Bilirubin

Elevated serum bilirubin levels may occur in all forms of liver disease. However, it must be remembered that a jaundiced patient does not necessarily have significant hepatic disease. Serum levels of bilirubin reflect production, hepatic uptake, processing (conjugation) and secretion. The physiology of bilirubin and an approach to diagnosis and management of jaundice is described in Chapter 23.

The value of the ratio between conjugated and non-conjugated bilirubin in distinguishing the nature of a liver disorder is limited. Conjugated bilirubin levels are highest in cholestatic disease and in fulminant hepatic failure. Unconjugated hyperbilirubinaemia may reflect haemolysis, neonatal physiological jaundice or genetic defects in bilirubin transport and conjugation (Gilbert’s and Crigler-Najjar syndromes). Haemolysis rarely produces total bilirubin levels greater than 50–90 μmol/L.

In acute liver disease, the bilirubin level is of little prognostic significance. On the other hand, rising serum bilirubin levels reflect the approach of end-stage disease in many chronic liver diseases. For example, in primary biliary cirrhosis this signals the need to consider liver transplantation. In secondary malignancy it is often a signal of a preterminal event.

In the presence of chronic liver disease, when hepatic reserve is limited, relatively small increases in bilirubin production (as with haemolysis) can produce a disproportionate increase in serum bilirubin. When there is cholestasis, renal failure will reduce the clearance of conjugated bilirubin sufficiently to increase serum levels. Furthermore, conjugated bilirubin binds irreversibly to albumin such that bound bilirubin will not be cleared until the albumin it is bound to is catabolised.

Tests reflecting hepatic function

Transaminases

The serum transaminases are best considered as tests of hepatocyte damage or injury. They do not reflect the functional capacity of the liver. Transaminases enter the circulation following hepatocellular lysis. However, sublethal hepatocyte injury can also release these enzymes. Budding of cytoplasm or leakage from breaches in the plasma membrane may occur.

Marked elevations in serum transaminase levels (over 1000 U/L) often reflect acute viral hepatitis. Drug reactions and acute exacerbations of chronic autoimmune hepatitis can produce similar levels. Non-hepatocellular disease including acute cholestasis, shock and cardiac failure can also produce substantial rises. Lesser rises in serum transaminases do not, however, exclude the diagnosis of these conditions.

Persistent elevation of serum transaminase levels may indicate significant chronic liver disease such as chronic viral or autoimmune hepatitis, and require investigation. Thus, treatable diseases can be identified and managed prior to the onset of symptomatic (often end-stage) liver disease. In Western countries such as Australia, non-alcoholic fatty liver disease is the most common cause for abnormal transaminase levels. That condition is present in 15–20% of these populations.

In the presence of malignant disease, increases in transaminases often indicate hepatic metastases.

Alanine aminotransferase

Alanine aminotransferase (ALT) is a liver-specific enzyme; thus, an isolated elevation of ALT is highly suggestive of liver disease. Persisting abnormalities should precipitate a search for the cause.

Aspartate aminotransferase

Aspartate aminotransferase (AST) is an enzyme found in liver, skeletal muscle, myocardium, kidney, pancreas and erythrocytes. Damage to any of these cell types will result in an elevation of serum AST. ALT levels are usually higher than AST levels in viral liver injury. When liver disease is present, and the AST level is more than twice that of ALT, alcoholic liver disease must be considered (see later). In the presence of cirrhosis, the diagnostic value of the AST:ALT ratio is lost. The mitochondrial isoenzyme of AST is especially elevated in the presence of alcoholic liver injury.

Alkaline phosphatase

Alkaline phosphatase (ALP) is an enzyme localised to the biliary membrane of hepatocytes. An elevation of the serum ALP level is a marker of biliary disease or a hepatic infiltrative disorder.

Although cholestasis may be present with a normal ALP level, in three-quarters of patients with cholestasis, serum ALP levels will be three or more times greater than the upper limit of normal. Mild elevations of hepatic ALP levels are often seen in hepatocellular injury. Serum ALP levels may also be elevated, at times in isolation, in other disorders affecting the liver, including congestive cardiac failure and lymphoma. A mild elevation is often seen in patients with a non-hepatic illness; this returns to normal over a period of weeks to months, after the underlying condition is treated.

ALP is also found in bone, intestine, kidney and placenta. Consequently, damage to these organs will elevate the serum ALP level. Furthermore, during pregnancy and periods of rapid growth (neonatal and adolescent periods), serum levels of this enzyme are higher. When the serum ALP level is elevated in the absence of other abnormalities in the liver function tests, a non-hepatic cause, such as Paget’s disease, tumours involving bone, acromegaly and fractures, should be considered. Milder rises in ALP may occur following infarction involving the heart, lung, gastrointestinal tract or kidneys.

5′-nucleotidase, a membrane-associated enzyme, is elevated in the plasma primarily in cholestatic liver disease. Although present in pancreas, brain, intestine and heart, this enzyme is more specific for liver disorders than is alkaline phosphatase.

Gamma glutamyl transpeptidase

Gamma glutamyl transpeptidase (GGT) is a membrane-bound enzyme present in the liver, pancreas, kidney, intestine and prostate. GGT levels increase with any liver disease. Its greatest value is its association with alkaline phosphatase in cholestatic disorders. An elevated serum GGT level supports a hepatic origin of an elevated alkaline phosphatase, as serum GGT is not raised in pregnancy or bone disease.

Although a marker of prognostic significance in alcoholic liver disease, not all heavy drinkers will display elevated serum GGT levels. Elevations of the serum levels of this enzyme are associated with biliary disease, pancreatitis, obesity, hyperlipidaemia, anorexia nervosa, diabetes mellitus, hyperthyroidism, porphyria, myocardial infarction and liver disease in general. Enzyme-inducing drugs, such as barbiturates, tricyclic antidepressants and anticonvulsants, are also associated with elevated serum GGT activity.

The serum levels of this enzyme can be raised in the absence of other liver function test abnormalities in obese individuals, with excessive alcohol consumption, and following the use of enzyme-inducing medications.

Lactate dehydrogenase

Lactate dehydrogenase (LDH) is a glycolytic enzyme present in all cells. Different isoenzymes occur with limited tissue specificity, and their measurement is of limited clinical value. However, when the LDH level is elevated out of proportion to the transaminases, ischaemic liver injury and secondary malignancy need to be considered.

Cholestasis versus hepatocellular disease

Liver function patterns may be used to guide the discrimination between cholestasis (e.g. due to stones or tumour obstructing the large bile ducts) and hepatocellular disease (e.g. cirrhosis or chronic hepatitis). These patterns can be used only as a broad guide and should not be relied on alone. However, if cholestasis is suspected, then looking for evidence of duct obstruction (e.g. by ultrasound) is the next step, while if hepatocellular disease is suspected, then a search for liver disease markers (e.g. virology, immunological tests) is the next step (see Table 23.1 in Ch 23).

Other tests useful in hepatic assessment

A marked elevation (over 1000 U/L) of alpha-fetoprotein is most often due to hepatocellular carcinoma. This test has been used for screening an individual with chronic hepatitis B for the development of hepatocellular carcinoma, having a sensitivity of 70%. It is of limited value, however, because the sensitivity falls to 30% in non-hepatitis B hepatocellular carcinoma. Milder elevations occur in both acute and chronic liver disease of many causes (Ch 25).

Autoantibodies are helpful in diagnosing certain forms of liver disease (Table 24.1). Serum concentration of caeruloplasmin and iron studies are important tools in the diagnosis of Wilson’s disease and haemochromatosis, respectively (Table 24.2), but are also altered by liver injury unrelated to either of these conditions. Tests for viral hepatitis are also important (Table 24.3).

Table 24.1 Tests for autoimmune liver disease

Table 24.2 Tests for metabolic disorders affecting the liver

Table 24.3 Tests for viral hepatitis

ag = antigen; ab = antibody; PCR = polymerase chain reaction.

History

All patients with abnormal liver function test results need to be questioned about their family history of liver disease, and their ingestion currently or in the past of alcohol and medications.

A history of diabetes mellitus, thyroid disease and high lipid levels should be sought; these together with obesity are associated with hepatic steatosis. The features of the metabolic syndrome with rising body weight and reduced physical activity are common in those with non-alcoholic fatty liver disease, especially when there is a family history of type 2 diabetes.

A history of overseas travel and exposure to blood products from transfusions or injection of drugs, legally or illegally, needs to be sought (e.g. hepatitis B or C). A history of known exposure to patients with infectious liver diseases should be asked about. A sexual history must be obtained because exposure to some viruses is much more common in individuals with multiple sexual partners (e.g. hepatitis B and HIV).

When there is a family history of liver disease, social background requires close review. ‘Learned’ excessive alcohol consumption can lead to liver disease without the patient being aware that their intake is potentially dangerous. The amount of alcohol the ‘social drinker’ consumes varies according to his or her background.

There is a possibility of genetic predisposition to alcoholic liver disease.

Migration from areas of high prevalence of hepatitis B or C (e.g. Southeast Asia) should be noted. These viruses, acquired at birth or in early childhood, may not generate symptoms for many years.

Haemochromatosis is preferably diagnosed prior to the onset of symptoms; abnormalities of liver function tests and abnormal iron study findings are clues. However, a history of joint pains, diabetes mellitus, cardiac disease or impotence in the patient or the existence of an affected relative suggests the possibility of haemochromatosis.

Wilson’s disease is likely to be asymptomatic only in younger children. At older ages, features of cirrhosis or neurological abnormalities are likely. Alpha-1 antitrypsin deficiency, homozygote or heterozygote, may present with the incidental finding of abnormal liver function profiles in an otherwise well patient.

In the otherwise well patient, a history of abdominal pain (e.g. biliary pain: Ch 4), loss of appetite or weight (Ch 17), or a change in the colour of stools or urine (Ch 23) needs to be sought but is almost invariably absent.

