Syllabus

CHAPTER 1

Esophageal disorders
Benson T. Massey, MD, FACP and Reza Shaker, MD, MACP

Educational objectives
After completing this chapter, the learner should be able to:
1. Recognize the typical and atypical presentations of esophageal disorders

2. Review the pathophysiology of gastroesophageal reflux disease (GERD)

3. List the risk factors associated with GERD

4. Recommend appropriate treatment options for GERD

5. Select the appropriate evaluation for patients who fail initial treatment for GERD

5. Identify the typical endoscopic and pathologic findings of eosinophilic esophagitis

6. List the differential diagnosis for esophageal eosinophilia

7. Describe the treatment options for eosinophilic esophagitis

8. Review the advantages and limitations of the various diagnostic tests available to
diagnose esophageal disorders

9. Understand the natural history of esophageal disorders as patients transition from

pediatric to adult care, and the differences in childhood and adult presentations.

Introduction
The list of symptoms that strongly suggest the presence of an esophageal disorder is relatively small
(Table 1.1). However, none of these typical symptoms is specific to a particular esophageal disorder.
In addition, there are a variety of symptoms or signs that (1) are infrequent, atypical manifestations of
esophageal disorders, (2) are more commonly seen with non-esophageal disorders, (3) represent extra
esophageal complications of the underlying esophageal disorder, or (4) have an inconsistent or unproven
relationship to esophageal disorders (Table 1.2). Symptoms may arise from disorders intrinsic to the
esophagus, or conditions that affect the esophagus secondarily.

Gastroesophageal reflux disease (GERD)

Pathophysiology
Multiple mechanisms can coexist and interact to drive the development and severity of gastroesopha-
geal reflux disease (Table 1.3). The mechanism by which most gastroesophageal reflux events occur (in

1
2 Digestive Diseases Self-Education Program®

Table 1.1 Between TLESR-related episodes, the LES

Cardinal symptoms of esophageal disorders combined with the diaphragmatic crura act as a
barrier to prevent reflux of gastric contents into the
•• Heartburn (pyrosis)
esophagus. Loss of tone of the LES or disruption of
•• Bland or sour regurgitation
the normal anatomic position of the LES relative to
•• Chest pain
the crura, as occurs with a hiatal hernia, can result
•• Dysphagia (solid/liquid/mixed)
•• Odynophagia
in reflux events. This most often occurs during pe-
•• Eructation/hiccup riods of increasing abdominal pressure or during
swallow induced LES relaxation. Pediatric patients
both health and reflux disease), is the transient exhibit similar mechanisms for reflux events.
lower esophageal sphincter relaxation (TLESR). Although ingested food buffers gastric acid-
This is a vagally mediated reflex, stimulated by ity, an “acid pocket” can persist in the proximal
gastric distension, that results in prolonged (more stomach post-prandially. This acid pocket extends
than 10 seconds) inhibition of the lower esopha- above the diaphragm and even up into the distal
geal sphincter, crural component of the diaphragm esophagus, particularly in GERD patients with
and esophageal body musculature. This reflex nor- hiatal hernia. In this situation, TLESR events are
mally serves to allow venting of swallowed air from more likely to be accompanied by acid reflux. In
the stomach. While healthy subjects and GERD addition, factors that increase the volume of gas-
patients show no consistent differences in post- tric contents available for reflux, such as ingestion
prandial TLESR rates, TLESRs are increased in the of large meals before bedtime or delayed gastric
setting of excess colonic fermentation, obesity and emptying, are associated with increased acid re-
sleep disturbance (e.g. obstructive sleep apnea). flux. Conditions that increase the pressure differ-
TLESR events in GERD patients are more likely to ential between the abdominal and thoracic cavities
be accompanied by acidic liquid reflux that extends will also promote gastroesophageal reflux. Obese
more proximally into the esophagus. subjects, who have higher intra-abdominal pres-
sures, have more acid reflux events on ambulatory
Table 1.2 pH monitoring and more proximal migration of re-
Atypical symptoms of esophageal disorders fluxate into the esophagus. Conversely, in patients
with lung disease, such as cystic fibrosis or severe
asthma, the lower inspiratory thoracic pressure in-
•• Dyspepsia (epigastric burning/fullness)
•• Nausea with or without vomiting
duces more proximal reflux.
•• Hematemesis Several mechanisms exist for clearing reflux-
•• Water brash ate from the esophageal lumen, and abnormalities
•• Globus sensation in all of these are associated with different mani-
•• Coughing festations of reflux disease. Patients with severe
•• Throat clearing esophagitis and Barrett’s esophagus have im-
•• Throat pain/ burning paired primary peristalsis. GERD patients have
•• Throat burning impaired bolus clearance following reflux events.
•• Hoarse voice Reflux patients with regurgitation symptoms have
•• Wheezing/stridor
abnormal UES relaxation responses to the pres-
•• Dyspnea
ence of acidic fluid in the esophagus. Immediate
•• Apnea
re-reflux of an initially cleared bolus, as seen in
•• Movement disorder in infants (Sandifer syndrome)
some patients with hiatal hernia, or partial out-
•• Halitosis
•• Sleep disturbance
flow obstruction, as can occur with a tight gastric
•• Anorexia/weight loss/failure to thrive
band, can effectively prolong the dwell time of re-
fluxate within the esophagus.
 Chapter 1 — Esophageal disorders 3

While appropriate motor responses clear the Table 1.3

volume of refluxate from the esophagus, the bicar- Mechanistic factors in GERD
bonate in swallowed saliva is required to restore
a normal intraluminal pH after acid reflux events. 1. Factors increasing volume/frequency of refluxate
a. Increased TLESR rate
Disorders and medications that impair salivary se-
i. Colonic fermentation
cretion will delay acid clearance from the esopha- ii. Sleep disturbance
gus. In addition, many patients with severe GERD b. Loss of lower esophageal sphincter tone
do not have the normal increase in salivary secre- c. Loss of normal reflux barrier anatomy: hiatal hernia
tion that occurs in response to prolonged esopha- d. Increased availability of refluxate
geal acidification and the development of heart- i. Proximal gastric acid pocket
ii. Larger gastric volume
burn. Reflux events that occur during sleep tend to
iii. Delayed gastric emptying
show long delays until a return to a normal intralu- e. Abnormal thoraco-abdominal pressure differential
minal pH, because salivary secretion and swallow- i. Increased abdominal pressure: obesity
ing are inhibited during sleep. ii. Reduced inspiratory thoracic pressure:
Overall, patients with GERD do not produce lung disease
more acid than healthy volunteers. However, pa- 2. Factors impairing clearance of refluxate
a. Impaired esophageal motility
tients with acid hypersecretory states, such as
b. Abnormal esophago-UES contractile reflex
Zollinger-Ellison Syndrome, have an increased c. Hiatal hernia
prevalence of severe esophagitis. Bile acids can in- d. Esophageal outflow obstruction
duce heartburn and patients with erosive esopha- e. Impaired salivary secretion
gitis and Barrett’s esophagus have more exposure 3. Factors increasing toxic potential of refluxate
to the contents of duodenogastric reflux. Other fac- a. Increased acid secretion: Zollinger-Ellison
Syndrome
tors disrupting the esophageal mucosa can poten-
b. Bile/pepsin in refluxate: duodenogastric
tiate the effects of noxious content of the refluxate reflux, surgical anatomy
(i.e. medication injury and inflammatory disor- 4. Factors affecting tissue resistance to refluxate toxicity
ders, such as eosinophilic esophagitis). a. Medication injury
Recent evidence suggests that the development b. Secondary mucosal disease
of reflux esophagitis in response to the noxious com- 5. Factors affecting sensory response to refluxate
a. Reduced sensory response
ponent of refluxate is not simply a direct chemical
i. Barrett’s esophagus
injury to the mucosa. In a study of healed esopha- ii. Age
gitis patients following medication withdrawal, the b. Heightened sensory response
earliest abnormalities seen were a T-lymphocyte i. Abnormal mucosal nerve terminals
predominant mucosal inflammation, basal cell/ ii. Sleep deprivation/stress
papillary hyperplasia, and dilation of intercellular iii. Affective disorders
iv. Visceral hypersensitivity/Hypervigilance
spaces, with associated changes in mucosal imped-
ance. Only after these initial changes occurred did
typical acute inflammatory changes and surface gitis despite lack of symptoms, and patients with
damage develop. These findings are consistent with Barrett’s esophagus have less sensitivity to acid
earlier work in an animal model of GERD and sug- than GERD patients without Barrett’s.2 Diabet-
gest a pathogenesis mediated by cytokine induced ics with autonomic dysfunction have reduced re-
inflammation, as has previously been demonstrated sponses to different esophageal stimuli. On the
in animal models of reflux esophagitis.1 other hand, some patients report symptoms from
Perceptions of pain in response to esophageal reflux that is out of proportion to the degree of mu-
injury caused by GERD requires intact afferent cosal injury. Preliminary evidence suggests that
neural and cortical pathways for nociception. The patients with non-erosive reflux disease (NERD)
elderly have a greater risk of having severe esopha- have a distribution of mucosal sensory fibers that
4 Digestive Diseases Self-Education Program®

