Detection of hepatitis C virus antibody in patients with autoimmune hepatitis and other chronic liver diseases

To clarify the relationship between autoimmune hepatitis (AIH) and the hepatitis C virus (HCV), we investigated the prevalence of antibodies to HCV (anti-HCV) by an enzyme-linked immunosorbent assay in patients with AIH, primary biliary cirrhosis (PBC), rheumatoid arthritis and multiple myeloma. The antibody was detected in 9 out of 18 patients with AIH (50%), in 3 out of 23 with PBC (23%), in 2 out of 10 with rheumatoid arthritis (20% ), and in 5 out of 9 with multiple myeloma (56% ). However, the optical density values in these patients were lower than those observed in non-A, non-B hepatitis (NANBH). Anti-HCV became negative immediately after the initiation of glucocorticoid therapy in all four antibodypositive AIH patients tested. The extracted immunoglobulin G fraction from sera of 5 anti-HCV negative AIH patients became positive for the antibody. This phenomenon was not observed in 5 normal volunteer sera. The 9 family members of three anti-HCV positive AIH patients showed no anti-HCV positivity. These results suggest that autoantibodies in AIH patients may cross-react with the HCV -related antigen. Direct association of the HCV influencing the development of AIH is unlikely. Therefore, care should be taken in the evaluation of anti-HCV positivity in patients with autoimmune diseases and multiple myeloma. This study was supported by the Ministry of Health, Science and Welfare of Japan.     

Impact of pretransplant antinuclear antibody and antismooth muscle antibody titers on disease recurrence and graft survival following liver transplantation in autoimmune hepatitis patients

Background and Aims: Disease recurrence following transplantation occurs in 20–45% of patients with autoimmune hepatitis (AIH). Factors associated with an increased risk of recurrence include human leukocyte antigen (HLA) DR3 and HLA DR4 positivity, inadequate immunosuppression, and severity of inflammation in the native liver. Titers of several autoantibodies can be elevated in patients with AIH, including antinuclear antibody (ANA) and antismooth muscle antibody (SMA); however, it is unclear whether or not the degree of elevation influences the risk of disease recurrence following transplantation. Methods: We conducted a retrospective study to evaluate the potential impact of pretransplant titers on post‐transplant outcomes for patients with AIH. Sixty‐three patients with AIH who underwent 72 liver transplants between 1 January 1989 and 1 January 2009 were included, with a median follow up of 10 months. Patients were divided into group A (ANA or SMA ≥ 1 : 160) and group B (titers ≤ 1 : 160). Results: There was no significant difference in the recurrence rates or death between patients in groups A and B, respectively. Only race appeared to impact outcomes, with African American patients having a higher incidence of death and recurrent disease post‐transplant compared to other ethnicities. Conclusions: Based on our findings, pretransplant ANA and SMA levels do not appear to impact recurrence rates or outcomes following liver transplantation for AIH.     

抗双链DNA抗体阳性肝功能异常患者临床及生化特征

目的 探讨抗双链DNA抗体阳性肝功异常患者的临床及生化特征.方法 收集肝功异常患者血清884例,采用免疫印迹法检测抗双链DNA抗体.结果 抗双链DNA抗体阳性患者16例(1.81%),女性患者14例,男性2例;平均年龄(48.94±17.57)岁(9岁～69岁).其中自身免疫性肝炎13例(81.25%).16例抗双链DNA阳性患者中肝硬化8例(50%),亚急型重型肝炎2例,急性重型肝炎1例.ALT平均值为(433.91±405.86)U/L,AST平均值为(535.05±513.92)U/L,TBil平均值(182.46±149.11)μmol/L,DB il平均值为(118.33±103.97)μmol/L,PTA平均值为(75.27±31.22)%,IgG平均值(23.48 ±13.26)g/L.16例患者ANA抗体均阳性,并伴有多种自身抗体.结论 在抗双链DNA抗体阳性的肝功异常患者中AIH发病率较高,且病情较重.对抗双链DNA抗体阳性的肝功异常患者临床应予以重视.     

