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

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

In each of the conditions generating chronic hepatitis there is an ongoing inflammatory attack directed toward the hepatocyte. This can be the result of direct hepatocyte injury, as is the case in hepatitis C infection (the most common cause of chronic hepatitis in Australia) and Wilson’s disease, which is rare. On the other hand, liver cell injury may be immune-mediated, as occurs with hepatitis B infection, autoimmune chronic hepatitis and certain drug reactions.

Evidence of continuing hepatic inflammation based on a persistent elevation of serum transaminases (6 months or more) is usually required to entertain the diagnosis of a chronic hepatitis. However, it can take many months for serum transaminases to return to normal levels following some acute hepatic illnesses. Once the presence of chronic hepatitis is considered likely, establish the aetiology of the illness, the extent of liver damage and the activity of the inflammatory process. These latter two features can be assessed only by the histological examination of a liver biopsy.

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

The patient with fulminant hepatic failure needs to be admitted directly to a unit capable of offering liver transplantation. Admission to intensive care is required with careful management of cerebral oedema, gastrointestinal bleeding, infection and renal failure.