Analysis Of The Clinical Characteristics And Prognosis Of Autoimmune-like Drug Induced Liver Injury

Objective:Drug-induced liver injury（DILI）may have serological and histological features similar to autoimmune hepatitis（AIH）.Clinically,it is called autoimmune drug-induced liver injury（AL-DILI）,which presents difficulties for clinicians in differential diagnosis.Antinuclear antibody（ANA）is the autoantibody with the high detection rate of DILI,accounting for about 70%,and is also the main antibody of type 1 AIH,accounting for 75%.The high detection rate of ANA in DILI and AIH makes liver histology examination an important method to differentiate the two,because AIH has some relatively specific histological appearance,while DILI has a complex and varied pathological features.However,a small number of DILI patients may present with histological autoimmunity,or AIH-like histological findings,making it difficult to distinguish from AIH.In addition,DILI patients with AIH-like histological findings have been identified as potentially at high risk for druginduced autoimmune hepatitis（DIAIH）.Therefore,the identification of histological findings in patients with ANA positive DILI is the key for differential diagnosis with AIH,vigilance against the occurrence of DIAIH,and timely treatment.However,it is not clear who is suitable for liver biopsy in ANA positive DILI,and the high detection rate of ANA is more likely to cause excessive biopsy to a certain extent.It is particularly important to find noninvasive,simple and easy screening indicators indicating the occurrence of AIH-like histological findings to indicate the suitable population for liver biopsy in ANA positive DILI.In this study,the clinicopathological and prognostic characteristics of 154 patients with DILI confirmed by liver biopsy were retrospectively analyzed,and the clinical and prognostic characteristics of simply ANA negative DILI and simply ANA positive DILI and ANA positive DILI with AIH-like histological findings were analyzed and compared.To explore the clinical and prognostic characteristics of simply ANA positive DILI and ANA positive DILI with AIH-like histological findings,search for the related risk factors and screening indicators of AIH-like histological findings,and describe the basic characteristics of patients with ANA negative DILI with AIH-like histological findings,so as to provide reference for clarifying the clinical and prognostic characteristics of AI-DILI and the application of assisted liver biopsy in AI-DILI.Methods:The general information,clinical manifestations,laboratory data,pathological and prognostic data of 154 patients with DILI diagnosed by medical history and liver biopsy in Department of hepatology of the first hospital of Jilin university from January 1,2017 to December 31,2020 were collected and sorted out.The data were analyzed and mapped with R-4.1.1 software.Results:1、Analysis of the overall clinical characteristics of DILI:154 patients with DILI,median age 51 years old,female 121 cases（78.6%）,male to female ratio 1:3.67.The main pathogenic drugs were traditional Chinese medicines or herbal and dietary supplements in 92 cases（65.2%）.The positive rate of ANA was 60.4%,among which,ANA1:100 32 cases（20.8%）,ANA1:320 37 cases（24.0%）and ANA≥1:1000 24cases（15.6%）.Most cases of DILI presented with hepatocellular injury（39.6%）,followed by cholestatic injury（53 cases）and mixed injury（40 cases）.16 cases（10.4%）were complicated with autoimmune diseases,including 6 cases of Sjogren’s syndrome（3.9%）,4cases of undifferentiated connective tissue disease（2.6%）,2 cases of Graves’ disease（1.3%）,1 case of Hashimoto’s thyroiditis（0.6%）,1 case of rheumatoid arthritis（0.6%）,and 1 case of ulcerative colitis（0.6%）,Rheumatic sarcoidosis was 1 case（0.6%）.The main histopathological changes（incidence > 50%）were Kupffer cell hyperplasia,mild dilatation of the portal area,mild hyperplasia of the capillary bile duct,mild fibrosis of the portal area,hepatic cell watery degeneration,and mixed inflammatory cell infiltration of the portal area.120 patients with DILI were followed up,with a follow-up rate of 77.9%,1-5 years and the median follow-up time of 3.3 years.Among them,38 patients（31.7%）had liver biochemical normalization within 6 months,and 73 patients（60.8%）were chronic,or 6 months after the onset of DILI,radiographic or histological evidence of persistent abnormal liver function indicators or chronic liver injury,cirrhosis in 5 cases（4.2%）,liver transplantation or death from liver disease in 4 cases（3.3%）.2、Analysis of clinical and prognostic characteristics of simply ANA positive DILI:In this study,there were 58 cases（37.7%）in the simply ANA negative group and 76cases（49.4%）in the simply ANA positive group.Comparison of basic conditions,the proportion of females in simply ANA positive group（84.2%）was higher than that in simply ANA negative group（67.2%）（P < 0.05）.Compared with the simply ANA negative group,alanine aminotransferase,Gamma-glutamyl transpeptidase,serum globulin,immunoglobulin G and immunoglobulin A were higher in the simply ANA positive group（P < 0.05）and lower cholinesterase（P < 0.05）.A total of 102 