Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis.

SETTING: Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins. AIM: To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients. METHODS: A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. RESULTS: Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01). CONCLUSION: Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.

The ongoing challenge of Pulmonary Tuberculosis in Southern Tunisia: A review of a 22-year period.

BACKGROUND: Despite the wide use of anti-tuberculosis drugs, pulmonary tuberculosis (PTB) remains one of the most important causes of mortality and morbidity, particularly in developing countries. Therefore, combining clinical and epidemiological approach would be of a great benefit. Our study aimed to describe the epidemiological and clinical specificities of PTB and its recent chronological trends. METHODS: We conducted a retrospective study of all PTB new cases of any age diagnosed between 1995 and 2016 in Southern Tunisia. We applied the direct method of age-standardization using the World Standard Population to compute the age standardized incidence rate (ASIR) and the age standardized mortality rate (ASMR) per 100 000 inhabitants. RESULTS: We recorded 1121 new cases with PTB among 2771 new cases of tuberculosis (40.5%). The ASIR of PTB was 5.3/100 000 inhabitants/year and didn't change over the study period (rho=0.3; P=0.2). Patients with PTB were mainly aged between 15 and 59 years (n=861; 76.8%) and came from urban areas (n=600; 55%). The median duration of treatment was 7.6 months (IQR=[6-8 months]). Successful outcome was notified in 1075 cases (95.9%). Forty-one patients died yielding an ASMR of 0.18/100 000 inhabitants/year. Factors statistically associated with unsuccessful outcome included age≥60 years (OR=5; P<0.001) and shorter treatment duration (6.15 months vs 7.76 months; P<0.001). CONCLUSION: In contrast to the decline in the global PTB incidence reported worldwide and in the neighboring countries, our study revealed no significant change in the PTB rates from 1995 to 2016. Therefore, tools and strategies used to manage PTB should be strengthened by a substantial effort in both basic science and epidemiology to have better incidence curves.