Clinical Analysis And Long-term Follow-up Of Cases With Acute Drug-induced Liver Injury And Clinical Study On Gene Polymorphism Of CYP2E1

Background Acute liver injury is the most common type of drug-induced liver injury(DILI).It's the focus of clinical monitoring and prevention of drug hepatotoxicity. It's also the professional risk problem that clinician possibly meet with druing their practice. In comparison with clinical research in developed nations, drug adverse reaction monitoring system is imperfect in our country. Clinical research reports of DILI are not standard and deep enough. We lacks the clinical research information of genetic polymorphism of liver enzyme . Therefore,it is necessary to standardly investigate and analyze the diagnosis and treatment of cases with acute drug induced liver injury by international received diagnostic criteria, then to make a follow-up visit and investigate the outcome of patients with acute DILI, and to discuss genetic polymorphism of relevant liver enzyme on cute DILI.Objective To investigate and analyze the circumstances and the rule of the diagnosis and treatment of inpatients with acute drug induced liver injury retrospectively in our hospital, to explore the clinical clues of acute DILI and to establish a simple diagnostic criteria.To evaluate the outcome of patients with acute DILI after discharge and the causality to cases of suspected drug-induced liver injury. To study the natural history of DILI and the strategy of prevention and cure. By detecting CYP2E1 genotypes, to evaluate whether the polymorphism of the CYP2E1 gene is associated with acute DILI.Methods 280 cases of inpaitients diagnosed with acute drug liver injury were collected from 2000 to 2007. There were 26 incomplete cases and evaluated 254 cases. The Rousssel Uclaf causality assessment method(RUCAM) was applied to assess the probability of a causal relationship between drug exposure and liver injury.To list the more frequently incriminated drugs.By clinic and telephone,we followed up these paitients who agree to attend follow-up,and took notes of monthely liver biochemistry , know about the course of recovering or aggravating of liver biochemistry. A polymerase chain reaction with restriction fragment length polymorphism method was used to determine the CYP2E1 genotypes of 63 patients with DILI and 73 healthy individuals.Results (1) The number of cases diagnosed with acute DILI increased year by year .Among evaluated 254 cases, the results of the causality between suspected drug and liver injury were as follows: 'highly probably relevant' (>8):11.4%, 'probably relevant' (6-8): 34.3%, 'possibly relevant'(3-5): 50.0%, 'possibly irrelevant' (1-2): 4.3%, 'irrelevant'( < 0): 0%. There were 11 cases which point-score were less than 2.They were considered unrelated to drugs.So there were 243 cases of drug-related liver injury which can be put into clinical analysis.(2)Among 25 cases with severe drug induced liver injury,6 patients died in hospital, 10 patients died after discharge .The mortality was 64%. 1 patient recorved.The other 8 patients discharged because they were worse.But we couldn't follow up their outcome.(3) The mortality of Hy's Law cases(hepatocellular jaundice)was 11.9%,while the mortality of cases with cholestatic/mixed jaundice was 2.2%. The mortality of cases with hepatocellular jaundice was significantly higher than that of cases with cholestatic/mixed jaundice(P<0.05).(4)The drug category that caused acute liver injury was of a great variety. Antituberculosis drug, Chinese traditional medicine and antitumor drug were the more frequently incriminated among them. Among 25 cases with severe drug induced liver injury, Antituberculosis drug, Chinese traditional medicine and antibiotics were the more frequently incriminated drugs.(5)Among 70 patients of follow-up, 10 patients with acute liver failure died in acute stage. 1 patient underwent liver transplantation and survived at present.The other 59 patients with mild to moderate drug-induced liver injury were followed up at least 6 months. They had a median follow-up of 28 months(6-84 months ). Patients with hepatocellular pattern of liver injury recovered faster than cholestatic/mixed damage(P=0.035). Among 3 patients who had persistent liver biochemical abnormality, 2 patients with hepatocellular pattern of liver injury recovered at last. 1 patient with cholestatic pattern of liver injury died of cirrhosis and seroperitoneum.(6) No significant differences were found in both CYP2E1 genetype frequencies (CYP2E1c₁/c₁ , CYP2E1c₁/c₂ , CYP2E1c₂/c₂) and allele frequencies (c₁ and c₂) betweeen cases and controls.Conclusions The definition of liver injury , the types of hepatic injury and the causality assessment method which the international consensus criteria established was helpful to standard clinical research of DILI. The number of cases diagnosed with acute DILI increased year by year. There was higher mortality and discharge ratio. They lack effective treatment measures.The follow-up investigation confirm that the majority of patients generally completely recovered, and they had a well prognosis.The minority of patients had a chronic clinical evolution, 1 patients progressed to cirrhosis and died.There is the polymorphism in CYP2E1 gene. C2 allele ratio is higher than European and American population.No association can be found in the involvement of CYP2E1 gene polymorphism and susceptibility of patients with acute DILI.