简化和传统积分标准对自身免疫性肝炎诊断的一致性研究

目的早期、准确、及时地诊断自身免疫性肝炎（AIH）对该病的预后至关重要。本文对国际AIH协作组1999年制定的积分诊断标准（下称传统标准）和2008年制定的简化标准对国人AIH诊断的一致性进行了研究。方法按照传统标准筛选北京协和医院1995年1月～2010年12月16年间诊治的63例AIH患者,对其临床资料进行回顾性研究,并以简化标准再次进行诊断评分,比较两种标准诊断的一致性。结果以传统标准诊断AIH患者63例,女性55例,男性8例,平均年龄（45.0±17.3）岁,其中确诊患者36例,疑诊27例。以简化标准诊断时,45例诊断为AIH,两种标准的总体诊断一致性为71.4%（45/63）。以传统标准确诊的36例患者中,以简化标准诊断14例为确诊,15例为疑诊,7例为否定诊断;以传统标准疑诊的27例患者中,以简化标准诊断5例为确诊,11例为疑诊,11例为否定诊断。诊断降级的33例病例中,24例IgG正常,21例缺病理检查结果;19例同时具备其他自身抗体,14例合并其他自身免疫病。诊断升级的5例病例中,男性2例,1例有确切用药史,2例抗线粒体抗体阳性,5例均具备病理检查结果。单因素及多因素回归分析结果均显示,IgG水平正常及病理检查缺如是造成诊断差异的主要因素。结论简化标准虽然诊断项目减少,但是更依赖于病理检查结果,在临床工作中并未明显简化操作程序,对于临床特点典型的患者可考虑应用;对简化标准不支持而临床表现高度怀疑AIH的患者,仍建议采用传统标准诊断。     

自身抗体谱测定在自身免疫性肝炎临床诊断中的应用

自身免疫性肝炎（AIH）是以肝细胞为靶抗原引起的自身免疫性疾病，也是一种病因不明，以肝脏门静脉周围病变为主的慢性炎症病变，同时外周血中常存在各种自身抗体及高球蛋白血症。主要影响女性，其临床表现是非特异的，AIH的诊断是在综合临床表现、血清学和免疫学的AIH特征性指标，并除外其他引起肝病的原因之后得出，若不经治疗，预后较差。我们对31例AIH患者及75例非AIH患者进行了自身抗体谱检测。     

自身免疫性肝炎简化诊断标准的介绍

自身免疫性肝炎（AIH）是一种累及肝脏实质的特发性疾病,以血清转氨酶升高、高γ球蛋白血症、循环中存在自身抗体、女性易患、肝组织学特征性改变（界面性肝炎和汇管区淋巴浆细胞浸润）和对糖皮质激素治疗应答为特点。然而,由于AIH缺乏特异性的临床表现及生化指标,故在临床工作中诊断该病仍存在一定困难。国际自身免疫性肝炎小组（IAIHG）分别于1993年及1999年制定并更新了AIH诊断积分系统。其中临床特征7分,实验室检查14分,组织病理学5分,确诊需大于15分。该系统主要适用于具有复杂表现的患者的诊断,提供了在不同人群中评估诊断力度的机制。对包含983例患者的6项研究资料进行总结,计算出该积分系统的诊断准确性为89．8％。     