extends closer to the luminal surface.3 Esopha- toms of GERD are seen frequently in both genders
geal pain pathways may develop both peripheral and all ethnic groups, lower rates of complicated
and central sensitization, wherein prior exposure reflux disease are seen in women and Blacks. The
to noxious stimuli lowers the threshold for sub- prevalence of GERD symptoms and complicated
sequent noxious stimuli to initiate symptoms, as disease tends to increase with age.
well as induce hyperalgesia and allodynia in adja- Epidemiologic studies have identified several
cent structures. Both acute and chronic stress can risk factors associated with the presence of GERD
lower the threshold for symptom perception, as and its complications (Table 1.4). Obesity is asso-
can sleep deprivation, the presence of psychiatric ciated with GERD symptoms and complications
co-morbidity, and hypervigilance. of esophagitis, Barrett’s esophagus, and esopha-
geal adenocarcinoma. The epidemic rise in obesity
Epidemiology, risk factors, likely explains a large part of the increased preva-
and natural history lence of GERD and its complications. On the other
GERD is the most commonly diagnosed gastroin- hand, the presence of infection with Helicobacter
testinal disorder, accounting for nearly nine million pylori (HP) and the subsequent development of
outpatient visits and over 100,000 hospitalizations chronic atrophic gastritis have been associated
annually in the United States. The prevalence var- with a reduced risk for reflux esophagitis, Barrett’s
ies widely in different regions of the world. GERD esophagus, and esophageal adenocarcinoma. In
occurs among all age cohorts. Typical reflux symp- parts of the world with historically higher rates of
toms such as regurgitation occur in the majority of HP infection, the progressive decline of this infec-
healthy infants, with the prevalence of such symp- tion with younger age cohorts is associated with an
toms progressively decreasing over the first one to increasing prevalence of GERD. Among patients
years of life. GERD symptoms are present in less with GERD, those infected with HP have more in-
than 10 percent of young children and adolescents. tact esophageal motor function and lower levels of
However, among infants diagnosed with reflux esophageal acid exposure.4 The presence of a hiatal
esophagitis, mucosal lesions persist over one year, hernia increases the risk for GERD symptoms and
even if symptoms resolve. A substantial fraction of complications in studies performed throughout
children diagnosed with GERD have persistence of the world. Among lifestyle factors, smoking has the
reflux symptoms and esophagitis into adolescence most consistently positive association with GERD
and early adulthood. and GERD complications, whereas the findings for
The estimates on prevalence of GERD among alcohol, caffeine, and other dietary components
adults vary among studies, depending on the cri- show either inconsistent or no such associations.
teria for establishing the diagnosis. Studies on Nonsteroidal anti-inflammatory drugs and aspirin
the prevalence of typical symptoms as an indi- are associated with GERD symptoms, ulceration,
rect marker for the presence of GERD indicate and stricture formation. The rate of co-occurrence
that about half of adults report such symptoms of GERD and irritable bowel syndrome in the com-
at some time, and about a fifth have symptoms at munity is more than would be expected by chance.
least weekly. Findings from population-based en- Both anxiety and depression are risk factors for the
doscopic screening studies indicate a lower preva- presence of GERD symptoms. Factors associated
lence of esophagitis (12–16 percent), with about with the development of new GERD symptoms
one-third of subjects identified reporting no reflux over time include older age, female sex, lower edu-
symptoms. Follow-up studies indicate that cohorts cational status, gain in BMI, and smoking. Family
of GERD patients can gain or lose symptoms and and twin studies have indicated a familial risk for
findings of esophagitis over time. There has been GERD, although no single gene mutation explains
an increase in the prevalence of GERD by about 50 this; familial risks are likely dominated by shared
percent over the past quarter-century. While symp- environmental exposures.
 Chapter 1 — Esophageal disorders 5

Clinical presentation Table 1.4

It is important to understand that no symptom Risk factors for GERD symptoms and complications
or constellation of symptoms is pathognomonic
for GERD, and that many patients with GERD do
Risk factor Symptoms Ulcer/stricture Barrett’s Adenocarcinoma
not develop symptoms unless a complication en-
sues. This is particularly true in the elderly. In Obesity + + + +
addition, symptom severity is a poor predictor of
HP infection 0 - - -
the extent of mucosal damage. The classic symp-
toms of GERD are heartburn (pyrosis) and acid re- Smoking + + + +
gurgitation. These symptoms commonly occur in Male Sex 0 + + +
the post-prandial period, but symptoms occurring
White race 0 + + +
at night are particularly troublesome and affect
sleep. However, only about half of GERD patients Aspirin/
+ + 0 -
NSAIDs
report heartburn or regurgitation as their domi-
nant symptom. About a third of GERD patients
+ = increased risk, - = decreased risk, 0 = inconsistent/weak association
report epigastric burning (dyspepsia), rather than
substernal burning, as their most troublesome
symptom. There is an overlap between patients symptom severity, less frequent complete healing
having symptoms of reflux or symptoms of dyspep- of esophagitis on therapy, and greater frequency of
sia, such that about a quarter of patients have both symptom relapse after a course of therapy. How-
types of symptoms.5 ever, lower grades of esophagitis are not always
The development of dysphagia, odynopha- accompanied by evidence of abnormal esopha-
gia, weight loss, and/or hematemesis suggests the geal acid exposure, making them less reliable for
presence of a major complication from GERD and a definitive diagnosis of GERD. In addition, many
should prompt endoscopic evaluation. The chest patients with grade D esophagitis lack the typical
pain of GERD can be indistinguishable from that risk factors for GERD, raising the possibility that
produced by cardiac ischemia. A variety of less typi- the mucosal damage may be occurring by other
cal symptoms have been attributed to GERD. A dif- mechanisms.
ficulty in ascribing these to GERD is that they more
commonly result from other conditions and are less Table 1.5
likely to respond to GERD-directed therapy. Los Angeles classification for erosive esophagitis

Complications Grade
One (or more) mucosal break, ≤5 mm long,
that does not extend between the tops of two
A
Esophagitis and ulceration mucosal folds

GERD-related mucosal erosions typically have One (or more) mucosal break, >5 mm long,
Grade
their base on the squamocolumnar junction and that does not extend between the tops of two
B
extend proximally in a flame-shaped pattern; se- mucosal folds
vere cases can involve nearly the entire esophageal
One (or more) mucosal break that is continuous
mucosa. The Los Angeles classification of erosive Grade
between the tops of two or more mucosal folds,
esophagitis has been demonstrated to have good C
but that involves <75% of the circumference
intra- and inter-observer agreement (Table 1.5 and
Figure 1.1). Validity of this classification scheme is Grade
One (or more) mucosal break that involves at
demonstrated by the association of higher grades D
least 75% of the esophageal circumference
with more esophageal acid exposure, greater reflux
6 Digestive Diseases Self-Education Program®

Figure 1.1
LA grade classification of esophagitis

Esophageal ulcers are more severe mucosal agitis is an etiology for iron deficiency anemia in
breaks, completely through the esophageal mu- all age groups.
cosa. The major complication from peptic esoph-
agitis is bleeding. About one-fifth of patients Strictures
undergoing endoscopic evaluation for upper gas- Peptic strictures may be ring-like or involve longer
trointestinal hemorrhage are found to have ero- segments of the esophagus with diffuse narrowing.
sive esophagitis. In certain patient groups, such Peptic strictures usually have a distal location near
as the elderly and those with developmental ab- the squamocolumnar junction and are commonly
normalities and/or cognitive impairment, reflux accompanied by other mucosal changes from pep-
esophagitis may be the most common cause for tic injury, such as erosions, ulcerations, and Bar-
upper gastrointestinal hemorrhage. Reflux esoph- rett’s mucosa. If a stricture is separated by more
 Chapter 1 — Esophageal disorders 7

than a few centimeters from the squamocolumnar range in length from the appearance of an irreg-
junction, with intervening normal mucosa, other ular z-line to nearly complete replacement of the
etiologies must be considered, including pill in- entire squamous mucosa in the esophageal body.
jury, neoplasia, and eosinophilic esophagitis. The The Prague C & M criteria for assessing the extent
diameter of the narrowest part of the stricture de- of the esophageal lumen involvement by Barrett’s
termines the risk for dysphagia, and nearly all pa- epithelium has shown good inter-observer agree-
tients having strictures less than or equal to 12 mm ment (Figure 1.2).
in diameter report difficulties with solid foods. The Barrett’s esophagus can be seen at any age, but
severity of esophagitis accompanying the stricture is more prevalent with increasing age. Endoscopic
also determines the degree of reported dysphagia. screening studies of adult populations have sug-
Additional symptoms associated with strictures gested an overall prevalence of one to two percent,
are hiccups and retching. with about half of subjects not reporting typical
GERD symptoms. The risk factors associated with
Barrett’s esophagus Barrett’s esophagus are similar to those for un-
Barrett’s esophagus is the term used for the re- complicated GERD, but severe erosive esophagitis
placement of the normal squamous epithelium is an additional risk factor, as are male sex, obesity
lining the esophagus with a columnar epithelium and white race. H. pylori infection reduces the risk
characterized by intestinal metaplasia containing of developing Barrett’s, by reducing the likelihood
goblet cells. The presence of Barrett’s esophagus is of developing GERD.6 As observed in patients with
suspected when the squamocolumnar junction is erosive esophagitis, hiatal hernia, reduced LES
displaced proximal to the anatomic gastroesopha- pressure, and esophageal peristaltic dysfunction
geal junction. The suspected diagnosis requires are commonly present and contribute to the excess
pathologic confirmation with biopsies of the ab- esophageal acid exposure. Reflux of duodenal con-
normal-appearing mucosa. Barrett’s mucosa may tents into the esophagus is also commonly seen in
patients with Barrett’s esophagus. The major clini-
Figure 1.2
cal concern for patients with Barrett’s esophagus
Prague classification of Barrett’s esophagus
is the greater risk for developing adenocarcinoma
of the esophagus. Esophageal adenocarcinoma is
covered in Chapter 14 Gastrointestinal Cancers.
Overall, the rate of progression to high grade dys-
plasia or invasive adenocarcinoma is less than 0.5
percent per year. However, the presence of certain
risk factors, including male sex, cigarette smoking,
longer segments of esophagus involved with Bar-
rett’s mucosa, and the presence of low-grade dys-
plasia can cumulatively increase the rate of pro-
gression to above 2% annually (Figure 1.3).7,8