The international autoimmune hepatitis score in chronic hepatitis C

SUMMARY. Clinical and laboratory findings of autoimmunity are common in chronic hepatitis C. Autoimmune hepatitis (AIH), a disease of unknown cause, has been defined by use of the International Autoimmune Hepatitis Group Score (AIH score), which quantifies clinical and laboratory parameters. To further validate the specificity of the International AIH score and investigate the similarities between hepatitis C and AIH, we measured the International Autoimmune Hepatitis Group Score in patients with well-defined chronic hepatitis C. Thirty consecutive non-cirrhotic patients with chronic hepatitis C were evaluated. Scoring was performed using both components of the AIH score: a set of minimum required parameters including laboratory and historical data and a second set of additional parameters dominated by histological criteria. Autoantibodies were positive in 21 of 30 hepatitis C patients and associated (patient or first-degree relative) autoimmune diseases were present in eight of 30 patients. Histologically, chronic active hepatitis with periportal piecemeal necrosis was seen in 24 of 30 patients and lymphoid follicles in 16 of 30 patients. No patient scored as probable or definite AIH using the minimum required parameters of the AIH score. When histological parameters were included, four of 30 patients scored as probable AIH but none as definite AIH. Therefore, AIH was excluded by the minimal and additional criteria of the AIH score in 86% of patients with hepatitis C despite a high prevalence of autoantibodies in these patients. We conclude that the criteria set forth by the International AIH scoring system defines a distinct disease although it shares some features with chronic hepatitis C. Modification of the AIH scoring system to include other commonly accepted risk factors for hepatitis C and additional histological parameters would further improve its specificity.     

Comparison of clinical features and liver histology in acute and chronic autoimmune hepatitis.

Aim: We investigated the clinical and morphological features between acute and chronic autoimmune hepatitis (AIH) with or without acute exacerbation. Methods & Results: Serum total bilirubin on average was elevated to 12 mg/dL in acute AIH, alanine aminotransferase and aspartate aminotransferase peaked to more than 1000 U/L, and serum gamma-glutamyl transpeptidase was higher in the acute type compared with the chronic type without exacerbation. Serum immunoglobulin G was lowest in all other types of AIH. A liver biopsy showed interface or lobular hepatitis with lympho-plasmacytic infiltration, and rosette formations were frequently seen in acute AIH. There were morphological changes of central necrosis with plasmacytic infiltration and giant cell hepatitis. CK19-positive cholangiolar cells had proliferated in the periportal area with massive necrosis, and bile duct injuries were seen in acute AIH more frequently than in the chronic type. Conclusion: Laboratory data and liver histology in acute AIH differed from those of chronic AIH and were clarified for the diagnosis of acute AIH.     

自身免疫性肝病与慢性乙型病毒性肝病超声影像对比分析

探讨自身免疫性肝病与慢性乙型肝病的超声表现的异同点,通过单因素、非条件Logistic回归测得AIH与CHB在性别、肝脏大小方面,存在明显差别(P<0.001);中晚期PBC与乙肝肝硬化超声表现在肝脏大小、肝脏回声(P<0.001、P=0.047)方面存在明显差异。AIH与CHB,PBC与乙肝肝硬化超声表现不同。     

Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases

Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC–AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC–AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.     