Examination

Patients with abnormal liver test results must be regarded as having a liver disorder and thus signs of chronic liver disease should be sought because cirrhosis may be completely asymptomatic (Fig 24.1). The patient’s weight and height should be measured during the examination to allow evaluation of the body mass index (weight in kilograms divided by the square of the height in metres: kg/m²). Truncal obesity is common and waist measurement should be taken.

Figure 24.1 Signs of chronic liver disease.

From Sherlock S, Dooley J. Diseases of the liver and biliary system. 11th edn. Oxford: Blackwell; 2002, with permission.

There should be an examination for signs of acute liver disease because the patient may be in the prodromal phase of a viral hepatitis (e.g. jaundice and encephalopathy).

In the usual patient presenting with no history of symptoms and no awareness of liver problems, it is likely that there will be no signs of liver disease. A minor degree of hepatomegaly should be expected in patients with alcohol-related fatty liver or non-alcoholic fatty liver disease (Ch 17). Mild splenomegaly may also be found.

Investigation

The approach to investigations is guided by the history, examination and liver function test pattern. Further testing is based on the provisional diagnosis and likely prognosis. When no hints as to the diagnosis have been found, a systematic investigation for potentially dangerous causes of liver disease needs to be considered. This would normally be done after a period of observation with serial liver function tests to determine whether there is a spontaneous recovery, a stable abnormality or deterioration.

Liver imaging is of value (Ch 23). Abdominal ultrasound scans can provide information about the size and shape of the liver and spleen. Often any mass lesions present can also be identified. Ultrasonography will often detect fatty liver. Abdominal CT will provide information on the presence or absence of space-occupying lesions while, in addition, providing insight into liver density, which may be increased in haemochromatosis. Magnetic resonance imaging will usually add little to the information provided by a CT scan but can be of value in certain circumstances, such as in the assessment of mass lesions and of the biliary tract.

Tests for evidence of viral hepatitis (Table 24.3), autoimmune liver disease (Table 24.1) and other causes of chronic liver disease (iron or copper overload, and other inherited liver diseases) (Table 24.2) should be done if hepatocellular disease is possible. If the diagnosis remains unclear and the prognosis of concern, a liver biopsy is required.

Chronic hepatitis is an ongoing inflammatory process. The causes are listed in Table 24.4. If fibrosis follows as part of the healing process consequent to this inflammation, progression to cirrhosis and eventual liver failure is possible. For this reason, potentially controllable chronic hepatitis needs to be identified and treated before irreversible injury has occurred.

Table 24.4 Important causes of chronic hepatitis and cirrhosis

Acute hepatitis

Definition

Liver failure occurring in a previously well patient is termed ‘acute’ or ‘fulminant’ hepatic failure; hepatic encephalopathy (an organic neurological syndrome) with elevated INR (impaired hepatocellular synthetic function) evolves within 8 weeks of the onset of the illness. Subfulminant or subacute hepatic failure is used to describe the onset of hepatic decompensation up to 26 weeks after the initial illness. These need to be differentiated from acute hepatic failure evolving in the presence of established chronic liver disease.

History

The historical features of acute hepatitis should be enquired about. However, details will need to be obtained from others when the patient has established encephalopathy. Acute infection with the hepatotropic viruses A, B, D or E (and very rarely C) can cause fulminant hepatic failure. In late pregnancy, acute fatty liver should be considered. Ask about drugs, which may cause direct toxic effects (e.g. following overdose of paracetamol) or cause idiosyncratic reactions (e.g. halothane and sulfonamides).

Following an acute overdose of 140 mg/kg or more of paracetamol, the glucuronide and sulfate pathways in the liver become saturated and hepatic glutathione becomes depleted, leading to reactive metabolites covalently binding to liver cells causing lysis. Hepatotoxicity manifests 24–48 hours after ingestion. The early identification of paracetamol overdose is crucial. Serum levels should be measured 4 and 24 hours after suspected ingestion; the administration of N-acetylcysteine will prevent progression to hepatic failure. It gives maximal benefit if instituted within 8–10 hours of ingestion (but is indicated after that time as well). ALT levels are typically very high while the bilirubin is relatively low. An intake of a normally subtoxic dose of paracetamol in the presence of chronic alcohol abuse may lead to acute hepatic failure. In the USA approximately 50% of paracetamol overdose is non-intentional with the drug taken over days. In these cases the serum drug levels are lower. Toxicity normograms are of no value in this circumstance.

Fluorinated hydrocarbon solvents (in glue sniffing) and mushroom poisoning have also been linked to acute hepatic failure. Wilson’s disease may rarely present in acute liver failure, and death usually follows without liver transplantation.

In fulminant hepatic failure there is a sudden loss of functional hepatocyte mass, often associated with portal hypertension. The associated complications of encephalopathy, coagulopathy, renal failure and sepsis evolve. Multi-organ failure often occurs, with the patient’s death from cerebral oedema or infection.

Assessment and management

Examination is directed towards assessing the possible aetiology and evolving complications of hepatic failure (outlined below). Serial liver function tests can be useful, but a falling ALT level may reflect either recovery or progression to massive hepatic necrosis. A temperature above 38°C or below 36°C, a pulse rate above 90 beats per minute and/or a white cell count above 12,000 or below 4,000 are associated with a greater mortality. The prognosis, and therefore need for liver transplantation, of a patient in acute liver failure can be assessed using the Kings College Criteria (Table 24.5).

Table 24.5 Kings College Criteria for listing of a patient in acute liver failure (ALF) for liver transplantation

Hepatic encephalopathy and cerebral oedema

This may develop rapidly and may even precede the onset of jaundice. Raised ammonia levels associated with liver failure cause brain swelling, inflammation, increased cerebral blood flow and a breakdown of the blood–brain barrier. Deeper grades (described later in this chapter) of encephalopathy are associated with a worse prognosis. Unlike the encephalopathy of chronic liver disease, there is often early agitation and delusional ideation. Cerebral oedema is more likely to occur when encephalopathy develops rapidly after the onset of jaundice. However, survival is worse in those in whom encephalopathy evolves slowly. Cerebral oedema, present in up to 80% of those in grade IV encephalopathy, is a significant cause of death. Clinically, this is reflected by systemic hypertension, bradycardia with progressive rigidity and decerebrate posturing. Direct pressure monitoring with a subdural or epidural transducer is the only reliable means of assessing cerebral pressure. Prognosis is particularly poor and liver transplantation inappropriate when the cerebral perfusion pressure is less than 50 mmHg, and is refractory to mannitol therapy. Grade III and IV encephalopathies (see below) are associated with a worse prognosis.

Management aims to reduce systemic vasodilatation and cerebral perfusion pressure, maintaining a low mean arterial pressure and central venous pressure. Mannitol, sodium, hypothermia (when there is hyperacute high grade encephalopathy and requiring vasopressors) and dialysis (in those developing renal impairment) have been used in the treatment of cerebral oedema.

Coagulopathy

Coagulopathy of acute hepatic failure occurs as the result of loss of hepatic synthetic function, sepsis, bleeding and intravascular coagulation. Platelet levels decrease and their function is impaired. Spontaneous bleeding is rare and postprocedural bleeding is uncommon. Platelet transfusion and fresh frozen plasma can be of value when there is active haemorrhage. There is no evidence that correcting an abnormal INR or platelet count is of value in the absence of bleeding. On the other hand the INR can be used to assess recovery in liver function. Patients with acute liver failure may be hypercoagulable despite a low INR.

Hypotension, renal failure and hypoglycaemia

Hypotension is common and renal failure is not unusual. The latter is usually associated with the hepatorenal syndrome. This syndrome represents a functional renal impairment and carries a poor prognosis. Normal renal function returns with recovery or liver transplantation. Acute tubular necrosis secondary to hypotension may also occur in acute hepatic failure. When renal failure does occur, therapy is supportive; dialysis is problematic because of the associated coagulopathy, hypotension and cerebral oedema. N-acetylcysteine may improve oxygen delivery.

In acute liver failure, peripheral circulatory changes lead to impaired oxygen delivery, tissue hypoxia and lactic acidosis (a poor prognostic sign). As the functional hepatocyte mass decreases, the liver is unable to sustain gluconeogenesis, and life-threatening hypoglycaemia follows. Blood sugar levels require close monitoring and are a measure of remaining hepatic function. Ten per cent glucose infusions are usually required. Hypokalaemia (with respiratory alkalosis) and dilutional hyponatraemia may also occur.

Infection

Evidence of infection must be actively sought in any episode of hepatic failure. The chest and urinary tract are common sites of infection. Multifactorial mechanisms leave these patients prone to severe bacterial and fungal infections. Death will rapidly follow unless aggressive antibiotic therapy, or drainage of pus if possible, is instituted once the possibility of infection is considered. Prophylactic antibiotics may be of value when there is renal failure or while awaiting transplantation. Empiric antibiotics therapy may increase encephalopathy.

Prognosis

The prognosis of acute hepatic failure related to paracetamol overdose, hepatitis A viral infection and fatty liver of pregnancy (if there has been prompt delivery) tends to be better than that of other causes. The outcomes appear worst in those in whom the cause is unclear.

Liver transplantation is a therapeutic option. The decision to transplant and the timing of transplantation are difficult. However, 1-year survival rates of approximately 70% can be achieved. This compares favourably with mortality rates from fulminant hepatic failure without transplantation of up to 90% although with optimal intensive care unit management 30–40% survival can be achieved. N-acetylcysteine may also improve overall survival and transplant-free survival in patients with non-paracetamol-related acute liver failure, especially if encephalopathy is limited to grade I or II.

Hepatitis B-associated fulminant hepatic failure should be managed with the antiviral agent entecovir. In herpes simplex hepatitis only about 50% of cases will have a rash, blood HSV DNA levels will be high and treatment with acyclovir should be initiated if the diagnosis is suspected.

In autoimmune acute liver failure the ALT will often be around 600 and there will be appropriate autoantibodies, raised IgG level and, if performed, liver biopsy will show pericellular venulitis, interface necrosis and plentiful plasma cells. Corticosteroids do not alter the transplant-free survival, which approximates 20%.

