Clinical Characteristics Of Patients With Drug-induced Liver Injury With Abnormal Autoimmune Indicators

backgroundDrug induced liver injury(DILI)refers to liver injury caused by all kinds of prescription or non-prescription chemical drugs,biological agents,traditional Chinese medicines,natural medicines,health care products,dietary supplements,their metabolites and even auxiliary materials.The incidence of DILI is closely related to the regional living standard,medical conditions and economic conditions.With the development of society,the progress of diagnosis and treatment and the improvement of people’s health awareness,the incidence of DILI is gradually increasing.Studies have reported that the morbidity in European countries fluctuates between 8.1 per 100,000 population and 19 per 100,000 population.Due to the lack of statistical analysis of large-scale clinical investigation data,the incidence of DILI in China is still unclear.Recently,article named "Incidence and Etiology of drug-induced Liver Injury in Mainland China" was published online in Gastroenterology by professor Mao YM of Gastroenterology,department of renji hospital affiliated to Shanghai jiaotong university school of medicine and professor Chen chengwei of the 85 th hospital of the Chinese people’s liberation army.This is the first report reflecting the overall status quo of epidemiology,etiology and clinical features of DILI in mainland China.This study was a multi-center collaborative retrospective study based on the "Hepatox" network platform,involving a total of 25927 patients with drug-induced liver injury in 308 hospitals in mainland China.Studies have shown that the annual incidence of DILI in the general population in China is at least 23.80/100,000,higher than that in western countries,and has become a problem that cannot be ignored in clinical practice.The specific pathogenesis of DILI is still unclear,and most researchers consider that the pathogenesis of DILI may be related to drug exposure,direct toxic effects of drugs or immune disorders caused by drug metabolite complexes.At present,most researchers consider that there are two ways for the pathogenesis of DILI.One is the direct toxicity of drugs or drug metabolites complex caused by direct liver damage.Another way is that gene polymorphism leads to abnormal function of metabolic enzymes and related transporters during drug metabolism,which induces immune respons.Studies have found that some patients with DILI have abnormal autoimmune indicators,which means that abnormal immunoglobulin and positive autoimmune antibodies can be found in the serum of patients with this type of DILI.Some scholars named this special type as autoimmune drug-induced liver injury(AL-DILI).It is reported that DILI with abnormal immunological indexes is relatively similar to Autoimmune hepatitis(AIH)in clinical characteristics,serology,histology and other aspects.As a result,it is difficult to differentiate the disease from AIH and the drug-induced auto-immune liver injury(DI-AIH).At present,it is of great significance to improve the understanding of clinical characteristics of DILI patients with abnormal autoimmune indicators for early clinical diagnosis,accurate treatment and improved prognosis.This study retrospectively analyzed the clinical data of patients diagnosed as DILI with concurrent autoimmune index test(The First Affiliated Hospital of Dalian Medical University)from December 2014 to April 2018.Through the comparative analysis of general situation,the cause of drugs,clinical features,laboratory tests and pathological results between the group with normal autoimmune indicators and the group with abnormal autoimmune indicators in patients with DILI,discuss the clinical characteristics and risk factors in patients with immunological abnormalities,so as to provide guidance for these patients the diagnosis and treatment.ObjectiveBy analyzing the clinical characteristics of DILI patients with abnormal autoimmune indicators,the risk factors of DILI patients with abnormal autoimmune indicators were discussed,so as to provide references for clinical diagnosis and treatment of such patients.MethodsFrom December 2014 to April 2018,151 patients who admitted to The First Affiliated Hospital of Dalian Medical University and diagnosed with DILI were selected.All patients met the diagnostic criteria of "guidelines for the diagnosis and treatment of drug-induced liver injury".All patients underwent the immunological examination.Positive ANA(1:100+)were regarded as abnormal autoimmune indicators,and the patients were divided into the group with normal autoimmune