Diagnosis, management and prevention of drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) is increasingly being recognised as a significant cause of both acute and chronic liver disease. The most commonly implicated agents are paracetamol, antimicrobials, non-steroidal anti-inflammatory drugs, statins, isoniazid and herbal remedies. Drug-induced hepatotoxicity is generally idiosyncratic in nature. The pathogenesis of DILI remains enigmatic, but involves exposure to the toxic agent, mitochondrial injury, failure of adaptation, and innate and adaptive immune responses. Diagnosis of drug-induced liver diseases can be difficult, but the key to causality is to diligently exclude other causes of liver injury, and to identify a characteristic clinical drug-related signature. Management of drug-induced liver injury is symptomatic, with early referral to a liver transplant unit at the first hint of liver failure, especially in those with non-paracetamol-induced liver injury. Prevention of drug hepatotoxicity includes increased vigilance during pre-clinical drug development and clinical trials, alanine aminotransferase monitoring with certain drugs, better marketing strategies, and the future identification of both diagnostic and prognostic biomarkers.

An Update on Drug-induced Liver Injury

“…Additionally, cholestatic and mixed hepatitis pattern have a small but definite risk of evolution to chronicity. 26 Reported mortality figures from the Spanish registry and the drug-induced liver injury network (USA) are 2% and 2.1% respectively for mixed hepatitis pattern; contrastingly, the mortality for hepatocellular hepatitis pattern of DILI are 7% and 7.5% and for the cholestatic hepatitis pattern the mortality reported are 5% and 14.3% respectively. 18,19 The hepatitis pattern is not static and may evolve over time; a hepatocellular hepatitis pattern at initiation may evolve to a cholestatic pattern in the course of the disease.…”

“…Although not exclusive, this is based less on the symptoms and signs but more importantly on the ratio of elevation of transaminases and alkaline phosphatase. 22,24,26 Based on the level of elevation of transaminases or alkaline phosphatase and the ratio (R) of elevation of baseline ALT to baseline alkaline phosphatase (ALT/ULN)/(ALP/ULN), drug-induced liver injury is classified as either hepatocellular, cholestatic or mixed types. 22,26 Hepatocellular DILI: ALT $ 3 ULN and R $ 5; Cholestatic DILI: ALP $ 2 ULN and R # 2; Mixed DILI: ALT > 3 ULN and ALP > 2 ULN and R > 2 < 5.…”

“…The degree of elevation in liver enzymes has poor correlation with severity of liver disease. 26 Instead, the pattern of liver disease indicates near term and long-term consequences. The cholestatic pattern of hepatitis has the lowest mortality but has a small risk of protracted course leading to a longer time for normalization of liver tests.…”

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

“…30 Approximately 5-10% of patients who have clinical symptoms of severe hepatitis including jaundice develop acute liver failure. 31 Age appears to be the most important factor in determining the risk of INH-induced hepatotoxicity. Hepatic damage is rare in patients less than 20 years old; it is observed in 0.3% of those in the 20-34 years age group, increasing to 1.2% in the 35-49 years age group and 2.3% in those older than 50 years of age.…”

“…Hepatotoxicity associated with RIF is usually idiosyncratic. 31 RIF may occasionally cause dosedependent interference with bilirubin uptake due to competition with bilirubin for clearance at the sinusoidal membrane, resulting in mild, asymptomatic unconjugated hyperbilirubinemia or jaundice without hepatocellular damage. Conjugated hyperbilirubinemia probably results from RIF inhibiting the major bile salt exporter pump, impeding secretion of conjugated bilirubin at the canalicular level.…”