History

Patients with cirrhosis may be asymptomatic, coming to medical attention following an incidental finding of abnormal laboratory tests or physical findings suggestive of chronic liver disease.

Such patients should be assessed to determine the likely aetiology as outlined in ‘The well patient with abnormal liver function profile’ above. Attention should be directed to identifying evidence of ongoing hepatic injury that may be modified by therapeutic intervention. A careful history of exposure to alcohol, drugs and potential hepatotropic agents (e.g. solvents) is required. Removal of exposure may help slow progression. Risk factors for exposure to hepatitis B and C viruses and family history of liver disease should be assessed.

Examination

Physical examination includes a search for signs of chronic liver disease (Box 24.1) and evidence of extrahepatic features of possible aetiological factors.

Investigation

Investigations are directed to (1) determining the aetiology of the cirrhosis (Table 24.4); and (2) assessing the severity of hepatic injury. When physical findings and investigations suggest cirrhosis, liver biopsy should be considered to establish its presence, to assess the activity of the fibroinflammatory process and to seek evidence of the aetiology. A past history of excessive ethanol consumption is often identified. In other cases, a specific aetiology can often be established by using special tests for autoantibodies, viral serology and metabolic disorders (Tables 24.1–24.3). Elevations in serum transaminase levels imply ongoing hepatocellular injury. Raised INR (prolonged prothrombin time) and hypoalbuminaemia suggest reduced hepatocellular synthetic function. Abdominal ultrasound scans with Doppler studies will provide evidence of portal hypertension (splenomegaly, portal flow and wave pattern), ascites and liver size (reflecting the remaining liver cell mass). Varices are excluded by upper endoscopy.

Management

The management of the well cirrhotic patient depends on the underlying cause. The cirrhotic should cease drinking alcohol completely. Failure to do so is likely to cause progression and early death. Abstinence, on the other hand, can allow a long and productive life despite the cirrhosis. Cirrhotic patients with autoimmune chronic hepatitis and significant inflammation on biopsy could benefit from corticosteroid therapy. Interferon is of limited benefit, and potentially dangerous in those with cirrhosis due to chronic hepatitis B. Oral antivirals, on the other hand, may be of value. Counselling of the patient and, if necessary, family members is required when infectious or genetic conditions are identified. Regular ultrasound screening for hepatocellular carcinoma should be performed at 6-monthly intervals. Upper gastrointestinal endoscopy should be performed to seek and, if present, treat significant oesophageal varices.

Apart from any treatment associated with the underlying cause, the asymptomatic patient with cirrhosis needs to maintain an adequate diet. Sufficient kilojoules, protein and micronutrients should be ingested. A complex carbohydrate snack before retiring in the evenings could help prevent the patient from becoming catabolic overnight as the hepatic glycogen stores become depleted. Regular follow-up is necessary, specifically seeking evidence of evolving complications of cirrhosis (namely, portal hypertension and ascites, portal vein thrombosis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and hepatocellular carcinoma). See Chapter 25 for more details.

Portal hypertension

In cirrhosis, the disturbed architecture of the liver and perivascular fibrosis increase the resistance of portal blood flow. Portal pressure is also increased consequent to sodium retention and expansion of the blood volume that follows the peripheral vasodilatation of cirrhosis. Cirrhotic patients suffer the combined effects of hepatocellular dysfunction and portal hypertension. Although cirrhosis is the commonest cause, primary liver disease is not the only basis for portal hypertension.

Portal and hepatic vascular disorders can also cause portal hypertension while leaving hepatocyte function relatively intact (Box 24.2). In these situations when liver cell function is maintained, portal systemic shunt surgery, rather than transplantation, may be appropriate for severe disease (Figs 24.2A and 24.2B). When vascular or thrombotic processes are found, an underlying cause for these should be sought and managed accordingly.

Figure 24.2 Portal systemic shunts. The operation aims to reduce portal pressure. Options include (A) porta-caval (end-to-side or side-to-side); (B) meso-caval (using a Dacron graft between the superior mesenteric vein and inferior vena cava) and distal splenorenal shunts (where veins feeding varices are ligated and a splenorectal vein shunt is created, preserving portal blood flow to the liver). Complications include hepatic encephalopathy (20–40%), ankle oedema, deterioration in hepatic function and shunt closure. The choice usually depends on local surgical expertise: if there is no ascites, a distal splenorectal shunt may be referable; if ascites is present, a side-to-side porta-caval shunt may be most optimal.

From Sherlock S, Dooley J. Diseases of the liver and biliary system. 11th edn. Oxford: Blackwell; 2002, with permission.

Acute upper gastrointestinal haemorrhage in patient with portal hypertension

History

A presentation of ascites in a patient known to have chronic liver disease often heralds end-stage disease. Similarly people with unrecognised cirrhosis can come to medical attention with the development of ascites. The history is of progressive abdominal distension, often with peripheral oedema. This can progress rapidly and be associated with significant abdominal discomfort. History should note details of known liver disease or, in de novo cases, historical evidence of the cause of liver disease. Acute hepatic disease is possible when the history is short, so risk factors for viral hepatitis and vascular disease should be noted. The history should also seek evidence of cardiac, renal or malignant disease.

Examination

Ascites is usually readily identified on physical examination. The demonstration of shifting dullness is not possible with volumes less than 2 L. Smaller amounts of fluid can be found by the finding of periumbilical percussion dullness with the patient on hands and knees. In obese patients, physical examination for ascites can be difficult and inconclusive. In such cases abdominal ultrasound examination is indicated.

Signs of chronic liver disease (Box 24.1) are expected in patients presenting with ascites and cirrhosis. Peripheral oedema is often present. Other complications of chronic liver disease or of the underlying condition may be present. Their absence should raise the possibility of acute hepatic disease or non-cirrhotic portal hypertension. Alternately, there may be a non-hepatic cause for the ascites. Physical examination may identify other causes of ascites, including cardiac failure and malignant disease. A pleural effusion, particularly on the right, may be present. Umbilical hernias commonly occur in ascites patients and surgical repair in this circumstance carries a high mortality.

Investigation

The diagnosis of the cause of ascites and exclusion of spontaneous bacterial peritonitis by paracentesis (tapping the peritoneal fluid) is mandatory. The gradient of albumin concentration between the serum and the ascitic fluid is particularly useful. A gradient greater than or equal to 11 g/L strongly suggests portal hypertension (as with cirrhosis). On the other hand, a gradient less than 11 g/L suggests malignancy or infection. If the patient is known to have cirrhosis, a low serum–ascites albumin gradient raises the possibility of spontaneous bacterial peritonitis or the development of hepatocellular carcinoma (Ch 20).

Abdominal ultrasound scans with Doppler studies will document the ascitic fluid and the state of the portal and hepatic vessels.

Management

Symptomatic ascites is initially managed with fluid and sodium restriction (no added salt). If this fails to control the ascites, spironolactone, up to 400 mg/day, can be used. It must be noted that spironolactone will take several days to have an effect. A loop diuretic, such as frusemide, may then be added in resistant cases, initially at 20–160 mg/day. Careful monitoring of renal function and serum electrolytes is needed as renal impairment and electrolyte disturbances followed by hepatic decompensation with encephalopathy can be precipitated by this therapy.

In profound ascites, paracentesis can also be used. Large volumes of ascitic fluid can be safely removed, especially if peripheral oedema is present; albumin should be infused during large volume paracentesis (greater than 5 L).

There is evidence that intravenous albumin may be of value in the therapy of ascitic patients when used in combination with diuretics or paracentesis and during treatment for spontaneous bacterial peritonitis or the hepatorenal syndrome.

Refractory ascites is an indicator of a poor prognosis. TIPS controls refractory ascites in more than 70% of cases. However, patients remain hyponatraemic and require ongoing diuretic therapy. The success of TIPS is tempered by portal systemic encephalopathy and shunt occlusion. The risk of encephalopathy increases with age, shunt size, liver function and prior portal systemic encephalopathy. In general, survival is similar with TIPS and large volume paracentesis, although TIPS may provide a survival advantage in those with higher MELD scores. The patient’s suitability for liver transplantation should be considered as transplant is the definitive therapy for refractory ascites.

Peritoneovenous shunts can be used but are fraught with problems including infection, blockage and stimulation of the coagulation cascade (causing disseminated intravascular coagulation).

Mechanism

The mechanism that generates ascites begins with the raised intrahepatic vascular resistance and consequent portal hypertension caused by the disruption of the hepatic architecture. A hepatovenous portal gradient greater than 10 mmHg is generally required to develop ascites. There is nitric oxide (NO) – induced vasodilation with a reduction in effective arterial blood volume and a neuroendocrine response leading to sodium and water retention. There is an increase in aldosterone production, and a reduction in its removal, often accompanied by inappropriate levels of antidiuretic hormone. With progression there is renal artery vasoconstriction, which leads to the hepatorenal syndrome. When renal adaption occurs the patient remains compensated, but if it does not, refractory ascites is the result.

History and examination

The presenting features of spontaneous bacterial peritonitis are ascites with fever, abdominal pain, jaundice, confusion and abdominal tenderness, but there may be no symptoms. There may be a history of severe acute or chronic liver disease. Ascitic fluid is a prerequisite for this condition. There is likely to be large volume ascites, but it is possible even when peritoneal fluid is not clinically detectable. Signs of peritonitis may be absent, and death rapid. As few as 10% of patients will have rebound tenderness or shock at presentation.

Investigation and mechanisms

Ascitic fluid must be sampled and examined in all patients with ascites and a recent decompensation (Ch 20); this should be done on admission regardless of clinical signs. Of all cirrhotic patients with ascites admitted to hospital, 12–15% will have spontaneous bacterial peritonitis. An ascitic polymorphonuclear leukocyte count greater than or equal to 250 cells/L is indicative of the condition. Ascitic fluid cultures should be collected and the samples inoculated into blood culture bottles, at the bedside. Cefotaxime is adequate antibiotic therapy in most cases. Outcomes may be improved by the addition of intravenous albumin: 1.5 g/kg of body weight at diagnosis, then 1 g/kg of body weight on the third day.