Clinical characteristics of patients with autoimmune hepatitis seropositive for anticentromere antibody

Aim: Recent studies have revealed that primary biliary cirrhosis patients with anticentromere antibody (ACA) commonly develop portal hypertension. However, the clinical characteristics of autoimmune hepatitis (AIH) remain uncertain. We investigated the clinical features of patients with AIH seropositive for ACA (ACA‐AIH), comparing them with those of patients with AIH seropositive for other immunofluorescent patterns of antinuclear antibodies (ANA) (other‐AIH). Methods: AIH was diagnosed on the basis of the scoring system proposed by the International Autoimmune Hepatitis Group. Seropositivity for ACA was determined by a discrete speckled pattern on HEp‐2 cells by an immunofluorescent technique. The severity of histological grading and staging was evaluated by the histological activity index (HAI) score. Results: Eight (17%) of 47 patients with AIH had ACA. No significant differences in age, sex, onset pattern of the disease, progression to hepatic failure and relapse rate were present between the ACA‐AIH and other‐AIH groups. The frequency of concurrent autoimmune diseases in ACA‐AIH was significantly higher than that in other‐AIH (75% vs 36%, P = 0.0406). Biochemical analysis revealed a significantly lower mean immunoglobulin G (IgG) level than that in other‐AIH (2176 ± 641 vs 3013 ± 923 mg/dL, P = 0.0150). However, there were no differences in serum alanine aminotransferase levels, titers of ANA, HAI scores or the positive rate of human leukocyte antigen (HLA)‐DR4 between the groups. Conclusion: These results suggest that the emergence of ACA is not a distinct entity of AIH, despite its clinical characteristics of a significantly higher frequency of concurrent autoimmune diseases and lower serum IgG levels.     

Autoimmune diseases of the liver, autoimmune hepatitis and primary biliary cirrhosis: Unfinished business

Autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have attracted much attention since their discovery 50 years ago, but there remain items of unfinished business. These relate to disease susceptibility including genetic influences (HLA and non-HLA genes, genes associated with female predisposition, and others) and environmental influences (infections, chemicals, xenobiotics and medications). Also needed is better characterization of autoantigenic molecules, particularly the anti-F-actin specificity characteristic of AIH, shown here to have functional effects in vitro . Deeper analysis of T-lymphocyte function in AILD should reveal relative contributions of eachof the multiple subsets of T cells now being defined in studies on laboratory animals, CD4⁺, CD8⁺, Th1, Th2, Th17, memory subsets and regulatory subsets. Diagnostic immunology providers now offer high-performance assay formats that call for systematic clinical assessments to achieve standardization, calibration and optimal information.     

Profiles of antinuclear antibodies in chronic active hepatitis,primary biliary cirrhosis and alcoholic liver disease

ABSTRACT— The profiles of specific antinuclear antibodies were determined in sera from 23 patients with the idiopathic type of chronic active hepatitis (CAH), 15 patients with primary biliary cirrhosis (PBC) and 25 patients with alcoholic liver disease (ALD). The indirect immunofluorescence test for antinuclear antibodies using cultured human embryonic fibroblasts as substrate was positive in 78% in CAH, in 73% in PBC and in 24% in ALD. Seventeen percent of CAH sera and 33% of PBC sera stained small speckles in interphase nuclei. This staining pattern probably represents a new subset of ANA as the centromeres (kinetochores) were not stained. Antibodies to native DNA by the Crithidia luciliae test were found in only one serum from a patient with CAH. In addition, 17 percent of the CAH sera reacted with the saline extract of rabbit thymus by double immunodiffusion. Antibodies to the Sm- or RNP-antigens were not found. SS-B antibodies could be demonstrated in 39% of the CAH sera by a sensitive immunoenzymatic technique. Patients with CAH also had significantly higher levels of antibodies against denatured, single-stranded DNA (ss-DNA) and a synthetic RNA molecule, poly(A) as compared to other groups. Patients with an atypical cholestatic CAH had an antinuclear-antibody profile resembling that of the other CAH patients, but different from that of PBC patients. Patients with alcoholic cirrhosis had significantly higher levels of ss-DNA- and poly(A)-antibodies than other patients with ALD. It is concluded that the determination of an antinuclear-antibody profile using the ELISA seems to be clinically useful in the classification of chronic liver diseases.     

