Prognostic implications of antibodies to Ro/SSA and soluble liver antigen in type 1 autoimmune hepatitis

Background: Antibodies to soluble liver antigen are frequently co‐expressed with antibodies to ribonucleoprotein/Sjögren's syndrome A (Ro/SSA) in autoimmune hepatitis. Aims: Our goals were to evaluate the prognostic implications of antibodies to Ro/SSA in type 1 autoimmune hepatitis and to determine their independence from antibodies to soluble liver antigen. Methods: Three hundred and seventy‐six serum samples from 170 patients were tested by enzyme immunoassays. Results: Sixty‐five patients (38%) had antibodies to Ro52; 11 patients (6%) had antibodies to Ro60; and 27 patients had antibodies to soluble liver antigen (16%). Twenty‐six patients with antibodies to Ro52 had antibodies to soluble liver antigen (40%), and 26 patients with antibodies to soluble liver antigen had antibodies to Ro52 (96%). Patients with antibodies to Ro52 and antibodies to soluble liver antigen had a higher frequency of human leucocyte antigen (HLA) DRB1^*03 (78 vs 50%, P=0.05) and lower occurrence of HLA DRB1^*04 (22 vs 57%, P=0.01) than patients with antibodies to Ro52 alone. Antibodies to Ro52 alone [hazard ratio (HR), 2.90; 95% confidence interval (CI), 1.18–7.14, P=0.02] and antibodies to Ro52 in conjunction with antibodies to soluble liver antigen (HR, 2.98; 95% CI, 1.07–8.43, P=0.04) were independently associated with the development of cirrhosis and hepatic death or liver transplantation. Conclusions: Antibodies to Ro52 alone and antibodies to Ro52 in conjunction with antibodies to soluble liver antigen are independently associated with a poor prognosis in type 1 autoimmune hepatitis. The prognostic implications ascribed to antibodies to soluble liver antigen may reflect their almost invariable concurrence with antibodies to Ro52.     

Anti-Saccaromyces Cerevisiae antibodies (ASCA) are elevated in autoimmune thyroid disease ASCA in autoimmune thyroid disease

Environmental factors have been implicated in the development of autoimmune thyroid disease (AITD). Anti-Saccaromyces Cerevisiae Antibodies (ASCA) were shown to be elevated in several autoimmune diseases. The aim of the study was to determine ASCA levels and their relationship with thyroid autoantibodies in patients with AITD. One-hundred and twelve patients with AITD (age 41.1±12.8 years; F/M:96/16) and 103 healthy controls (38.5±10.3 years; F/M:82/21) were included. Twenty-four patients had Graves disease (GD), and 88 had Hashimoto's thyroiditis (HT). ASCA IgA and IgG, TSH, free T4, anti-thyroglobulin, and anti-thyroid peroxidase antibody concentrations were determined. ASCA IgA positivity in patients with GD (16.6%) was similar to patients with HT (13.6%) and was higher than controls (5.8%). No significant difference was present between the frequencies of IgG positivity among GD (12.5%), HT (7.9%), and control groups (5.8%). The mean levels of ASCA IgA and IgG were comparable within the groups. No correlation of ASCA and anti-thyroglobulin and anti-thyroid peroxidase levels was observed. Increased IgA ASCA positivity is observed in patients with GD, suggesting a role of environmental stimuli in its pathogenesis. The role of ASCA in the etiology of AITD needs to be further examined.     

Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis

OBJECTIVE: Antibodies to soluble liver antigen/liver-pancreas are highly specific markers of type 1 autoimmune hepatitis that have been associated with relapse. Our aim was to determine if these antibodies are reflective of a genetic predisposition for recrudescent disease. METHODS: One hundred forty-four white North American patients were evaluated by an enzyme immunoassay and by Western blot using recombinant soluble liver antigen/liver-pancreas; 122 were assessed for class II human leukocyte antigens (HLAs). RESULTS: Twenty-two patients (15%) had antibodies to soluble liver antigen/liver-pancreas. These patients were indistinguishable from seronegative patients by clinical, laboratory, and histological features at presentation. Patients with antibodies to soluble liver antigen/liver pancreas had HLA DR3 (79% vs 50%, p = 0.02) more commonly and HLA DR4 less often (16% vs 47%, p = 0.02) than patients with smooth muscle antibodies and/or antinuclear antibodies. Seropositivity was associated with DRB1*0301 and seronegativity was associated with DRB1*0401. Relapse after drug withdrawal occurred in all patients with antibodies to soluble liver antigen/liver-pancreas and at a higher frequency than in patients with conventional antibodies (100% vs 78%, p = 0.05). CONCLUSIONS: Antibodies to soluble liver antigen/liver pancreas are associated with HLA DR3 and the susceptibility allele, DRB1*0301. Antibodies to soluble liver antigen/liver-pancreas may be surrogate markers of a genetic propensity for recrudescent disease or the target autoantigen. They may be complementary to antinuclear antibodies and smooth muscle antibodies in diagnosis and management.     

Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases

BACKGROUND/AIMS: The clinical relevance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver disease is unclear. Defining the antigenic specificities of ANCA in these diseases may improve their clinical significance. METHODS: We studied the target antigens of ANCA in 88 patients with autoimmune hepatitis, 53 patients with primary biliary cirrhosis, and 55 patients with primary sclerosing cholangitis by indirect immunofluorescence, antigen-specific enzyme-linked immunosorbent assays, and immunodetection on Western blot, using an extract of whole neutrophils as a substrate. We related the data to clinical symptoms of autoimmune liver disease. RESULTS: By indirect immunofluorescence, ANCA were present in 74% of patients with autoimmune hepatitis, 26% of patients with primary biliary cirrhosis, and 60% of patients with primary sclerosing cholangitis. Major antigens were catalase, alpha-enolase, and lactoferrin. The presence of ANCA as detected by indirect immunofluorescence was associated with the occurrence of relapses in autoimmune hepatitis, with decreased liver synthesis function in primary biliary cirrhosis and in primary sclerosing cholangitis, and with increased cholestasis in primary sclerosing cholangitis. ANCA of defined specificities had only limited clinical relevance. CONCLUSIONS: ANCA as detected by indirect immunofluorescence seem associated with a more severe course of autoimmune liver disease. The target antigens for ANCA in these diseases include catalase, alpha-enolase, and lactoferrin. Assessment of the antigenic specificities of ANCA in autoimmune liver disease does not significantly contribute to their clinical significance.     

Simultaneous occurrence of autoimmune hepatitis type III and autoimmune thyroiditis type III (Graves disease)

The case of simultaneous clinical manifestation of autoimmune hepatitis (AIH) and autoimmune thyroiditis was described. The authors presented diagnostic difficulties often related to AIH. The interdependence between the liver and thyroid gland function was emphasized. Correlative occurrence of different diseases of autoimmune origin in the same patients indicates a particular genetic predisposition.     

自身免疫性肝病抗原抗体研究及临床意义

自身免疫性肝病(autoimmune liver disease,AILD)主要包括自身免疫性肝炎、原发性胆汁性胆管炎和原发性硬化性胆管炎。不同类型的AILD有不同特征的自身抗体谱,自身抗体不仅具有诊断价值,在发病机制、疾病分型、早期诊断甚至预后判断方面也有重要作用。本文就AILD抗原抗体研究进展及临床意义作一综述。     

Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2

A new autoantibody was detected by immunoprecipitation in the serum of 21 patients with chronic active hepatitis. The antibody reacted against a soluble cytosolic antigen in liver. The antibody was organ specific but not species specific and was therefore called anti-liver cytosol antibody Type 1 (anti-LC1). In seven of 21 cases, no other autoantibody was found; the remaining 14 cases had anti-liver/kidney microsome antibody Type 1 (anti-LKM1). With indirect immunofluorescence, a distinctive staining pattern was observed with the seven sera with anti-LC1 and without anti-LKM1. The antibody stained the cytoplasm of hepatocytes from four different animal species and spared the cellular layer around the central veins of mouse and rat liver that we have called juxtavenous hepatocytes. The immunofluorescence pattern disappeared after absorption of sera by a liver cytosol fraction. The 14 sera with both antibodies displayed anti-LC1 immunofluorescent pattern after absorption of anti-LKM1 by the liver microsomal fraction. The anti-LC1 was found in the serum only in patients with chronic active hepatitis of unknown cause. Anti-LC1 antibody was not found in sera from 100 patients with chronic active hepatitis associated with anti-actin antibody classic chronic active hepatitis Type 1, 100 patients with primary biliary cirrhosis, 157 patients with drug-induced hepatitis and a large number of patients with liver and nonliver diseases. This new antibody was considered a second marker of chronic active hepatitis associated with anti-LKM1 (anti-LKM1 chronic active hepatitis) or autoimmune chronic active hepatitis Type 2.     