Common organisms include Escherichia coli, Streptococcus pneumoniae and Klebsiella spp. Spread to the peritoneum appears to be via the blood. Bacteria may also breach a mucosal barrier as occurs during gastrointestinal haemorrhage or instrumentation.

The lower the ascitic fluid protein concentration, the more likely spontaneous bacterial peritonitis becomes. Peritoneal macrophage dysfunction and reduced opsonic capacity of ascitic fluid may allow progression of colonisation of infection.

Secondary peritonitis, following perforation of a viscus, needs to be excluded, as this would also require surgical intervention. Such surgery would carry a very high mortality. Cirrhotic patients with ascites and secondary peritonitis can also display a paucity of clinical signs.

History and examination

The clinical features and grades of hepatic encephalopathy are shown in Table 24.7 and its classification in Box 24.3.

Table 24.7 Grades of severity of hepatic encephalopathy

History

Patients presenting with liver disease in pregnancy require prompt assessment and close follow-up because severe life-threatening illness may rapidly follow a seemingly mild prodrome.

Timing of the onset of illness should be noted. Hyperemesis gravidarum evolves early in the pregnancy. Cholestasis of pregnancy, acute fatty liver and preeclampsia usually occur in the third trimester.

In cholestasis of pregnancy, itch is a predominant feature. There may be a history of a similar problem in previous pregnancies or after taking oral contraceptives.

Nausea and vomiting with abdominal pain, especially in late pregnancy, indicate a need for complete and careful assessment for preeclampsia and acute fatty liver, especially if there is right upper quadrant pain. However, right upper quadrant pain at any stage in pregnancy could reflect a hepatitic process, biliary disease, a change in a hepatic mass lesion or vascular disease (Table 24.11).

Drug and alcohol consumption must be considered, and history of potential exposure to infectious agents sought.

Examination

Scratch marks with or without jaundice are the physical findings in cholestasis of pregnancy. Hypertension and proteinuria (on urinalysis) and hyperreflexia suggest preeclampsia. Jaundice, right upper quadrant tenderness and hepatomegaly are non-specific, but warrant intensive investigation. Signs of hepatic decompensation with fulminant hepatic failure, progressive jaundice, encephalopathy, haemorrhage or sepsis may mark preterminal disease. Conditions not specifically associated with pregnancy present with the same clinical features as are seen in the non-pregnant patient.

Investigation

Elevations in serum ALP levels may be predominant in cholestasis and biliary disease. Serum transaminase levels can also rise in these conditions. Evaluation of serum bile acid levels is helpful in the assessment of cholestasis of pregnancy.

Marked elevations (over 1000 U/L) of transaminase levels are likely to indicate viral hepatitis. Levels greater than 500 U/L may accompany preeclampsia, whereas in acute fatty liver, transaminase levels generally are between 300 U/L and 500 U/L.

Assessment of the full blood count, blood film and coagulation profile is vital in liver disease in late pregnancy. Abnormalities in these mark severe life-threatening disease (e.g. acute fatty liver of pregnancy or HELLP syndrome), requiring prompt intervention.

When acute fatty liver or severe preeclampsia is considered likely, the need for urgent intervention (delivery) is determined on the basis of the clinical assessment and basic blood test results. In less urgent circumstances, organ imaging with ultrasound may be used to exclude gallstones or hepatic mass lesions or, with Doppler studies, vascular disease (e.g. Budd-Chiari syndrome). Viral and autoimmune serology where the clinical setting is suggestive should also be considered.

Viral hepatitis

Hepatitis B

Hepatitis B virus (HBV) is a hardy, highly infectious DNA virus. There is an incubation period of 30–180 days (mean: 60–90 days) (Fig 24.3). Acute hepatitis occurs in approximately 25% of those who acquire the virus, with approximately 1% developing fulminant hepatic failure. The majority of cases are asymptomatic and recover completely, unaware of the infection. In hepatitis B infection, liver injury is mediated by T-lymphocytes; the virus itself does not seem to cause hepatocyte death.

Figure 24.3 Hepatitis B serology in acute infection with viral clearance and chronic infection without viral clearance.

From the Australian Gastroenterology Institute.

The treatment of acute hepatitis B is supportive.

Five to 10% of adults who acquire hepatitis B progress to chronic infection (Figs 24.4 and 24.5). In these, the prognosis is dependent on the degree of liver injury and the duration of infection. Chronic infection is characterised by the persistence of hepatitis B surface antigen, and IgG antibodies to core protein with or without e-antigen. Chronic hepatitis B infection can progress through four phases: immune tolerance, immune clearance, immune control and immune escape. The management of patients depends on which phase they are in (Table 24.9). During active phases of infection, liver biopsy can be of great value in assessing the degree of inflammation and determining whether cirrhosis has developed.

Figure 24.4 Viral hepatitis, acute, classic type. The inflammatory infiltrate has a perivenular accentuation, which is typically seen in the early phase of acute viral hepatitis.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Figure 24.5 Viral hepatitis, chronic, type B. The haematoxylin-eosin (H & E) stain shows discrete intracytoplasmic inclusions having a finely granular ‘ground-glass’ appearance, with peripheral cytoplasmic clearing. This staining characteristic represents proliferation of the endoplasmic reticulum synthesising the hepatitis B antigen (HBsAg) particles.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Table 24.9 Phases of chronic hepatitis B infection

After a period of chronic infection, hepatitis B virus DNA may integrate into the hepatocyte genome, preventing its complete removal and predisposing to hepatocellular carcinoma. Worldwide, this virus is the most significant cause of hepatocellular carcinoma. Supercoiled hepatitis B DNA within hepatocytes is also resistant to removal by current therapies.

Eventually, chronic hepatitis B results in cirrhosis and/or hepatocellular carcinoma. Well-compensated, chronic hepatitis B liver disease has a 5-year survival of 84%. Five-year survival in decompensated chronic hepatitis B is only 14%. It is possible for a patient with chronic hepatitis B to spontaneously clear the virus as he or she mounts an immune response to the virus. This is usually associated with an episode of clinical hepatitis and is associated with loss of viral antigens and the development of antibodies. The tests used in the assessment of hepatitis B infection are outlined in Table 24.3.

The hepatitis B virus is physically resilient and extremely infectious. It is present in most body fluids of those infected and can readily be transmitted to close contacts. People living in the same house as the patient are at risk and should be vaccinated. Sharing needles amongst intravenous drug users, sexual exposure and inadequately sterilised skin-piecing equipment (e.g. that used for tattooing) carry a very high risk of transmitting the virus. Vertical transmission readily occurs. This is usually at the time of birth, and immunisation provides good protection to the infant. The presence of hepatitis B infection also needs to be considered in patients born in areas where there is a high prevalence, such as southern and eastern Europe and Southeast Asia.

Passive immunity against hepatitis B can be achieved with an injection of hyperimmune immunoglobulin directed against hepatitis B (HBIG) within 72 hours of exposure. Active immunity through a course of three injections of surface antigen is safe and effective. However, a small proportion of individuals are not capable of mounting a response to this vaccine. This is especially a problem with increasing age, in immunocompromised people, in those on dialysis and in obese individuals.

The aim of treatment for chronic hepatitis B infection is to suppress viral replication (reduced hepatitis B DNA levels), thereby reducing liver injury as reflected by normalization of ALT. In hepatitis B e-antigen positive patients seroconversion is associated with improved prognosis.

Pegylated interferon is administered subcutaneously for 12 months with the advantages of the absence of viral resistance, durability of seroconversion and a defined duration. Side effects of interferon, on the other hand, include a flu-like syndrome early, and later headaches, weight loss, alopecia and bone marrow suppression; depression may also occur. With interferon, higher ALT levels, recent acquisition of the virus and low HBV DNA titres are associated with good long-term responses. Thirty to 50% of selected cases lose circulating HBV DNA and HBeAg and become anti-HBeAg positive. Clearance of surface antigen is possible in a small proportion of patients. Improvement may continue for years after the completion of treatment. Five to 10% of patients relapse over 5 years after treatment. In HBe antigen-positive patients HBV genotype may help predict response to interferon therapy, the best candidates being those with genotype A, high ALT levels and low HBV DNA titres. Interferon therapy is generally not useful if there is combined infection with hepatitis C or D. Response in the presence of HIV infection is poor.

Oral nucleosides and nucleotides effectively suppress viral replication and are well tolerated but require long-term therapy to prevent relapse. Entecavir and tenofovir are effective while adefovir can be used as second-line therapy. Lamivudine is effective but its use is often associated with the development of resistance (YMDD variant) and relapse. Other oral agents include telbivudine and emtricitabine. Combination therapy using these agents may prove more effective but requires further investigation. The optimal duration of oral therapy is not clear but in e-antigen positive patients who seroconvert with undetectable hepatitis B DNA, withdrawal may be considered after a further 6–12 months of treatment. In e-antigen negative patients therapy may need to be lifelong.

Liver transplantation is a therapeutic option in those with end-stage chronic hepatitis B. If the patient is HBV DNA negative, a good response to transplantation is possible. On the other hand, liver transplantation into a HBV DNA-positive patient is often followed by severe recurrent disease, often rapidly progressing to graft destruction (fibrosing cholestatic hepatitis). Antiviral therapy and HBV immunoglobulins may improve outcomes.

A number of mutant varieties of hepatitis B have been identified. A ‘precore’ mutant, which does not produce e-antigen, may be associated with more severe acute hepatitis and fulminant hepatic failure. The serum of patients infected with this variant is negative for e-antigen but positive for surface antigen and HBV DNA. Another form of hepatitis B has evolved an alteration in the surface antigen that allows it to escape the immunity afforded by antibodies to this antigen (and thus vaccination).