Extra esophageal manifestations

Gastroesophageal reflux can affect structures
Prague classification measurements from the gastroesoph- proximal to the esophagus, either through the di-
ageal junction. A, Extent of circumferential (C) Barrett’s rect exposure of these structures to the noxious
esophagus. B, Maximal (M) extent of Barrett’s esophageal effects of the refluxate, or via the activation of va-
segment, including tongues. (Reprinted with permission
govagal reflexes. The conditions and symptoms
from Everson MA, Bhandari P, Lovat L, et al., Gastroenterol-
ogy 2018; 154:1222-26). for which extra-esophageal reflux has been impli-
cated are listed in Tables 1.2 and 1.6. Structures
8 Digestive Diseases Self-Education Program®

Figure 1.3
Progression in Barrett’s (PIB) risk score

Progression in Barrett’s (PIB) Risk Score. (Reprinted with permission from Parasa S, Vennalaganti S, Gaddam S, et al.
Gastroenterology 2018;154:1282-9)

located above the esophagus are not normally ex- pathologic laryngopharyngeal reflux. However,
posed to any acid or non-acid liquid refluxate and attempts to ascribe less severe laryngeal findings
do not have mechanisms available for acid neutral- and symptoms have been hampered by poor intra-
ization and clearance. Even brief episodes of rela- and inter-observer agreement on the presence of
tively minor exposure to noxious refluxate could laryngoscopic findings that are attributable to re-
have major pathologic and symptomatic conse- flux. Furthermore, the majority of patients with
quences. Extra-esophageal symptoms are present these milder laryngeal findings have no evidence
in about a third of patients with GERD. for esophagitis or hiatal hernia, and do not re-
Several factors make it difficult to attribute any spond to medical therapy for GERD. Finally, some
individual patient’s extra-esophageal symptoms degree of supra-esophageal reflux can be seen in
and findings to GERD. First, the association may normal subjects, as can the laryngoscopic findings
not be one of cause-and-effect, but reflect a high frequently attributed to reflux disease. The natu-
degree of co-occurrence of the two conditions by ral history of laryngeal symptoms in patients with
unclear mechanisms. Second, the patient’s symp- GERD is that these symptoms resolve in most pa-
toms and findings may more likely result from an- tients over time, regardless of the severity of the
other undiagnosed disorder. For example, chronic underlying reflux disease or whether acid suppres-
cough as an isolated symptom is more likely to sive therapy was given.
result from unidentified reactive airways disease,
bronchiectasis, allergic laryngitis, or sinus disease. Management
Third, initial descriptions of the association of se-
vere extra-esophageal manifestations with severe Lifestyle modifications
reflux disease have not consistently been replicat- There is evidence that certain lifestyle modifica-
ed with milder forms of these conditions. For ex- tions can reduce symptoms and/or esophageal
ample, the initial descriptions of severe ulcerative acid exposure in GERD patients.9 Patients should
laryngitis and tracheal stenosis were seen as com- be encouraged to quit smoking and lose weight if
plications in patients with severe reflux disease, overweight or obese. Small studies report short-
and brought to clinical awareness the concept of term improvement in symptoms when patients fol-
 Chapter 1 — Esophageal disorders 9

low a low-carbohydrate diet. Patients with night-

time symptoms should elevate the head of the bed
Table 1.6
and avoid eating shortly before lying down. Pa-
Extra-esophageal manifestations of GERD
tients should be advised to curtail their use of non-
steroidal anti-inflammatory drugs; if continued, •• Asthma
these should be swallowed with a full glass of liq- •• Aspiration pneumonitis/pulmonary fibrosis
uid. While overall beneficial, these interventions •• Laryngitis/vocal cord lesions
by themselves are inadequate for most patients •• Laryngeal cancer
•• Chronic cough
with more severe GERD.
•• Dental erosions
•• Sinusitis
Medical therapy •• Otitis media
The mainstay for medical treatment of GERD is •• Sudden infant death
proton pump inhibitor (PPI) therapy, which re-
duces the acidity of refluxate, rather than the
number of reflux events. Most patients with GERD cognitive decline. In essentially all of these stud-
respond adequately to a single daily PPI dose, ies, the quality of evidence is low to very low, and/
taken 30-45 minutes before the first meal of the or the associations identified have not been repli-
day. With escalation to split dose therapy twice cated by subsequent studies. The absolute risks
daily before meals and then double dose therapy, identified are quite small and none to date have
the vast majority of patients with erosive reflux been substantiated in prospective, placebo-con-
disease will heal and their symptoms will resolve trolled trials.10 Nevertheless, an attempt to taper
on PPI therapy. There is no evidence to support PPI to the lowest effective dose is recommended.
more frequent dosing. The different available PPI For patients who have intolerance to or con-
agents, used at equivalent potency, are similar in traindications for PPI therapy, the histamine2-
their efficacy, and in the United States, the choice receptor antagonists (H2RAs) and sucralfate have
of agent for any given patient is increasingly driv- demonstrated efficacy above placebo, although the
en by the patient’s insurance plan. Nevertheless, benefits are less than for PPI therapy. Baclofen, by
some patients will unpredictably respond to one reducing TLESR events, may be of adjunctive ben-
agent and not another, so switching agents is a efit for some patients, but central nervous system
reasonable approach. Maintenance therapy at the side effects limit its utility. Agents combining al-
dose needed for healing has the highest chance ginate with an antacid can reduce esophageal acid
of maintaining remission, but patients may be ti- exposure in the post-prandial period, likely by dis-
trated down to the lowest daily dose that permits placing the acid pocket below the gastroesophageal
control of symptoms. Patients with nonerosive junction. Metoclopramide is not recommended as
reflux disease [NERD] and abnormal results on a primary or adjunct therapy for GERD, given lack
ambulatory reflux testing respond equally well to of clear benefit and the risk for irreversible tardive
PPI therapy. Many NERD patients can use short- dyskinesia with prolonged use.
course therapy for symptom recurrence, rather The efficacy for currently available anti-
than continuous daily PPI therapy. An increasing secretory therapies is greater for symptoms of
concern for users and prescribers of long-term PPI heartburn than for regurgitation, and many pa-
are an enlarging number of published case-control tients with GERD continue to report incomplete
studies employing large patient databases that symptom control on PPI therapy. Risk factors
have associated PPI therapy with an increased rel- for failure of typical symptoms to respond to PPI
ative risk for a diverse range of adverse outcomes, therapy include lack of esophagitis or obesity and
including bone fractures, Clostridium difficile in- the presence of functional dyspepsia or irritable
fection, vitamin B12 deficiency, renal failure and bowel syndrome. Patients with lower acid expo-
10 Digestive Diseases Self-Education Program®

Table 1.7 patient has more typical symptoms like heartburn

Reasons for PPI failure in patients with confirmed that respond to therapy, but atypical symptoms
diagnosis of GERD like chronic cough that do not, one should consid-
er the possibility that the patient has both GERD
•• Noncompliance and another condition, such as reactive airways
•• Improper timing disease. Finally, failure to respond to appropriate
•• Inadequate dosage escalations in therapy should prompt a review of
•• Inadequate delivery/bioavailability the criteria by which the diagnosis of GERD was
•• Rapid medication metabolizer; originally made.
true PPI resistance
•• Nocturnal acid breakthrough Surgery
•• Symptoms result from nonacid/weakly acidic/
Laparoscopic anti-reflux surgery (ARS) also has
duodenogastric reflux
efficacy similar to PPI therapy in long-term follow-
•• Patient has GERD plus another disorder
up studies.11 For surgery, a somewhat higher im-
o Esophageal disorder
provement in primary GERD symptoms is offset
(eosinophilic esophagitis, candidiasis)
o Functional disorder
by more symptoms of dysphagia and gas-bloat.
(functional heartburn, rumination) About half of patients undergoing ARS require
o Non-esophageal disorder surgical revision or medical therapy over time.
(cardiac disease, asthma) Up to a fifth of patients undergoing ARS develop
•• Patient does not have GERD (prior testing false- evidence of vagal nerve injury, which impairs the
positive, inadequate) long-term clinical response to the procedure.12
Magnetic sphincter augmentation (MSA) in-
volves the laparoscopic placement of an individu-
sure times on ambulatory reflux testing are also ally sized bracelet of magnetized titanium beads
less likely to have symptom improvement on PPI around the gastroesophageal junction, to serve
therapy. Factors to consider in patients experienc- as an artificial sphincter. Intermediate term (5
ing PPI failure are listed in Table 1.7. About half year) data for this device are currently confined
of patients fail to continue medication or take it to patients with no more than small hiatal hernias
at the proper times. Patients with breakthrough and intact esophageal peristalsis.13 In this group,
heartburn on PPI therapy may benefit from the symptomatic improvement is similar to that seen
addition of an H2RA at bedtime, although tachy- with ARS, but with less gas-bloat. MSA is substan-
phylaxis may limit the efficacy with ongoing use. tially better than twice daily PPI for improving re-
PPIs are unlikely to be of benefit when symptoms gurgitation symptoms.14 Complications from MSA
are driven by the volume of reflux, rather than its include persistent dysphagia, and there have been
acidity. Patients with functional heartburn (heart- increasing reports of the need for repeat surgery
burn symptoms without objective evidence of ab- due to device failure, erosion, and migration, as
normal esophageal acid exposure or association the procedure has become more widely imple-
of symptoms with reflux events) comprise about mented. For patients with medically-complicated
a third of patients with heartburn who fail to re- obesity that warrants bariatric surgery, Roux-en-Y
spond to high dose PPI therapy. Up to half may gastric bypass can be an effective anti-reflux pro-
have symptom improvement with neuromodulato- cedure. However, the presence of a hiatal hernia,
ry agents, including tricyclic antidepressants (e.g., a hypotensive lower esophageal sphincter, and
imipramine), serotonin reuptake inhibitors (e.g., impaired esophageal motility are factors in pa-
trazodone), selective serotonin reuptake inhibitors tients with persistent reflux disease after gastric
(e.g., citalopram), and serotonin-norepinephrine bypass.15 Sleeve gastrectomy should not be used
reuptake inhibitors (e.g., venlafaxine). When a in obese patients with GERD, as GERD symptoms
 Chapter 1 — Esophageal disorders 11

