Antituberculosis drug- induced hepatitis, an unpredictable phenotype

<b>Introduction:</b> Drug-induced hepatitis a feared adverse side effect of tuberculosis treatment whose etiology remains obscure. <b>Aim:</b> This study was developed to asses clinical and genetic predictors for susceptibility to antituberculosis drug – induced liver injury. <b>Methods:</b> A prospective case-control study was designed, with a total of 217 Caucasian patients treated for pulmonary tuberculosis. Cases included 96 patients withsome grade of liver damage. Social and demographic data, co-morbidities and variants of four candidate genes, NAT2 (INH-metabolism), ABCB11 (bile-salts transport), IL6 (immuno-inflammation and liver regeneration) and NBAS (liver failure) were analyzed and included in a logistic multivariate regression analysis. <b>Results:</b> Age ≥ 60 years old (OR: 2.93; 95% CI: 1.58 – 5.43; p = 0.001), female gender (OR: 2.16; 95% CI: 1.16 – 4.03; p = 0.015) and slow acetylator genotype (OR: 1.82; 95% CI: 1.02 – 3.27; p = 0.044) were associated with liver damage. The model explains 15% of the phenotype. When analyzing only mild hepatitis, the correlation between slow acetylator and hepatotoxicity was only observed in the subgroup of females &lt;60 year old, but not in older males. The presence of the CC genotype of rs2287622 variant in ABCB11 gene among males was associated with increased risk only in men &gt; 60 years old (OR: 7.39; 95% CI: 1.33 – 41.04; p = 0.022). For more severe hepatitis, only older age and female were identified as risk factors. <b>Conclusion:</b> Antituberculosis drug-induced hepatotoxicity is a complex phenotype, for which age, female gender and variants of NAT2 and ABCB11 genes, have a modest contribution. Moreover, different risk factors determine susceptibility to mild and severe liver damage.