Mitochondrial DNA Variants in Patients with Liver Injury Due to Anti-Tuberculosis Drugs.

BACKGROUND: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid's metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. METHODS: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. RESULTS: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I's NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. CONCLUSIONS: Variants in complex I's subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.

Risk factors of hepatitis during anti-tuberculous treatment and implications of hepatitis virus load.

OBJECTIVES: Hepatitis during anti-tuberculous treatment (HATT) has been an obstacle in managing patients with tuberculosis (TB). We evaluate the risk factors of HATT and the clinical implications of serum viral loads in those with concomitant hepatitis B or C viruses (HBV/HCV) infection. METHODS: We did a prospective study on patients with pulmonary tuberculosis in a medical center. HATT was defined as an increase in serum transaminase level of >3 times the upper limit of normal (ULN) with symptoms, or an increase in serum transaminase level of >5 times ULN without symptoms. RESULTS: 360 TB patients were studied. The prevalence of concomitant HBV and HCV infection was 11.7% and 6.7%, respectively. HATT developed in 68 (18.9%). Cox regression analysis revealed that severe chronic kidney disease without hemodialysis, N-acetyltransferase (NAT2) slow acetylator, high initial HBV/HCV viral load, and women in those without HBV/HCV infection were significant predictors of drug-induced HATT, whereas severe chronic kidney disease without hemodialysis and men with high initial HBV/HCV viral load were significantly associated virus-induced HATT. CONCLUSION: HBV/HCV viral load interacts with gender and, together with severe chronic kidney disease without hemodialysis and NAT2 slow acetylator, were predictors of HATT. TB patients with these characteristics need close follow-up.