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Cirrhosis 163
haemorrhage is designated decompensated cirrhosis. Cirrhosis without any
of these complications is termed compensated cirrhosis.
Investigations
These are performed to assess the severity of liver disease, identify the
aetiology and screen for complications.
Severity
• Liver biochemistry: This may be normal. In most cases there is
at least a slight elevation of the serum alkaline phosphatase and
aminotransferases.
• Full blood count: This commonly shows thrombocytopenia at diagnosis
with macrocytosis, leucopenia and anaemia developing later.
• Liver function: Prothrombin time and serum albumin are the best
indicators of liver function.
• Serum electrolytes: A low sodium concentration indicates severe liver
disease secondary to either impaired free water clearance or excess
diuretic therapy. An elevated serum creatinine is associated with a worse
prognosis.
• Serum α-fetoprotein (AFP): This is normally undetectable after fetal
life,but raised levels may occur in chronic liver disease. A level
greaterthan 200 ng/mL is strongly suggestive of the presence
of a HCC.
Aetiology
Cirrhosis develops in response to chronic liver injury from any cause which
is often apparent from the history and the laboratory investigations (see
Table4.1). A liver biopsy may be performed to confirm the severity and type
of liver disease.
Further investigations
Oesophageal varices are sought with endoscopy. Primary prophylaxis is
offered to those with varices to reduce bleeding. An US is useful for detection
of HCC and to assess the patency of the portal and hepatic veins. Adualenergy X-ray absorptiometry (DXA) scan is performed for osteoporosis.
Management
Cirrhosis is irreversible and frequently progresses. Management focuses
on complications associated with decompensated cirrhosis. Correcting the
underlying cause, e.g. abstinence from alcohol for alcoholic cirrhosis or
venesection for haemochromatosis, may halt the progression of liver disease.
Screening for HCC (measurement of serum AFP and US every 6 months) is
performed to identify tumours at an early stage. Liver transplantation may
be considered in patients with end-stage cirrhosis. Patients should also be
offered influenza immunization.
164 Liver, biliary tract andpancreatic disease
Prognosis
This is variable and depends on the aetiology and presence of complications. The severity and prognosis of liver disease can be graded according
to the modified Child–Pugh classification (dependent on five variables:
encephalopathy, ascites, prothrombin time, serum bilirubin and albumin)
or the MELD score (modification of end-stage liver disease dependent on
serum bilirubin, creatinine, and the INR). Overall, the 5-year survival rate is
approximately 50%.
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
(TABLE4.7)
Portal hypertension
The portal vein is formed by the union of superior mesenteric vein (from the
gut) and splenic vein (from the spleen) and transports blood to the liver. It
accounts for 75% of hepatic vascular inflow; 25% is via the hepatic artery.
Blood vessels enter the liver via the hilum (porta hepatis) where blood then
passes into the hepatic sinusoids via the portal tracts and leaves the liver
through the hepatic veins to join the inferior vena cava. The normal portal
pressure is 5–8 mmHg. The inflow of portal blood to the liver can be partially
or completely obstructed at a number of sites, leading to high pressure
proximal to the obstruction and the diversion of blood into portosystemic
collaterals, e.g. at the gastro-oesophageal junction (varices) where they are
superficial and liable to rupture, causing massive gastrointestinal haemorrhage (p. 165).
The main sites of obstruction are:
• Prehepatic, due to blockage of the portal vein before the liver
• Intrahepatic, resulting from distortion of the liver architecture
• Posthepatic, due to venous blockage outside of the liver (rare).
Table 4.7 Complications and effects of cirrhosis
Portal hypertension and gastrointestinal haemorrhage
Ascites
Portosystemic encephalopathy
Acute kidney injury (hepatorenal syndrome)
Hepatopulmonary syndrome
Hepatocellular carcinoma
Bacteraemias, infection
Malnutrition
Osteoporosis
Complications and Effects of Cirrhosis (Table4.7) 165
Table 4.8 Causes of portal hypertension
Prehepatic Portal vein thrombosis
Intrahepatic Cirrhosis
Alcoholic hepatitis
Idiopathic non-cirrhotic portal hypertension
Schistosomiasis
Veno-occlusive disease
Posthepatic Budd–Chiari syndrome
Right heart failure (rare)
Constrictive pericarditis
Inferior vena caval obstruction
Aetiology
The most common cause (Table 4.8) of portal hypertension is cirrhosis.
