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European Journal of Clinical Pharmacology

, Volume 62, Issue 6, pp 423–429 | Cite as

CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis

  • Nicolas VuilleumierEmail author
  • Michel F. Rossier
  • Alberto Chiappe
  • Florence Degoumois
  • Pierre Dayer
  • Bernadette Mermillod
  • Laurent Nicod
  • Jules Desmeules
  • Denis Hochstrasser
Pharmacogenetics

Abstract

Objective

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.

Methods

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.

Results

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%).

Conclusion

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.

Keywords

Cosmopolite population CYP2E1 TaqI polymorphism Isoniazid-induced hepatitis NAT2 genotype Negative predictive value Positive predictive value 

Abbreviations

ALT

Alanine transaminase

AST

Aspartate transaminase

CDS

Clinical diagnostic scale

CI

Confidence interval

FN

False negative

FP

False positive

IA

Intermediate acetylator

INH

Isoniazid

INH-ELE

Isoniazid-induced elevated liver enzymes

INH-H

Isoniazid-induced hepatitis

NAT2

N-acetyltransferase type 2

NPV

Negative predictive value

OR

Odds ratio

PPV

Positive predictive value

RA

Rapid acetylator

RFLP

Restriction fragment length polymorphism

SA

Slow acetylator

SP

Specificity

SN

Sensitivity

TN

True negative

TP

True positive

infinity

URL

Upper reference limit

Notes

Acknowledgements

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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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Nicolas Vuilleumier
    • 1
    Email author
  • Michel F. Rossier
    • 1
    • 5
  • Alberto Chiappe
    • 1
  • Florence Degoumois
    • 1
  • Pierre Dayer
    • 2
  • Bernadette Mermillod
    • 3
  • Laurent Nicod
    • 4
  • Jules Desmeules
    • 2
  • Denis Hochstrasser
    • 1
  1. 1.Central Clinical Chemistry Laboratory, Department of Clinical PathologyGeneva University HospitalGeneva 14Switzerland
  2. 2.Clinical Pharmacology and ToxicologyGeneva University HospitalGeneva 14Switzerland
  3. 3.Service of Medical InformaticsGeneva University HospitalGeneva 14Switzerland
  4. 4.Service of PneumologyGeneva University HospitalGeneva 14Switzerland
  5. 5.Service of Endocrinology and DiabetologyGeneva University HospitalGeneva 14Switzerland

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