Patients with chronic hepatitis B who are to undergo chemotherapy or other immunosuppressive therapy should be treated to prevent a severe reactivation hepatitis.

Hepatitis C virus

Hepatitis C virus (HCV) is an RNA virus, which is thought to be directly cytopathic to the hepatocyte (Figs 24.6 and 24.7). Prior to routine screening for this virus, it was responsible for at least 90% of cases of post-transfusion non-A non-B hepatitis. The carrier rate in the general population is unclear, but is probably between 0.2% and 1%. The incubation period for acute hepatitis C is 15–160 days (mean: 50 days). In the majority of cases, the acquisition of hepatitis C virus is not associated with an acute symptomatic illness. Chronic infection is common, however, occurring in up to 80% of infected cases. Of those who acquire hepatitis C, approximately 10–15% develop severe liver disease, which can take decades to develop. Hepatic failure and hepatocellular carcinoma may then follow. Significant hepatitis or liver injury (on liver biopsy) can be associated with normal serum ALT levels. Conversely, some people with mild histological liver damage have serum ALT levels greater than two or three times the upper limit of normal. From this it is apparent that ALT measurements are of limited value in the assessment of the severity of hepatitis C virus infection.

Figure 24.6 Viral hepatitis, chronic, type C. Mild microvesicular fatty change is usually present.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Figure 24.7 Cirrhosis in a patient with chronic hepatitis C. Note the regenerative nodules of hepatocytes separated by thick bands.

Hepatitis C virus appears to infect and replicate in both hepatocytes and mononuclear cells. Its antigenic structure is variable and appears able to escape immune surveillance. Furthermore, there are multiple genotypes (varieties) of the virus. Prior or current infection with hepatitis C virus does not protect an individual from acquiring further hepatitis C infections. One patient may harbour a number of varieties of hepatitis C virus. The genotype will influence the severity of the infection, the response to therapy and the infection’s prognosis.

Transmission of hepatitis C in Western society is primarily by sharing needles. In the past, blood transfusion was a major mode. Other modes of parenteral transmission, such as needlestick injuries, are possible. Under normal circumstances, the risk of sexual transmission is very low: approximately 0.1% per year in a monogamous sexual partnership. Sexual transmission is more likely when another sexually transmitted disease or HIV/AIDS is present. Vertical transmission is also unusual, occurring in approximately 5% of cases, particularly when the maternal viral load is high. Alcoholics are also at higher risk of acquiring hepatitis C.

Risk factors for the progression of hepatitis C infection to more significant liver injury include excessive alcohol consumption, the presence of fatty liver, acquisition of the virus after the age of 40 years, male gender and coinfection with human immunodeficiency virus or hepatitis B.

Pegylated alpha-interferon (given by once-weekly injection) in combination with oral ribaviron can be very effective in patients with chronic hepatitis C. Response to treatment is more likely with HCV genotypes 2 and 3, histologically less hepatic fibrosis, shorter duration of infection and lower viral titres. Moreover, the viral genotype may influence the severity of the disease and the viral titres. Patients with cirrhosis are less likely to respond to interferon and ribaviron therapy, but significant benefit can still be achieved. The addition of the investigational oral protease inhibitor telaprevir to standard therapy may improve treatment success in non- responders.

In general, those without cirrhosis and genotypes 2 and 3 can expect a sustained virological response (the loss of HCV RNA from the blood and cure in most) in 80% or more who complete 24 weeks of treatment. Patients with genotype 1 will require treatment for 48 weeks and can reach response rates of over 50%.

HCV therapy failure is associated with excessive alcohol consumption, insulin resistance, obesity, treatment non-compliance, adverse events requiring dose reduction and insufficient duration of therapy. An individual’s genetic make-up may also influence his or her responsiveness to therapy.

Liver transplantation is a therapeutic option in end-stage hepatitis C. Following transplantation, viraemia is common. Among transplanted patients, 75–90% will develop chronic hepatitis C within 2–3 years (usually within 1 year).

Hepatitis C is responsibly for approximately 25% of hepatocellular carcinoma across the world. The incidence is increasing in Western countries and surveillance should be considered in cirrhotic patients. It is of note, however, that antiviral therapy reduces the risk of developing this malignancy. Six-monthly surveillance abdominal ultrasound examinations should be performed to screen cirrhotic patients for the development of hepatocellular carcinoma.

Vaccinate hepatitis C patients to protect against hepatitis A and B. Hepatitic C can cause extrahepatic disease, including porphyria cutanea tarda (skin blisters—think C!), mixed cryoglobulinemia (palpable purpura) and lichen planus.

Non-alcoholic fatty liver disease and steatohepatitis

Non-alcoholic fatty liver disease is the most common cause for abnormal liver function tests in Australia, the USA and the UK. The prevalence of approximately 20% has been increasing dramatically over recent years as the average body weights of these communities increase. It is often associated with mild (usually up to twice the upper limit of normal) rises in serum transaminase levels, often with elevated GGT levels. Typical patients are overweight with the features of the metabolic syndrome. Thus, strong associations exist with obesity, type 2 diabetes, hypertension and hyperlipidaemia. There is commonly a family history of type 2 diabetes and evidence of insulin resistance.

When associated with hepatic inflammation (non-alcoholic steatohepatitis), non-alcoholic fatty liver disease can unusually progress to produce significant hepatic fibrosis and eventual cirrhosis. Insulin resistance is likely to be the main pathogenic mechanism by which fatty liver occurs in these patients. A subsequent insult or ‘second hit’ (e.g. endotoxaemia) is thought to precipitate the more aggressive inflammatory steatohepatitis.

Usually there is fatty infiltration of the liver on ultrasonography, with no other apparent cause for abnormal liver function test results. CT scan of the abdomen can also identify hepatic fatty infiltration, often with associated marked visceral fat deposition. In the typical case, liver biopsy is not necessary. However, if a biopsy is performed, this condition may have histological findings indistinguishable from alcoholic liver injury. Careful history taking and viral serology are required to clarify the diagnosis in uncertain cases. A carbohydrate-deficient transferrin test will be negative (Table 24.10), but no other biochemical features are diagnostically helpful. High BMI, age greater than 50 years, ALT greater than twice the upper limit of normal and triglycerides greater than 1.7 μmol/L have been associated with a greater risk of hepatic fibrosis in non-alcoholic fatty liver disease.

Table 24.10 Tests useful in alcoholic liver disease

Management is directed towards weight loss and exercise, which can improve insulin sensitivity. When successful, this can result in biochemical and histological improvement. Sudden weight loss may be accompanied by further rises in serum transaminase levels. The rate of weight reduction should be less than 1 kg/week. When the patient’s weight fluctuates, the transaminase levels may vary in parallel. Clearly, optimal diabetic control is essential. When hyperlipidaemia is present, it should be managed as usual with diet and medications (e.g. statins) as normally indicated. The use of metformin, ursodeoxycholic acid and glitazones requires further investigation.

Bariatric surgery has been found to improve non-alcoholic fatty liver disease as well as other complications of morbid obesity.

Other causes of hepatic steatosis include excessive alcohol consumption, recent profound weight loss, hyperalimentation, intestinal bypass surgery and thyroid dysfunction. In these cases the condition is asymptomatic and may be discovered when an abnormal liver function profile or hepatomegaly is detected incidentally.

Certain drug toxicity reactions, fatty liver of pregnancy and Reye’s syndrome are also associated with hepatic steatosis, but cause no clinically apparent illnesses.

Alcoholic liver disease

Although alcohol is a direct hepatotoxin, a patient’s nutritional state and genetic make-up will influence the degree of hepatic injury caused by excessive intake of this agent. Alcohol-induced liver injury is generally classified into fatty liver, alcoholic hepatitis and cirrhosis (Fig 24.8). The mainstay of therapy is abstinence from alcohol.

Figure 24.8 Alcoholic fatty liver. The majority of hepatocytes show a microvesicular fatty change in an active alcoholic.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Fatty liver is in general considered reversible if excessive alcohol consumption is ceased. Recovery and good hepatic function is expected. However if drinking continues, the degree of fatty change is a prognostic indicator of significant long-term liver injury. Clinically there is hepatomegaly. There are no peripheral signs of chronic liver disease. Serum transaminases and especially GGT levels are moderately raised. When serum AST levels are two or more times greater than the ALT level, alcoholic liver disease is more likely the cause. (This does not apply in the presence of cirrhosis.) Fatty infiltration may be apparent on ultrasonography.

In alcoholic hepatitis there is active inflammatory injury to the liver. This may be mild, even subclinical, or severe and life-threatening. The severe form is typified by a mild fever, jaundice, neutrophil leucocytosis, moderate elevations of serum transaminase levels (usually < 300 U/L) and tender hepatomegaly. There may be a hepatic bruit. Liver failure with encephalopathy, ascites, gastrointestinal bleeding (often from oesophageal varices) and sepsis may occur.

Treatment is in general supportive. If the patient is malnourished, aggressive nutritional support may improve the short-term outcome; high kilojoule, high protein diets are appropriate.

Corticosteroids may improve short-term survival in those with severe acute alcoholic hepatitis and jaundice, a high INR or prolonged encephalopathy but no gastrointestinal bleeding. However, the available data do not support the use of corticosteroids in alcoholic hepatitis. In these patients enteral nutritional supplementation may also improve survival. Furthermore, pentoxifylline (400 mg t.d.s.) has been shown to improve survival in severe acute alcoholic hepatitis, by reducing the risk of developing the hepatorenal syndrome. Antioxidants have been shown not to be of benefit.

Propylthiouracil may be of some value in alcoholic hepatitis, increasing survival, but it is not widely used. Colchicine may be of benefit in cirrhosis, but data are limited and conflicting.

Cirrhosis caused by alcohol consumption is similar clinically to that of other causes. Liver injury can progress to cirrhosis after overt alcoholic hepatitis or in the absence of clinically apparent hepatitis. If alcohol consumption continues, there may be superimposed alcoholic hepatitis and rapid progression to decompensated, end-stage liver disease and death.