Clinical features
The only evidence of portal hypertension may be splenomegaly. The common
presenting features are:
• Gastrointestinal bleeding from oesophageal or less commonly gastric
varices
• Ascites
• Hepatic encephalopathy.
Variceal haemorrhage
Most patients with cirrhosis will eventually develop varices but only a third will
bleed from them. Bleeding is often massive and mortality is as high as 50%.
Management
The general management of varices is summarized in Fig. 4.7.
Active bleeding. Patients should be resuscitated and undergo urgent
gastroscopy to confirm the diagnosis and exclude bleeding from other sites.
• Endoscopic therapy is the treatment of choice. The common endoscopic
methods are band ligation (small elastic bands are placed over the
varices) or sclerotherapy (injection of a sclerosant solution, e.g.
ethanolamine, into the varices).
• Pharmacological treatment is used for emergency control of bleeding
while waiting for endoscopy. Terlipressin, a synthetic analogue of
vasopressin, restricts portal inflow by splanchnic arterial constriction.
It is administered intravenously but is contraindicated in patients with
ischaemic heart disease. An intravenous infusion of somatostatin lowers
166 Liver, biliary tract andpancreatic disease
Bleeding varices
Terlipressin,
somatostatin or
octreotide
Resuscitate
Prophylactic antibiotics
Target transfusion Hb 80 g/L
Urgent endoscopy
Early
re-bleeding
Repeat endoscopic
therapy
Sengstaken
tube
Fig. 4.7 Management of gastrointestinal haemorrhage due to oesophageal
varices and transjugular intrahepatic portosystemic shunt. TIPS, transjugular
intrahepatic portosystemic shunting.
with banding or
injection
Bleeding
stops
TIPS
If not available consider
surgery or use of injectable
adhesive glues or thrombin
Assess for
beta-blockade, if
contraindication/
intolerance use
banding
portal pressure by a similar mechanism but is less effective. It can be
used, however, when there are contraindications to terlipressin.
• Balloon tamponade with a Sengstaken–Blakemore tube is used if
the medical or endoscopic treatment described above has failed, is
contraindicated, or if there is exsanguinating haemorrhage. Following
insertion, the gastric balloon is inflated and pulled back against the
gastro-oesophageal junction to prevent cephalad variceal blood flow to
the bleeding point. It is associated with serious complications such as
aspiration pneumonia, oesophageal rupture and mucosal ulceration. To
reduce the complication rate, the airway should be protected and the
tube left in situ for no longer than 12 hours. It is removed just before
endoscopy.
• Transjugular intrahepatic portosystemic shunting (TIPS) is used when
there is a second re-bleed after treatment. A metal stent is passed over
a guidewire in the internal jugular vein. The stent is then pushed into the
liver substance under radiological guidance to create a shunt between
the portal and hepatic veins, lowering portal pressure.
• Surgery (oesophageal transection and ligation of varices) is occasionally
necessary if bleeding continues in spite of all the above measures.
Complications and Effects of Cirrhosis (Table4.7) 167
Additional treatment:
• Patients should be managed in a critical care environment. Antibiotic
prophylaxis is given to prevent infection, reduce re-bleeding and
prevent early mortality. Lactulose is given to prevent portosystemic
encephalopathy and sucralfate to reduce oesophageal ulceration, a
complication of endoscopic therapy.
Prevention of recurrent variceal bleeding. Following an episode
of variceal bleeding, there is a high risk of recurrence (60%–80% over a
2-year period), and treatment is given to prevent further bleeds (secondary
prophylaxis). The main options are:
• Propranolol (in a dose sufficient to reduce the resting pulse rate by 25%)
lowers portal pressure but some patients are intolerant of treatment.
Propranolol is also given to patients with varices who have never bled
(primary prophylaxis).