significantly worsen after this procedure. A variety Barrett’s esophagus

of endoscopic approaches to create an anti-reflux Therapy in patients with Barrett’s esophagus is
barrier have been developed. None to date have to control the symptoms of GERD, since medi-
demonstrated convincing durable efficacy.16 cal and surgical treatment infrequently induce
clinically meaningful regression of Barrett’s mu-
Extra-esophageal Syndromes cosa. The current consensus recommendation is
Placebo-controlled trials of acid suppressive thera- to control symptoms and esophageal inflamma-
py have not found significant benefit in the findings tion, not normalize esophageal acid exposure.
and symptoms of reflux laryngitis or in the treat- However, a recently completed prospective ran-
ment of asthmatics without reflux symptoms, even domized trial showed that high dose PPI therapy,
if abnormal esophageal acid exposure is present. compared to low dose, significantly reduced the
When symptoms suggestive of supra-esophageal occurrence of a composite endpoint (develop-
reflux fail to respond to PPI therapy, ambulatory ment of high-grade dysplasia, adenocarcinoma,
reflux testing shows normal patterns of reflux.17 or death) at a nine-year follow-up, an effect that
Anti-reflux surgery is very unlikely to be helpful for was further increased by combining high-dose
extra-esophageal symptoms in the patient without PPI therapy with daily aspirin.20 Smoking cessa-
a symptomatic response to acid suppression ther- tion should be recommended to all patients with
apy.18 Extra-esophageal symptoms in isolation are known Barrett’s esophagus.
more likely to result from disorders in other organ Management of Barrett’s esophagus involves
systems, and evaluation by allergists, pulmonolo- endoscopic surveillance for the development of
gists, and/or otolaryngologists should precede that dysplasia and cancer. Current guidelines recom-
of the gastroenterologist. When aggressive therapy mend surveillance every three to five years in pa-
fails to control symptoms and ambulatory reflux tients without dysplasia, with biopsies taken in all
testing (pH while off therapy or pH-impedance four quadrants every one to two cm throughout
while on therapy) is normal, the symptoms are un- the Barrett’s segment.21 Recent studies have iden-
likely to be due to GERD.19 tified that patients who are found to have persis-
tent low-grade dysplasia (LGD) have a risk of pro-
Peptic stricture gressing to high-grade dysplasia and/or cancer of
Dilation of peptic strictures improves symptoms up to 20 percent annually.22, 23 However, there is
of dysphagia. If dysphagia is the dominant symp- considerable inter-observer variability among pa-
tom and the stricture diameter is less than 12 mm thologists in diagnosing LGD,24 and dysplasia is
diameter, then initial treatment with dilation will difficult to identify in the presence of inflamma-
produce immediate benefit. For more patent and tion. Therefore, current guidelines suggest that
less symptomatic strictures, the option exists for an patients found to have LGD should have repeat
initial trial of PPI therapy. Control of GERD with biopsies after eight to 12 weeks of twice daily PPI
PPI therapy reduces the need for repeat stricture therapy and in the absence of visible esophagitis.
dilation. For newly diagnosed strictures, if there is Persistent findings of LGD should be confirmed by
question about the peptic etiology, obtaining mu- a pathologist expert in the diagnosis of dysplasia.25
cosal biopsy specimens is prudent to evaluate for Patients with persistent LGD and high-grade dys-
eosinophilic esophagitis or malignancy; repeat bi- plasia should be referred to expert centers with
opsy should also be considered if a presumed pep- the capability of endoscopic ablation and resec-
tic stricture fails to respond to intervention. Pa- tion of all identifiable Barrett’s mucosa. Manage-
tients with strictures should be cautioned to avoid ment of Barrett’s associated neoplasia is reviewed
medications with a high risk for esophageal injury, in Chapter 14 on Gastrointestinal Cancers.
such as non-steroidal anti-inflammatory drugs and
bisphosphonates.
12 Digestive Diseases Self-Education Program®

Figure 1.4
Endoscopic images of EoE used to derive an endoscopic reference score

Endoscopic images of EoE used to derive an endoscopic reference score. Edema, white exudates, and furrows are
markers of acute inflammation. Rings and strictures indicate scarring. (Reprinted with permission from Straumann A,
Katzka DA. Gastroenterology 2018;154:346-59.)

genes likely to play a role in the processes of eo-

Eosinophilic esophagitis sinophil activation and recruitment, loss of bar-
Eosinophilic esophagitis (EoE) is a clinicopatho- rier function, and tissue remodeling.26 A higher
logic disease characterized by symptoms result- concordance rate among dizygotic twins than non-
ing from esophageal dysfunction accompanied twin siblings suggests that epigenetic influences
by pathologic evidence of a predominantly eo- from the environment are important in the patho-
sinophilic inflammatory response confined to the genesis of EoE. The majority of pediatric and adult
esophagus. By consensus, in untreated patients patients exhibit allergic responses to food and/or
the accepted density of eosinophilic infiltration is aeroallergens, and most patients have other atopic
15/high-powered field. Other conditions can cause disorders. However, IgE does not appear to play
esophageal eosinophilia, and these need to be ex- a major role in the pathogenesis of EoE, although
cluded (Table 1.8) before a diagnosis of primary tissue resident IgG4 may. EoE is a T helper cell
EoE can be confidently established, especially type 2 (Th2)-mediated disease, with elevations in
when the typical endoscopic features of EoE are chemokines and cytokines, such as eotaxin-3, and
absent. interleukins 5 and 13.
The epithelial barrier dysfunction seen in EoE
Pathophysiology likely leads to increased migration of antigens into
A genetic basis for the disorder was first suggested the mucosa, activating the inflammatory response,
by a high concordance for the disease among fam- which further impairs mucosal barrier integrity.
ily members and monozygotic twins. Genome- The inflammatory response induces a fibrotic and
wide association studies have identified the several remodeling process within the esophageal wall,
 Chapter 1 — Esophageal disorders 13

with longer histories of untreated inflammation be- Table 1.8

ing associated with greater degrees of stricturing. Conditions associated with esophageal eosinophilia
The fibrosis appears to be mediated in part by acti-
vation of the TGF-β pathway, and it is noteworthy •• GERD
that some genetic disorders with abnormal TGF-β •• EoE
signaling (e.g., Loeys-Dietz syndrome), have an in- •• Eosinophilic gastritis/gastroenteritis/enteritis
creased prevalence of EoE. Taken together, these •• Celiac disease
findings support the concept of EoE as an allergic •• Inflammatory bowel disease
disorder, driven by exposure to common allergens •• Drug reactions
and other environmental factors. Specific variants •• Hypereosinophilic syndromes
•• Infections
in the genetic control of the immune response to
•• Autoimmune disorders
antigenic stimulation likely result in the charac-
•• Primary esophageal motor disorders (ie, achalasia)
teristic inflammatory/fibrotic responses within the
•• Graft-versus-host disease
esophagus.
groups. Pediatric patients may fall off the normal
Epidemiology and natural history growth curve. No constellation of symptoms is
Epidemiologic studies suggest that the overall pathognomonic for EoE. Most patients will have
incidence is about 4/100,000/year, with consid- a history of other atopic (asthma, eczema, allergic
erable variability in different parts of the United rhinitis, food allergy) conditions. Over time, pa-
States and world.27 The overall prevalence is 1 per tients may learn to gradually modify their eating
2000, again with considerable regional variability. habits and dietary choices to reduce symptoms.
These rates are somewhat higher in adults than in Therefore, the severity of symptoms is not a reli-
children. There is a male predominance of 3:1, and able predictor of the presence or severity of more
the vast majority of cases are seen in non-Hispanic objective manifestations of the disease.
Whites. Studies of pathology databases suggest a Endoscopy with biopsy is the conventional
rapid increase in the incidence and prevalence of method to make the diagnosis of EoE, assess the
EoE over the past few decades. severity of disease, and exclude the presence of
Among unselected adult patients undergoing other conditions. The presence of characteristic
clinical endoscopic evaluation, esophageal eosino- endoscopic features of EoE (Figure 1.4) can be
philia may be found in up to seven percent, with quantified in an endoscopic reference score. It
higher rates for patients having endoscopy to eval- is important to recognize that about 5 percent of
uate dysphagia (up to 23 percent) or manage food patients may not have these endoscopic features,
impaction (more than 50 percent). In adults, the and this is particularly true in Black patients.28
diagnosis is made less frequently in winter months, Prior therapy may reduce the odds of endoscopic
suggesting an effect of aeroallergens on the disease reference score features being identified. Endos-
course in some patients. HP infection is inversely copy can be insensitive to detect mild or gradu-
associated with EoE27. ally tapering strictures. Barium radiography shows
greater sensitivity for subtle strictures, especially
Clinical presentation and evaluation when combined with a solid bolus (e.g., barium
The most common clinical presentation in adults tablet) challenge. Impedance planimetry can also
is solid food dysphagia, and EoE has become the be employed at the time of endoscopy to identify
most common diagnosis in patients presenting regions of reduced luminal distensibility.
with food impactions. Pediatric patients are more The presence of eosinophilic inflammation
likely to present with recurrent vomiting or food within esophageal mucosal biopsy specimens is
intolerance, but other esophageal symptoms, such required to make the diagnosis. By current con-
as heartburn and chest pain, may be seen in all age sensus, eosinophil counts of greater than or equal
14 Digestive Diseases Self-Education Program®

