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

Test	Condition	Comment
Antinuclear antibody (ANA)	Autoimmune chronic hepatitis	Diagnosis requires liver biopsy
Smooth muscle antibody (SMA) (anti-actin)	Autoimmune chronic hepatitis	Diagnosis requires liver biopsy
Anti-liver kidney microsomal antibody (anti-LKM1)	Autoimmune chronic hepatitis	Diagnosis requires liver biopsy
Antimitochondrial antibody (AMA)	Primary biliary cirrhosis(95%)	Diagnosis requires liver biopsy
Antineutrophil cytoplasmic antibody (pANCA)	Primary sclerosing cholangitis	Diagnosis requires magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography

Table 24.2 Tests for metabolic disorders affecting the liver

Test	Condition	Comment
Iron studies	Haemochromatosis	See text
Copper and caeruloplasmin	Wilson’s disease	See text
Alpha-1 antitrypsin level and phenotype	Alpha-1 antitrypsin deficiency	Heterozygotes may have abnormal liver function tests without significant liver disease
Thyroid function tests	Hypothyroidism	Fatty liver
Blood glucose level	Diabetes mellitus	Fatty liver, haemochromatosis
Insulin/C-peptide	Insulin resistance	Fatty liver, metabolic syndrome
Cholesterol and triglycerides	Primary and secondary hyperlipidaemia	Fatty liver, alcoholic liver disease

Table 24.3 Tests for viral hepatitis

Test	Meaning of a positive result	Comment
1. Tests for hepatitis A virus (HAV)
Anti-HAV IgM	Recent acquisition of HAV	Acute hepatic illness likely to be HAV
Anti-HAV IgG	Past infection/vaccination	Immunity
2. Tests for hepatitis B virus (HBV)
HBsAg (surface ag)	Present/chronic infection	Structural component of virus
Anti-HBsAg (surface ab)	Past infection/vaccination	Immunity
Anti-HBc IgM (core ab)	Recent acquisition of HBV	The test for acute HBV infection
HBeAg (e ag)	Marker of viral replication	High risk of infectivity
Anti-HBeAg (e ab)	Suggests no viral replication	Unlikely to be infectious
HBV DNA	Presence of complete virus	High risk of infectivity
3. Tests for hepatitis C virus (HCV)
Anti-HCV	Exposure to HCV	Interpret in conjunction with other clinical and laboratory data
HCV RNA by PCR	Presence of virus	–
HCV genotyping	–	Treatment planning and response
4. Tests for hepatitis D virus (HDV)
Anti-HDV IgG/IgM	Exposure to HDV	Acute or chronic HDV
Delta antigen	HDV present	Acute or chronic HDV
5. Tests for hepatitis E virus (HEV)
Anti-HEV IgM	Recent acquisition of HEV	Acute hepatitic illness likely to be HEV
6. Tests for other organisms
Cytomegalovirus (CMV) IgM	Recent acquisition of CMV	Acute hepatitic illness likely to be CMV
Epstein-Barr virus (EBV) IgM	Recent acquisition of EBV	Acute hepatitic illness likely to be EBV
Anti-HIV	HIV-AIDS	Opportunistic hepatobiliary infections
Toxoplasmosis serology	–	Consider toxoplasmosis
Q fever serology	–	Consider Q fever

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

Liver biopsy

Histological and, on occasion, chemical analysis and microbiological examination of the liver are essential in the diagnosis of many hepatic disorders. The usual technique for obtaining a liver biopsy involves a percutaneous approach through a lower intercostal space in the right midaxillary line. Ultrasound scanning or CT can be used to optimise the needle entry point or target specific abnormalities. Haemorrhage from the biopsy wound to the liver or injury to adjacent organs are the major risks. These may be significant in approximately 1% of biopsies. The risk of haemorrhage is minimised by ensuring a platelet count greater than 80 × 10⁹/L (80,000/mm³) and an INR less than 1.2. When coagulopathy or gross ascites prevents a percutaneous biopsy, a transjugular approach can be used.

The decision to proceed to liver biopsy is reached when the potential information gained outweighs the risks of the procedure. In particular, obtaining information about the patient’s prognosis or diagnostic information that might alter therapy is the important consideration. Although it is not always appropriate to perform a liver biopsy to only achieve a diagnosis, it is not unusual for the clinical diagnosis to be altered by the information gained at biopsy. The clinical course of the illness should also be considered. The patient with improving liver function test profiles and resolving symptoms is probably best observed rather than biopsied early. It should be noted, however, that, in certain conditions such as chronic hepatitis C and haemochromatosis and in some alcoholic patients, hepatic fibrosis can progress to cirrhosis with little clinical or laboratory evidence of aggressive liver disease.

