Risk Factors And Prediction Model For Relapse Of Chronic Drug-induced Liver Injury

Objective1.To analyze the risk factors associated with relapse of chronic drug-induced liver injury(DILI).2.To establish a noninvasive prediction model for the relapse of chronic DILI,then verified and evaluated the new model.3.To explore the relationship between relapse risk of chronic DILI and hepatic fibrosis.MethodsThe clinical data of patients with chronic DILI from the Fifth Medical Center of PLA General Hospital and other eight medical centers in different region from January 2008 to January 2022 were retrospectively collected.All these patients were followed up for no less than one year.And they were divided into relapse group and non-relapse group.The risk factors for relapse of patients with chronic DILI were screened based on logistic univariable and multivariable regression analysis,and then constructed a risk prediction model.C-index or AUC value,Hosmer-Lemeshow test or calibration curve,and clinical decision curve analysis(DCA)were used to evaluate of discrimination,calibration and clinical application value,respectively.And the model was validated by N-fold K-cross validation method and brier score.Spearman or Kendall’s tau-b correlation was used for correlation analysis.The ROC curve was drawn to determine the optimal critical value according to the AUC value,and then calculated the corresponding sensitivity,specificity,negative predictive value and positive predictive value.P<0.05 indicates that the difference is statistically significant.Results1.A total of 1660 patients with chronic DILI from the Fifth Medical Center of PLA General Hospital from January 2012 to June 2017 were retrospectively enrolled to analyze risk factors for relapse of chronic DILI,and the results showed that inflammation grade≥G3,fibrosis stage≥S2,high AST,high TBIL,high LSM,low CHE and low PLT were risk factors for relapse of chronic DILI.2.Totally,5326 patients with chronic DILI from 9 medical centers in different regions of China from January 2008 to June 2020 were retrospectively screened,and finally,3655 patients(including 2673 patients in the internal cohort and 982 patients in the external cohort)were eligible for analysis.Histologically,with the increase of liver inflammation grade and fibrosis stage,the proportion of relapse increased.And significant inflammation(HAI≥10)was an independent risk factor for relapse with OR value up to 21.3(P<0.001).Biochemically,female,older age,high AST,high TBIL,prolonged PT and low PLT were identified as high risk factors of relapse.Based on the above six variables,the noninvasive nomogram prediction model(BNR-6)was constructed with C index as 0.824(95%CI:0.798-0.849).The calibration curve and DCA curve showed that the new model had a good prediction ability.This model was highly consistent with liver histology and can be individualized to calculate the risk of relapse for patients with chronic DILI(BNR-6≤28 as low risk,28-50 as medium risk,and>50 as high risk),and its efficacy was demonstrated both in internal and external cohort.The stability of the model was further verified by 400-time 10-fold cross validation.3.A total of 1138 patients with chronic DILI hospitalized in the Fifth Medical Center of PLA from January 2017 to January 2022 were retrospectively included to analyze the correlation between relapse risk and hepatic fibrosis.The results showed that the degree of hepatic fibrosis in the relapsed group was more severe than that in the non-relapsed group.The proportions of S0,S1,S2,S3 and S4 in the relapsed group were 1.9%,13.1%,42.2%,27.9%and 14.9%,respectively,while those in the non-relapsed group were 8.9%,43.5%,26.1%,17.1%and 4.4%,respectively.The ACLS model was established based on LSM,CHE and AST,and correlation analysis showed that ACLS score was positively correlated with the degree of hepatic fibrosis(rho=0.530),and the cut off value of ACLS score in the diagnosis of moderate hepatic fibrosis was 3 points(AUC 0.78),which was better than APRI and FIB-4.The cut-off value for the diagnosis of severe hepatic fibrosis was 6 points(AUC 0.83),which was better than APRI,but had no significant difference with FIB-4.Conclusion1.Inflammation grade≥G3,fibrosis stage≥S2,high AST,high TBIL,high LSM,low CHE and low PLT were risk factors for relapse of chronic DILI.2.The novel and noninvasive BNR-6 model constructed by AST,TBIL,PLT,PT,sex and age,could predict the risk of relapse for in patients with chronic DILI,which is easy-to-use,reproducible and robust,and could be widely used in clinical practice.3.The relapse risk of chronic DILI is highly correlated with the degree of hepatic fibrosis.