Characterization of anti-histone antibodies in patients with type 1 autoimmune hepatitis

We have recently found that antibodies to total histones are common in a group of American patients with type 1 autoimmune hepatitis (AIH). In an attempt to determine the profile and clinical association of anti-histone antibody (AHA), 45 Japanese AIH patients were studied for serum isotypic reactivity with individual histones (H1, H2A, H2B, H3, H4) by enzyme-linked immunosorbent assay and western blotting. The results revealed that 40% of sera had reactivities with at least one of individual histones and that the antibodies were detected in all three classes of immunoglobulins (IgG, IgM, IgA). Immunoglobulin G type anti-H3 showed the dominant reactivity and it characterized 72% of sera with AHA. The titre of anti-H3 decreased significantly ( P < 0.0075) after steroid therapy and the index of decrease for anti-H3 was correlated in individuals with that for serum aminotransferase. In general, patients with AHA showed higher serum level of alanine aminotransferase ( P < 0.05), immunoglobulin G ( P < 0.025), and higher frequency of A2-DR4 haplotype (53 vs 17%) than their seronegative counterparts. However, the titre of AHA was low in this disease condition and histone class-specific antibodies did not distinguish patients with distinctive clinical features, although patients with anti-H3 tended to be younger than those without AHA.     

Anti-neutrophil cytoplasmic antibodies in patients with chronic liver diseases: prevalence, antigen specificity and predictive value for diagnosis of autoimmune liver disease. Swedish Internal Medicine Liver Club (SILK)

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 are diagnostic of Wegener's granulomatosis, but ANCA occur also in patients with other inflammatory disorders, such as ulcerative colitis, primary sclerosing cholangitis (PSC) and autoimmune hepatitis. As their predictive value for autoimmune liver disease remains unknown, we analysed the prevalence and antigen specificity of ANCA in patients with various chronic liver diseases (CLD). METHODS: We studied sera from 100 patients with primary biliary cirrhosis (PBC), from 76 with PSC and from 279 with various CLD, consecutively drawn during a 5-year period at the time of liver biopsy. The ANCA were detected by indirect immunofluorescence (IIF) while the antigen specificity was characterized by ELISA by using lactoferrin, neutrophil elastase, cathepsin G and BPI (bactericidal/permeability increasing protein) as antigens. RESULTS: In PBC, ANCA were detected by IIF in 39 patients (39%). The antigen reactivity by ELISA was lactoferrin in seven, elastase in 15, BPI in 20 and cathepsin G in four patients. Four patients had reactivity against more than one antigen. In PSC, IIF demonstrated ANCA in 49 patients (65%). The antigen reactivity was lactoferrin in 17, elastase in 14, BPI in 20 and cathepsin G in four patients. Twelve patients showed reactivity against more than one antigen. In CLD, ANCA were observed in sera from 55 patients (20%). Nineteen of 45 patients (42%) with autoimmune liver disease were ANCA positive versus 36/234 (15%) with non-autoimmune liver disease (P = 0.0002). Among IIF-positive patients, antibody reactivity against lactoferrin was noted in 14, elastase in 28, BPI in 25 and cathepsin G in five patients. Twenty-one patients had reactivity against more than one antigen. Elastase and BPI antibodies occurred more frequently in patients with autoimmune compared to non-autoimmune liver disease (P < 0.01). CONCLUSIONS: Anti-neutrophil cytoplasmic antibodies are prevalent in patients with chronic liver diseases, but although they occur more frequently in patients with autoimmune liver disease their specificity and sensitivity for autoimmune liver disease is low. The predominant antigens are lactoferrin, elastase and BPI, but the correlation between IIF findings and ELISA reactivity against these antigens is weak.     

Insoluble particulate antigen(s) in cell-mediated immunity of autoimmune thyroid disease.

Cell-mediated immunity (CMI) in patients with Grave's disease, chronic thyroiditis, and primary hypothyroidism was observed by assay of lymphocyte-mediated cytotoxicity (LMC) and leukocyte migration inhibition (LMC). Lymphocyte responsivity to phytohemagglutinin (PHA) is normal in these disease. In the LMC assay, lymphocytes of patients in each category responded to the antigens of thyroid homogenates, but not purified human thyroglobulin. Cytotoxicity is least in Graves disease and most obvious in primary hypothyroidism. In the LMI assay, patients lymphocytes responded to thyroid microsomal--mitochondrial antigens, but not to thyroid cell sap. Lymphocytes of Graves disease patients also responded to liver microsomal mitochondrial antigens. The particulate antigens lost activity when solubilized by ultrasonication or KCL extraction. There is no correlation between the PHA responsivity of lymphocytes and thyroid function, or between CMI and serum antithyroid antibodies or thyroid size. Treated and untreated patients had similar evidence of CMI. These data indicate that function of thymus-derived lymphocyte in vitro is not disturbed in autommune thyroid disease and that CMI against thyroid antigens can be demonstrated by assay of LMC and LMI. Insoluble particulate antigens appear more important than soluble antigens in CMI. LMC, resumably induced by soluble cytotoxic factor, "lymphotoxin," may play an important role in the progress of the autoimmune thyroid disease to hypothyroidism.     