It is important to note that severe alcohol-related liver disease can be associated with a substantial reversible component if alcohol is stopped. Hepatocyte function will improve and, with the resolution of hepatocyte swelling, portal hypertension can also ameliorate. With abstinence a remarkable degree of recovery may occur, even though it is possible for liver injury to progress once drinking has ceased.

Liver transplantation is a valid therapy, particularly in decompensated post-alcoholic cirrhosis where the long-term outcomes are similar to those of transplantation for other conditions. However, the patient’s condition can improve to such a degree with abstinence that transplantation is not required. Care must be taken to exclude alcohol-related injury to other major organs, such as the brain and heart, prior to considering transplantation.

The prevalence of hepatitis C virus is greater in alcoholics than in the general population. The reason for this is not clear. However, the consumption of excessive amounts of alcohol accelerates hepatitis C-associated liver disease. Interface hepatitis seen on liver biopsy in an alcoholic is likely to be due to hepatitis C infection.

In assessing a patient’s alcohol consumption, an estimate of the number of grams of ethanol consumed per day is useful. The National Health and Medical Research Council of Australia recommends that consumption by males and females should not exceed an average of 20 g per day, with two alcohol-free days per week. Ethanol consumption above these levels is associated with increasing risk of injury. The clinician should aim to identify those individuals at risk. Once they are identified, brief counselling is often effective in reducing ethanol consumption towards safer levels. When applied by the general practitioner, this approach is effective in reducing a community’s overall alcohol consumption and reducing alcohol-related social and physical trauma and pathology. ‘Skid row’ type alcoholics will not respond to this approach. These severe cases may require more intensive management, but are much less likely to respond favourably.

Systematic questionnaires in relation to alcohol dependency are useful. A number of screening questions have been devised. One of the simplest is the CAGE screening test. In this, patients are asked if they ever felt:

The greater the number of positive responses, the more likely the patient is to have an alcohol-dependency problem.

The GGT level could be used to monitor abstinence, but it is non-specific. GGT levels should normalise over 2–5 weeks of abstinence. Up to one-third of heavy drinkers do not have a raised GGT level. An isolated binge does not usually elevate the GGT level. The carbohydrate deficient transferrin (CDT) test is of more value but is not readily available. The CDT test detects a variant of transferrin in the serum that carries fewer sialic acid moieties than the usual form. The presence of CDT reflects the consumption of excessive amounts of ethanol. Levels rise after several weeks of excessive drinking and remain elevated for approximately 2 weeks after drinking has ceased.

Haemochromatosis

This is the commonest genetic disorder in the Australian Anglo-Celtic population. Untreated, this condition, producing iron overload, significantly reduces life expectancy. Moreover, haemochromatosis treated before there is end organ damage is associated with a normal life expectancy. Patients often present because of the incidental finding of abnormal liver function test results or iron studies, or come to medical attention after a relative has been diagnosed. Adequate screening and an accurate diagnosis are essential in first and second order relatives of confirmed cases.

One of the commonest presenting symptoms is unexplained fatigue. Haemochromatosis may be present in 1% of patients in diabetic and rheumatological outpatient clinics, where they may go unrecognised. Cardiac failure in the presence of a cardiomyopathy is another presenting feature, albeit unusual.

Clinically apparent advanced haemochromatosis presents between 50 and 70 years of age (Fig 24.9). The male to female ratio is between 4:1 and 5:1, depending on the study that measures it. Presenting features may include unexplained hepatomegaly, fatigue, loss of libido and hypogonadism (from pituitary iron deposition), cardiac dysfunction from cardiomyopathy, skin pigmentation (from melatonin and iron) and arthralgias with arthropathy. The arthropathy may involve the second and third metacarpophalangeal joints as well as proximal interphalangeal joints, the knees, wrists and hips. The liver is usually the first organ damaged, and patients may present with cirrhosis or hepatocellular carcinoma. However, a diagnosis of haemochromatosis is not excluded by normal liver function test results.

Figure 24.9 Clinical features of advanced haemochromatosis.

The defect responsible for iron loading in haemochromatosis appears to lie in malregulation of metabolism and intestinal iron absorption. Haemochromatosis is an autosomal recessive condition. The responsible gene (HFE) lies on chromosome 6 near the HLA site. There is an approximately 70% linkage with HLA-A3. Approximately 1 in 300 (0.3%) Australians of northern European (including UK) descents are homozygous for the C282Y mutation. People who are homozygous for the C282Y mutation and those with both C282Y and H63D mutations (compound heterozygotes) are at greatest risk of significant iron overload. However, only a limited number of those with these genotypes develop disease. A second defect in iron metabolism may be required to cause pathological iron accumulation. A defect in the hepatic iron-regulatory peptide hepcidin may determine the phenotypic expression of haemochromatosis. Juvenile haemochromatosis has been associated with mutation of the HFE2 (haemojuvelin) gene on chromosome 1.

Iron studies (serum iron, transferrin and ferritin) are used to determine the likelihood of haemochromatosis. In this situation, the transferrin saturation and the serum ferritin concentration are of most value, especially the former. A normal transferring saturation makes haemochromatosis unlikely.

In males, a transferrin saturation over 62% (in females, over 50%) identifies more than 90% of homozygotes. The serum ferritin concentration, a measure of tissue iron stores, predicts approximately 70% of homozygotes. It must be noted that ferritin is an acute phase reactant and can be non-specifically elevated in many conditions (e.g. alcoholic hepatitis, chronic hepatitis, hepatoma, hyperthyroidism, chronic inflammation and histiocytosis). Moreover, it will be elevated as a direct consequence of hepatocellular injury. As with the transaminases, cytoplasmic ferritin will be lost to the serum when hepatocytes are damaged. Similarly other components of the iron studies are influenced by many conditions. Gene testing (homozygous C282Y) confirms the diagnosis.

The diagnosis of haemochromatosis when in doubt is established by the measurement of the tissue iron concentration on liver biopsy. The hepatic iron index (HII) is calculated by dividing the liver iron concentration (μmol/g dry weight) by the patient’s age in years. An HII >2 is indicative of haemochromatosis. This is complemented by hepatic histology with staining for iron (Fig 24.10). In haemochromatosis, excess iron occurs predominantly within hepatocytes (as opposed to Kuppfer cells in cases of secondary iron overload). A key role of liver biopsy is also to identify the presence of cirrhosis with its implications for long-term prognosis.

Figure 24.10 Haemochromatosis. Abundant haemosiderin pigment is present diffusely throughout the liver.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Those individuals who are heterozygote for the C282Y mutation may also have abnormal iron test results, especially if they consume excessive amounts of alcohol. In these individuals, iron overload can become significant in the presence of other disorders such as hereditary spherocytosis, beta-thalassaemia minor, idiopathic sideroblastic anaemia and porphyria cutanea tarda.

Screening of first- and second-degree relatives of patients with haemochromatosis using HFE analysis, fasting serum transferrin saturation and ferritin levels is necessary to identify cases prior to the onset of clinical disease.

The treatment of haemochromatosis is phlebotomy. Venesections may be commenced at weekly intervals and adjusted according to the estimated iron load and the patient’s tolerance. Treatment is monitored with serial haemoglobin levels and iron studies. The aim is to achieve and maintain normal iron studies. The haemoglobin level will usually remain stable until the patient is ‘de-ironed’, then it can fall rapidly. If anaemia becomes problematic before the iron status has been normalised, lower volume or less frequent venesections can be used. Maintenance venesections are started, and continued indefinitely. If the patient is ‘de-ironed’ within 18 months and there is no end organ damage, life expectancy is normal.

Haemochromatosis may be complicated by the development of hepatocellular carcinoma, with a relative risk of more than 200. This is more likely in males, in those over the age of 50 years, in the presence of cirrhosis, chronic alcoholism, smoking and past transfusion. It is not related to the amount of iron removed during treatment and only unusually occurs in a non-cirrhotic liver.

Wilson’s disease

Wilson’s disease occurs in approximately 1 in 40,000 people and is the consequence of mutation of the ATP7B gene on chromosome 13, leading to defective copper trafficking and thereby the progressive accumulation of copper with ongoing liver injury through childhood into adult life. More than 60 polymorphisms have been identified, making genetic testing unhelpful in clinical practice. ATP7B is a trans-Golgi membrane hepatocyte copper-transporting ATPase involved in biliary copper excretion.

Catastrophic haemolysis and an acute hepatic illness are unusual complications. In those who do not succumb to liver disease in early life, neurological abnormalities can evolve in early adulthood (including psychiatric diseases, dysarthria, ataxia, incoordination and tremor). Patients with Wilson’s disease may also be at elevated risk of intraabdominal malignancy.

Low serum caeruloplasmin levels suggest the diagnosis, although this may remain normal in some cases. The presence of Kayser-Fleischer rings (brown deposits around the periphery of the iris, best seen at slit-lamp examination) suggests this diagnosis. However, Kayser-Fleischer rings are also rarely found in chronic cholestatic liver diseases. Liver biopsy will often demonstrate excessive copper staining but this occurs in other diseases; chemical analysis of liver tissue copper concentration is usually a reliable indicator of the diagnosis. Urinary copper excretion and copper dynamic studies may also be needed to establish the diagnosis.

Effective therapy is available for Wilson’s disease. D-penicillamine (250 to 500 mg daily increasing incrementally to 1000–1500 mg in two to four divided doses) chelates copper and allows its removal from the body. An alternative chelating agent for patients unable to take penicillamine is trimethylene tetramine dihydrochloride. Therapy is supplemented with oral zinc, which leads to the inhibition of gastrointestinal copper absorption. Effective chelation therapy early in the disease will stabilise, improve or prevent end organ injury.

In early, presymptomatic Wilson’s disease, zinc (50 mg b.d.) therapy can prevent progression to clinical disease.

Liver transplantation should be considered when there is liver failure or when chelation therapy fails in the presence of advanced liver disease. Medical therapy is the preferred therapy in those with neurological Wilson’s disease, as it is unclear whether transplantation provides any extra benefit in that circumstance.

