Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients

Introduction: Previous studies have shown controversial results on whether slow acetylators or rapid acetylators cause isoniazid-induced hepatotoxicity (IIH).Moreover, the contribution of CYP2E1, a hepatic enzyme implicated... [ view full abstract ]

Introduction: Previous studies have shown controversial results on whether slow acetylators or rapid acetylators cause isoniazid-induced hepatotoxicity (IIH).Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear.The objectives of this study were 1) to assess the risk factors of IIH occurrence, including demographic, kinetic and genetic factors and 2) to evaluate the extent of implication of the NAT2 and CYP2E1 polymorphisms genes in inducing this disorder. Material and methods: A total of 71 patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using PCR-RFLP. Therapeutic drug monitoring (TDM) of isoniazid was performed using Vivian’s method. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Logistic regression was used to assess the relationship between each risk factor and the development of IIH.  Univariate analysis, including demographic factors (age, weight, gender) and genetic factors (NAT2, CYP2E1 (1053C>T) and CYP2E1 (7632T>A) polymorphisms were performed separately for each risk factor, and then for combined (NAT2/CYP2E1) and (CYP2E1/ CYP2E1) genotypes. The variables having a p value less than 0.2 in the univariate analyses were included in the multivariate analysis model. Receiver Operating Characteristics (ROC) curve analysis was used to assess the cut_off values of factors showing a significant influence on IIH. Results: Eleven (15.4%) patients have developed IIH. Logistic regression has demonstrated that only CYP2E1 (7632T>A) gene polymorphisms was found to be a significant factor in IIH development (OR: 1.6; CI: 1.02-25.7)Multivariate regression including combined genotype has shown that the association of NAT2_Slow acetylor genotype and CYP2E1_C/D (7632T>A) was a risk factor of IIH (OR: 11.9;CI: 2.07-68.4). Moreover, Patients with both CYP2E1_C1/C1  (1053C>T) and  CYP2E1_C/D (7632T>A) genotype have an increased risk of IIH (OR: 4.6; CI: 1.02-21.3). Also, INH concentration of isoniazid was found to be a risk factor of IIH, with a cut-off value over 3.69 mg/l (OR: 13.2, CI : 2,9-59), as shown by ROC analysis.Conclusion: TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.