19th May 2025

Aetiology

Risk factors

Factors which increase the risk of developing idiosyncratic DILI include: 

• Female gender – in addition, women are more likely to be of younger age and have hepatocellular DILI, whereas affected males are more likely to be older and demonstrate cholestatic DILI. Women are also more likely to demonstrate severe hepatotoxicity.
• Increased age
• Drug factors – increased duration of use, higher dose
• Genetic factors – certain HLA genotypes appear to confer greater risk of DILI caused by certain drugs such as flucloxacillin
• Race and ethnicity – the commonest agent causing DILI in African Caribbean population groups is co-trimoxazole, while for Caucasian population groups it is co-amoxiclav
• Pre-existing liver disease – however the evidence is as yet unclear as to whether this is a true risk factor
• Methotrexate induced liver injury is 3-4x more likely in patients with a history of alcohol excess, chronic viral hepatitis or those with risk factors predisposing to non-alcoholic fatty liver disease (diabetes, obesity).

Causative Agents 

Paracetamol is the leading cause of drug-induced acute liver failure (ALF) in Western civilisation. Antibiotics are the commonest cause of idiosyncratic DILI, with co-amoxiclav as the most commonly implicated individual drug. Complementary and herbal medicines and dietary supplements, antiepileptics, cardiovascular drugs, anti-neoplastic agents and analgesics are among the other most commonly involved drug classes. On a global scale, over half of the total cases of DILI are attributable to antibiotics and antiepileptics alone. 

Drugs which are associated with relatively high incidences of severe liver injury include isoniazid and methotrexate. 

Drugs which have been seen to cause idiosyncratic DILI include isoniazid, methyldopa, phenytoin, and diclofenac.

Drugs which have been seen to cause asymptomatic progression to cirrhosis include methotrexate, methyldopa and amiodarone.

Pathophysiological mechanisms

The pathogenesis of idiosyncratic DILI is unclear. Current schools of thought are that drug-related factors (dosage, metabolic pathways, duration of treatment) and patient factors (age, gender, genetic factors) and their interactions are together responsible for the development of hepatotoxicity.