The hepatic safety of drugs pose a significant challenge for the pharmaceutical industry throughout the whole process of drug development. The intrinsic toxicity of few drugs becomes evident during the early stages of this process, however, for majority of medications, the hepatotoxicity profile may remain hidden in both preclinical and clinical phases. Although, clinical trials report a relatively common adverse reaction, they are generally underpowered to detect the low incidence of idiosyncratic drug-induced liver injury (DILI).

Various methods have been used to assess the epidemiology of DILI. Numerous population-based case–control studies have included general practice research database that allows associate prescription data to clinically meaningful events such as death, hospital admission and diagnosis at discharge. This database was used to explore large population, i.e.>5 million person-years and 5000 controls subjects from 1994 to 1999 the crude incidence of DILI that was found to be 2.4 per 100,000 persons per year. The patients that were referred to a consultant or hospitalized for a liver-related diagnosis were recorded and reviewed manually. The list of drugs that were hepatotoxic in nature were chlorpromazine, amoxicillin-clavulanic acid, flucloxacillin, macrolides and tetracyclines, metoclopramide, chlorpheniramine and betahistine. Other retrospective study cohorts used another database as a surrogate of a wide population sample to assess the incidence of serious DILI leading to acute liver failure and death, however, its limitation was inclusion of ICD-9 (international classification of diseases) code to define liver events which had poor accuracy, resulting in low specificity and sensitivity for DILI recognition. A recent population-based undertook  250,000 adults over a 2-year period. Among which, 96 patients qualified for DILI (56% female), indicative of an incidence of 19 cases per 100,000 per year. DILI occurred due to a single prescription medication in 75% of the cases, dietary supplements in 16% and multiple agents in 9%. This study was a pioneer in assessing both an accurate denominator (the exposed population) and the incidence of DILI for specific drugs. The results of these studies showed that antibiotics were considered as primary culprits, the estimated risk of liver injury for amoxicillin/clavulanate being 1 per 2350 users. However, the proportion of jaundice (27% of the patients) and hospitalization (23%) showed that the majority of cases were asymptomatic.

Thus, population-based studies are a vital approach to determine the incidence of DILI, however, while considering the effect of genetic susceptibility on idiosyncratic DILI, it is difficult to evaluate the estimated risk associated with specific drugs from people with a specific genetic ancestry to populations with different genetic backgrounds. 

Thus, DILI has emerged as a global health problem concerning transversally to a wide spectrum of audience ranging from clinical practitioners to several medical and surgical specialties, clinical and basic investigators, as well as people from regulatory affairs and pharmaceutical companies.  Moreover, DILI poses a huge diagnostic concern, as it is capable of mimicking any other liver disorder and is considered being a diagnosis of exclusion due to absence of biomarkers, which is seen as a major obstacle for advancing in correct phenotyping and genotyping of affected subjects. Western countries like Europe and US has introduced large DILI prospective registries in the last two decades that collect reliable information on DILI causal agents, phenotypes and risk factors, and comparable efforts in India are undergoing.

Source: Andrade RJ, Ortega-Alonso A, Lucena MI. "Drug-Induced Liver Injury Clinical Consortia: a global research response for a worldwide health challenge". Expert Opin Drug Metab Toxicol. 2016 Jun;12(6):589-93.