Paracetamol (acetaminophen) hepatotoxicity

Paracetamol toxicity accounts for approximately 40% of cases of ALF in the UK and the US. Hepatotoxicity is dose-related; most ingestions leading to ALF exceed 10 g/day and mortality is higher with doses over 48 g. While most episodes result from deliberate acts of self-harm, a significant proportion of cases result from therapeutic use. Factors increasing susceptibility to hepatotoxicity include regular alcohol consumption, antiepileptic therapy, preexisting hepatic dysfunction and malnutrition.

Idiosyncratic drug toxicity

A variety of prescription drugs, including various antiepileptics (e.g. phenytoin, sodium valproate), non-steroidal antiinflammatory drugs (e.g. diclofenac) and antibiotics (e.g. isoniazid) have been implicated in acute liver failure (Table 47.1). Most cases occur within the first 4–6 weeks of initiating treatment, but can occur years after the drug is commenced. Certain herbal preparations and other nutritional supplements have been found to cause liver injury. In addition, a variety of illicit substances, including synthetic amphetamines, have been linked to ALF.

TABLE 47.1 Aetiologies of acute liver failure

Viral hepatitis

Hepatitis A virus and hepatitis B virus are the chief causes of ALF in India and other parts of the developing world. However, ALF is an uncommon complication of viral hepatitis, occurring in 0.2%–4% of cases depending on the underlying aetiology. The risk of developing ALF from hepatitis E approaches 20% in pregnant women. Other viral aetiologies of ALF include hepatitis D virus coinfection or superinfection (Table 47.1), Epstein-Barr virus, cytomegalovirus, herpes simplex virus and varicella zoster.

Miscellaneous

There are a number of other less common causes of ALF. Pregnancy-related liver disease may result in ALF, usually in the third trimester. A variety of presentations may be seen with thrombocytopenia and features of pre-eclampsia often present. Wilson’s disease may present as ALF, typically in young patients accompanied by the abrupt onset of haemolytic anaemia. The fulminant presentation carries a poor prognosis without transplantation. Autoimmune hepatitis, Budd-Chiari syndrome, toxins (mushroom poisoning, aflatoxins), ischaemic hepatitis and malignant infiltration of the liver are other infrequent causes of ALF (Table 47.1). A definite cause is unable to be identified in approximately 15%–40% of cases of ALF worldwide.

Hepatic encephalopathy and cerebral oedema

Hepatic encephalopathy is a defining characteristic of ALF. Severity is graded on a scale of 1 to 4. In stage 1, patients have subtle impairments in concentration and altered sleep patterns. Stage 2 is marked by drowsiness and confusion often accompanied by asterixis or tremor. Stage 3 is marked by increasing somnolence and incoherence, which progresses to frank coma in stage 4. Hyperreflexia, clonus and muscular rigidity may be present in the latter stages.

Progressive cerebral oedema with the development of elevated intracranial pressure (ICP) plays a major role in the pathogenesis of this condition and has long been recognised as the most serious complication of ALF. The classic signs of raised ICP include systemic hypertension, bradycardia and irregular respirations (Cushing’s triad). Intracranial hypertension can result in cerebral hypoperfusion and hypoxia leading to irreversible neurologic damage, uncal herniation and brain death. Direct intracranial pressure monitoring is commonly used in patients with ALF and severe encephalopathy.

Other complications of ALF, including hypoglycaemia, sepsis, fever, hypoxaemia and hypotension, may also contribute to neurologic abnormalities in these patients.