Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management

Abstract

Development of idiosyncratic hepatotoxicity is an intricate process involving both concurrent as well as sequential events determining the direction of the pathways, degree of liver injury and its outcome. Decades of clinical observation have identified a number of drug and host related factors that are associated with an increased risk of antituberculous drug-induced hepatotoxicity, although majority of the studies are retrospective with varied case definitions and sample sizes. Investigations on genetic susceptibility to hepatotoxicity have so far focused on formation and accumulation reactive metabolite as well as factors that contribute to cellular antioxidant defense mechanisms and the environment which can modulate the threshold for hepatocyte death secondary to oxidative stress. Recent advances in pharmacogenetics have promised the development of refined algorithms including drug, host and environmental risk factors that allow better tailoring of medications based on accurate estimates of risk-benefit ratio. Future investigations exploring the pathogenesis of hepatotoxicity should be performed using human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical applications.

Keywords: ALT, alanine transaminase; ART, anti-retroviral therapy; AST, aspartate transaminase; ATP, adenosine triphosphate; ATS, American Thoracic Society; BSEP, bile salt exporter pump; BTB, broad complex, tramtrack, bric-a-brac domain; BTS, British Thoracic Society; CNC, cap‘n’collar type of basic region; CYP, cytochrome P450; DILI, drug-induced liver injury; DOTS, directly observed short-course therapy; FDA, Food and Drug Administration; GST, glutathione S-transferase; HAART, highly active anti-retroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HLA, human leukocyte antigen; INH, isoniazid; MHC, major histocompatibility complex; MPT, mitochondrial permeability transition; MnSOD, manganese superoxide dismutase; NAC, N-acetyl cysteine; NAT2, N-acetyltransferase 2; NICE, National Institute for Clinical Excellence; Nrf2, nuclear factor erythroid 2-related factor-2; OR, odds ratio; PXR, pregnane X receptor; ROS, reactive oxygen species; SH, sulfhydryl; SNP, single-nucleotide polymorphism; TB, tuberculosis; ULN, upper limit of normal range; WHO, World Health Organization; drug-induced liver injury; genetic; hepatotoxicity; pathogenesis; tuberculosis.

Figure 1

Pathways involved in the metabolism of isoniazid.

Figure 2

Hypothetical model of DILI due to anti-TB agents with potential drug and host related factors (in blue) involved in the pathogenesis.