The significance of liver biopsy features is considered in relation to specific disorders later in this chapter. The extent, nature and activity of inflammatory and fibrotic processes are of particular concern. The presence of fibro-inflammatory changes is more likely to be related to a progression to cirrhosis. The absence of such changes carries a better prognosis. Sampling error can be a problem as the tissue sample represents only a tiny proportion of the liver mass and the disease process may not be uniform across the organ. Cirrhosis can be missed in 10–20% of cases, depending on the size and number of samples taken.

The Well Patient with Abnormal Liver Function Profile

Many patients now present to their practitioner apparently in good health but with an abnormal set of liver function test results, often found at routine insurance medical examination. These patients raise a whole range of diagnostic possibilities and, in evaluating them, a full history and examination is required. The most common causes of abnormal liver function test results in otherwise well individuals are non-alcoholic fatty disease (which may or may not be associated with significant inflammation) and alcohol-related liver damage. Another common cause will be the ingestion of medications. However, the presence of other serious, progressive and eventually potentially life-threatening conditions needs to be considered.

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

Chronic hepatitis	Cirrhosis
• Hepatitis C virus • Hepatitis B virus • Autoimmune • Drug-induced • Wilson’s disease • Alpha-1 antitrypsin deficiency

• Alcohol

• Hepatitis C and B

• Drugs (as for chronic hepatitis)

• Non-alcoholic steatohepatitis (fatty liver disease)

• Primary sclerosing cholangitis

• Primary biliary cirrhosis

• Haemochromatosis

• Wilson’s disease

• Chronic constrictive pericarditis

• Alpha-1 antitrypsin deficiency

• Idiopathic (cryptogenic)

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.

The Sick Patient with Jaundice: Acute Liver Disease

Acute hepatitis

Acute Liver Failure

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

Type	Criteria
Paracetamol-induced ALF	Arterial pH < 7.30 after fluid resuscitation or all of: • INR > 6.5; • creatinine > 259 μmol/L; • grade 3 or 4 encephalopathy.

Non-paracetamol-induced ALF INR > 6.5 or any three of:

non-A, non-B viral hepatitis, drug-induced or indeterminate aetiology

Time from jaundice to encephalopathy > 7 days

Age < 10 years or > 40 years

INR > 3.5

Serum bilirubin > 297 μmol/L

INR = International Normalized Ratio.

From O’Grady JG, Alexander GJM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445.

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.

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%.

Patients Presenting with Cirrhosis and its Complications

Cirrhosis represents the non-specific end-stage of hepatic disease that has disrupted the structural organisation of the liver. The presence of cirrhosis is established on a liver biopsy. Fibrosis or scarring surrounding regenerative nodules of hepatocytes is its hallmark. Although cirrhosis is a histological diagnosis, its presence is clinically suspected by finding signs of chronic liver disease and portal hypertension (Box 24.1) or on high quality imaging. Symptomatic liver disease and eventually liver failure occur as the result of impaired hepatocellular function within the distorted architecture of the regenerative nodules and, with progression, eventual loss of an effective liver cell mass. Distortion of the hepatic circulation contributes to portal hypertension and inefficient/ineffective perfusion of parenchymal cells. Portal systemic shunts may develop, allowing blood from the gastrointestinal tract to flow directly to the systemic circulation.

Cirrhosis should be considered as either compensated, with no signs of complications and a relatively good prognosis, or decompensated (Ch 25). Those with compensated cirrhosis are likely to be asymptomatic and the diagnosis may be made incidentally during the investigation of an unrelated condition. In this situation, counselling regarding diet, ethanol consumption and the identification and management of any underlying treatable condition are warranted (see ‘The well patient with abnormal liver function profile’ above). Recent data have indicated that the removal or cure of the underlying disease process can be followed by a reduction in hepatic fibrosis (e.g. after the cure of hepatitis C).

The serum levels of liver enzymes (ALT, AST and ALP) can be mildly abnormal or even normal in compensated cirrhosis. However, because of reduced hepatic synthetic function or poor nutrition, the serum albumin concentration is often reduced, and the INR may be increased. There may be thrombocytopenia related to splenomegaly from portal hypertension. Anaemia can be multifactorial but is often related to gastrointestinal blood loss, poor nutrition (e.g. in alcoholics), chronic disease and hypersplenism.

The Child-Pugh score (Table 24.6) provides a useful means of assessing the severity of cirrhosis and the prognosis. A Child-Pugh ‘A’ classification applies to a score of less than 7; ‘B’, a score between 7 and 9; and ‘C’, greater than 9. The 1-year survival of these classification groups is 100%, 80% and 45%, respectively. A higher score also indicates those more likely to succumb to complications during hepatic and no hepatic surgical procedures.

Table 24.6 Child-Pugh score