Long-term outcome of autoimmune hepatitis in children

BACKGROUND AND AIM: Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology, which usually progresses to cirrhosis if not diagnosed and treated promptly. Data on long-term follow up in children with AIH are scant. The aim of this study is to assess the long-term outcome of autoimmune hepatitis in children with respect to clinical and laboratory features at presentation. METHODS: Data were extracted from the medical records of patients presenting over a 28-year period (1972-2000) to the Royal Children's Hospital, Melbourne, Australia. Additional information was obtained by interviewing patients, and their current physicians. Of the 30 patients (22 females, mean age 9 years) identified, 18 had type I, three had type II, four had autoimmune-polyendocrinopathy syndrome type 1, one had infantile giant-cell hepatitis associated with Coomb's-positive hemolytic anemia, and four were seronegative (antinuclear antibody (ANA), smooth muscle antibody (SMA) and liver-kidney microsomal antibody (LKM)). RESULTS: Clinical features at presentation included hepatomegaly (86%), jaundice (66%) and splenomegaly (50%). Initial investigations revealed a median serum bilirubin level of 55 micromol/L (range 6-425), median aspartate aminotransferase level of 678 IU (range 70-2548), and abnormal clotting in 33% of patients. Liver biopsies were performed on all patients at presentation and 11 showed cirrhosis (36%). The mean follow-up period was 10.0 +/- 7.8 years with 43% being followed for > 10 years. Only two patients died and one required transplantation. Fourteen (50%) patients continue to be on low dose prednisolone with azathioprine, two (7%) are on prednisolone alone, and six (21%) are on no therapy. When the cirrhotic and non-cirrhotic patients were compared, the albumin level at presentation was significantly lower in the cirrhotic group (P=0.01). Of the patients who were cirrhotic at presentation, six (54%) remain compensated with a mean follow-up period of 8 years. All 24 patients currently under follow up are engaged in age-appropriate activities including school, part- or full-time work. CONCLUSION: Autoimmune hepatitis has a favorable long-term outcome with a transplant-free survival rate of 90% over a mean period of 10.0 +/- 7.8 years (range: 0.5-23), and a normal or near-normal lifestyle irrespective of presenting clinical, laboratory or histological features.     

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.     

Frequency and significance of antibodies to chromatin in autoimmune hepatitis type I

AIMS AND METHODS: To assess the frequency and clinical significance of antibodies to chromatin (ACA) in autoimmune hepatitis (AIH), 36 Japanese patients with AIH type I were studied for serum reactivity with chromatin by using an ELISA. RESULTS: Antibodies to chromatin were detected in 19 of 36 patients with AIH type I. There was a significantly higher frequency of ACA in patients with AIH type I than in patients with primary biliary cirrhosis, chronic hepatitis C and B (52.8 vs 13.2, 5.4 and 6.7%, respectively; P<0.01). None of the 19 healthy subjects had positive reactions. Sixteen of 19 patients with seropositive sera (44.4%) had reactivities with other nuclear antigens (recombinant nucleoproteins U1RNP-A, U1RNP-70; recombinant ribonucleoprotein complexes SSA/Ro 52K, SSA/Ro 60K; recombinant centromere Cenp-B; dsDNA and histones). Adsorption with double-stranded DNA (dsDNA) and histones could not remove the majority of antichromatin reactivity as 81.9% of the antibody reactivity still remained. In five sera samples from AIH type I patients positive for anti-dsDNA and antihistones, the antibody activities for dsDNA and histones were inhibited after the absorbtion of sera with chromatin. The patterns of antinuclear antibodies (ANA) detected by using indirect immunofluorescence were similar between patients with and without ACA. Patients with ACA had significantly high serum levels of gamma-globulin and immunoglobulin G. The ACA titers dropped significantly after corticosteroid treatment (P< 0.01). CONCLUSIONS: Antibodies to chromatin are frequently present in patients with AIH type I and they are one of the dominant autoantibodies associated with ANA reactivity in AIH type I. Antibodies to chromatin cannot be used to characterize distinct clinical subgroups of AIH type I.     

Juvenile autoimmune hepatitis: Spectrum of the disease

Juvenile autoimmune hepatitis(JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific andorgan-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoan-tibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.     

Clinical features of autoimmune hepatitis diagnosed based on simplified criteria of the International Autoimmune Hepatitis Group