to 15 per high-powered field (HPF) are needed for PPI therapy is a reasonable first line medical
the diagnosis. The pathologic changes of EoE can therapy for patients with EoE because it can treat
be seen throughout the esophagus, but are often coexisting GERD, if present. In addition, many pa-
patchy in distribution. Therefore, at least six to tients with EoE without evidence of abnormal acid
eight biopsies should be obtained from throughout exposure will have clinical and histologic respons-
the esophageal length for adequate sensitivity at es to PPI monotherapy. This is directly related to
detecting the disease. Diagnostic eosinophil counts PPI effects on blocking eotaxin-3, which is a potent
may not be present during seasons with low levels chemoattractant of eosinophils. These patients are
of aeroallergens in some patients, or when patients indistinguishable by any parameter from other
have been previously treated with PPI. Additional EoE patients who do not so respond. Dosage is
pathologic findings include eosinophilic microab- typically twice daily at double dosage. There are
scesses, basal cell hyperplasia, elongation of der- no long-term studies of efficacy. Therefore, EoE
mal pegs, superficial layering of eosinophils, ex- patients should be started on PPI therapy first, and
tracellular eosinophil granules, and subepithelial endoscopy performed at eight to 12 weeks to evalu-
fibrosis. The mucosal inflammation increases mu- ate for response. If eosinophils and inflammation
cosal conductance of the epithelium, which can be are still present, further therapy is warranted.
detected by a mucosal impedance probe at the time Several short-term placebo-controlled trials
of endoscopy, or an intraluminal impedance probe have shown the benefit of topical steroid therapy
overnight (when the esophageal lumen is empty). in both adults and children.29, 30 Approximately
EoE patients with comorbid atopic illnesses or half of patients experienced symptomatic and/or
history of food allergies should be evaluated by an histologic responses, using doses of one to two mg
allergist. However, routine allergy testing for food of budesonide in a viscous suspension swallowed
and aeroallergens is not otherwise recommended. twice daily. For adults, fluticasone is typically used
at a dose of 440-880 mcg twice daily. In adults,
Therapy sustained benefit of continued topical steroid ther-
There are diverse goals for the treatment of EoE. apy has been seen for up to five years, although
These include control of symptoms, which them- only about a sixth of patients had complete clini-
selves depend on the varying degrees of inflamma- cal, histologic, and endoscopic remission.31 Some
tion and fibrosis that are present. In addition, a subjects may develop oral or esophageal candidia-
goal for control of inflammation is to reduce the sis on topical steroid therapy, and there are isolat-
development of fibrosis and stricture formation ed reports of adrenal suppression.
over the long term. Leukotriene inhibitors, such as montelukast
at high doses may improve symptoms, but without
Medical therapy resolution of the mucosal eosinophilic infiltrate.
No drug therapy is currently approved for the treat- They have not been shown to maintain a steroid-
ment of EoE by the US Food and Drug Administra- induced remission and are not currently recom-
tion. This has necessitated off-label use of differ- mended. Cromolyn sodium has not been shown
ent medications for this expanding population of to be beneficial. The anti–interleukin-5 antibody
patients, which can be extremely expensive for pa- agents mepolizumab and reslizumab reduce tis-
tients when not covered by their insurance plans. sue eosinophil levels without significant symptom
Few pharmacies are often available to compound resolution, so are not recommended.
the repurposed agents for use in the esophagus.
Cessation of therapy for EoE results in relapse of Diet therapy
pathologic changes and symptoms, and the effect Elemental diets to reduce antigenic stimulation have
of therapy on the long-term need for stricture dila- been beneficial in children, but this often requires a
tion frequency is unclear. percutaneous gastrostomy for delivery, due to their
 Chapter 1 — Esophageal disorders 15

unpalatability. A six-food elimination diet has been

shown to improve symptoms and resolve eosino- Other intrinsic structural
philic inflammation in both children and adults. This disorders of the esophagus
diet eliminates milk, wheat, egg, soy, tree nuts and
shellfish. The results of food allergy (skin prick) test- Congenital esophageal
ing are not reliable in predicting the causative foods stenosis, atresia, and
on rechallenge. Recently, a less-restrictive four-food tracheoesophageal fistula
elimination diet (cow’s milk, wheat, egg, soy) achieved Abnormal embryonic development arising in the
a response in over half of pediatric patients.32 A ma- esophageal and tracheal anlagen can result in
jor challenge of elimination diets at present is the incomplete separation of the esophagus from
need to perform repeated endoscopies and biopsies the trachea and incomplete development of the
to confirm the responses to food re-challenges. Less esophagus. The resulting defects range in sever-
invasive technologies, such as swallowed, retriev- ity from esophageal stenosis to tracheoesophageal
able abrasive sponges to obtain brushings from the fistula to esophageal atresia. Most of these pres-
esophagus show promise for monitoring the inflam- ent in the perinatal period with feeding difficul-
matory activity within the esophageal mucosa. ties, vomiting, cough productive of feedings, and
pneumonia. Patients with more subtle stenoses
Endoscopic therapy may not present with dysphagic symptoms until
The first therapy needed for many patients with adulthood. The defects can often be bridged using
EoE is removal of food impactions; flexible en- a gastric tube reconstruction, but with the obligate
doscopy is safe in this setting and allows diagnosis absence of a lower esophageal sphincter and nor-
of the underlying condition. A longer duration of mal esophageal motility, these patients are at high
symptoms at the time of initial diagnosis is a pre- risk for subsequent complications of GERD. Cur-
dictor of the need for dilation therapy. Dilation of rent guidelines favor empiric PPI therapy starting
rings and strictures is safe and effective therapy for at time of diagnosis, with periodic objective test-
improving dysphagia, but the need for repeat dila- ing for GERD if discontinuation of therapy is con-
tions over time is common. The mucosa in untreat- templated.33 These patients frequently require di-
ed EoE can tear easily, and dilation can produce lation of peptic or anastomotic strictures. As they
deep rents into the mucosa that cause chest pain transition to adulthood, patients with esophageal
and odynophagia severe enough to require brief atresia are at increased risk to develop Barrett’s
hospitalization for pain control and hydration. esophagus and squamous cell carcinoma of the
If care is taken to avoid excessive dilation in any esophagus.34
one treatment session, the risk of perforation is
less than one percent. The passage of single large- Inlet patch (Gastric heterotopia)
caliber (54–60 French) bougies to treat a seem- About 1–10% of individuals have an inlet patch
ingly isolated distal ring in EoE can be hazardous of columnar mucosa located at or below the dis-
because endoscopically unrecognized stenoses tal aspect of the UES; the detection rate is higher
may coexist proximally; dilation with graduated when endoscopic examination is focused on iden-
balloon catheters may be safer in this instance. tifying these lesions and narrow-band imaging is
Dilation therapy does not alter the underlying in- employed (Figure 1.5). Whether the origins are
flammatory process. Therefore, unless there is a congenital or develop secondarily is not clear, as
dominant, localized stricture that is the obvious reflux esophagitis and Barrett’s esophagus are
driver of severe dysphagia or food impactions, the commonly associated findings. Most inlet patches
current trend in EoE management is to defer dila- are asymptomatic, but some larger patches appear
tion until the response to dietary and/or medical capable of secreting acid and may be complicated
therapy is known. by symptoms of globus and dysphagia. Complica-
16 Digestive Diseases Self-Education Program®

Figure 1.5
Endoscopic images of inlet patch

Endoscopic images of inlet patch on right in proximal esophagus with white light imaging (left) and narrow band imaging (right).

