophageal in gastric neoplasms, 177
tuberculosis, 125 for inflammatiory bowel disease,
Tuberculosis 250–251
enteric, 246, 246t Urinalysis
esophageal, 125 for acute abdomen, 82, 82t
Tubular polyps, 269. See also Colonic polyps for diverticulitis, 238
Tubulovillous polyps, 269. See also Urine output monitoring, in
Colonic polyps gastrointestinal bleeding, 86
Tumor markers, for pancreatic cancer, 328 Ursodeoxycholic acid (UDCA, ursodiol,
Tumor necrosis factor (TNF), 245 Actigall), 114, 353
Tumors. See also Carcinoid tumors; for cystic fibrosis, 435–436
Gastric neoplasms; Small- for primary biliary cirrhosis,
intestinal neoplasms 414–415
anorectal, 286 for primary sclerosing cholangitis, 419
benign, 179
and dysphagia, 142, 145 V
of the exophagus, 154 Vaccine
malignant, 178 for hepatitis A virus, 364
Turcot’s syndrome, 272 for hepatitis B virus (HBV)
Turner’s sign, 306, 311 Vagotomy, for peptic ulcer disease, 167
Twinrix-Glaxo Smith Kline vaccine, 364, 376 Valacyclovir, 124, 294
Tylenol, 401 Varicella zoster, 123
TZDs (thiazolidinediones), 398 Varices, 19, 438–443
acute gastrointestinal bleeding due to,
U 91–94, 92t
UDCA. See Ursodeoxycholic acid aortoenteric fistula, 94
UES. See Upper exophageal sphincter balloon tamponade by Sengstaken-
Ulcerative colitis (UC) versus Crohn’s Blakemore tube, 93
disease, 244–245, 244t, 245t. See endoscopic banding of, 92, 94
also Inflammatory bowel disease in gastrointestinal bleeding, 91–94, 92f
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516 Index

Varices (contd.) Whipple’s disease, and malabsorption,

Mallory-Weiss gastroesophageal tear, 94 218–219
transjugular intrahepatic portosystemic White blood cell count (WBC), 81
shunt (TIPS), 93–94 White blood cells, radiolabeled for
Vascular disease of the bowel, 263–268. scans, 43
See also Ischemic colitis WHR. See Waist-to-hip ratio
angiodysplasia, 267 Wilson’s disease, 104, 396, 421–426
background of, 263 copper metabolism, 421–422
mesenteric vascular insufficiency, 263–267 copper toxicity, 422
intestinal circulation, 263 diagnosis, 422–425
nonocclusive vascular disease, 264–267 bone and joint disease, 423
occlusive vascular disease, 263–264 hematologic disease, 423
vascular-enteric fistulas, 267–268 K-F rings, 423
Vasopressin (Pitressin), for varices, 441 kidney disease, 423
Venous thrombosis, in central liver disease, 422–423
catheterization, 64 neurologic disease, 423
Verner-Morrison syndrome, 332–333 diagnostic studies of, 424–425
Vertical banded gastroplasty (VBG), 482. genetics in, 421
See also Obesity pathogenesis of, 421
Vibrio cholerae, 200 treatment of, 425–426
Vibrio parahaemolyticus, 201 Wireless pH monitoring (Bravo) device,
Video monitoring systems, in 37, 132
endoscopy, 15
Vigorous achalasia, 145 X
Villous polyps, 269. See also Colonic Xenical (orlistat), 481
polyps Xifaxan (rifaximin), 193, 195
Viokase, 322, 323 for small-bowel bacterial overgrowth, 216
VIPomas, 332–333
Viral esophagitis, 122–124
Viral gastroenteritis, 197–199 Y
Viral hepatitis. See Hepatitis, viral YAG-laser therapy, for esophageal cancer,
Viral infections, in hepatobiliary disease in 156
AIDS, 297–298 Yersinia enterocolitica, 206–207, 246
Virtual colonoscopy, for colorectal cancer, y-Glutamyl transpeptidase (GGT), 339
275
Visceral pain in acute abdomen, 79 Z
Visicol, 22 Zalcitabine (ddC), 293
Visual-evoked potentials, in hepatic Zantac (ranitidine), in peptic ulcer
encephalopathy, 108 disease, 165
Vital HN, 58 Zegerid (omeprazole sodium
Vital signs, in acute abdomen, 81 bicarbonate), 136
Vitamin E, for alcoholic liver disease, 393 in peptic ulcer disease, 166
Vitamin requirements, 55, 54t Zelnorm (tegaserod)
Vitamins, in parenteral nutrition, 71 for constipation, 242
Vomiting, in acute abdomen, 79 for irritable bowel syndrome, 230
von Willebrand’s disease, 303 ZES. See Zollinger-Ellison syndrome
Zidovudine (AZT), 293
W Zinc
Waist circumference, 476, 478 for hepatic encephalopathy, 452
Waist-to-hip ratio (WHR), 478 in Wilson’s disease, 425–426
Warfarin, in occult bleeding, 303 Zofran, 113
Water brash, in GERD, 130 Zollinger-Ellison syndrome (ZES), 332
Watery diarrhea, 202t. See also Diarrhea diarrhea in, 190
Weight, 49 and gastric carcinoid tumors, 224
Weight loss, in postgastrectomy, 181 in peptic ulcer disease, 163
Weight reduction, 479–48, 479t. See also Zovirax (acyclovir), 124, 294
Obesity Zymase, 322