BackgroundRecently, simplified diagnostic criteria for autoimmune hepatitis have been proposed.AimWe aimed to evaluate usefulness of the simplified criteria.MethodsWe applied the simplified criteria to 176 autoimmune hepatitis patients diagnosed according to the revised scoring system proposed in 1999 (original criteria). Furthermore, in order to compare predictabilities between these two diagnostic criteria, we included 168 patients with other liver disease than autoimmune hepatitis.ResultsOf 176 autoimmune hepatitis patients, 85% were diagnosed with autoimmune hepatitis according to the simplified criteria, and patients diagnosed according to the simplified criteria showed a higher frequency of antinuclear antibodies and/or smooth muscle antibodies of 1:80 or greater and slightly higher serum levels of immunoglobulin G than those diagnosed according to the original criteria. However, 30% of male patients, 23% of patients with acute presentation, 50% of patients showing histological acute hepatitis and 46% of patients negative for antinuclear antibodies at presentation were not diagnosed with autoimmune hepatitis according to the simplified criteria. The simplified criteria showed lower sensitivity (85% vs. 100%) and higher specificity (99% vs. 93%) for autoimmune hepatitis than the original criteria.ConclusionsThe simplified criteria may be useless for the diagnosis of patients with atypical features, especially patients with histological acute hepatitis.     

A comparison of a fluorescence enzyme immunoassay versus indirect immunofluorescence for initial screening of connective tissue diseases: Systematic literature review and meta-analysis of diagnostic test accuracy studies

The aim was to compare indirect immunofluorescence (IIF) and fluorescence enzyme immunoassay (FEIA) for initial screening of connective tissue diseases (CTDs) and to evaluate whether combining IIF with FEIA adds value.A comprehensive systematic literature review was conducted to identify fully paired, cross-sectional or case–control studies on ANA screening of CTD reporting results for IIF and FEIA. Study quality was assessed using the QUADAS-2 checklist. The reference standard was assessed against established classification criteria. The meta-analysis used hierarchical, bivariate and mixed-effects models to allow test results to vary within and across studies.Eighteen studies of good to fair quality were included in the review. IIF had a higher sensitivity than FEIA [cut-off 1:160, 7 studies, 3251 patients, 0.83 (95% CI 0.75–0.89) versus 0.73 (95% CI 0.64–0.80); cut-off 1:80, 7 studies, 12,311 patients, 0.89 (95% CI 0.84–0.93) versus 0.78 (95% CI 0.71–0.84)] but lower specificity [1:160, 0.81 (95% CI 0.73–0.87) versus 0.94 (95% CI 0.91–0.95); 1:80, 0.72 (95% CI 0.62–0.81) versus 0.94 (95% CI 0.90–0.96)]. A double-positive test had a higher likelihood ratio (LR) for CTD (26.2 (95% CI 23.0–29.9)) than a single positive test (14.4 (95% CI 13.1–15.9) FEIA+, 5.1 (95% CI 4.8–5.4) IIF+). A double-negative test result had more clinical value for ruling out CTD than a single negative test (LR 0.15 (95% CI 0.12–0.18) versus 0.21 (95% CI 0.18–0.25) IIF; 0.33 (95% CI 0.29–0.37) FEIA-). A FEIA+/IIF- discordant result had a higher LR than an IIF+/FEIA- discordant result (LR 2.4 (95% CI 1.7–3.4) versus 1.4 (95% CI 1.2–1.7)).Because of the comparatively higher specificity of FEIA and higher sensitivity of IIF, the combination of FEIA and IIF increases the diagnostic value. Clinicians should be acquainted with the clinical presentation of CTD and aware of the advantages and disadvantages of FEIA and IIF to avoid misinterpretation.     

Present status of autoimmune hepatitis in Japan - correlating the characteristics with international criteria in an area with a high rate of HCV infection

Background/Aims: A nationwide survey of autoimmune hepatitis (AIH) was carried out in Japan.Methods: Four hundred and ninety-six patients were enrolled by questionnaires sent to 101 hospitals with hepatology specialists.Results: The clinical features of Japanese AIH were as follows: most patients were middle-aged women; serum autoantibodies, especially antinuclear antibody, were frequently positive, serum IgG level was high, and HLA-DR4 was the major HLA allotype. Liver-kidney microsomal type 1 antibody was positive in nine of 79 patients tested. Eight of these antibody positive patients were also positive for antinuclear antibody and five for anti-smooth muscle antibody. Ninety-two percent of the patients showed piecemeal necrosis and 60% bridging necrosis; plasma cell infiltration in the portal areas was observed in 50% of the patients. Only 12.3% were diagnosed as having liver cirrhosis. A favorable effect of corticosteroid, normalization of serum transaminases, was observed in 89% of 317 patients, who were treated with an initial dose of over 30 mg/day. Sixty-two patients were positive for hepatitis C virus (HCV) markers. In these patients, however, only one patient was liver-kidney microsomal type 1 antibody positive. Corticosteroid was effective in 30 (81%) of 37 HCV-marker-positive patients treated with this agent. Thus the efficacy of corticosteroid did not differ from that in AIH patients without HCV infection (90%). Similarly, interferon treatment was used in 20 patients, all of whom were positive for HCV-RNA, and resulted in 50% efficacy as determined by normalization of the serum transaminase level 6 months after treatment. The International Diagnostic Scoring System for the diagnosis of AIH worked well in these patients, except for HCV-infected individuals, that is, approximately 10% of the total of AIH patients     