tions include esophageal strictures, ulcers, and flux. Patients with diabetes may also be less sensi-
rare neoplastic progression. Obliteration of inlet tive to the presence of abnormal amounts of reflux
patches by argon plasma coagulation or radiofre- and thus may not come to clinical attention until
quency ablation has been shown to reduce cervical they develop more severe complications of peptic
symptoms, such as globus, sore throat, or chronic esophagitis. Reflux esophagitis is the most common
cough, in small case studies. finding in patients with diabetic ketoacidosis and
upper gastrointestinal hemorrhage. Diabetes is also
a risk factor for developing Candida esophagitis.
Esophageal manifestations
Connective tissue disorders
of systemic disorders In patients with progressive systemic sclerosis or
Many systemic conditions can affect the esophagus mixed connective tissue disease, the reduction in
secondarily. In some cases, esophageal complica- LES pressure and peristaltic function from atrophy
tions first bring the disorder to medical attention of the smooth muscle predisposes these patients to
and can be the most problematic manifestation for severe reflux disease. The delayed gastric emptying
some patients. that is also frequently present in these patients can
predispose to GERD. Uncontrolled reflux may be
Diabetes a risk factor for chronic aspiration and pulmonary
Several factors predispose diabetic patients to de- fibrosis in these patients. Patients with Sjögren’s
velop GERD and its complications. Importantly, the (sicca) syndrome have reduced ability to neutralize
majority of patients with type 2 diabetes are obese. refluxed acid. The loss of the lubricating properties
Additionally, hyperglycemia increases the rate of of saliva also causes dysphagia for solids. Patients
TLESR response to gastric distension in healthy with connective tissue disorders are at risk for iat-
subjects, and diabetic patients with higher glyco- rogenic complications from immunosuppression
sylated hemoglobin values are more likely to report (infectious esophagitis) or pill injury (nonsteroidal
GERD symptoms. Many patients with diabetes have anti-inflammatory drugs and bisphosphonates for
delayed gastric emptying, predisposing them to re- arthritis and osteoporosis).
 Chapter 1 — Esophageal disorders 17

Dermatologic disorders Table 1.9

Due to its squamous epithelium, the esophagus is Primary dermatologic disorders affecting the
subject to several systemic diseases typically af- esophagus

fecting the skin (Table 1.9). These immune-medi-

•• Epidermolysis bullosa
ated disorders can manifest on endoscopy as blis-
•• Bullous pemphigoid
ters, a positive Nikolsky’s sign, erosions, plaques, •• Pemphigus vulgaris
ulcers, and strictures. The presence of skin and •• Stevens-Johnson syndrome
oral lesions usually provides clues to the diagnosis, •• Lichen planus
although esophageal involvement is rarely the pre-
senting manifestation. Immuno-fluorescent stain-
ing of biopsy specimens can confirm the diagnosis. patients with coronary artery disease, and esopha-
geal acid exposure can reduce coronary blood flow
Infection via a vagal reflex.
The major clinical infections of the esophagus are Congenital or acquired abnormalities of the
Candida, herpes, and cytomegalovirus. The most cardiovascular system can obstruct the esopha-
common symptom of infectious esophagitis is ody- gus via extrinsic compression (dysphagia lusoria).
nophagia. Risk factors for all infections include Dissection of the thoracic aorta may cause acute
profound suppression of the immune system, as esophageal necrosis. Rupture of an aortic aneu-
can be seen in patients with acquired immunode- rysm into the esophagus is usually a fatal event,
ficiency syndrome or in patients on immunosup- presenting as massive hematemesis.
pressive therapy for transplants or chemotherapy
for malignancy. Poorly controlled HIV infection
itself can be associated with large ulcers without Accidentals and iatrogenic
other infectious agents. Additional risk factors for
fungal infections include diabetes, recent antibiot-
esophageal disorders
ic exposure, and swallowed or inhaled topical cor-
ticosteroid therapy. Fungal infections usually have
Esophageal pill injury, caustic inges-
an endoscopic appearance of a whitish exudate tion, and foreign bodies
(“cottage cheese”), while viral infections typically Well over 100 medications have been reported to
cause esophageal ulceration. Diagnosis is made by cause pill-induced esophageal injury. The most
pathologic examination of biopsy specimens. common agents in clinical practice are listed in
(Table 1.10). Doxycycline is notorious for causing
Cardiovascular disorders severe odynophagia, but this symptom, as well as
The major clinical issue regarding cardiovascular symptoms of heartburn, chest pain, and dysphagia
disorders and the esophagus is the need to avoid is seen with many other agents. Injury can range
ascribing symptoms from cardiac disease to the from erosions to deep ulcers to perforation, and
esophagus. While GERD may cause chest pain in the initial lesion may evolve into a refractory stric-
patients with known coronary artery disease, the ture. A clue to the etiology of these lesions is their
converse is also true. Patients with coronary artery common locations above the level of the lower
disease may present with vague chest symptoms esophageal sphincter and above the aortic arch,
ascribed to heartburn, or atypical gastrointestinal unlike lesions from GERD, which are usually based
symptoms such as nausea or eructation, and there on or just above the squamocolumnar junction. A
is some evidence in population studies that mis- common history preceding such injury is that the
diagnosis of myocardial infarction as GERD is an patient swallowed the pill dry and/or while recum-
important problem. Complicating matters further bent. Risk factors for pill injury are old age and
is the fact that GERD is a common comorbidity in sustained release preparations.
18 Digestive Diseases Self-Education Program®

Table 1.10 ingestion. A lack of oral lesions does not exclude

Common medications for pill-induced severe injury more distally in the esophagus.
esophageal injury Inadvertent or intentional ingestion of sharp or
pointed foreign bodies, such as bones, pins, and ra-
•• Aspirin and other nonsteroidal anti-inflammatory zor blades, places the patient at risk for esophageal
drugs (NSAIDs) laceration or perforation, with subsequent develop-
•• Bisphosphonates ment of mediastinitis or fistula into the cardiovascu-
•• Potassium chloride lar system. Retained button batteries can produce a
•• Doxycycline/tetracycline deep tissue injury. Retained esophageal foreign bod-
•• Ascorbic acid
ies constitute an endoscopic emergency.
•• Ferrous sulfate
•• Crizotinib
Medication and radiation effects
Medications that inhibit smooth-muscle tone or
Extremely acidic (pH less than 2) or alkaline contractility can theoretically place patients at
(pH greater than 12) solutions can cause severe higher risk for gastroesophageal reflux and delayed
esophageal injury. A full thickness injury may re- clearance of refluxate. Such agents include calcium
sult in perforation acutely and chronic stricture channel blockers, theophylline, and beta-agonists,
formation, requiring repeated courses of dila- the latter two being used frequently in asthmatics,
tion. Some patients will require esophageal re- who commonly have coexisting GERD. Agents with
placement. Early endoscopy (within 24 hours) is anticholinergic properties can also decrease sali-
safe and warranted to assess the severity of inju- vary secretion, resulting in dysphagia and pyrosis
ry in patients who have symptoms after reported due to impaired neutralization of refluxed acid.

Table 1.6
Endoscopic images of abnormal fundoplications

Endoscopic images of abnormal fundoplications. A. Slipped wrap, with gastroesophageal junction above hiatus. B.
Loose wrap, allowing retroflexed views back into esophageal lumen. C. Completely broken down wrap. D. Paraesopha-
geal herniation alongside wrap. E. Twisted wrap. F. Herniation of part of fundus above wrap.
 Chapter 1 — Esophageal disorders 19

Ionizing radiation has both early and delayed

Sensori-motor, neoplastic, and
effects on the esophagus. Acutely, the inflamma-
portal hypertensive disorders
tory response may cause dysphagia and odyno-
of the esophagus
phagia severe enough to require alternate means
These topics are covered in separate chapters. The
of alimentation. More severe injury can lead to
clinician must remain aware that these can coexist
extensive transmural necrosis, with hemorrhage
with other esophageal disorders. For example, pa-
and perforation. Later effects tend to be from ste-
tients with esophageal achalasia may suffer from
nosis, which may progress to complete luminal
pill injury, Candida esophagitis, reflux disease (fol-
occlusion, especially in the retrocricoid area. Con-
lowing surgical myotomy), or esophageal cancer.
current chemotherapy increases the risk of injury
Patients with GERD and Barrett’s esophagus may
for any given course of radiation therapy. Patients
develop adenocarcinoma of the esophagus. Patients
with radiation-induced xerostomia have a higher
may develop esophageal strictures from efforts to
frequency of abnormal esophageal acid exposure
eradicate varices. Patients with motor disorders
and reflux esophagitis.
can develop Zenker’s and other pulsion diverticula.

