862 • HEPATOLOGY
22.19 Clinical features suggesting an underlying (Box 22.20). The most common liver tumour in Western countries
cause of cholestatic jaundice* is liver metastasis, whereas primary liver cancer complicating
chronic viral hepatitis is more common in the Far East. Unlike
Clinical feature Causes
carcinoma metastases, those from neuro-endocrine tumours
Jaundice typically cause massive hepatomegaly but without significant
Static or increasing Carcinoma weight loss. Cirrhosis can be associated with either hepatomegaly
Primary biliary cholangitis
or reduced liver size in advanced disease. Although all causes
Primary sclerosing cholangitis
Fluctuating Choledocholithiasis of cirrhosis can involve hepatomegaly, it is much more common
Stricture in alcoholic liver disease and haemochromatosis. Hepatomegaly
Pancreatitis may resolve in patients with alcoholic cirrhosis when they stop
Choledochal cyst drinking.
Primary sclerosing cholangitis
Abdominal pain Choledocholithiasis Ascites
Pancreatitis
Choledochal cyst Ascites is present when there is accumulation of free fluid in the
Cholangitis Stone peritoneal cavity. Small amounts of ascites are asymptomatic,
Stricture but with larger accumulations of fluid (> 1 L) there is abdominal
Choledochal cyst distension, fullness in the flanks, shifting dullness on percussion
Abdominal scar Stone and, when the ascites is marked, a fluid thrill/fluid wave. Other
Stricture features include eversion of the umbilicus, herniae, abdominal
Irregular hepatomegaly Hepatic carcinoma striae, divarication of the recti and scrotal oedema. Dilated
superficial abdominal veins may be seen if the ascites is due
Palpable gallbladder Carcinoma below cystic duct
(usually pancreas) to portal hypertension.
Abdominal mass Carcinoma Pathophysiology
Pancreatitis (cyst)
Ascites has numerous causes, the most common of which are
Choledochal cyst
malignant disease, cirrhosis and heart failure. Many primary
Occult blood in stools Ampullary tumour disorders of the peritoneum and visceral organs can also cause
ascites, and these need to be considered even in a patient with
*Each of these diseases can give rise to almost any of the clinical features shown
but the box indicates the most likely cause of the clinical features listed. chronic liver disease (Box 22.21). Splanchnic vasodilatation is
thought to be the main factor leading to ascites in cirrhosis.
This is mediated by vasodilators (mainly nitric oxide) that are
released when portal hypertension causes shunting of blood
that jaundice is due to a malignant biliary obstruction (e.g.
into the systemic circulation. Systemic arterial pressure falls due
pancreatic cancer). Cholangitis is characterised by ‘Charcot’s
to pronounced splanchnic vasodilatation as cirrhosis advances.
triad’ of jaundice, right upper quadrant pain and fever. Cholestatic
This leads to activation of the renin–angiotensin system with
jaundice is characterised by a relatively greater elevation of ALP
secondary aldosteronism, increased sympathetic nervous activity,
and GGT than the aminotransferases.
increased atrial natriuretic hormone secretion and altered activity
Ultrasound is indicated to determine whether there is evidence
of mechanical obstruction and dilatation of the biliary tree (Fig.
22.15). EUS provides an additional investigation modality for
investigation of lower common bile duct obstruction.
Management of cholestatic jaundice depends on the underlying
22.21 Causes of ascites
cause and is discussed in the relevant sections below. Low SAAG (exudative) High SAAG (transudative)
Common causes
Hepatomegaly Malignant disease: Cardiac failure
Hepatic Hepatic cirrhosis
Hepatomegaly may occur as the result of a general enlargement Peritoneal
of the liver or because of primary or secondary liver tumour Other causes
Acute pancreatitis Hypoproteinaemia:
Lymphatic obstruction Protein-losing enteropathy
Infection: Malnutrition
22.20 Causes of change in liver size Tuberculosis Hepatic venous occlusion:
Nephrotic syndrome Budd–Chiari syndrome
Large liver (hepatomegaly) Sinusoidal obstruction syndrome
• Liver metastases (Veno-occlusive disease)
• Multiple or large hepatic cysts Rare causes
• Cirrhosis (early): non-alcoholic fatty liver disease, alcohol, Hypothyroidism Meigs’ syndrome*
haemochromatosis Constrictive pericarditis
• Hepatic vein outflow obstruction
• Infiltration: amyloid *Meigs’ syndrome is the association of a right pleural effusion with or without
ascites and a benign ovarian tumour. The ascites resolves on removal of the
Small liver
tumour.
• Cirrhosis (late) (SAAG = serum ascites albumin gradient; see text)
Presenting problems in liver disease • 863
Cirrhosis
22.22 Ascitic fluid: appearance and analysis
Portal
hypertension Cause/appearance
• Cirrhosis: clear, straw-coloured or light green
Reduced • Malignant disease: bloody
aldosterone
metabolism • Infection: cloudy
Reduced • Biliary communication: heavy bile staining
albumin • Lymphatic obstruction: milky-white (chylous)
Aldosterone
Useful investigations
Activation of • Total albumin (plus serum albumin) and protein*
renin– angiotensin • Amylase
↓ Oncotic system • Neutrophil count
pressure • Cytology
Under-filling • Microscopy and culture
of circulation
*To calculate the serum–ascites albumin gradient (SAAG).