自身免疫性多内分泌腺病综合征Ⅱ型合并自身免疫性肝病的病例报道

自身免疫性多内分泌腺病综合征(autoimmune polyendocrine syndromes, APS)指两个或两个以上的内分泌腺体,因自身免疫因素而同时存在功能减退或亢进,可同时合并非内分泌腺自身免疫性疾病,如结缔组织病、消化道器官自身免疫疾病等 [1]。本文通过分析1例APS-Ⅱ型的患者资料,探讨A...     

Heterogeneity of liver/kidney microsomal antibody type 1 in autoimmune hepatitis and hepatitis C virus related liver disease.

Liver/kidney microsomal antibody type 1 (LKM-1), the serological marker of a subset of autoimmune hepatitis, is also present in a proportion of patients with hepatitis C virus (HCV) related chronic liver disease. To characterise further this autoreactivity and to evaluate whether an autoantibody giving an identical immunofluorescence staining, and detected in two different clinical conditions, involves the same antigenic target(s), sera from autoimmune and HCV infected patients were tested with native, recombinant, and synthetic antigens. Sixty five sera were selected on the basis of the typical immunofluorescence pattern: 50 patients had serological markers of HCV infection, the remaining 15 suffered from autoimmune hepatitis. The reactivity of each serum with rat and human microsomal fractions, full length human recombinant CYP2D6, and two synthetic peptides spanning the amino acid regions 257-269 and 373-398 of CYP2D6 was systematically investigated by immunoblotting. Fourteen (93%) sera from autoimmune hepatitis patients and 39 (78%) from HCV infected patients reacted with rat and/or human microsomal polypeptides of 39 kD, 50 kD, 58 kD, and 66 kD in different associations, the 50 kD band being the most frequently observed. Reactivity to CYP2D6 and its amino acid sequence 257-269 was significantly more common in autoimmune hepatitis than in HCV infected patients (p < 0.001 and p < 0.0003, respectively). LKM-1 reactivity is directed against heterogeneous and not entirely defined autoantigens. The main target in autoimmune sera is CYP2D6 and its 257-269 amino acid region, while sera from patients with HCV infection are more likely to recognise other microsomal targets, the molecular identity of which is currently unknown.     

Clinical significance of autoantibody to hepatocyte membrane antigen in type 1 autoimmune hepatitis

OBJECTIVE: By using HepG2 as flow cytometry target, we have reported that autoantibody to hepatocyte membrane antigen (anti-HMA) was frequently found in autoimmune hepatitis (AIH) patients. In this study, we have examined this autoantibody in relation to clinical features in these patients. METHODS: HepG2 cells were incubated with diluted serum and subsequently with FITC-conjugated antihuman immunoglobulin. The results were expressed as relative fluorescence intensity. The prevalence of anti-HMA was estimated by setting the upper limit of mean +/- 3 SD obtained from healthy subjects. RESULTS: We found that the mean relative fluorescence intensity was 1.67+/-0.5 in AIH with low serum ALT level (group 1 AIH), 4.20+/-1.9 in AIH with high serum ALT level (group 2 AIH), and 1.92+/-0.9 in age-matched chronic hepatitis C virus-positive patients. Their positive rate was 37.5% (three of eight) in group 1 AIH, 95.0% (19 of 20) in group 2 AIH, and 33.3% (four of 12) in chronic hepatitis C patients. In 12 group 2 AIH patients, their mean relative fluorescence intensity was significantly decreased during immunosuppressive therapy. The association between serum ALT level and anti-HMA was confirmed by the facts that a significant direct quantitative relationship existed between these two levels and by serial studies of anti-HMA in four AIH patients. Anti-HMA was also detected in five non-B, non-C hepatitis patients having clinical features resembling those of AIH. CONCLUSIONS: The present results have shown that the anti-HMA was tightly associated with the degree of hepatocyte inflammation and that the measurement of anti-HMA may have some advantage in clinical evaluation of some of non-B, non-C hepatitis patients.