Drug‐Induced Liver Injury Unique to India

Content available: Audio Recording The drugs causing drug-induced liver injury (DILI) tend to vary geographically based on specific disease states. In India, it is compounded by the ubiquitous use of traditional and complementary medicines. Although the true incidence of DILI in India is unknown, it is likely to be higher than in the Western countries. The idiosyncratic form of DILI constitutes ~99% of all DILI cases in India, and intrinsic DILI as it occurs in acetaminophen/paracetamol hepatotoxicity accounts for <1% of cases.1 Intrinsic hepatotoxicity such as from rodenticide toxicity (yellow phosphorus poisoning) is a much more common cause of acute liver failure (ALF) in India than acetaminophen/paracetamol hepatotoxicity.2 India had an estimated 2.7 million cases of tuberculosis (TB) in 2019 (World Health Organization) and more than 50% of Hansen’s disease burden in the world.3 In addition, the burden from HIV, epilepsy, and non-TB infections is substantial. All these conditions are treated with first-generation drugs with known hepatotoxic potential resulting in a high likelihood of DILI. This is reflected in the 1.5% to 2.5% hospitalizations for DILI among all admissions to gastroenterology service in a tertiary academic hospital.4 Of the 1288 patients in the Indian Network of DILI (INDILI), the top six causes were due to combination anti-TB drugs (46%), traditional and alternative medicines (14%), antiepileptic agents (first-generation drugs) (8%), non-TB antimicrobials (6.5%), antiretroviral agents (3.5%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (2.6%).1 Ten percent of patients with idiosyncratic DILI progressed to ALF in the INDILI series.1 Combination anti-TB drugs are the most common cause of drug-induced ALF5 and the second most common cause of drug-induced acute-on-chronic liver failure (ACLF).6 It accounts for 46% to 58% of DILI,1, 4 65% to 71% of drug-induced ALF,1, 5 and 23% of drug-induced ACLF in India.6 The substantially large number of patients taking combination anti-TB drugs, the combined large daily doses that are involved, the involvement of cytochrome P450 enzymes, the drug-drug interactions (between isoniazid, rifampicin, and pyrazinamide), the high lipophilicity of drugs, and malnutrition act in concert to increase the risk for anti-TB DILI. DILI from anti-TB drugs mostly occurs within the first 2 months of treatment.7 Acute hepatitis E is a confounding factor in India and needs to be excluded before making a diagnosis of DILI. Genetic risk factors, particularly N-acetyltransferase 2 (NAT 2) and CYP2E1 polymorphisms, have been implicated in anti-TB DILI. However, a recent genome-wide association study failed to detect genome-wide significance and CYP2E1 polymorphisms as risk factors in the Indian population.8 NAT 2 gene polymorphisms, particularly the slow acetylator genotype, have been variably linked to the development of DILI, whereas the recent study in the Indian patients with DILI found “ultraslow acetylator subtype” NAT 2*6 to be a risk factor for anti-TB DILI.8 Notably, the frequency of slow acetylator phenotype is 50% to 60% in the Indian population and is a likely contributing factor to the increased risk for anti-TB DILI in the Indian population. Traditional and complementary medicines account for 14% of 1288 cases of DILI in INDILI.1 Although not integrated with the conventional health care system of medicine, traditional medicines (i.e., Ayurveda, Unani, Siddha, and Homeopathy [AYUSH]) are used by a large population, but only a small proportion of them develop DILI. These generally contain unlabeled, multi-ingredient preparations, which makes it difficult to identity the “culprit” agent in the preparation. These are poorly regulated, poorly monitored, inadvertently contaminated, and adulterated with volatile organic compounds and metals.9 First-generation antiepileptic drugs (AEDs), such as phenytoin, carbamazepine, and phenobarbitone, are the third leading cause of DILI.1 With the greater use of newer drugs with a better liver safety profile, such as levetiracetam and clobazam, the incidence of DILI from AEDs is decreasing. First-generation AED-induced liver injury is commonly associated with hypersensitivity features, including drug reaction with eosinophilia and systemic symptoms or Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).10, 11 Mortality in SJS/TEN is higher, particularly when associated with jaundice.11 The presence of cutaneous features is associated with earlier presentation, cessation of the offending drug, and treatment with steroids. These agents are cheaper than the newer agents. Non-TB antimicrobials constitute the fourth largest group, accounting for 6.5% in INDILI.1 Dapsone (2.7%), amoxicillin-clavulanate (1.8%), and cotrimoxazole (1.5%) are the top three drugs in this group, accounting for 91% of non-TB antibiotics. Sulfonamides (dapsone and cotrimoxazole)12 and an antiretroviral drug (nevirapine) are disproportionately associated with hypersensitivity features. Comparisons between Indian1 and US13 patient series are shown in Table 1, and differences among the top five groups of drugs in INDILI are listed in Table 2. Antimetabolites largely from methotrexate (3.8%), antiretroviral drugs including nevirapine and zidovudine (3.5%), female sex hormone drugs, androgenic anabolic steroids and hormone antagonists (2.5%), statins (1.4%), and others made up the rest of the cases in INDILI.1 DILI accounts for 10% of all causes of ACLF.6 Traditional and complementary medicines and anti-TB drugs account for 72% and 27% of all causes of drug-induced ACLF, respectively. The overall mortality from DILI in India is higher; 17% in the single center4 and 12% in the national registry.1 Mortality varied by drug class, 15% with anti-TB and AEDs and 0% with NSAIDs (Table 2). Mortality from drug-induced ACLF is much higher at 47%.6 Mortality is largely attributed to DILI from anti-TB drugs and traditional and alternative medicines. Mortality from anti-TB drug-induced ALF varies from 67% to 71% across India.5, 14 Women tend to have greater severity and mortality from anti-TB DILI.15