indicators and the group with abnormal autoimmune indicators.The gender,age,drugs for liver injury,symptoms,signs,laboratory examination indexes,pathological results and other clinical datas of all patients were collected,and the clinical data were statistically analyzed.The information of gender,age,initial symptoms,physical signs and laboratory examination were compared between the two groups.Results1.General information: There were 45 males and 106 females,with the ratio of male to femalewas 1:2.4;The average age was 51.9 ± 14.6 years.Drugs causing liver injury include traditional Chinese medicine(52.3%),antibiotics(12.6%),non-steroidal anti-inflammatory drugs(9.9%),health products(6.6%),chemotherapy drugs(2.6%),anti-tuberculosis drugs(2%),lipid-lowering drugs(2.6%),anti-thyroid drugs(2%)and multiple factors(3.3%).The liver injury types of 151 DILI patients were divided to hepatocyte injury type 0.325%(49/151),cholestasis type 34.4%(52/151)and mixed type 33.11%(50/151).2.There were 64 cases(42.6%)in the group with abnormal autoimmune indexes of 151 DILI patients.There was no significant difference in the proportion of various drugs between the abnormal group and the normal group(P>0.05).There was no significant difference in gender between the two groups.There was no statistically significant difference between the two groups in the proportion of patients in clinical manifestations including physical examination findings,fatigue,abdominal distension,poor appetite,nausea,vomiting,diarrhea,itchy skin,yellow urine,and fever,as well as jaundice,abdominal tenderness,and enlarged liver(P>0.05).The proportion of patients with large spleen(6.4%)was higher than that in the group with normal immunological indicators(0%),and the difference was statistically significant(P<0.05).3.Its immunological abnormalities group Glob averages(32.1 + 7.6)g/L,normal group is higher than the immunological indexes(24.7 + 4.7)of the g/L,the difference was statistically significant(P < 0.05),the comparison of the liver function(ALT,AST,propagated,ALP,GGT,T-Bil,D-Bil and associates),blood routine(WBC,PLT,Hb),ESR,and clotting like(PT,APTT,TT,Fib,INR,PTA),Ig G,Ig M and Ig A,C3 and C4 comparison between groups showed no significant difference(P>0.05).4.Cholestasis was the most common type of liver injury in the group with abnormal autoimmune indexes(42.2%),while hepatocellular injury was the most common type in the group with normal immunological indexes(41.4%).The proportion of hepatocyte injury types in the patients with abnormal autoimmune indexes was compared with that in the normal group,and the results were statistically different(P<0.05).There was no significant difference in the proportion of mixed type and cholestasis type liver injury between the two groups(P>0.05).5.In 64 patients with its immunological abnormalities,there were 64 cases in positive antinuclear antibody(ANA),12 cases smooth muscle antibodies(SMA)positive,8 antimitochondrial antibody(AMA)positive,positive AMA-M2 subtypes(3 cases),anti liver cytosol antibody positive in 7 cases,soluble liver antigen positive resistance in 2 cases,resistance to dot protein 100 antibody positive in 1 case,nuclear membrane protein resistance gp210 antibody positive in 2 cases,the PML antibody positive(3 cases).6.Pathological results: pathological examination of liver biopsy was performed in3 patients in the group with abnormal autoimmune indexes.Case 1: moderate lobular hepatitis with early regeneration reaction;Case 2: part of the liver plate was widened with double rows of hepatocytes and a small amount of lymphocyte infiltration around the central vein.Combined with clinical manifestations,this was consistent with DILI.Case 3: lobular hepatitis with chronic bile duct injury,which was consistent with DILI.7.In terms of treatment,3 people applied hormones.Conclusion1.The drugs causing DILI are mainly traditional Chinese medicine,antibiotics and non-steroidal drugs,but the liver damage caused by health care products also increases year by year.2.Patients with DILI are often accompanied by abnormal autoimmune indicators.3.DILI patients with large spleen and elevated blood Glob may have abnormal autoimmune indicators,which should be distinguished from autoimmune hepatitis.4.Hepatocyte type was the main type of liver injury in DILI patients,and cholestasis type was the main type of DILI patients with abnormal autoimmune indexes.5.Liver biopsy is of great value in the identification of DILI and patients with abnormal autoimmune indexes.6.For patients with significant abnormal immune indicators,glucocorticoid can be applied to improve the efficacy.