GLDH Combined With Inflammatory Cytokines As Biomarkers Of Anti-tuberculosis Drugs Induced Liver Injury

Background and objectives:Drug-induced liver injury(DILI)is a common adverse drug reaction,which can lead to poor prognosis.It is of great significance for its prevention and early diagnosis.Anti-tuberculosis drug-induced liver injury(ATB-DILI)is the most common cause of DILI in some countries.In order to prevent and sensitively and specifically diagnose ATB-DILI,we analyzed the clinical characteristics and risk factors of patients with ATB-DILI,and explored the diagnostic value of glutamate dehydrogenase(GLDH)combined with inflammatory cytokines IL-2,IL-4,IL-6,IL-10,TNF-α,IFN-γ,and IL-17 as a biomarker of ATB-DILI.Methods:Tuberculosis patients who received anti-tuberculosis treatment in an infectious disease hospital from December 2020 to March 2022 were selected as subjects of the study.The basic data of the patients,including clinical characteristics,drug use and liver function index,were collected.The residual serum from the patients after liver function tests were also collected.Serum GLDH levels were determined by ELISA kit.The content of inflammatory cytokines IL-2,IL-4,IL-6,IL-10,TNF-α,IFN-γ,and IL-17 in serum of patients was determined using cytokine combination detection kit.Patients were divided into different groups by“Guidelines for Diagnosis and Treatment of Liver Injury Caused by Anti-tuberculosis Drugs(2019 Edition)”.The differences among different groups were compared.Univariate and multivariate logistic regression were used to analyze the risk factors of ATB-DILI.Logistic regression model was established for GLDH combined with inflammatory cytokines and risk factors such as age by multi-factor logistics stepwise forward regression.Hosmer-lemeshow test was used to evaluate the calibration degree of logistic model,and ROC curve was used to evaluate the model.Results:(1)In the analysis of clinical characteristics and risk factors of patients with ATB-DILI,a total of 128 tuberculosis patients without other liver disease and HIV infection were included,including 34 patients with ATB-DILI.The estimated incidence of ATB-DILI was 26.6%.79%patients occurred ATB-DILI in the first two months of anti-tuberculosis treatment.Among the patients with ATB-DILI,38% had no obvious clinical symptoms.The proportions of patients with mild,moderate,severe liver injury and liver failure were 65%,20%,12% and 3%,respectively.According to clinical classification,22 patients were of the hepatocellular injury type,6 patients of the cholestatic type,and 6patients of the mixed type.Among the patients with type of cholestatic liver injury,83.3% had moderate and severe liver injury.The serum levels of direct bilirubin(DBIL),total bile acid(TBA)and alkaline phosphatase(ALP)in patients with type of cholestatic liver injury were significantly increased.In univariate logistic regression analysis,the location of tuberculosis,the use of anti-tuberculosis drugs,and the levels of DBIL,albumin(ALB),and total protein at the baseline were associated with the risk of ATB-DILI.In the results of multivariate logistic regression analysis,DBIL and ALB levels at the baseline were independent risk factors for ATB-DILI.Patients with higher DBIL at the baseline had a42.4% increased risk of ATB-DILI,and those with higher ALB levels at the baseline had a 20.9% lower risk of ATB-DILI.(2)A total of 161 tuberculosis patients were included in the diagnostic markers study of ATB-DILI,including 108 normal liver function group,53 abnormal liver function group.Two subgroups of abnormal liver function group were mild abnormal liver function group(n= 23)and ATB-DILI group(n = 30).The levels of serum GLDH,IL-6and IL-10 were significantly different among the groups.Compared with normal liver function group,serum GLDH and IL-10 levels were significantly increased in patients with abnormal liver function,and serum GLDH,IL-6 and IL-10 levels were significantly increased in patients with ATB-DILI.In addition,the levels of serum GLDH and IL-6in ATB-DILI group were higher than those in mildly abnormal liver function group.The levels of serum GLDH and IL-10 were moderately correlated with DBIL,total bilirubin and TBA,IL-6 were moderately correlated with TBA and ALP(0.3< |R|< 0.5 P< 0.05).ROC curve showed that the AUC of serum GLDH,IL-6 and IL-10 for the diagnosis of ATB-DILI were 0.870,0.714 and 0.811,respectively,and the optimal thresholds were 9.58 m IU/m L,12.47pg/m L and 2.25pg/m L,respectively.The AUC of diagnosis of patients with abnormal liver function of serum GLDH,IL-2 and IL-10 were 0.622 and 0.657,respectively,with the optimal thresholds of 7.19 m IU/m L,1.24 pg/m L and 2.68 pg/m L,respectively.In logistic regression modeling,the AUC of serum GLDH combined with IL-10 as a marker of ATB-DILI was 0.912.Conclusion:(1)The incidence of ATB-DILI in tuberculosis patients without other liver disease and HIV infection was 26.6%.ATB-DILI mainly occurred in the first two months of anti-tuberculosis treatment,and most of them were type of hepatocellular and mild liver injury.When ATB-DILI occurs,nearly one-third of patients did not have clinical symptoms.High DBIL levels and low ALB levels at the baseline could increase the risk of ATB-DILI.(2)Serum GLDH,IL-6 and IL-10 levels were correlated with the severity of liver injury.GLDH,IL-6 and IL-10 had good diagnostic efficacy for ATB-DILI.Logistic regression model established by GLDH and IL-10 had better diagnostic efficacy.