patients were followed up,including 45 patients in the simply ANA negative group with a median follow-up of 3.6（1.1-5.0）years,and 57 patients in the simply ANA positive group with a median follow-up of 2.7（1.0-5.1）years.There were no statistically significant differences between the two groups in the incidence of liver biochemical normalization,chronicity,cirrhosis,liver transplantation,or liver disease death within 6 months（P < 0.05）;In terms of rediagnosis of DIAIH,no patients in either group were rediagnosed with DIAIH（P < 0.05）.3、Analysis of clinical and prognostic characteristics of ANA positive and AIH-like histological findings of DILI:In this study,there were 76 cases（49.4%）in the simply ANA positive group and 17cases（11.0%）in the ANA positive group with AIH-like histological findings.The proportion of ANA positive DILI with AIH-like histological findings combined with autoimmune underlying diseases（35.3%）was higher than that of simply ANA positive group（11.8%）（P < 0.05）.Compared with the simply ANA positive group,the levels of serum globulin and immunoglobulin G in ANA positive group with AIH-like histological findings were higher（P < 0.05）,ANA titer of patients with ANA positive DILI with AIHlike histological findings was mainly distributed in ≥ 1:1000.A total of 73 patients were followed up,57 patients in the simply ANA positive group were followed up for a median of 2.7（1.0-5.1）years,and 16 patients in the ANA positive group with AIH-like histological findings were followed up for a median of 2.7（1.4-4.4）years.There were no statistically significant differences between the two groups in the incidence of liver biochemical normalization,chronicity,cirrhosis,liver transplantation,or liver disease death within 6months（P < 0.05）;No cases were rediagnosed as DIAIH in the simply ANA positive group,and 5 cases（31.3%）in the ANA positive group with AIH-like histological findings were rediagnosed as DIAIH,and the difference was statistically significant（P < 0.001）.The incidence of DIAIH in ANA positive DILI was 5.7%.4、Analysis of related factors of ANA positive and AIH-like histological findings:Multivariate analysis showed that ANA titer ≥1:1000（OR=6.363,95%CI: 1.296-47.444,P=0.035）and globulin level（OR=1.136,95%CI: 1.029-1.273,P=0.017）were independent factors influencing the occurrence of ANA positive with AIH-like histological findings.5 、 Evaluation value of globulin and ANA titer on ANA positive with AIH-like histological findings:The area under ROC curve（AUC）of globulin was 0.770,the cut-off value was 31.5g/L,the sensitivity was 88.2%,and the specificity was 63.2%.When ANA titer ≥1:1000 and globulin > 31.5g/L were used to independently evaluate ANA positive with AIH-like histological findings,the AUC was 0.702 and 0.757,the sensitivity was 58.8% and 88.2%,the specificity was 81.6% and 63.2%,and the positive predictive value was 41.7% and 34.9%,respectively.The negative predictive values were89.9% and 96.0%,and the Kappa values were 0.348 and 0.322,respectively.ANA titer ≥1:1000 and globulin > 31.5g/L tandem assessment of ANA positive with AIH-like histological findings was 0.670（95%CI: 0.541-0.798）,the sensitivity was 47.1%,the specificity was 86.8%,the positive predictive value was 44.4%,the negative predictive value was 88.0%,the Kappa value was 0.331;The AUC of ANA positive with AIH-like histological findings evaluated in parallel with ANA titer ≥1:1000 and globulin > 31.5g/L was 0.790（95%CI:0.734-0.845）.The sensitivity,specificity,positive predictive value and Kappa value were 100.0%,57.9%,34.7%,100.0% and 0.335 respectively.6 、 Clinical features and prognosis of ANA negative with AIH-like histological findings of DILI:Three of the 154 patients（1.9%）had ANA negative with AIH-like histological findings.All 3 patients were middle-aged（≥40 years old）,including 2 females;The drugs involved include chemical poisons,traditional Chinese medicines and antibiotics;All autoantibodies were negative.2 cases were hepatocellular and 1 case was mixed.Conventional drugs were used to protect liver,and no immunosuppressive therapy was performed.1 case was lost to follow-up,and 2 cases were followed up for 4.1 and 4.5 years,respectively.All cases were chronic drug-induced liver injury,and no recurrence after improvement.Conclusions:1.The main pathological features of DILI are Kupffer cell proliferation,mild dilation of the portal area,mild hyperplasia of the capillary bile duct,mild fibrosis of the portal area,watery degeneration of liver cells,and mixed inflammatory cell infiltration of the portal area.2.ANA positive DILI patients with AIH-like histological findings are potentially highrisk groups for DIAIH.3.AIH-like histological findings were mainly distributed in ANA titer ≥ 1:1000.4.ANA titer ≥ 1:1000 and globulin level were independent factors influencing the occurrence of ANA positive with AIH-like histological findings.The optimal cut-off value,sensitivity and specificity of globulin were 31.5g/L,88.2% and 63.2% respectively.5.For patients with ANA positive DILI,when ANA titer ≥ 1:1000 or globulin >31.5g/L,liver biopsy is recommended to confirm the presence of AIH-like histological findings.