The platelet adhesion immunofluorescence test: A modification of the platelet suspension immunofluorescence test

Summary Platelets can adhere to surfaces by forming pseudopods. This ability is made use of here to simplify conventional platelet suspension immunofluorescence tests, since steps like serum and FITC incubations, washings and microscopic evaluation are done on platelets adhered to glass surfaces. By eliminating time-consuming manipulations like washing in individual test tubes and mounting platelets to microscopic slides, large scale studies can now be performed (up to 480 tests per day and technician). Antibodies can be detected with fresh as well as with frozen platelets from a well defined cell panel. The PAIFT is 2 to 3 times more sensitive than the NIH-standard-micro-lymphocytotoxicity-test (NIH-LCT), thus allowing earlier recognition of alloimmunization of patients.Supported by Deutsche Forschungsgemeinschaft (Projekt Leukämieforschung, Tübingen)     

Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group criteria in acute‐onset autoimmune hepatitis

Background: The diagnosis of autoimmune hepatitis (AIH) is already difficult, and that of acute‐onset AIH with atypical features is even more challenging, even though the revised original diagnostic criteria created by an international AIH group were widely accepted and incorporated into clinical practice. Aims: Recently, simplified diagnostic criteria were proposed. We compared the performance parameters of the simplified scoring system in patients with acute‐onset AIH and examined its usefulness and limitations. Methods: Fifty‐five patients with acute‐onset AIH (29 non‐severe, 14 severe and 12 fulminant) were assessed according to the simplified scoring system and compared with the revised original one. Results: Of the 55 patients, 22 (40%) were diagnosed as ‘definite’ AIH, 28 (51%) as ‘probable’ and five (9%) as ‘non‐diagnostic’ based on the revised original scoring system. By the simplified scoring system, six (11%) were diagnosed as ‘definite’ AIH, 16 (29%) as ‘probable’ and 33 (60%) as ‘non‐diagnostic’. Anti‐nuclear antibody titres did not differ among the three groups. The immunoglobulin G level was higher in fulminant than in non‐severe patients (P=0.01). Sixty‐five per cent showed acute hepatitis (massive necrosis, submassive necrosis and severe acute hepatitis) and 35% showed chronic hepatitis. Conclusions: The revised original scoring system performed better in patients with acute‐onset AIH than the simplified scoring system.     

Diagnostic criteria for autoimmune hepatitis in children: A challenge for pediatric hepatologists

Autoimmune hepatitis (AIH) is a progressive inflammatory liver disorder that is rare in children and adolescents. AIH has a broad clinical spectrum and a quick response to treatment with corticosteroids and immunosuppressive medication. The available diagnosis criteria have limitations and should be evaluated in pediatric populations. Recently, some studies reported that the 2008 simplified diagnostic criteria for AIH could be used in children with high sensibility and specificity. In addition, the authors reported that globulin and immunoglobulin G levels can be used interchangeably for diagnostic purposes. They also demonstrated that the 2008 simplified criteria fail in identifying patients with fulminant hepatic failure. Here, we discuss the limitations of the use of these criteria in pediatric patients and the requirement of more studies to improve the diagnosis of AIH in children.     