Reduced
renal
blood flow
Transudation
of fluid Splanchnic indicated by an albumin gradient of > 11 g/L (1.1 g/dL) but, unlike
vasodilatation
in cirrhosis, the total protein content is usually > 25 g/L (2.5 g/dL).
High protein ascites (‘exudate’; protein concentration > 25 g/L
Salt Lymph
and water formation (2.5 g/dL) or a SAAG of < 11 g/L (1.1 g/dL) raises the possibility
retention exceeds of infection (especially tuberculosis), malignancy, pancreatic
lymph return ascites or, rarely, hypothyroidism. Ascites amylase activity of
> 1000 U/L identifies pancreatic ascites, whereas low ascites
glucose concentrations suggest malignant disease or tuberculosis.
Ascites Cytological examination may reveal malignant cells (one-third
of cirrhotic patients with a bloody tap have a hepatocellular
carcinoma). Polymorphonuclear leucocyte counts of > 250 × 106/L
Fig. 22.16 Pathogenesis of ascites. strongly suggest infection (spontaneous bacterial peritonitis; see
below). Laparoscopy can be valuable in detecting peritoneal
disease.
The presence of triglyceride at a level > 1.1 g/L (110 mg/dL)
of the kallikrein–kinin system (Fig. 22.16). These systems tend to is diagnostic of chylous ascites and suggests anatomical or
normalise arterial pressure but produce salt and water retention. functional abnormality of lymphatic drainage from the abdomen.
In this setting, the combination of splanchnic arterial vasodilatation The ascites in this context has a characteristic milky-white
and portal hypertension alters intestinal capillary permeability, appearance.
promoting accumulation of fluid within the peritoneum.
Management
Investigations Successful treatment relieves discomfort but does not prolong 22
Ultrasonography is the best means of detecting ascites, particularly life; if over-vigorous, it can produce serious disorders of fluid
in the obese and those with small volumes of fluid. Paracentesis and electrolyte balance, and precipitate hepatic encephalopathy
(if necessary under ultrasonic guidance) can be used to obtain (p. 864). Treatment of transudative ascites is based on restricting
ascitic fluid for analysis. The appearance of ascitic fluid may sodium and water intake, promoting urine output with diuretics
point to the underlying cause (Box 22.22). Pleural effusions are and, if necessary, removing ascites directly by paracentesis.
found in about 10% of patients, usually on the right side (hepatic Exudative ascites due to malignancy is treated with paracentesis
hydrothorax); most are small and identified only on chest X-ray, but fluid replacement is generally not required. During management
but occasionally a massive hydrothorax occurs. Pleural effusions, of ascites, the patient should be weighed regularly. Diuretics
particularly those on the left side, should not be assumed to should be titrated to remove no more than 1 L of fluid daily, so
be due to the ascites. body weight should not fall by more than 1 kg daily to avoid
Measurement of the protein concentration and the serum– excessive fluid depletion.
ascites albumin gradient (SAAG) can be a useful tool to distin-
guish ascites of different aetiologies. Cirrhotic patients typically Sodium and water restriction
develop ascites with a low protein concentration (‘transudate’; Restriction of dietary sodium intake is essential to achieve negative
protein concentration < 25 g/L (2.5 g/dL)) and relatively few cells. sodium balance and a few patients can be managed satisfactorily
In up to 30% of patients, however, the total protein concentration by this alone. Restriction of sodium intake to 100 mmol/24 hrs
is > 30 g/L (3.0 g/dL). In these cases, it is useful to calculate the (‘no added salt diet’) is usually adequate. Drugs containing
SAAG by subtracting the concentration of the ascites fluid albumin relatively large amounts of sodium, and those promoting sodium
from the serum albumin. A gradient of > 11 g/L (1.1 g/dL) is 96% retention, such as non-steroidal anti-inflammatory drugs (NSAIDs),
predictive that ascites is due to portal hypertension. Venous must be avoided (Box 22.23). Restriction of water intake to
outflow obstruction due to cardiac failure or hepatic venous 1.0–1.5 L/24 hrs is necessary only if the plasma sodium falls
outflow obstruction can also cause a transudative ascites, as below 125 mmol/L.
864 • HEPATOLOGY
22.23 Some drugs containing relatively large 1 month). There is usually no proteinuria, a urine sodium excretion
amounts of sodium or causing sodium retention of less than 10 mmol/24 hrs and a urine/plasma osmolarity ratio
of more than 1.5. Other non-functional causes of renal failure
High sodium content
must be excluded before the diagnosis is made. Treatment
• Alginates • Effervescent preparations (e.g. consists of albumin infusions in combination with terlipressin (or
• Antacids aspirin, calcium, paracetamol) octreotide and midodrine where terlipressin is not approved for
• Antibiotics • Sodium valproate
use) and is effective in about two-thirds of patients. Haemodialysis
• Phenytoin
should not be used routinely because it does not improve the
Sodium retention outcome. Patients who survive should be considered for liver
• Carbenoxolone • Non-steroidal anti- transplantation, which, along with TIPSS, is an effective treatment
• Glucocorticoids inflammatory drugs in appropriate patients.
