NAGPA And TCF4 Gene Polymorphism Study And Pathological Analysis Of Patients With Drug Induced Liver Injury In Fujian Province

PART 1 Association between the polymorphisms of NAGPA and TCF4 genes and drug-induced liver injury in patients from Fujian ProvinceObjects:To investigate the relationship between the polymorphism of NAGPA and TCF4 genes and the incidence of drug-induced liver injury(DILI)in Fujian Province.Methods:109 cases of DILI in Fujian Province were divided as the study group,and 120 healthy subjects in the same area were as the control group.Using the first-generation sequencing technique to detect the polymorphisms of NAGPA rs7188856 and TCF4 rs9955026,alleles and genotype frequencies of the above loci were calculated;Hardy-Weinberg equilibrium test was performed in control group;genetic statistical methods and Logistic regression were used to analyze the association between alleles and their genotypes at the two loci with the pathogenesis of DILI.Results:1.The NAGPA rs7188856 genotype in the control group were consistent with the Hard-Weinberg equilibrium test(χ2=0.925,P=0.34).2.Two alleles(A and G)and three genotypes(AA,AG and GG)were detected at the two loci,the rs7188856 polymorphisms of NAGPA gene is correlated with the incidence of DILI,Individuals with allele A have an increased risk of DILI(P=0.019,OR=1.821),the rs9955026 polymorphisms of TCF4 gene were no statistically difference between the two groups(P=0.107).3.We used multivariate logistic regression analysis to adjust the gender and age,and found that people with AA/AG genotype at NAGPA rs7188856 had an increased risk of DILI(P=0.009,OR=2.170),after the correction of TCF4 rs9955026 which deviated from the H-W equilibrium test,there were no statistically difference in the risk of DILI between the mutant genotype(AG/GG)and wild genotype(AA)(95%CI 0.908-2.595).4.There were no statistically difference in clinical classification,severity grading and drug species between the wild genotype and mutant genotype at NAGPA rs7188856 and TCF4 rs9955026 in the study group.Conclusion:1.The rs7188856 polymorphisms of NAGPA gene is correlated with the incidence of DILI in Fujian Province,the allele A is the susceptible allele of DILI,Individuals with the allele A may be at an increased risk of developing DILI2.No significant difference was found between the rs9955026 polymorphisms of TCF4 gene and the risk of DILI.PART 2 Pathological Characteristics of 56 Patients with DILI in Fujian ProvinceObjects:To observe the pathological characteristics of DILI,and the consistency between pathological types and clinical types.Methods:56 cases of DILI diagnosed at Pathology Department in our hospital from January 2010 to December 2018 were observed.Their RUCAM scores were≥6.We analyzed the general conditions,the pathological characteristics of liver,the pathological characteristics of different types of drugs,the consistency of pathological type and clinical type of DILI patients.Results:1.Thirty-four of the 56 patients were male and 22 were female.The mean age of the 56 patients was 46.27±16.00 years old.The top three drugs causing DILI were traditional Chinese medicine,anti-infective drugs and immunosuppressive drugs.2.Clinical types:34 cases(60.71%)were of hepatocellular injury,14 cases(25%)were of cholestasis,and 8 cases(14.29%)were the mixed type.3.Pathological Characteristics of 56 Patients with DILI:Hepatic lobular lesion was the major finding,and some severe cases were combined with portal lesions.The hepatic lobules lesion was mainly exhibited as hepatocyte edema and degeneration,bullous/vesicular steatosis,hepatocyte/capillary cholestasis,spotted/focal necrosis,fusion necrosis,bridging necrosis of hepatocytes around the central vein,and cytoplasmic cytoplasm in the hepatic sinus.The major findings of the portal area were inflammation of the portal area,and/or fibrous tissue hyperplasia(fibrous septum/bridging fiber/arcuate fiber formation);Inflammatory cells were mainly lymphocytes/monocytes,followed by eosinophils.4.There were no statistically difference in the major pathological findings caused by the several common drugs in our study(P>0.05).5.DILI pathological types:mixed type in 27 cases(48.22%),hepatocellular injury in 25 cases(44.64%),cholestasis in 4 cases(7.14%).Mixed type mainly manifested as hepatocellular turbidity and swelling degeneration,feather-like degeneration,point/focal necrosis,hepatic cell/capillary cholestasis,interlobular bile duct injury and proliferation of the bile duct.The hepatocellular injury type was mainly lobulitis,mainly exhibited as hepatocyte edema and steatosis,spotted/focal necrosis,and peri-central venous hepatocyte necrosis.The hepatocyte injury of cholestasis type was mild,and the hepatocyte turbidity and swelling denaturation were the main type,and the cholestasis was mainly in the capillary bile duct.6.Compared the consistency of pathological type and clinical type,the Kappa was 0.221(P<0.05),the Kappa value<0.4,the consistency between the two methods were poor,but the mixed injury type was more common in the pathological type.We found that the accuracy matching rate of the two methods was 50%,and the approximate matching rate was 44.64%.A total of 94.64%of DILI patients achieved accuracy or approximate matching between two types.Conclusion:1.The most common drugs causing DILI in our center are traditional Chinese medicine,and the most common clinical type is hepatocellular type.2.The mainly pathological characteristics of DILI were lobular hepatocyte edema and degeneration,with the necrosis/inflammation of hepatocytes around the central vein as the most common ones.Some severe cases had portal inflammation,fibrous tissue hyperplasia and/or fibrous septum/bridging fiber formation.3.In our study,mixed type was the most common pathological type of DILI.Compared with clinical type,the consistency of the two methods was poor.After further analysis with approximate matching method,the accuracy or approximate matching degree of the two methods was high.