自身免疫性肝炎患者自身抗体的测定及意义

目的:探讨自身抗体测定对诊断自身免疫性肝炎的临床意义．方法:采用间接免疫荧光法(IIF)检测47例自身免疫性肝炎患者、158例非自身免疫性肝炎患者及40例健康体检者体内抗核抗体(ANA)、抗平滑肌抗体(SMA)、抗中性粒细胞胞质抗体(ANCA)、抗线粒体抗体(AMA)等自身抗体,ELISA法检测抗MPO抗体,并对结果进行回顾性分析．结果:ANA、SMA及ANCA检出率的比较,结果显示AIH中阳性率最高为SMA(66．0％, 31／47),而非AIH中则为6．3％(10／158),两组差异有非常显著性意义(P<0．01)．经X2检验, SMA、AMA和MPO抗体检测在AIH与PBC中,均有非常显著性意义(P<0．01)．AIH各型自身抗体检测结果表明,AIH-Ⅰ与ANA、SMA和ANCA相关,AIH-Ⅱ与LKM相关,而AIH=Ⅲ与SLA和ANCA相关．结论:血清自身抗体的检测对诊断、治疗和阻止自身免疫性肝炎的发展有着十分重要作用,对提高AIH在临床上同其他肝病鉴别诊断和治疗有着非常重要的意义．     

Role of international criteria in the diagnosis of autoimmune hepatitis

AIM: To study the clinical and laboratory characteristics of autoimmune hepatitis (AIH), and compare them with International Autoimmune Hepatitis Group (IAHG) criteria. METHODS: Sixty consecutive patients with AIH attended the University Clinic at Tabriz University of Medical Sciences, Iran for a 12mo period and were assessed in a case series study. Serological and biochemical evaluations were carried out in all patients. Autoantibodies, such as antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver-kidney microsomal antibody (ALKM-1) type 1, and perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) were evaluated in these patients. A liver biopsy was performed after diagnosis of the disease. Patients were evaluated in terms of their signs and symptoms, and laboratory results and the degree to which they corresponded with the diagnostic criteria of IAHG. In this study, both a comprehensive diagnostic scoring system and a simplified diagnostic scoring system were employed for AIH.RESULTS: Sixty patients, 2-0 male, 40 female, mean age 39.45 ± 17.50 years, participated in the study. Treatment began immediately after enrolment into the study. The percent distribution of the study population into definite and probable did not change after the treatment. The most common symptoms in descending order were fatigue (100%), icter (66.7%), abdominal discomfort (33.3%), abdominal distension (2-8.3%), dark urine (2-3.3%), edema (2-3.3%), hematemesis (2-0.0%), pruritus (2-0.0%), melena (11.7%) and pale stool (10.0%). At the physical examination, splenomegaly, ascites, hepatomegaly, epigastric tenderness and an abdominal mass were found in 50.0%, 16.7%, 13.3%, 5.0% and 3.3% of patients, respectively. Hypergammaglobulinemia was detected in 95.0% of cases. ALKM-1, P-ANCA, ANA and ASMA were positive in 71.4%, 66.7%, 42-.4% and 19.4% of cases, respectively. Portal hypertensive gastropathy (45.0%), esophageal varices (41.7%) and cirrhosis (40.0%) were the most prevalent complications of AIH, and there was     

Enzyme-linked immunosorbent assays for antibodies to poly(A), poly dAT and histones: possibly useful tools for the evaluation of prognosis and disease activity in systemic lupus erythematosus

Summary In a prospective study 222 sera from 56 patients with systemic lupus erythematosus (SLE) were tested for antibodies to poly(A), poly dAT and histones using enzyme-linked immunosorbent assay (ELISA). Patients with active disease had significantly more often antibodies to poly(A), poly dAT and histones than patients with inactive disease. There was a positive correlation between the activity score of the disease and the levels of poly(A)-antibodies of IgG and IgM class, poly dAT-antibodies and antibodies to histones.Patients with SLE-nephritis had a higher level of poly dAT and IgG class poly(A) antibodies than patients without nephritis. Interestingly, patients with an SLE-nephritis had lower levels of IgM-poly(A)-antibodies than those without nephritis. Attempts to use the ELISAs in predicting the SLE exacerbations were unsuccessful. However, the assays can be used as parameters in the estimation of the disease activity.