An Update on Drug-induced Liver Injury

Abstract

Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of hepatotoxicity, the pathogenesis and associated risk factors besides its clinical management.

Keywords: ADR, adverse drug reaction; AED, antiepileptic drugs; BSEP, bile salt export pump; CDS, clinical diagnostic scale; CIOMS, Council for International Organization of Medical Sciences; CXR, constitutive androstane receptor; DIAIH, drug-induced autoimmune hepatitis; DIALF, drug-induced acute liver failure; DILI; DILI, idiosyncratic drug-induced liver injury; FXR, farnesoid X receptor; GWAS, genome wide association studies; HBV, hepatitis B virus; HIV, human immunodeficiency virus; INH, isoniazid; LPS, lipopolysaccharide; MHC, major histocompatibility complex; MRP, multi-drug resistance proteins; NAC, N-acetylcysteine; NAPQI, N-acetyl-p-benzoquinone imine; NRH, nodular regenerative hyperplasia; PXR, pregnane X receptor; PZA, pyrazinamide; RIF, rifampicin; RUCAM, Roussel Uclaf Causality Assessment Method; TEN, toxic epidermal necrolysis; UDCA, ursodeoxycholic acid; causality; drug-induced; hepatotoxicity; liver injury.