• Metoclopramide • Oestrogens
Type 2 hepatorenal syndrome This usually occurs in patients with
refractory ascites, is characterised by a moderate and stable
increase in serum creatinine, and has a better prognosis.
Diuretics Spontaneous bacterial peritonitis
Most patients require diuretics in addition to sodium restriction. Spontaneous bacterial peritonitis (SBP) may present with
Spironolactone (100–400 mg/day) is the first-line drug because abdominal pain, rebound tenderness, absent bowel sounds and
it is a powerful aldosterone antagonist; it can, however, cause fever in a patient with obvious features of cirrhosis and ascites.
painful gynaecomastia and hyperkalaemia, in which case amiloride Abdominal signs are mild or absent in about one-third of patients,
(5–10 mg/day) can be substituted. Some patients also require and in these individuals hepatic encephalopathy and fever are the
loop diuretics, such as furosemide, but these can lead to fluid main features. Diagnostic paracentesis may show cloudy fluid,
and electrolyte imbalance and renal dysfunction. Diuresis may and an ascites neutrophil count of > 250 × 106/L almost invariably
be improved if patients are rested in bed, perhaps because indicates infection. The source of infection cannot usually be
renal blood flow increases in the horizontal position. Patients determined, but most organisms isolated are of enteric origin
who do not respond to doses of 400 mg spironolactone and and Escherichia coli is the most frequently found. Ascitic culture
160 mg furosemide, or who are unable to tolerate these doses in blood culture bottles gives the highest yield of organisms.
due to hyponatraemia or renal impairment, are considered to SBP needs to be differentiated from other intra-abdominal
have refractory or diuretic-resistant ascites and should be treated emergencies, and the finding of multiple organisms on culture
by other measures. should arouse suspicion of a perforated viscus.
Treatment should be started immediately with broad-spectrum
Paracentesis antibiotics, such as cefotaxime or piperacillin/tazobactam).
First-line treatment of refractory ascites is large-volume paracen- Recurrence of SBP is common but may be reduced with
tesis. Paracentesis to dryness is safe, provided the circulation is prophylactic quinolones, such as norfloxacin or ciprofloxacin.
supported with an intravenous colloid such as human albumin Prophylactic antibiotics reduce the incidence of SBP and improve
(6–8 g per litre of ascites removed, usually as 100 mL of 20% or survival in cirrhotic patients with gastrointestinal bleeding. In
25% human albumin solution (HAS) for every 1.5–2 L of ascites patients with a previous episode of SBP and continued ascites,
drained) or another plasma expander. Paracentesis can be used norfloxacin (400 mg/day) prevents recurrence.
as an initial therapy or when other treatments fail.
Prognosis
Transjugular intrahepatic portosystemic stent shunt Only 10–20% of patients survive for 5 years from the first
A transjugular intrahepatic portosystemic stent shunt (TIPSS; appearance of ascites due to cirrhosis. The outlook is not
p. 870) can relieve resistant ascites but does not prolong life; it universally poor, however, and is best in those with well-maintained
may be an option where the only alternative is frequent, large- liver function and a good response to therapy. The prognosis is
volume paracentesis. TIPSS can be used in patients awaiting also better when a treatable cause for the underlying cirrhosis is
liver transplantation or in those with reasonable liver function, present or when a precipitating cause for ascites, such as excess
but can aggravate encephalopathy in those with poor function. salt intake, is found. The mortality at 1 year is 50% following the
first episode of bacterial peritonitis.
Complications
Renal failure
Renal failure can occur in patients with ascites. It can be pre-renal
Hepatic encephalopathy
and due to vasodilatation from sepsis and/or diuretic therapy,
Hepatic encephalopathy is a neuropsychiatric syndrome caused
or due to hepatorenal syndrome.
by liver disease. As it progresses, delirium is followed by coma.
Hepatorenal syndrome Simple delirium needs to be differentiated from delirium tremens
and Wernicke’s encephalopathy, and coma from subdural
This occurs in 10% of patients with advanced cirrhosis
haematoma, which can occur in alcoholics after a fall (Box 22.24).
complicated by ascites. There are two clinical types; both are
Features include changes of intellect, personality, emotions and
mediated by renal vasoconstriction due to under-filling of the
consciousness, with or without neurological signs. The degree of
arterial circulation.
encephalopathy can be graded from 1 to 4, depending on these
Type 1 hepatorenal syndrome This is characterised by progressive features, and this is useful in assessing response to therapy (see
oliguria, a rapid rise of the serum creatinine and a very poor Box 22.9). When an episode develops acutely, a precipitating
prognosis (without treatment, median survival is less than factor may be found (Box 22.25). The earliest features are very
