Drug-induced liver injury (DILI) is a vital cause of hospitalisation and of medication deregistration. Susceptibility to DILI in elderly is influenced by changes in physiology and increased interindividual variability, along with an increased prevalence of disease and the frailty syndrome. Although various preclinical trials has assessed the dose-related or predictable DILI reactions, rare hypersensitivity or idiosyncratic reactions cannot be anticipated from preclinical studies or clinical trials. Moreover, the inadequate enrolment of older adults in clinical trials causes insufficiency in evaluating DILI.

It has been observed that drug-induced hepatotoxicity has been increasingly become the cause of withdrawal of a number of drugs shortly after being put onto the market. A recent investigation by the WHO Collaborating Centre for International Drug Monitoring documented that the five most frequently used drugs associated with fatalities during 1969–1990 were paracetamol, troglitazone, valproate, stavudine and halothane. After 1990, paracetamol has become the most common drug associated with a fatal outcome (dose-dependent DILI).

Paracetamol is the most common drug causing intrinsic hepatotoxicity. Studies suggest that accidental overdose is responsible for 15% of cases in the general population, however, causes 55% of cases in older adults. It has been reported that hepatotoxicity may occur with chronic therapeutic use of paracetamol, even without the presence of risk factors such as chronic alcoholism and malnutrition. The main pathological process behind the hepatotoxicity of paracetamol causing hepatocyte damage and death is the bio-activation of paracetamol to its toxic metabolite via cytochrome P450 (CYP) 2E1, and further binding of the toxic metabolite to liver macromolecules.

Liver biopsy shows a centrilobular necrosis, with periportal sparing and little or no inflammatory reaction. Acute renal failure may occur in severe cases. Increased age is related with increased time to presentation, resulting in poorer prognosis. Paracetamol metabolism and toxicity depend on decreased liver volume with age, frailty and malnutrition.

Similarly, hepatocellular injury has been observed as the most common form of diclofenac-associated hepatic injury. Liver injury from isoniazid is mediated by the toxic metabolite hydrazine and its monoacetyl derivative. Moreover, flucloxacillin, is one of the leading causes of drug-induced cholestasis. 

Source: Mitchell SJ, Hilmer SN. Drug-induced liver injury in older adults. Therapeutic Advances in Drug Safety. 2010;1(2):65-77.