• Repeat variceal banding every 2 weeks until the varices are obliterated.
Varices may recur, so follow-up endoscopy is required.
• TIPS or occasionally a surgical portosystemic shunt is performed if
endoscopic or medical therapy fails. Hepatic encephalopathy is a
complication of both procedures. Liver transplantation should always be
considered when there is poor liver function.
Ascites
This is the presence of fluid in the peritoneal cavity. Cirrhosis is the commonest cause (Table 4.9).
Aetiology
In cirrhosis, peripheral arterial vasodilatation (mediated by nitric oxide and
other vasodilators) leads to a reduction in effective blood volume, with activation of the sympathetic nervous system and renin–angiotensin system,
Table 4.9 Causes of ascites
Transudate Exudate
Portal hypertension, e.g. cirrhosis Peritoneal carcinomatosis
Hepatic outflow obstruction Peritoneal tuberculosis
Budd–Chiari syndrome Pancreatitis
Hepatic veno-occlusive disease Nephrotic syndrome
Cardiac failure Lymphatic obstruction (chylous ascites)
Tricuspid regurgitation
Constrictive pericarditis, Meigs’
syndrome*
*Meigs’ syndrome is the triad of benign ovarian fibroma, ascites and pleural effusion.
168 Liver, biliary tract andpancreatic disease
thus promoting renal salt and water retention. The formation of oedema is
encouraged by hypoalbuminaemia and mainly localized to the peritoneal
cavity as a result of the portal hypertension.
Clinical features
On clinical examination there is fullness in the flanks with shifting dullness.
Tense ascites is uncomfortable and can lead to respiratory distress. A pleural
effusion (usually right-sided) and peripheral oedema may also be present.
Investigations
A diagnostic aspiration of 10–20 mL of ascitic fluid should be carried out in
all patients and the following performed:
• Albumin: An ascitic albumin concentration of >11 g/L below the serum
albumin suggests a transudate; a value of <11 g/L suggests an exudate
(see Table 4.9)
• A neutrophil count >250 cells/mm3 in cirrhotic ascites indicates
underlying (usually spontaneous) bacterial peritonitis
• Gram stain and culture for bacteria and acid-fast bacilli
• Cytology for malignant cells
• Amylase to exclude pancreatic ascites.
Management
Treatment depends on the cause. The management of ascites due to portal
hypertension is described below. In other cases, ascites will improve with
treatment of the underlying condition.
Diuretics. The management of ascites resulting from cirrhosis is based
on a step-wise approach, starting with dietary sodium restriction to 40 mmol/
day and oral spironolactone 100 mg daily, increasing the dosage gradually to
500 mg daily if necessary. Furosemide can be added if the response is poor.
The aim of treatment is to lose approximately 0.5 kg of body weight each day
because the maximum rate of transfer of fluid from the ascitic to the vascular
compartment is only about 700 mL/day. If the diuresis occurs too rapidly
intravascular volume depletion and hypokalaemia can occur which can in
turn precipitate encephalopathy. Efficacy and side effects of treatment are
monitored by body weight, serum creatinine and sodium. A rising creatinine
level or hyponatraemia indicates inadequate renal perfusion and the need for
temporary cessation of diuretic therapy.
Paracentesis. In the presence of tense ascites or where the ascites is
resistant to standard medical therapy, paracentesis may be performed. The
ascites can be removed over several hours providing rapid symptom relief.
Intravenous infusion of albumin administered immediately after paracentesis
increases the circulating volume (ascites reaccumulates at the expense of
the circulating volume).
TIPS. In rare circumstances a TIPS may be inserted to treat resistant ascites,
providing there is no spontaneous portosystemic encephalopathy (PSE) and
Complications and Effects of Cirrhosis (Table4.7) 169
there is minimal disturbance of renal function. Frequency of paracentesis and
diuretic use is reduced and nutrition is enhanced. Survival may also improve.
