| Background:Drug-induced liver injury(Drug-induced liver injury,DILI)is an important cause of liver injury,with high morbidity and mortality.Hepatotoxicity is the most common adverse reaction of drugs,and it is also one of the main reasons why some drugs fail to obtain regulatory approval after initial approval.Early accurate diagnosis of DILI is extremely important,but because it is difficult to identify the drugs that cause liver injury,and there is a lack of reliable markers to assist the diagnosis,and the diagnosis process is complex and does not form a unified standard,it will be difficult to achieve the purpose of early diagnosis.Drug hepatotoxicity can simulate the clinical manifestations or pathological features of almost any liver disease.Diagnosis can not only be based on histomorphology,but liver biopsy can determine the histopathological types of injury.Therefore,a comprehensive understanding of the pathological features of liver biopsy and its relationship with clinical condition,clinical classification and disease severity is helpful to early judge DILI and evaluate its condition and prognosis.Objectives and Research methods:We retrospectively collected 304 patients who were diagnosed with DILI by liver biopsy in the Department of Hepatobiliary and Pancreatic Medicine,the First Hospital of Jilin University from August 1,2010 to January 31,2022,and collected medical records,suspicious drugs causing liver damage,Roussel Uclaf Causality Assessment Method(RUCAM),clinical biochemical indexes,liver pathological characteristics,and disease severity grading.According to the biochemical results at the time of onset,the "R" ratio was calculated to obtain the clinical classification:hepatocellular type,cholestatic type,mixed type,and common pathological injury classification according to Kleiner et al.: inflammatory necrosis type(acute/chronic hepatitis),cholestatic type(Acute/chronic cholestasis,cholestatic hepatitis),steatosis and steatohepatitis,vascular injury type.We analyze general characteristics of each pathological type,and compare the consistency of clinical type and pathological injury type at onset and within 3 days before and after liver biopsy.To analyze the correlation between pathological characteristics of common pathological injury types and disease severity.Results:(1)In this study,the number of patients with hepatocyte injury subtype and cholestasis subtype was similar according to the R value at the time of onset,127 cases(41.8%)and 121 cases(39.8%)respectively,and 56 cases(18.4%)of mixed type.The overall age of the patients was 48.55±11.51 years old,and there were significantly more female patients than males,accounting for 76% of the total.Among the common clinical symptoms,there are significant differences between fatigue and jaundice,and the incidence of fatigue and jaundice is higher in the subtype of liver cell injury.In the clinical symptoms,fatigue,jaundice symptoms in the three clinical types of statistical significance(P < 0.05),after further comparison found that,there were significant differences in the symptoms of fatigue and jaundice between the two groups of hepatocellular injury type and cholestasis type.According to the analysis of laboratory indexes,the peak values of red blood cell count,hemoglobin,ALT,AST,INR and cholesterol in the three groups were higher than those in the other two groups(P< 0.05),the peak values of neutrophil count,TB,HDL and LDL were higher in the two groups than those in the other two groups(P < 0.05).As can be seen from the RUCAM score,all included patients had a score of 3 or more,with the highest proportion of patients with a score of 6-8 and the highest proportion of patients with hepatocellular injury.(2)The types of suspected causative drugs in this study were arranged in order:traditional Chinese medicine and proprietary Chinese medicine,combined drug use,environmental poisons,non-steroidal anti-inflammatory drugs,health products and dietary supplements,immunosuppressants,etc.(3)Analysis of pathological characteristics of clinical classification at the onset of DILI: The pathological characteristics of liver damage targets were mainly lobular inflammation,followed by hepatocyte cholestasis and small bile duct cholestasis,steatosis,hepatic vascular damage,and average fibrosis stage(S)is class 1.From the analysis of the pathological characteristics of inflammation and necrosis,81.2% of DILI pathological tissues had hepatocyte necrosis,mainly focal necrosis(58.2%),bridging necrosis and sub-mass and massive necrosis accounted for 23%;24.7% of patients Interface inflammation can be seen,and the infiltration of neutrophils,plasma cells and eosinophils is obvious in the pathological tissue.The pathological features of lobular inflammation,neutrophils,and necrosis of hepatocyte injury type were significantly different from those of the other two subtypes.From the analysis of the pathological features of cholestasis,hepatocellular cholestasis was more common with smaller bile duct cholestasis,but there was no significant difference in the distribution among the three subtypes.After summarizing all the pathological features of DILI in this study sample,no cases classified as steatosis or steatohepatitis were identified.(4)Analysis of consistency between clinical classification and liver pathological classification: a total of 206 patients had the results of liver function examination at onset and within 3 days before and after liver puncture.According to the R ratio calculated according to the liver function index at admission,The clinical classification was compared with the pathological classification of liver puncture after calculating R ratio according to the liver function index at admission,the clinical classification of hepatocellular vs necroinflammatory findings in the biopsy(Kappa = 0.146,P < 0.05)and cholestasis type vs cholestatic findings in the biopsy(Kappa=0.287,P<0.05)are poor.The clinical classification was carried out according to the R’ ratio calculated by the results of liver function within 3 days before and after liver puncture,the clinical classification of hepatocellular vs necroinflammatory findings in the biopsy(Kappa=0.101,P >0.05)and cholestasis type vs cholestatic findings in the biopsy(Kappa=0.148,P < 0.05)also are poor.(5)After the statistics of the pathological characteristics of the patients’ liver pathological classification,the total number of acute hepatitis,cholestatic hepatitis and chronic hepatitis occupied the top three.The patients with pathological manifestations of acute hepatitis had the most severe inflammation,including interface inflammation,mixed inflammatory cell infiltration,bridging necrosis and apoptosis.These characteristics are mild in cases of acute cholestasis.The degree of cholestasis III in patients with cholestatic hepatitis was more severe than that in patients with acute cholestasis,but there were more inflammation and hepatocyte damage,representing the overlap between the two different histological subtypes.Mild fibrosis was found in all cases of different subtypes,but it was most obvious in cases classified as chronic hepatitis.From the subtype of vascular injury,this type of inflammation is mild,and there may be pathological changes of cholestasis.(6)By comparing the clinical severity with the pathological features of the liver,it was found that the degree of necrosis,fibrosis stage,neutrophil infiltration,eosinophil infiltration,cholestasis and bile duct reaction were all closely related to the severity of the disease.Conclusions:(1)The main age group of DILI patients is 40-60 years old,and female patients account for 76% of the total.The most suspected pathogenic drugs are traditional Chinese medicine and proprietary Chinese medicine,often with fatigue,jaundice and digestive tract symptoms.Comparing the clinical classification of R value within 3 days before and after liver puncture,it can be seen that the proportion of the former is higher than that of the latter,while the proportion of cholestasis type and mixed type is higher than that of the latter.The RUCAM score of 68 points was the highest in patients with DILI,and the highest in patients with hepatocyte injury.(2)According to the biochemical results at the time of onset and 3 days before and after liver puncture,the consistency between clinical classification and pathological classification was poor after calculating "R ratio".(3)The degree of necrosis,fibrosis stage,neutrophils,eosinophils,bullous steatosis,bile duct cholestasis,and small bile duct reaction in the liver pathological features were all correlated with the severity of the disease. |
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