Alpha-1 antitrypsin deficiency

This autosomal-recessive genetic disorder may present in childhood or adult life with features suggestive of chronic hepatitis or with established cirrhosis. This often occurs in the absence of pulmonary disease.

The diagnosis is obtained by measuring the level of alpha-1 antitrypsin in the blood and determining the phenotype. More than 75 variants of the gene have been identified. PiZ and PiS are the most common defective alleles, with the former most commonly associated with emphysema. Of homozygous deficient (PiZZ) children, approximately 10% will develop significant progressive liver disease. In adults, asymptomatic cirrhosis is a common presentation. Serum levels of alpha-1 antitrypsin in homozygotes are often 15% of normal.

People who are heterozygous for PiZ may also be predisposed to developing significant liver disease. Heterozygotes may have serum levels of alpha-1 antitrypsin between 40% and 60% of normal, and can develop abnormal liver function test profiles without significant liver injury.

Liver biopsy will show the extent of liver injury and the presence of cirrhosis. Histology is characterised by the presence of periodic acid-Schiff (PAS) positive globules within hepatocytes. These globules represent precipitated accumulations of the abnormal alpha-l antitrypsin protein, which is synthetised but not secreted. Treatment is with liver transplantation.

Idiopathic, autoimmune chronic hepatitis

Idiopathic, autoimmune chronic hepatitis (IACH) is an uncommon condition predominantly affecting women. It is characterised by the presence of progressive liver disease and a polyclonal hyperglobulinaemia associated with a variety of autoantibodies. Responsiveness to corticosteroid therapy is also typical.

The onset of IACH is usually insidious with progressive fatigue, anorexia and jaundice. Seventy-five per cent of patients are female, mostly between 10 and 40 years of age. In the more aggressive forms, there is progression to cirrhosis and eventually liver failure. Untreated, more than 50% of patients die in 3–5 years.

The aetiology of this condition is unclear, but once established there is progressive cytotoxic T-cell-mediated injury of hepatocytes. In certain circumstances, it appears that viral hepatitis could be the initiating event of IACH.

Autoantibodies, commonly anti-actin (anti-smooth muscle) and antinuclear antibodies, are present. There is a prominent polyclonal hypergammaglobulinaemia. In an often aggressive variant that usually affects young females, the smooth muscle antibody and antinuclear antibody can be absent while an anti-liver/kidney microtonal antibody (anti-LKM1) is found.

On liver biopsy in aggressive disease, the chronic inflammatory infiltrate, including plasma cells, typically expands the portal areas and extends into the liver lobule, causing erosion of the limiting plate (interface necrosis, Fig 24.11). Varying degrees of fibrosis may be present. Fibrotic linkages between portal tracts or cirrhosis are markers of aggressive disease.

Figure 24.11 Autoimmune hepatitis. The portal infiltrate consists of lymphocytes and plasma cells. The interlobar duct is partially infiltrated by lymphocytes.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Corticosteroid treatment is appropriate when liver biopsy shows more aggressive chronic hepatitis, gammaglobulin levels are greater than twice normal, and ALT levels are greater than five times normal. Corticosteroids (tapering from 30 mg/day to 60 mg/day) with or without azathioprine improve the clinical syndrome and survival. Azathioprine (1–2 mg/kg) may be used to supplement corticosteroid therapy or to act as a steroid-sparing agent. In some the corticosteroid can be withdrawn and remission maintained with azathioprine. A positive response to treatment supports the diagnosis. Mortality is reduced, hepatic inflammation and fibrosis are suppressed and symptoms improve on steroids. Sufficient therapy is required to keep the serum transaminase levels below twice the upper limit of normal, preferably normal, and normalised IgG concentration. Slower progression of the disease may continue, however. Although some patients can cease therapy after several years, treatment will need to be lifelong in the majority of cases. If the disease progresses, liver transplantation will eventually need to be considered. The benign, generally non-progressive, milder form of autoimmune hepatitis may not require therapy.

Especially when long-term corticosteroid therapy is required, weight control and protection of bone density (calcium and vitamin D supplementation with or without a bisphosphonate) are particularly important. Chronic infection with strongyloides (stool examination) and tuberculosis (chest x-ray) and currency of vaccination could help prevent significant infectious complications.

Primary biliary cirrhosis

In primary biliary cirrhosis there is an immune-mediated destruction of the small intrahepatic bile ducts. This illness follows a prolonged course with eventual development of cirrhosis and liver failure. Primary biliary cirrhosis typically presents in a middle-aged female with pruritus, a raised alkaline phosphatase level and a positive antimitochondrial antibody (AMA) result.

ALP and, to a lesser extent, serum transaminase levels are usually elevated in patients with primary biliary cirrhosis. AMA is present in the serum in 95% of cases. Its presence is highly suggestive of the diagnosis. IgM levels are often elevated. Differentiation between AMA-negative primary biliary cirrhosis and IACH may be difficult. Smooth muscle antibody and antinuclear antibody may be present in the former, and low titres of AMA can occur in IACH. A true overlap syndrome can occur, and will present features of both conditions. Furthermore, on liver biopsy, primary biliary cirrhosis can share features with IACH, although differentiation is usually possible (Fig 24.12). If uncertainty remains, a therapeutic trial of corticosteroids is likely to induce an improvement in IACH but not in primary biliary cirrhosis.

Figure 24.12 Primary biliary cirrhosis. The interlobar bile duct is slightly hyperplastic and exhibits lymphocytes within the duct wall.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

Adverse prognostic signs in primary biliary cirrhosis include a high serum bilirubin concentration (over 100 μmol/L), a low serum albumin concentration, ascites, gastrointestinal bleeding, advanced age, cirrhosis or central cholestasis on liver biopsy and low serum IgM levels.

Pruritus is a common clinical feature of primary biliary cirrhosis. This will often respond to ursodeoxycholic acid. Alternative therapy includes cholestyramine. Fat-soluble vitamin deficiency (A, D, E and K), which is secondary to cholestasis, should be sought and treated accordingly. Osteopenia due to osteoporosis may result in disabling fractures. There may be evidence of autoimmune disorders involving other organs such as the eyes, joints and thyroid. Hypercholesterolaemia with xanthelasmas and xanthomas are further features of primary biliary cirrhosis.

Ursodeoxycholic acid (13–15 mg/kg/day) is effective therapy for primary biliary cirrhosis, improving survival and delaying the need for transplantation. In the overlap syndrome a combination of ursodeoxycholic acid and corticosteroids may be required.

End-stage primary biliary cirrhosis is a common indication for liver transplantation in adults, with a success rate of 80% or more. Transplantation should be considered when the serum bilirubin concentration rises progressively above 100 μmol/L, or when there is uncontrolled gastrointestinal bleeding, ascites or intractable pruritus.

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PGS) is characterised by the inflammatory destruction of bile ducts larger than those involved in primary biliary cirrhosis. This condition is considered to be due to an autoimmune process. Approximately 70% of cases of PSC occur in patients with inflammatory bowel disease. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common, especially in those with associated ulcerative colitis (up to 90% of cases).

The diagnosis of primary sclerosing cholangitis relies on cholangiography identifying focal biliary strictures with associated beadlike dilatations. Liver biopsy is of limited diagnostic value (Fig 24.13). Because of the presence of portal inflammation, there may be difficulty in differentiating primary sclerosing cholangitis from other chronic inflammatory conditions on liver biopsy.

Figure 24.13 Primary sclerosing cholangitis. Periductal fibrosis is striking with fibro-obliterative ‘onion-skinning’ a common feature. Eventually duct depletion occurs.

From Kanel GC, Korula K. Liver biopsy evaluation. Philadelphia: WB Saunders; 2000, with permission.

The progression of primary sclerosing cholangitis is difficult to predict. Advanced age, severe changes on liver histology, splenomegaly and high serum bilirubin concentrations are adverse prognostic features.

When localised strictures occur, endoscopic therapy can be considered. Placing stents across strictures or balloon dilation may be of value. The risk of bacterial contamination of the biliary tract needs to be considered, especially if foreign bodies (stents) are left in situ. Recurrent cholangitis is a problem, with and without intervention. Liver transplantation is the only effective treatment for primary sclerosing cholangitis. A successful outcome is expected in more than 70% of well-selected cases. The use of high doses of ursodeoxycholic acid has been reported in PSC. This treatment is of no proven value and may shorten the patient’s survival time.

Primary cholangiocarcinoma complicates 10–20% of cases of primary sclerosing cholangitis. Sudden rapid progression of pruritus, jaundice and weight loss suggest malignancy. However, this diagnosis can be difficult and may not be made until postmortem. Brush cytology on ERCP provides a positive result in only 20% of patients with cholangiocarcinoma. If transplant takes place, the outcome is poor when primary cholangiocarcinoma is present.

Drugs and the liver

A careful history of medication use is vital in the assessment of the patient with abnormal liver function test results. Toxic or idiosyncratic adverse reactions may occur with many therapeutic agents (Table 24.11). Immune mechanisms are responsible for many of these reactions. The contraceptive pill may be associated with a number of liver diseases including hepatic adenoma (rare—usually single), hepatocellular carcinoma (very rare), peliosis hepatis (large blood-filled cavities), Budd-Chiari syndrome (see below), cholestasis and cholesterol gallstones (because of more lithogenic bile).

Table 24.11 Drugs and the liver

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AMA = anti-mitochondrial antibody; LFTs = liver function tests; NSAIDs = non-steroidal anti-inflammatory drugs; OCS = oral contraceptive steroids.

From Farrell G. Drug induced liver disease. Edinburgh: Churchill Livingstone; 1994, with permission.

Paracetamol overdose, deliberate or accidental, is a relatively common cause of severe acute liver disease. In this case toxic metabolites of the drug are generated by cytochrome p450s and damage hepatocytes. The induction of these enzymes, as occurs with chronic alcohol consumption, may enhance paracetamol toxicity.