Complications
Spontaneous bacterial peritonitis (SBP) occurs in 8% of cirrhotic patients
with ascites and has a mortality rate of 10%–15%. The most common
infecting organism is Escherichia coli. Clinical features may be minimal and
the diagnosis should be suspected in any patient with cirrhotic ascites who
deteriorates. Diagnostic aspiration should always be performed and empirical antibiotic therapy with a third-generation cephalosporin, e.g. intravenous
cefotaxime, is started if the ascitic fluid neutrophil count is ≥250 cells/mm3.
Antibiotics can subsequently be adjusted on the basis of culture results.
Antibiotic prophylaxis with oral norfloxacin is indicated in patients after one
episode or in patients at high risk (ascites protein <10 g/dL or severe liver
disease). SBP is also an indication for referral to a liver transplant centre.
Portosystemic encephalopathy
PSE is a neuropsychiatric syndrome which occurs with either chronic (cirrhosis) or acute (fulminant hepatic failure) advanced hepatocellular disease.
It is also seen in patients following surgical or TIPS shunts.
Pathophysiology
The mechanism is unclear but is believed to involve ‘toxic’ substances
normally detoxified by the liver, bypassing the liver via the collaterals and
gaining access to the brain. Ammonia plays a major role and is produced
from breakdown of dietary protein by gut bacteria. In chronic liver disease,
there is an acute-on-chronic course with acute episodes precipitated by a
number of possible factors (Table 4.10).
Table 4.10 Factors precipitating portosystemic encephalopathy
High dietary protein
Gastrointestinal haemorrhage (i.e. a high protein load)
Constipation
Infection including spontaneous bacterial peritonitis
Fluid and electrolyte disturbance (spontaneous or diuretic-induced)
Sedative drugs, e.g. opiates, diazepam
Portosystemic shunt operations and TIPS
Any surgical procedure
Progressive liver damage
Development of hepatocellular carcinoma
TIPS, transjugular intrahepatic portocaval shunting.
170 Liver, biliary tract andpancreatic disease
Clinical features
An acute onset often has a precipitating cause; the patient becomes increasingly drowsy and eventually comatose (see Table 4.5). There is increased
tone and hyperreflexia. Chronically, the patient may be irritable, confused
with slow, slurred speech and a reversal of the sleep pattern. The signs are
fetor hepaticus (a sweet smell to the breath), a flapping tremor of the outstretched hand (asterixis), inability to draw a five-pointed star (constructional
apraxia) and a prolonged trail-making test (the ability to join numbers and
letters within a certain time). Serial attempts are easily compared and used
to monitor patient progress.
Differential diagnosis
None of the manifestations of hepatic encephalopathy are specific to this disorder. Alternative diagnosis such as other metabolic or toxic encephalopathies
or intracranial mass lesions may present similarly and should be considered.
Investigations
The diagnosis is clinical. An electroencephalogram (EEG) (showing δ waves),
visual evoked potentials and arterial blood ammonia are sometimes used in
difficult diagnostic cases.
Management
The aims of management are to identify and treat any precipitating factors
(see Table 4.10) and to minimize the absorption of nitrogenous material,
particularly ammonia, from the gut. This is achieved by the following:
• Laxatives: Oral lactulose (10–30 mL three times daily) is an osmotic
purgative that reduces colonic pH and limits ammonia absorption. It
may be given via a nasogastric tube if the patient is comatose. The dose
should be titrated to result in two to four soft stools daily.
• Antibiotics: These are administered to reduce the number of bowel
organisms and hence the production of ammonia. Rifaximin is mainly
unabsorbed and well tolerated. Oral metronidazole (200 mg four times
daily) is also used.
• Nutrition: Maintenance of nutrition with adequate calories is essential.
Protein is initially restricted but increased after 48 hours as
encephalopathy improves.
Hepatorenal syndrome
This is the development of acute kidney injury in a patient who usually
has advanced liver disease, either cirrhosis or alcoholic hepatitis. Marked
peripheral vasodilatation leads to a fall in systemic vascular resistance and
effective hypovolaemia. This in turn results in vasoconstriction of the renal
Types of Chronic Liver Disease and Cirrhosis 171
circulation with markedly reduced renal perfusion. The diagnosis is made on
the basis of oliguria, a rising serum creatinine (over days to weeks), a low
urine sodium (<10 mmol/L), absence of other causes of acute kidney injury,
lack of improvement after volume expansion (if necessary) and withdrawal
of diuretics. Prognosis is poor, and renal failure will often respond only if liver
function improves. Albumin infusion and terlipressin have been used with
some success.
