Drug-induced liver injury (DILI) is an unpredictable and feared side effect of antituberculosis treatment (AT). The present study aimed to identify clinical and genetic variables associated with susceptibility to AT-associated hepatotoxicity in patients with pulmonary tuberculosis treated with a standard protocol. Of 233 patients enrolled, 90% prospectively, 103 developed liver injury: 37 with mild and 66 with severe phenotype (DILI). All patients with mild hepatitis had a RUCAM score ≥4 and all patients with DILI had a RUCAM score ≥ 6. Eight clinical variables and variants in six candidate genes were assessed. A logistic multivariate regression analysis identified four risk factors for AT-DILI: age ≥ 55 years (OR:3.67; 95% CI:1.82–7.41; p < 0.001), concomitant medication with other hepatotoxic drugs (OR:2.54; 95% CI:1.23–5.26; p = 0.012), NAT2 slow acetylator status (OR:2.46; 95% CI:1.25–4.84; p = 0.009), and carriers of p.Val444Ala variant for ABCB11 gene (OR:2.06; 95%CI:1.02–4.17; p = 0.044). The statistical model explains 24.9% of the susceptibility to AT-DILI, with an 8.9 times difference between patients in the highest and in the lowest quartiles of risk scores. This study sustains the complex architecture of AT-DILI. Prospective studies should evaluate the benefit of NAT2 and ABCB11 genotyping in AT personalization, particularly in patients over 55 years.

Introduction: Drug-induced hepatitis a feared adverse side effect of tuberculosis treatment whose etiology remains obscure. Aim: This study was developed to asses clinical and genetic predictors for susceptibility to antituberculosis drug – induced liver injury. Methods: 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. Results: 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 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. Conclusion: 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.