Free Content Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis [Review article]

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BACKGROUND: Although some case-control studies have investigated the association between drug-metabolising enzyme (DME) gene polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury (ATLI), their results are conflicting, mainly due to limited power.

OBJECTIVE: To review the literature systematically, by means of a meta-analytical review, to evaluate the putative association and provide a quantitative summary estimate on the association with ATLI.

DESIGN: We searched the databases of MEDLINE, PubMed, EMBASE and CBMdisc from 1966 to May 2007 using ‘DME’, ‘hepatotoxicity’, ‘genetic polymorphism’, ‘genetic susceptibility’ in combination with ‘antitubercular agents’, performed a manual search of citations from relevant original studies and review articles, and corresponded with authors.

RESULTS: Nine eligible articles were included in this meta-analysis, including five on N-acetyltransferase 2 (NAT2), four on cytochrome P450 2E1 (CYP2E1) and two on glutathione S-transferase (GST) studies, separately. The overall ORs of ATLI risk associated with NAT2 homozygous variant genotype (mt/mt), CYP2E1 homozygous wild genotype (*1A/*1A), GSTM1 homozygous null genotype (null/null) and GSTT1 homozygous null genotype (null/null) were respectively 1.93 (95%CI 0.81–4.62), 2.22 (95%CI 1.06–4.66), 2.62 (95%CI 1.45–4.75) and 1.18 (95%CI 0.61–2.29). In addition, the OR for Asian ATLI associated with the NAT2 homozygous variant (mt/mt) and the combined genotype (w/w + w/mt) was 2.52 (95%CI 1.49–4.26).

CONCLUSIONS: NAT2 mt/mt, CYP2E1*1A/*1A and GSTM1 null/null were observed to increase the risk of ATLI in tuberculosis patients. Our results support the hypothesis that NAT2 mt, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to ATLI, but no significant evidence for GSTT1 null/null.

Keywords: anti-tuberculosis drug-induced liver injury; arylamine N-acetyltransferase; cytochrome P450 2E1; drug-metabolising enzymes; glutathione-S-transferase; meta-analysis

Document Type: Review Article

Affiliations: 1: Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China 2: Pharmacoepidemiology and Pharmacoeconomics Division of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, Ohio, USA 3: Department of Epidemiology, School of Public Health, Xinjiang Medical University, China

Publication date: September 1, 2008

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  • The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on tuberculosis and lung health world-wide.

    Certain IJTLD articles are selected for translation into French, Spanish, Chinese or Russian. They are available on the Union website

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