CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis
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To determine whether pharmacogenetic tests such as N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genotyping are useful in identifying patients prone to antituberculosis drug-induced hepatotoxicity in a cosmopolite population.
In a prospective study we genotyped 89 patients treated with isoniazid (INH) for latent tuberculosis. INH-induced hepatitis (INH-H) or elevated liver enzymes including hepatitis (INH-ELE) was diagnosed based on the clinical diagnostic scale (CDS) designed for routine clinical practice. NAT2 genotypes were assessed by fluorescence resonance energy transfer probe after PCR analysis, and CYP2E1 genotypes were determined by PCR with restriction fragment length polymorphism analysis.
Twenty-six patients (29%) had INH-ELE, while eight (9%) presented with INH-H leading to INH treatment interruption. We report no significant influence of NAT2 polymorphism, but we did find a significant association between the CYP2E1 *1A/*1A genotype and INH-ELE (OR: 3.4; 95% CI:1.1-12; p=0.02) and a non significant trend for INH-H (OR: 5.9; 95% CI: 0.69–270; p=0.13) compared with other CYP2E1 genotypes. This test for predicting INH-ELE had a positive predictive value (PPV) of 39% (95% CI: 26–54%) and a negative predictive value (NPV) of 84% (95% CI: 69–94%).
The genotyping of CYP2E1 polymorphisms may be a useful predictive tool in the common setting of a highly heterogeneous population for predicting isoniazid-induced hepatic toxicity. Larger prospective randomized trials are needed to confirm these results.
KeywordsCosmopolite population CYP2E1 TaqI polymorphism Isoniazid-induced hepatitis NAT2 genotype Negative predictive value Positive predictive value
Clinical diagnostic scale
Isoniazid-induced elevated liver enzymes
N-acetyltransferase type 2
Negative predictive value
Positive predictive value
Restriction fragment length polymorphism
Upper reference limit
We are indebted to Dr, J.-D. Graf for the resolution of Hardy-Weinberg equation, to Dr. V. Rollason for the revision of the manuscript, to the nurses of the Anti-tuberculosis Centre and the staff of the Central Laboratory of Chemistry for their technical support. This experiment complies with the current laws of Switzerland in which it was performed inclusive of ethics approval.
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