Polymorphisms of certain p450s may also influence an individual’s risk of drug-induced liver injury by affecting the rate of production of toxic metabolites (e.g. nefazodone). The generation of toxic metabolites may also be responsible for liver damage associated with non-steroidal anti-inflammatory drugs.

Liver injury may follow idiosyncratic drug-induced metabolic modification. For example, the statins may induce a mild asymptomatic rise in liver enzymes, but occasionally cause more severe, acute cholestatic hepatitis. The effect seems to be mediated by changes in mevalonic acid metabolism.

Jaundice and other symptoms of drug-induced liver injury generally persist for a limited period after the withdrawal of the offending agent but long-term abnormalities in liver function tests and of hepatic histology may not be as unusual as previously believed. However, late liver failure is not expected. In particular, hepatic injury associated with methyldopa, amiodarone, nitrofurantoin, diclofenac and clavulanic acid/amoxicillin may be followed by chronic, ongoing liver disease.

Vascular and perfusion disorders of the liver

Vasculitis and thrombotic disorders can affect the vessels of the liver. These conditions often produce portal hypertension with varying degrees of hepatocellular dysfunction.

Obstruction of the portal vein may occur in association with sepsis or thrombotic disorders and presents usually with bleeding from varices, or splenomegaly is detected on examination. This results in portal hypertension, often with preservation of hepatocyte function. Portal vein thrombosis can also complicate cirrhosis.

Veno-occlusive disease of the liver is associated with obstruction of the terminal hepatic venules. Precipitating events include bone marrow transplantation and exposure to chemotherapeutic agents and certain plant alkaloids. Clinically, there is right upper quadrant tenderness, hepatomegaly, ascites and jaundice. Progression to liver failure may occur.

Budd-Chiari syndrome involves thrombosis of the hepatic veins. It presents with pain, hepatomegaly and ascites (Ch 4). There is portal hypertension and loss of hepatocyte function. There are acute and chronic forms of this syndrome. Progression to liver failure is not unusual.

Thrombotic conditions involving the portal and hepatic vessels are associated with hypercoagulable states such as paroxysmal nocturnal haemoglobinuria, polycythaemia rubra vera, pregnancy, the contraceptive pill, lupus anticoagulant, malignancy (e.g. renal, adrenal, testicular and thyroid), a fibrous membrane, amoebic abscess or hydatid cyst and drugs (e.g. azathioprine).

The diagnosis of portal and hepatic vein obstruction can often be established with ultrasonography and Doppler flow studies. Portal venography may be necessary. The definitive diagnosis of veno-occlusive disease requires liver biopsy although the diagnosis is often made clinically.

Cardiac disease may cause an abnormal liver function profile. Hepatic ischaemia in association with hypotension, as occurs during cardiac arrest, will result in a marked elevation of serum transaminase levels, often to several thousand units per litre. Unlike other conditions, the serum lactate dehydrogenase level is also markedly elevated. Recovery of the liver is prompt. Liver dysfunction does not interfere with the clinical course of the cause of the hypotension nor the prognosis. Moreover, the final prognosis is determined by the underlying illness.

Right-sided heart failure and tricuspid regurgitation cause hepatic congestion, and associated abnormalities in liver function test results are not unusual. Elevations in alkaline phosphatase levels are common and will improve with control of the cardiac failure. Persistent hepatic congestion can eventually lead to fibrosis and cirrhosis.

Hepatocellular carcinoma

Both the incidence of and mortality from hepatocellular carcinoma are increasing in Australia and other Western countries, primarily as a consequence of chronic viral hepatitis. Treatment options depend on the size and location of the tumour and as such early detection is important. The diagnosis of hepatocellular carcinoma can be made on good quality imaging, such as triple phase CT scan or MRI, without the need for biopsy.

Surgical resection of single lesions less than 2 cm in diameter leads to a 80% 5-year survival. This approach is appropriate when the liver disease is compensated without significant portal hypertension. It is important to have an understanding of the liver segments. There are eight segments. Each has a separate blood supply from the hepatic artery and portal vein, and a segmental bile duct drains into the right or left hepatic ducts. Removal of separate segments of the liver is feasible and this is important when considering surgical resection of a malignancy.

When there is a single hepatocellular carcinoma (less than 5 cm) or up to three lesions less than 3 cm in diameter, liver transplantation can be potentially curative and should be considered. If transplantation is contraindicated local ablative therapy (radiofrequency ablation or ethanol injection) can be of value. With advanced hepatocellular carcinoma transarterial chemoembolisation and for those with more severe underlying liver disease, oral sorefenib can slow the progression of the disease. Patients with terminal disease should be managed symptomatically (see Ch 28).

Cirrhosis is an important predisposing factor in the development of hepatocellular carcinoma. Cirrhosis of any cause may be considered potentially premalignant. However, the most significant aetiological factors include hepatitis B or hepatitis C infection, haemochromatosis and alcohol consumption. Hepatitis B infection and possibly hepatitis C can induce hepatocellular carcinoma without prior cirrhosis. Symptomatic hepatocellular carcinoma carries a poor prognosis. Screening of groups at high risk should be performed routinely. Ultrasonography can identify small, potentially curable lesions and should be performed in cirrhotic patients at 6-monthly intervals.

The fibrolamellar variant, usually found in young Caucasian females, responds well to local resection.

Benign tumours

Benign hepatic mass lesions are often identified incidentally during investigation (imaging) for unrelated symptoms. Adenomas, focal nodular hyperplasia and focal fatty change produce ‘masses’. Normal liver function test results are expected. Intervention is not required for focal nodular hyperplasia or fatty change. Hepatic adenoma may bleed (50% risk), may be difficult to differentiate from low-grade hepatocellular carcinoma and can progress to carcinoma. Imaging is often non-specific in the differentiation between focal nodular hyperplasia and adenoma. If an adenoma is suspected, segmental resection is usually indicated (Ch 26).

Haemangiomas and hepatic cysts are common benign conditions often found incidentally during hepatic imaging. Simple fluid-filled cysts need no further investigation. If a lesion is typical of haemangioma on ultrasound or computed tomography, again no further tests should be necessary. If, however, there remains uncertainty as to the nature of the lesion, a nuclear-labelled red cell scan or MRI can be helpful. Angiography is not usually necessary. Small lesions require no treatment but large symptomatic lesions may need segmental resection (Ch 26).

Acute fatty liver of pregnancy

This condition occurs in approximately 1 in 13,000 pregnancies. It carries with it a high fetal and maternal mortality. A brief non-specific prodrome may rapidly progress to fulminant hepatic failure. The onset is in the third trimester, generally after 32 weeks of gestation. Twin, male and primipara pregnancies are at greater risk of acute fatty liver.

Nausea and vomiting are features of the clinical illness. Polydipsia may occur in association with diabetes insipidus. There may be abdominal pain. This can be epigastric or centred in the right upper quadrant. Malaise and fatigue is followed by pruritus and jaundice that rapidly progresses to liver failure. Ascites occurs in 50% of cases. Encephalopathy, hypoglycaemia, coagulopathy and renal failure follow. The mortality, without hepatic transplantation, is greater than 80% in advanced cases.

Commonly there is mild hypertension, oedema and proteinuria, suggesting a possible relationship to preeclampsia. Haematology reveals leucocytosis, thrombocytopenia and evidence of microangiopathic haemolysis. Creatinine is elevated with a greater elevation in uric acid levels. Bilirubin and ALP levels are raised, while serum transaminase levels are between 300 U/L and 500 U/L. Hypoglycaemia and coagulopathy may be severe and represent significant management problems.

Abdominal ultrasound scans have poor sensitivity in identifying acute fatty liver but are of use in excluding Budd-Chiari syndrome and gallstones. If necessary, a fine-needle aspiration biopsy will confirm the diagnosis. However, once the clinical diagnosis is made, performing a biopsy could waste valuable time and in so doing adversely affect the outcome.

The treatment of acute fatty liver of pregnancy is emergency delivery of the fetus. This reduces the mortality to approximately 20%. It is of note that the mother’s condition may worsen after delivery. Liver transplantation may be required. There is no chronic disease following recovery. Recurrent acute fatty liver with subsequent pregnancies is not expected, but has rarely been reported.

Benign intrahepatic cholestasis of pregnancy

This condition presents with pruritus and jaundice, often in the third trimester of pregnancy. Liver function tests are ‘cholestatic’, but the mother is otherwise well. Occasionally there may also be a significant rise in serum transaminase levels. The condition resolves with delivery. There is a strong genetic predisposition. Recurrence with subsequent pregnancy and during oestrogen therapy is likely. Cholestasis of pregnancy is associated with increased fetal loss. Severe symptomatic cases with progressively rising levels of serum bile acids or abnormal liver function results should be considered for early delivery. Symptomatic treatment of the pruritus has limited success.

Ursodeoxycholic acid has been shown to be effective in relieving the maternal symptoms and appears to reduce fetal mortality. Numerous other measures have been tried in the control of the pruritus. These include cholestyramine, evening primrose oil, antihistamines, rifampicin, opiate antagonists, phenobarbitone and S-adenosylmethionine. The effectiveness and safety in pregnancy of all these agents has not been objectively established.

Preeclampsia and the HELLP syndrome

Liver disease occurs in approximately 10% of cases of preeclampsia. In general, hepatic injury is secondary to the underlying condition, and reflects advanced disease. Preeclamptic signs may be mild. Symptoms include right upper quadrant and epigastric pain, nausea and vomiting. Jaundice, often mild, occurs in 40% of those affected. ALT levels are, in general, greater than 500 U/L.

Most maternal deaths are cerebral, but hepatic involvement may contribute to death when infarction, haemorrhage or haematoma formation (with or without rupture) occurs.

A special case of preeclampsia is the HELLP syndrome. This syndrome consists of Haemolysis, Elevated Liver function tests and Low Platelets. There is a microangiopathic haemolytic anaemia. Early aggressive management with delivery is appropriate.