Xiang Yang, Ma Long, Wu Weidong, Liu Wei, Li Yongguang, Zhu Xia, Wang Qian, Ma Jinfeng, Cao Mingqin, Wang Qian, Yao Xuemei, Yang Lei, Wubuli Atikaimu, Merle Corinne, Milligan Paul, Mao Ying, Gu Jiayi, Xin Xiumei
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
The Red Cross of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China.
PLoS One. 2014 Jan 23;9(1):e85905. doi: 10.1371/journal.pone.0085905. eCollection 2014.
Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury.
In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays.
2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT25 genotypes, with ATLI more common among patients with the NAT25*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes.
In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.
在三种一线抗结核药物中，异烟肼最常与肝毒性相关。异烟肼诱导的毒性差异归因于几个基因座（NAT2、CYP2E1、GSTM1和GSTT1）的基因变异性，这些基因座编码药物代谢酶。本研究评估了这些酶的多态性是否与患者抗结核药物性肝炎风险增加相关，以及是否有可能用于识别有肝损伤风险的患者。
在一项横断面研究中，对2244例结核病患者在治疗开始两个月后进行评估。抗结核药物性肝损伤（ATLI）定义为谷丙转氨酶（ALT）、谷草转氨酶（AST）或胆红素值超过正常上限两倍。使用聚合酶链反应/连接酶检测反应分析法测定NAT2、CYP2E1、GSTM1和GSTT1基因型。
共评估了2244例患者，其中89例发生ATLI，患病率为4%。9例患者（0.4%）的ALT水平超过正常上限5倍。男性ATLI患病率高于女性，且与NAT25基因型存在弱关联，NAT25*CT基因型患者中ATLI更常见。CT基因型识别ATLI患者的敏感性为42%，阳性预测值为5.9%。与快乙酰化者相比，慢乙酰化者中CT型ATLI更常见（患病率比为2.0（9
