Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BACKGROUND: Antibodies to a cytosolic soluble liver antigen (SLA) are specifically detected in patients with autoimmune hepatitis (AIH). The target of anti-SLA has been identified as a ~50 kDa UGA serine tRNA-associated protein complex (tRNP(Ser)Sec), through the screening of cDNA libraries. A recent report questioned the identity of tRNP(Ser)Sec as the real SLA antigen. The latter study identified alpha-enolase as a major anti-SLA target, through proteomic analysis. METHODS: In an attempt to explain the observed discrepancy we have investigated reactivity of SLA positive sera against alpha-enolase and tRNP(Ser)Sec using rat and primate liver homogenate and the recombinant antigens. Thirty-three serum samples, 11 from SLA-positive patients and 22 from SLA negative controls were investigated. SLA antibodies were detected by an inhibition ELISA and confirmed by immunoblot using human liver homogenate. Autoantibody reactivity was further evaluated using preparations of primate and rat liver homogenates. Anti-alpha-enolase antibody reactivity has been tested by immunoblot using recombinant alpha-enolase. An affinity purified goat polyclonal anti-alpha-enolase IgG antibody was used as reference serum sample. Anti-tRNP(Ser)Sec antibody reactivity was detected by ELISA or dot blot using recombinant tRNP(Ser)Sec antigen. RESULTS AND DISCUSSION: The affinity purified IgG antibody directed to human alpha-enolase gave a band of approximately 48 kDa in both human and rat liver homogenates. A high titre anti-tRNP(Ser)Sec antibody serum gave a single band of ~50 kDa in both liver preparations. All but one anti-SLA antibody positive sera reacted with a ~50 kDa but none immunofixed a 48 kDa band. All anti-SLA antibody positive sera reacted strongly with the recombinant full length tRNP(Ser)Sec protein. None of the anti-SLA negative sera reacted with tRNP(Ser)Sec. Anti-SLA positive, and anti-SLA negative sera reacted equally against recombinant alpha-enolase by immunoblot. Pre-incubation of anti-SLA positive sera with tRNP(Ser)Sec completely abolished the 50 kDa band. The findings of the present study indicate that alpha-enolase and tRNP(Ser)Sec are both expressed in primate and rat liver and have a respective MW of 48 and 50 kDa. They also show that anti-tRNP(Ser)Sec - but not anti-alpha-enolase - correlates with anti-SLA antibody reactivity. CONCLUSION: Our findings indicate that tRNP(Ser)Sec is the most likely target of anti-SLA.
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PMID:Antibodies to soluble liver antigen and alpha-enolase in patients with autoimmune hepatitis. 1567 47

Autoimmune hepatitis can affect diverse ethnic groups, and its clinical expression and outcome can vary accordingly. An asymptomatic presentation may identify patients who respond more readily to medication. Celiac sprue is important to recognize and treat by gluten restriction. Centrilobular necrosis and coincidental destructive cholangitis do not preclude the diagnosis, and antibodies to soluble liver antigen/liver pancreas may identify patients susceptible to relapse. Women, who have non-DRB1*0401 DR4 alleles more commonly than do men, may respond to a diverse range of autoantigens. DRB1*1301 is associated with autoimmune hepatitis in Brazil, especially among children, and it may favor an indigenous triggering agent. Variant syndromes are heterogenous conditions that probably reflect referral biases, and molecular mimicry between foreign and self-antigens is the basis for most theories of pathogenesis. Immunosuppressive medications (eg, cyclosporine, mycophenolate mofetil) have been used empirically with success, and recurrent and de novo disease after liver transplantation must be considered in all patients with graft dysfunction.
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PMID:Autoimmune liver disease. 1570 63

Autoimmune hepatitis has a global occurrence, diverse clinical phenotype, and evolving treatment options. The goals of this report are to review the codified diagnostic criteria, spectrum of clinical presentations, proposed pathogenic mechanisms, conventional treatment strategies, and promising interventions. The literature published in English from 1980-2005 was reviewed and an updated current perspective provided. Autoimmune hepatitis affects all ages, may be asymptomatic, frequently has an acute onset, and can present as fulminant hepatitis. Perivenular (zone 3) necrosis is within the histological spectrum. Autoimmune hepatitis can recur or develop de novo after liver transplantation. CD4+ T-helper cells and natural killer T cells have been implicated in the pathogenesis, and molecular mimicry may break self-tolerance. DRB1*0301 and DRB1*0401 are the susceptibility alleles among white North Americans and northern Europeans, whereas diverse alleles of HLA DR4 have been associated with the disease in Japan, mainland China, and Mexico. DRB1*1301 is associated with autoimmune hepatitis in South American children, and it may predispose to an indigenous etiologic agent. Antibodies to soluble liver antigen/liver pancreas may have prognostic importance, and cyclosporine and mycophenolate mofetil must be assessed by clinical trial before incorporation into management algorithms. Site-specific interventions are feasible, and they require a confident experimental animal model for evaluation. Variant syndromes lack diagnostic and therapeutic guidelines. In conclusion, autoimmune hepatitis must be considered in all patients with acute and chronic liver disease and those with allograft dysfunction after transplantation. New immunosuppressive agents and site-specific interventions promise to improve care.
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PMID:Current concepts in autoimmune hepatitis. 1579 57