A case of autoimmune hepatitis with a high titer of antimitochondrial antibody and normal γ-globulinemia

We report here a patient with chronic active hepatitis who had no markers for hepatitis viruses and no hyper-gamma-globulinemia, but had high titers of antimitochondrial antibody. Serum levels of alkaline phosphatase were normal, and antinuclear antibody, antismooth muscle antibody, and antiliver kidney microsome antibody tested negative. The titers of antimitochondrial antibody exceeded 1:640, and the positivity for anti-M2 was ascertained by using both ELISA and immunoblot with beef-heart mitochondria and a recombinant pyruvate dehydrogenase E2 subunit as antigens. This patient responded to ursodeoxycholic acid (UDCA) therapy in the beginning, but her hepatitis flared up during UDCA therapy. In contrast, she responded completely to corticosteroid therapy. The clinical course and histological findings of this patient strongly suggest that this patient has autoimmune hepatitis.     

慢性丙型肝炎合并自身免疫性肝炎的研究进展

有关慢性丙型肝炎合并自身免疫性肝炎的研究不多,到目前为止,临床针对该类疾病的诊疗仍面临诸多困难。虽然相关的文献给出了一些建议,但目前没有标准指南来指导其诊断和治疗,临床医师常常需根据个人的临床经验治疗这部分患者。就报道的慢性丙型肝炎合并自身免疫性肝炎相关文献进行总结,旨在为临床医师遇到这类临床问题提供帮助。     

High prevalence of antibody to hepatitis C virus in heavy drinkers with chronic liver diseases in Japan

To investigate the prevalence of antibody to hepatitis C virus (anti-HCV) in heavy drinkers with liver disease in Japan, we tested serum samples from 113 heavy drinkers with liver disease and 121 without liver disease. All were negative for HBsAg with no history of blood transfusion. These subjects had consumed more than 80 g of ethanol daily for 5 years or more. Findings for anti-HCV determined by recombinant immunoblot assay testing were positive in 14 (35.9%) of the 39 patients with liver cirrhosis, 14 (58.3%) of the 24 patients with hepatocellular carcinoma and in 8 (53.3%) of the 15 patients with chronic hepatitis. The anti-HCV positive rate in the drinkers with these liver diseases was significantly higher than in those with such disorders as fatty liver (0/10), hepatic fibrosis (0/22), and alcoholic hepatitis (0/3), as well as in the alcoholics without liver disease (5/121, 4.2%). Considering histologic findings in the anti-HCV positive cirrhotics, the occurrence of lymph follicle formation (71.4%), piecemeal necrosis (78.6%) and loose fibrosis (64.3%) were observed to a significantly higher extent than in cirrhotics who were negative for anti-HCV. These findings suggest that advanced chronic liver disease among heavy drinkers in Japan, especially of hepatocellular carcinoma, is closely associated with HCV infection. In the livers of heavy drinkers who were positive for anti-HCV, histologic findings indicated the possibility of viral infection.     

药物性肝损伤、药物诱导性自身免疫性肝炎和自身免疫性肝炎鉴别诊断研究进展

本文就药物性肝损伤( drug-induced liver injury, DILI)、药物诱导性自身免疫性肝炎( drug-induced autoimmune hepatitis,DIAIH)、自身免疫性肝炎( auto-immune hepatitis, AIH )三者的定义、病因及发病机制、临床特征、临床诊断、...     

CD11C抗体在自身免疫性肝病的表达研究

[目的]研究原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)及自身免疫性肝炎(autoimmune hepatitis,AIH)的病理特点,寻找有效的病理诊断指标。[方法]从2006~2012年昆明医科大学病理教研室肝穿活检病例中筛选病理诊断PBC 47例[其中血清检测抗线粒体抗M_2亚型(AMA-M_2)阳性30例、AMA-M_2阴性17例],自身免疫性肝炎(autoimmune hepatitis,AIH)20例。采用免疫组化方法检测所有病例肝组织内CD11C的表达情况。[结果]PBC AMA-M_2阳性组与PBC AMA-M_2阴性组CD11C阳性单位相比差异无统计学意义(P0.05),PBC AMA-M_2阳性组、PBC AMA-M_2阴性组分别与AIH组CD11C阳性单位相比,均差异有统计学意义(P0.05)。[结论]CD11C主要表达于肝脏门管区肉芽肿内,有助于PBC的诊断。     

Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis

Aim:  Antinuclear antibodies (ANA) are the main serologic markers of type 1 autoimmune hepatitis (AIH); however 20–30% of patients are negative for ANA. We assessed the clinical features of ANA-negative patients.
Methods:  A retrospective analysis was performed of 176 patients with type 1 AIH (153 females, median age 55 years). A diagnosis of AIH was made based on the revised scoring system proposed by the International Autoimmune Hepatitis Group. ANA titers were measured using a standard indirect immunofluorescence technique.
Results:  Thirty-eight patients (22%) had low titers of ANA (1:40 or 1:80), and 114 (65%) had high titers (≥ 1:160). Of 24 ANA-negative patients, 15 were positive for smooth muscle antibodies (SMA). Three of nine both ANA- and SMA-negative patients developed ANA during follow-up. The other six were diagnosed based on histological characteristics. Thirteen ANA-negative patients relapsed after the normalization of serum alanine aminotransferase (ALT) levels. ANA-negative patients more frequently showed acute presentation and, at presentation, had lower serum immunoglobulin G levels, higher serum levels of bilirubin and transaminase, and higher frequencies of histological acute hepatitis and zone 3 necrosis than those with high titers. However, the frequency of advanced stage of fibrosis was similar. The response to corticosteroids was not different among the three groups.
Conclusions:  ANA-negative type 1 AIH shows acute-onset more frequently but may include not only acute autoimmune hepatitis, but also acute exacerbation of inactive chronic disease. Regarding the diagnosis of ANA-negative AIH, the determination of ANA during follow-up and the response to immunosuppressive treatment may be helpful.     

自身抗体在自身免疫性肝病中的预测价值

自身抗体作为自身免疫性肝病的诊断标志物已经在临床上得到了广泛应用,但其在病情严重程度及预后判断方面的价值报道并不多,事实上某些自身抗体除本身的诊断价值外,还具有预测病情的作用：如抗可溶性肝抗原抗体、抗肌动蛋白抗体、抗肝细胞溶质抗原Ⅰ型抗体、抗去唾液酸糖蛋白受体抗体、抗染色体抗体、抗环瓜氨酸多肽抗体和抗肝肾微粒体Ⅲ型抗体与自身免疫性肝炎的发生、发展及恶化有一定的相关性,其中抗可溶性肝抗原抗体与某些自身免疫性肝炎患者严重肝组织学改变、长期维持治疗、停药后再度恶化以及肝衰竭的发生相关;抗gp210抗体、抗Sp100抗体和抗着丝点抗体在原发性胆汁性肝硬化中有一定的预测意义,其中抗gp210抗体可提示原发性胆汁性肝硬化患者有较严重的界面性肝炎、小叶炎症以及易进展为肝衰竭等。     

Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal antibody, rituximab: case report and review of literature.

Rituximab, a chimeric monoclonal anti-CD20 antibody, has shown activity in several autoimmune disorders. We describe a case of a 52 years old female who was diagnosed with idiopathic thrombocytopenic purpura and concomitant autoimmune hepatitis (AIH), both non-responsive to steroids. She was subsequently treated with rituximab, which resulted in a rapid increase in her platelet count and an unexpected normalization of her hepatic biochemical tests. Both her platelet count and her hepatic biochemical tests remained normal for over 5 months. In this case, rituximab showed an impressive clinical response for the treatment of AIH, and it may be considered as an alternative treatment in patients who do not respond to corticosteroid therapy. Prospective randomized studies in AIH are needed to validate this observation.