Consequences of endoscopic
and surgical procedures Approach to patients with
Passage of instruments into the esophagus carries
a small risk of abrasion, laceration, hematoma, or suspected esophageal
frank perforation. This risk becomes much great- disorders
er in the presence of structural disorders, such as
rings and strictures, particularly since subtle stric- The patient history remains the cornerstone of
tures may not be easily recognized at the time of evaluation when esophageal disorders are suspect-
endoscopy. Perforation is the dreaded complica- ed, with emphasis on the presence, severity, time
tion of stricture dilation, emphasizing the need course, and associations of cardinal and atypical
for cautious technique. Treatments to eradicate symptoms. History taking should also address the
abnormal mucosa (Barrett’s) and varices in the presence of conditions that secondarily affect the
esophagus may produce strictures. esophagus, as should the physical examination
Immediate iatrogenic injuries from esophageal (which is typically normal for primary esophageal
surgery include mucosal tears, frank perforations, disorders). Additional testing is usually necessary
intramural hematomas, ischemic necrosis, and to obtain an accurate diagnosis of esophageal dis-
anastomotic strictures and leaks. Patients under- orders, with the sequence of testing guided by find-
going anti-reflux surgery may have immediate or ings from the history and physical examination in
delayed symptoms from overly tight or long wraps, conjunction with knowledge regarding the back-
slipped wraps, or development of a paraesopha- ground prevalence, clinical associations, and risk
geal hernia35 (Figure 1.6) Symptoms and find- factors of the different esophageal disorders.
ings of GERD occur frequently following surgical
treatment of achalasia, with higher rates seen in Diagnostic strategies and
patients undergoing per-oral endoscopy myotomy options for testing
(POEM) than laparoscopic Heller myotomy.36 Rational and cost-effective testing and treatment
Patients undergoing radiofrequency ablation in the twenty-first century is based on the knowl-
for cardiac arrhythmias are at risk to develop ther- edge that the most prevalent esophageal disorder
mal injury to the adjacent esophagus. Such lesions by far is GERD. Even patients presenting with
are not always symptomatic, but the concern is for atypical symptoms are more likely to have GERD
the rare development of fatal cardioesophageal fis- than another esophageal disorder. This high pre-
tulas following such transmural esophageal injury. test probability of GERD drives the diagnostic ap-
20 Digestive Diseases Self-Education Program®

proach, which has to be tempered, particularly in Careful consideration must be given to the
younger subjects, by the rising prevalence of EoE. patient presenting only with chest discomfort
For patients presenting with the classical symp- atypical for GERD. The concern is that the pa-
toms of heartburn (typically postprandial substernal tient has undiagnosed coronary artery disease
burning with upward radiation) and/or sour regur- (CAD). CAD and GERD share many of the same
gitation, who have recognized risk factors for GERD, risk factors and commonly occur together. Such
the likelihood that these symptoms result from patients warrant rigorous evaluation to exclude a
GERD is so great that initiation of PPI therapy is the cardiac source of pain before evaluation of pos-
most reasonable action. If the patient responds ap- sible esophageal sources. For patients with these
propriately, no other testing is necessary to confirm atypical coronary syndromes, resting EKG and
the diagnosis. The utility of evaluating such patients routine exercise stress testing alone may not be
for asymptomatic complications of GERD, such as adequately sensitive.
Barrett’s esophagus, is controversial. Any such test- Following a negative cardiac evaluation, pa-
ing should be guided by the presence of known risk tients with chest pain, a negative EGD off therapy,
factors for Barrett’s esophagus. and symptoms of heartburn and regurgitation, the
Patients fitting the above scenario who fail to most likely diagnoses are non-erosive reflux disease
achieve symptom control with standard or high split (NERD), esophageal hypersensitivity, functional
dose PPI therapy should have symptoms evaluated heartburn, or an esophageal motor disorder. As
by upper endoscopy (EGD) after they have been off NERD in this setting remains the most prevalent
therapy for at least two weeks. Patients with a previ- diagnosis, a trial of high-dose twice-daily PPI thera-
ously negative EGD while on therapy (and poor re- py for at least eight weeks is a reasonable next step.
sponse to therapy) are also candidates to undergo If the patient has adequate symptomatic response,
repeat EGD while off therapy. This is to avoid miss- the next step is to taper down therapy to the mini-
ing erosive esophagitis and EoE. Patients with these mal that provides acceptable relief of symptoms.
“classic” reflux symptoms but no GERD risk factors Patients with a negative EGD and failure to
(e.g., a 20 year-old woman, BMI 20, non-smoking, respond to PPI therapy in the scenario described
not taking NSAIDs, no family history of GERD) in the above paragraph require additional test-
should be considered for EGD first, rather than ini- ing, which involves esophageal manometry and/
tially starting PPI therapy, due to the higher likeli- or ambulatory reflux testing. Factors favoring
hood for other esophageal disorders. manometry as the next test include 1) presence of
Patients presenting with odynophagia or trou- dysphagia and 2) need for manometric informa-
blesome dysphagia should undergo early EGD, tion to position a catheter-based reflux probe. If a
because of the greater likelihood of GERD compli- wireless ambulatory reflux test is performed first,
cations or the presence of another serious esopha- this should be conducted off acid suppression
geal disorder. Endoscopic evaluation of dysphagia therapy; if this test is normal, esophageal manom-
should include random biopsies from the proximal etry should be performed. Esophageal manom-
and distal esophagus (if no other explanation for etry may also be of value when the ambulatory
dysphagia is seen), to identify otherwise unsus- reflux test is abnormal, because it may provide
pected EoE. Early EGD should also be performed insight into the mechanisms for abnormal reflux
in patients with additional alarm signs/symp- in a patient with a normal EGD (i.e., hypotensive
toms, such as weight loss, repetitive vomiting, he- LES, extremely impaired motility). Esophageal
matemesis, anemia or family history of upper GI manometry and ambulatory reflux testing are also
malignancy. Patients with a combination of car- required for the patient with a negative EGD and a
dinal esophageal and atypical symptoms are also good response to therapy who is considering sur-
candidates for early EGD, as are patients over age gical therapy for GERD. This is to 1) be certain the
55 with dyspeptic symptoms. patient actually has GERD, rather than a placebo
 Chapter 1 — Esophageal disorders 21

response to PPI therapy and 2) assure that the pa- impedance testing can be performed on therapy in
tient does not have a major esophageal motility this setting, as it may help identify patients whose
abnormality that would be a contraindication for therapy is not controlling their reflux. Such pa-
anti-reflux surgery. tients will require esophageal manometry, if not
If the patient’s dominant symptom is solid performed previously, and are candidates for an-
food dysphagia, and EGD is normal, the next test ti-reflux surgery. However, many patients in this
should be a barium pharyngoesophagram that in- setting have no evidence of persistent reflux on
corporates a solid bolus challenge, to assess for therapy and thus have both GERD and functional
previously missed subtle rings, webs, and steno- heartburn37.
ses. If the esophagram is negative, the next test For the patient who fails to respond to anti-re-
should be an esophageal manometry to detect the flux surgery, or relapses after initial success, EGD
presence of an esophageal motor disorder, such as is the first test, the goal being to assess integrity
achalasia or distal esophageal spasm. Manometry of the surgical repair and evaluate forcomplica-
should be the next test after a normal endoscopy tions such as the development of a paraesophageal
if liquid dysphagia and bland regurgitation are hernia. EGD can also detect whether the patient
prominent symptoms. has a new, or previously missed, esophageal disor-
Patients with a negative endoscopy and fail- der. If EGD is unrevealing, the next test should be
ure of a PPI trial, followed by normal esophageal esophageal manometry, especially if this was not
manometry and ambulatory reflux testing, likely performed preoperatively, followed by ambulatory
have a functional disorder, characterized by vis- reflux testing off therapy. If these tests are all nega-
ceral hypersensitivity, hypervigilance, and/or tive the patient may have a functional disorder as
maladaptive behavioral responses. Another pos- the cause of symptoms.
sibility at this point is that the symptoms do not
arise from the esophagus. Performance characteristics of
Patients presenting with candidate extra- diagnostic tests
esophageal symptoms without concurrent cardi- The capabilities and caveats for the major tests to
nal esophageal symptoms have such a low pretest evaluate esophageal disorders are described be-
probability of having an esophageal disorder that low. The lack of perfect sensitivity and specificity
a source for symptoms in other organ systems of these tests must be considered when they are
should be investigated first. This is also true when used to evaluate patients with a low pretest like-
cardinal symptoms from a known esophageal dis- lihood of an esophageal disorder, such as those
order have responded appropriately to therapy, with only atypical symptoms. In this setting, neg-
but extra-esophageal symptoms persist. If evalu- ative test results are often the most helpful, be-
ation of other organ systems is negative, EGD cause the post-test probability is sufficiently low
followed by ambulatory reflux testing off therapy that esophageal etiologies can be removed from
should be performed. further consideration.
A common clinical scenario is the patient in
whom prior testing supported the diagnosis of Endoscopy
GERD, but who fails to respond to GERD-directed Endoscopy allows the visual identification of mu-
therapy. The first pstep is to confirm the reliability cosal and structural abnormalities in the esopha-
of previous testing. For patients treated medically, gus and affords the opportunity to obtain diagnos-
the next step is to investigate correctable causes tic mucosal biopsies. Treatment of some disorders
for medication failure, as well as to identify factors (stricture dilation, control of bleeding) can also
that would cause even optimized medical therapy be performed at the time of testing. False-posi-
to fail (e.g., symptoms of regurgitation in a patient tive results from endoscopy are usually related to
with a large hiatal hernia). Repeat ambulatory pH/ misinterpretation of identified lesions (mistaking
22 Digestive Diseases Self-Education Program®

white spots of EoE for candidiasis, or ulcers from era when many patients are already on a PPI at the
viruses or pill injury for GERD, or EoE strictures time of endoscopy.
for peptic strictures). Preventable causes for false-
negative endoscopies include failure to (1) examine Radiology
the esophageal inlet carefully for webs and inlet Barium fluoroscopic studies are insensitive to flat
patches, (2) recognize the characteristic features of mucosal lesions, and the findings of reflux events
EoE, (3) obtain mucosal biopsy specimens to diag- during these studies do not reliably predict the
nose EoE and 4) recognize abnormal post-opera- presence of GERD. These studies can be useful for
tive anatomy. There is also considerable subjectiv- identifying subtle webs, rings, and stenoses that
ity to the reports of endoscopic findings, such that are not detectable by endoscopy, but this requires
endoscopists are more likely to interpret an endo- the additional use of an adequate-sized solid bo-
scopic exam as having features supporting a diag- lus challenge (e.g., a 13mm barium tablet). Bari-
nosis of GERD when they are provided a clinical um studies can also assess the detail of strictures
history that suggests GERD rather than peptic ul- too tight to allow endoscope passage and identify
cer disease. Despite careful technique, subtle webs esophageal fistulas. Computed tomography (CT)
and stenoses may remain undetected. In addition, imaging can detect pathologic thickening of the
nearly half of patients with GERD do not have de- esophageal wall and extrinsic pathologic processes
tectable endoscopic abnormalities, especially in an that compress or invade the esophagus.

