Review Article
Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management

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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.

Section snippets

Drug Related Factors

It is difficult to estimate the incidence of hepatotoxicity due to individual agents as majority of patients are on combination of medications throughout the course of anti-TB therapy. While isoniazid, rifampicin and pyrazinamide are known to cause hepatotoxicity, ethambutol and streptomycin are considered not to be hepatotoxic. Information related to hepatotoxicity from isoniazid (INH), rifampicin17 and pyrazinamide18, 19 are derived from observations made during monotherapy for latent TB or

Genetic Susceptibility

Anti-TB DILI remains unpredictable even when variables such as drug regimen and environmental factors are taken into account. Neither the drug related factors nor the concurrent risk factors adequately explain why, in the vast majority of cases, hepatotoxicity occurs during the early phase of anti-TB therapy. In addition, observations such as Asian males have double the rate of isoniazid hepatitis than white males and nearly 14 times that of black males11, 12 indicate that genetic

Pathophysiology: unifying hypothesis

Development of idiosyncratic DILI 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 (Figure 2). The key upstream events include drug specific pathways triggered by particular drugs or their metabolites. Increased formation of reactive metabolites generally as a result of phase I metabolism or failure of detoxification usually a function of phase II metabolism is likely to be an

Management

Despite the huge global burden of TB and decades of experience in the use of anti-TB medications, studies investigating DILI lack scientific rigor, consistent methodology and large enough scale to generate the evidence on which recommendations can be based upon. Therefore, approaches to prevent, monitor and manage hepatotoxicity have been based primarily on retrospective observational studies. Recommendations from the American Thoracic Society (ATS),17 the British Thoracic Society (BTS)99 and

Future developments

Anti-TB drug induced hepatotoxicity is a serious adverse effect and continues to be a problem worldwide. Efforts at prevention and/or early recognition of anti-TB DILI are severely hampered by limited understanding of its pathogenesis. Future investigations exploring the mechanisms underlying the pathogenesis of anti-TB DILI should be performed using human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical applications. Clear and consistent

Conflicts of interest

All authors have none to declare.

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