外周血白细胞端粒长度对抗结核药药物性肝损伤的预测价值

Analysis of predictive value of leukocytes telomere length of peripheral blood against drug-induced liver injury induced by tuberculosis drugs

目的评价外周血白细胞端粒长度(LTL)对结核病(TB)患者抗结核药药物性肝损伤(DILI)的预测价值。方法纳入2017年10月至2020年11月东部战区总医院收治的抗结核药DILI患者78例,选取同期未诊断为DILI的TB患者100例。行单因素和多因素分析,确定影响TB患者DILI发生的独立预测因素。ROC曲线分析确定TB患者DILI发生的独立预测因素的截断点,计算诊断敏感度和特异度。结果比较临床资料,TB合并DILI患者(DILI组)皮疹、疲乏及食欲不振为18例(23.1%)、56例(71.8%)及72例(92.3%),与TB无DILI患者(非DILI组)[7例(7.0%)、23例(23.0%)及28例(28.0%)]相比,差异有统计学意义(χ^(2)=-9.382、-42.267及-73.612,P<0.05)。DILI组ALT、AST、ALP、TBil、INR、LTL及MELD评分为(232.8±80.1)U/L、(134.8±40.5)U/L、(172.4±62.2)U/L、(2.4±1.0)mg/dL、(2.2±0.8)、(0.70±0.31)及(17.3±6.3)分,与非DILI组[(37.8±8.4)U/L、(36.6±8.5)U/L、(121.5±38.5)U/L、(0.8±0.3)mg/dL、(1.2±0.3)、(1.68±0.61)及(8.2±3.2)分]相比,差异有统计学意义(t=-60.128、-12.147、-8.136、-17.305、-14.736、12.018及-11.114,P<0.05)。以TB患者是否发生DILI(赋值0=无DILI,1=DILI)作为因变量,皮疹、疲乏、食欲不振、ALT、AST、TBil、INR、LTL及MELD评分为自变量,进行多因素logistic回归分析,结果显示ALT、AST、INR、LTL及MELD评分为影响TB患者DILI发生的独立预测因素(P<0.05)。ROC曲线发现,LTL在区分TB患者发生DILI与未发生DILI的最佳截断点为0.93,敏感度为73.1%(57/78),特异度为64.0%(64/100),AUC值0.73(P<0.05),而AST和ALT诊断AUC值差异无统计学意义(P>0.05)。结论外周血LTL异常可反映TB患者抗结核药物所致的肝损伤,是早期发现DILI的潜在生物标志物。

Objective To analyse the value of leukocytes telomere length(LTL)of peripheral blood in predicting of drug-induced liver injury(DILI)by anti-tuberculosis drugs in patients with tuberculosis(TB).Methods A total of 78 patients with anti-TB drug induced DILI from October 2017 to November 2020 were included,and 100 patients with TB who were not diagnosed with DILI in the same period were selected.Univariate and multivariate analysis were performed to determine the independent predictors of DILI in TB patients,and ROC curve analysis was used to determine the cutoff point of independent predictors of DILI in TB patients,and the diagnostic sensitivity and specificity were calculated.Results According to the clinical data,there were 18 cases(23.1%),56 cases(71.8%)and 72 cases(92.3%)of rash,fatigue and anorexia in TB patients with DILI(DILI group),compared with 7 cases(7.0%),23 cases(23.0%)and 28 cases(28.0%)in TB patients without DILI(non-DILI group),with statistically significant(χ^(2)=-9.382,-42.267 and-73.612,P<0.05).The alanine aminotransferase(ALT),aspartate transaminase(AST),alkaline phosphatase(ALP),total bilirubin(Tbil),international normalized ratio(INR),LTL and model for end-stage liver disease(MELD)scores in DILI group were(232.8±80.1)U/L,(134.8±40.5)U/L,(172.4±62.2)U/L,(2.4±1.0)mg/L,(2.2±0.8),(0.70±0.31)and(17.3±6.3)points,compared with(37.8±8.4)U/L,(36.6±8.5)U/L,(121.5±38.5)U/L,(0.8±0.3)mg/dL,(1.2±0.3),(1.68±0.61)and(8.2±3.2)points in non-DILI group,with statistically significant(t=-60.128,-12.147,-8.136,-17.305,-14.736,12.018 and-11.114,P<0.05).Multivariate logistic regression analysis was performed with whether TB patients had DILI(assigned value 0=non-DILI,1=DILI)as the dependent variable and rash,fatigue,anorexia,ALT,AST,TBil,INR,LTL and MELD scores as the independent variables.The results showed that rash,fatigue,anorexia,ALT,AST,TBil,INR,LTL and MELD scores were independent predictors of DILI in patients with TB(P<0.05).Receiver operating characteristic(ROC)curve showed that the optimal cut-off point of LTL point in differentiating patients with and without DILI was 0.93,the sensitivity and specificity were 73.1%and 64.0%,respectively,while the area under the curve(AUC)values of AST and ALT were not statistically significant(P>0.05).Conclusion The abnormality of LTL in peripheral blood can reflect the liver injury caused by anti-TB drugs in patients with TB,which is a potential biomarker for early detection of DILI.