Figure 1.7
pH/impedance study

change MII to impedance and add first parenthesis before the word light. Should read: Example of a reflux event on
pH/impedance testing. Probe has two pH sensors, the distal one placed 5 cm above the top of the lower esophageal
sphincter and six impedance channels. Liquid reflux is seen at the distal two impedance channels and gas reflux on the
impedance channels proximal to these. Neither acid nor liquid reaches the proximal-most pH/ impedance sensors. In this
example, bolus presence time (light blue shaded region) is much shorter than the duration of intraluminal acidification.
 Chapter 1 — Esophageal disorders 23

Manometry ing reflux events. Limitations are failure to have a

Manometry has minimal utility in the diagnosis symptom occur during the recording period as well
of GERD. Manometry is used to diagnose symp- as inaccurate reporting of symptom events by pa-
tomatic major esophageal motor disorders and tients. Symptom associations on studies with few
to exclude their presence in patients proposed for events are unreliable. For cough, it is often not
anti-reflux surgery. Manometry may be helpful in possible to distinguish between coughs caused by
identifying symptomatically tight fundoplication reflux events or vice versa.
wraps when endoscopic and radiologic testing is
inconclusive. Manometry is also used for locating Intraluminal impedance planimetry
the position of the LES for placement of pH probes. Intraluminal impedance planimetry is a method-
ology for assessing the cross-sectional area along
pH/impedance monitoring a length of the esophageal lumen and how this
Ambulatory pH monitoring allows the quantifica- changes in response to increasing distension pres-
tion of the degree of esophageal acid exposure and sures. This allows detection of regions with poor
the correlation of symptoms with reflux events. A distensibility. The resolution is 1 cm. It is insensi-
major problem with such testing is that no cutoff tive to radial asymmetry in stenosis and cannot dis-
value for acid exposure completely separates normal tinguish between reduced distensibility resulting
subjects from those with GERD. The accuracy of pH from a structural disorder vs a motor disorder at
testing is at best about 90% in patients with GERD. the gastroesophageal junction. Current clinically
Testing can be performed with either catheter-based available devices usually require sedation and en-
or mucosally-attached wireless sensors. The lat- doscopic placement to be tolerated by the patient.
ter have the advantage of better tolerability by the
patient and longer recording times. Disadvantages
include lack of impedance measurements, the cost
Illustrative clinical case
of a second endoscopy often used to place the probe A 53-year-old woman presents with a 3-month his-
(and occasionally a third to remove probes causing tory of worsening heartburn and a 1-month history
intolerable pain), and premature dislodgement and of persistent dysphagia for breads and meats. She
migration of the sensor into the stomach. This lat- has had occasional heartburn for years that she
ter event can give the false appearance of prolonged treated with over-the-counter antacids. However,
esophageal acid exposure time. she has been having more heartburn in the evening
Probes are also available that record intralu- and night, and started taking an over-the-counter
minal pH and impedance changes, the latter being histamine2-receptor antagonists at bedtime last
used to detect weakly acidic reflux events (Figure month without much improvement. Her medi-
1.7). These probes can also detect aerophagia and cal history is pertinent for asthma, hypertension,
supra-gastric belching. Impedance can also be hyperlipidemia, obesity, and degenerative joint
used to prevent mistaking undocumented inges- disease. Her other medications are albuterol and
tion of acid foods as reflux events, which is a prob- fluticasone inhalers, simvastatin, enalapril, and
lem for single-point pH sensors. over-the-counter ibuprofen. Physical examination
Ambulatory studies can be performed off or on shows a blood pressure (BP) of 134/80 mmHg and
acid suppressive therapy, depending on whether a body mass index (BMI) of 32 kg/m2, but is oth-
the goal is to help make the initial diagnosis of erwise unremarkable.
GERD or to try to determine if persistent symp- Because of the new-onset solid-food dyspha-
toms while on therapy result from GERD that is gia, she undergoes an upper endoscopy, with find-
not adequately treated under the current regimen. ings of Los Angeles class B erosive esophagitis at
These studies can also assess the temporal as- the gastroesophageal junction, a 13-mm diameter
sociation of the patient’s symptoms with preced- ring-type stricture at the gastroesophageal junc-
24 Digestive Diseases Self-Education Program®

tion, and a 2-cm fixed hiatal hernia. The ring is

disrupted with a 16-mm diameter balloon dilator,
and the patient is switched to a PPI before break- Pearls and pitfalls
fast and advised to use acetaminophen instead of for the board exam
ibuprofen for joint pain. On follow-up one month •• Beware of “white spots” in the esophagus:
later, dysphagia has resolved, but she is having these could be from Candida or EoE!
heartburn three nights per week. Addition of a sec- •• Be able to recognize reflux events on pH/
ond dose of PPI before the evening meal results in impedance tracings
•• Endoscopy shows Los Angeles Grade C
essentially complete resolution of her symptoms
erosive esophagitis and Barrett’s mucosa with
after two additional months. low-grade dysplasia? Repeat biopsies after
She does well until two years later, when she healing esophagitis, with confirmation of
develops burning substernal pain that can last for persistent dysplasia by an expert pathologist
hours and can awaken her, even though she contin- before considering ablation.
•• Know the exact criteria for diagnosis of
ues on her reflux medication. She at times notices
EoE, as well as the differential diagnosis of
pain when swallowing her pills. Interval history is esophageal eosinophilia.
of a new diagnosis of osteoporosis, which is being •• Be familiar with the appropriate dosage,
treated with alendronate. She undergoes repeat timing, and duration of PPI administration
•• Watch out for the dysphagia patient with a
endoscopy, showing erosions at 25 cm from the in-
“negative” EGD in which no biopsies were
cisors and at four cm above the gastroesophageal taken. What could have been missed: EoE,
junction. Biopsies are negative for EoE or infec- subtle ring/stricture, major motor disorder.
tion, and she is advised to discontinue the alen- •• Be aware of what normal and abnormal post-
dronate, with resolution of her symptoms over the fundoplication anatomy looks like on EGD.
•• Esophageal ulcers distant from the z-line?
next week.
Think bugs and drugs (pill injury).
She again does well until 2 years later, when she •• Upper abdomen or chest discomfort not
develops substernal chest discomfort at mealtime responding to PPI? Don’t forget the heart!
or when walking her dog. An associated symptom
is nausea, and additional over-the-counter antacid
tablets do not help. Examination is unchanged ex-
cept for BMI of 34 and BP of 148/92 mmHg. She
is referred to a cardiologist who performs a coro- Most efficient source
nary angiogram, showing a 90 percent occlusion reviews for examination
in the right coronary artery. A drug eluting stent
is placed, and she is begun on clopidogrel and low-
preparation
•• Gastroenterology: Special Issue on Esophageal
dose aspirin, with resolution of these symptoms.
Diseases. 2018 (January); 154 (2): 263-452.
This case illustrates several important concepts •• Rosen R, Vandenplas U, Singendonk M, et al.
in the evaluation and management of esophageal Pediatric Gastroesophageal Reflux Clinical Practice
disorders. The patient had several risk factors for Guidelines: Joint Recommendations of the North
her primary esophageal disorder of GERD. She had American Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and the European
symptoms that should prompt endoscopic evalu-
Society for Pediatric Gastroenterology, Hepatology,
ation (and treatment). She required medication and Nutrition. https://www.ncbi.nlm.nih.gov/
adjustments to provide adequate symptom relief. pubmed/29470322”J Pediatr Gastroenterol Nutr.”
While her condition is a chronic one, she required 2018;66:516-54.
•• Straumann A, Katzka DA. Diagnosis and
careful reevaluation when she later experienced new
Treatment of Eosinophilic Esophagitis.
symptoms while on effective therapy, due to the Gastroenterology 2018;154:346–359
subsequent development of a new esophageal disor-
der and subsequently coronary artery disease.
 Chapter 1 — Esophageal disorders 25

Development and validation of a model to

determine risk of progression of barrett’s
•• Freedberg DE, Kim LS, Yang Y-X. The risks and esophagus to neoplasia. Gastroenterology
benefits of long-term use of proton pump in­ 2018;154:1282-1289.
hibitors: expert review and best practice advice 9. Ness-Jensen E, Hveem K, El-Serag H, et al.
from the American Gastroenterological Associa­ Lifestyle intervention in gastroesophageal
tion. Gastroenterology 2017;152:706-15. reflux disease. Clin Gastroenterol Hepatol
•• Vaezi MF, Katzka D, Zerbib F. Extra esophageal 2016;14:175-82.
symptoms and diseases attributed to gerd: 10. Freedberg DE, Kim LS, Yang Y-X. The risks and
where is the pendulum swinging now? Clin benefits of long-term use of proton pump in-
Gastroenterol Hepatol 2018;16:1018-1029. hibitors: expert review and best practice advice
from the American Gastroenterological Associa-
tion. Gastroenterology 2017;152:706-15.
11. Hatlebakk JG, Zerbib F, Bruley des Varannes S,
et al. Gastroesophageal acid reflux control 5
years after antireflux surgery, compared with
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