Hepatopulmonary syndrome
Intrapulmonary vascular dilatation in patients with advanced liver disease
causes hypoxaemia. In severe cases, patients are breathless on standing.
Diagnosis is by echocardiogram and the changes improve with liver transplantation.
LIVER TRANSPLANTATION
Indications for liver transplantation include acute or chronic liver failure of
any cause. Triggers for referral in chronic liver disease include progressive
jaundice, diuresis-resistant ascites, an episode of spontaneous bacterial
peritonitis and some cases of HCC. Careful selection of patients is crucial.
Psychological assessment and education of patients and their families is
essential before transplantation. Absolute contraindications include active
sepsis outside the liver and biliary tree, malignancy outside the liver, liver
metastases (excluding neuroendocrine) and a lack of psychological commitment by the patient.
With rare exceptions, patients over 65 years are not offered transplant.
A 6-month abstinence rule prior to transplantation applies to patients
with alcohol-related liver disease. The aim is for long-term abstinence
after transplantation and possible improvement of liver function to avoid
transplantation. Graft rejection is reduced by immunosuppressive agents
such as ciclosporin. Early complications include haemorrhage, sepsis and
acute rejection (<6 weeks), which is reversible with methylprednisolone.
Late complications include recurrence of disease (hepatitis B and C,
autoimmune liver disease), chronic rejection (the ‘vanishing bile duct
syndrome’) and the consequences of immune suppression (malignancy,
cardiovascular disease, diabetes mellitus). Overall, the 5-year survival rate
after liver transplantation is 70%–85%.
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
Alcoholic cirrhosis
See alcoholic liver disease.
172 Liver, biliary tract andpancreatic disease
Primary biliary cholangitis
Primary biliary cholangitis (PBC) is a chronic disorder in which there is progressive destruction of intrahepatic bile ducts causing cholestasis, eventually
leading to cirrhosis.
Epidemiology
It affects predominantly women in the age range 40–50 years.
Aetiology
An inherited abnormality of immunoregulation leads to a T-lymphocytemediated attack on bile duct epithelial cells. It is thought that disease expression
results from an environmental trigger, possibly infective, in a genetically susceptible individual. Antimitochondrial antibodies (AMAs) are present in most
(>95%) patients, but their role in disease pathogenesis is unclear.
Clinical features
Pruritus, with or without jaundice, is the single most common presenting
complaint. In advanced disease, there is, in addition, hepatosplenomegaly
and xanthelasma (PBC is a cause of secondary hypercholesterolaemia).
Asymptomatic patients on routine examination or screening may be found to
have hepatomegaly, a raised serum alkaline phosphatase or autoantibodies.
Patients with advanced disease may have steatorrhoea and malabsorption of
fat-soluble vitamins due to decreased biliary secretion of bile acids, resulting in low concentrations of bile acids in the small intestine. Autoimmune
disorders such as Sjögren’s syndrome, scleroderma and rheumatoid arthritis
occur with increased frequency.
Investigations
• A raised serum alkaline phosphatase is often the only abnormality in liver
biochemistry.
• Serum AMAs are found in more than 95% of patients and a titre of 1:160
or greater makes the diagnosis highly likely. M2 antibody is specific.
Other non-specific antibodies such as antinuclear factor may also be
present.
• Serum IgM may be high.
• Liver biopsy shows loss of bile ducts, lymphocyte infiltration of the
portal tracts, granuloma formation in 40% of cases and, at a later stage,
fibrosis and eventually cirrhosis.
• An US scan is sometimes performed in the jaundiced patient to exclude
extrahepatic biliary obstruction.
PBC is almost certainly present if the serum alkaline phosphatase and
IgM concentrations are both raised and the antimitochondrial antibody test is
positive. Liver biopsy provides information about disease stage and prognosis
but is not essential to make the diagnosis.