A 37-year old woman presented with a 9-year history of hepatitis of unknown origin and aminotransferases within a 3-fold upper limit of normal. Autoimmune hepatitis (AIH) was diagnosed on the basis of elevated aminotransferases, soluble liver antigen/liver pancreas (SLA/LP) autoantibodies and characteristic histology. Immunosuppressive therapy led to rapid normalization of aminotransferases. Two years later, the patient developed left sided hemisensory deficits under maintenance therapy of prednisolone and azathioprine (AZT). Later she developed right foot drop and paraesthesia in the ulnar innervation territory on both sides. Magnetic resonance imaging (MRI) and cerebral panangiography suggested cerebral vasculitis. Neurological investigation and electromyography disclosed multiplex neuritis (MN) probably due to vasculitis. Consistent with this diagnosis, autoantibodies to extractable nuclear antigens were detectable in serum. Immunosuppression was changed to oral 150 mg cyclophosphamide (CPM0) per day. Prednisolone was increased to 40 mg/d and then gradually tapered to 5 mg. Oral CPM was administered up to a total dose of 40 g and then substituted by 6 times of an intervall infusion therapy of CPM (600 mg/m(2)). Almost complete motoric remission was achieved after 3 mo of CPM. Sensibility remained reduced in the right peroneal innervation territory. Follow-up of cranial MRI provided stable findings without any new or progressive lesions. This is the first report of multiplex neuritis in a patient with autoimmune hepatitis.
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PMID:Multiplex neuritis in a patient with autoimmune hepatitis: a case report. 1698 Dec 76

Autoimmune hepatitis in children may be associated with sclerosing cholangitis in the absence of inflammatory bowel disease. Wilson disease can have clinical and laboratory features that resemble autoimmune hepatitis, and it may respond initially to corticosteroids. Soluble HLA-DR antigens reflect clinical activity, and they may be useful markers of treatment response. Polymorphisms of the cytotoxic T lymphocyte antigen-4 gene may synergize with other autoimmune promoters or HLA risk factors to increase susceptibility and alter disease expression. DRB1*1301 distinguishes Argentine children from Argentine adults and identifies a unique subgroup. Antibodies to soluble liver antigen/liver-pancreas do not characterize a separate clinical entity. Their target antigen has been isolated, and it shares homologies with a selenocysteine-specific protecting factor (tRNP((Ser)Sec)). CYP2D6 is expressed on the hepatocyte surface, and it can be targeted by antibodies in autoimmune hepatitis and chronic hepatitis C. Perinuclear antineutrophil cytoplasmic antibodies lack sensitivity and specificity for autoimmune hepatitis, and they have diverse antigen specificities. Activation-induced cell death may be impaired in autoimmune hepatitis, and, in contrast to budesonide, mycophenolate mofetil has been effective in a small study of problematic patients.
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PMID:Autoimmune liver disease. 1703 Nov 68

The diagnostic criteria for autoimmune hepatitis have been codified, and a scoring system can quantify the strength of the diagnosis. Centrilobular (zone 3) necrosis signifies acute disease, and severe acute and fulminant presentations of autoimmune hepatitis are recognized. The absence of symptoms at presentation may identify some patients who do not require treatment, but therapeutic decisions must be based on disease activity not symptoms, especially since 26-70% of asymptomatic patients become symptomatic. Elderly patients have more advanced disease at presentation, but they respond well to treatment. Antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1 have prognostic value. Molecular mimicry between viral and self-antigens is the likely basis for the autoimmune response. Susceptibility alleles optimize antigen presentation. Polymorphisms influence immunocyte activation, counter-regulatory actions within the cytokine milieu, and apoptotic pathways for hepatocyte and immunocyte death. Perturbations in the populations of T regulatory cells and natural killer T cells disrupt immune homeostasis. Cyclosporine, mycophenolate mofetil, and budesonide afford new treatment opportunities, and molecular interventions at critical pathogenic pathways are feasible, especially within the cytokine network. Confident animal models of the human disease and a collaborative network of clinical investigators are the requisites for progress.
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PMID:Evolving concepts in the diagnosis, pathogenesis and treatment of autoimmune hepatitis. 1741 44

Autoimmune hepatitis (AIH) is a chronic and progressive disease characterized by histological interface hepatitis, hypergammaglobulinemia, and circulating autoantibodies. Multiple factors, including molecular mimicry, a genetic background including major histocompatibility complex class II, and defective function of regulatory T-cells, are involved in the pathogenesis. The diagnosis is made based on the scoring system of the International Autoimmune Hepatitis Group, the sensitivity and specificity of which are > 90%, respectively. AIH is classified into 3 sub-types based on the profiles of circulating autoantibodies: anti-nuclear antibody and/or smooth muscle antibody-positive (type 1), anti-liver-kidney microsomal antibody-positive (type 2), and anti-soluble liver antigen/liver-pancreas antigen antibody- positive (type 3). Recently, however, the number of atypical cases lacking the usual features has increased--for example, patients with acute-onset or fulminant-type AIH, autoantibody-negative patients, male patients, and patients with bile duct injury--and thus the clinical features of AIH have been diversified. AIH is responsive to immunosuppressive treatment in most cases; however, relapse occurs in more than 80% of patients within 1 year after immunosuppressive treatment withdrawal. The 10-year survival rate and the 10-year hepatocellular carcinoma-free rate are > 90%, respectively, indicating that some patients reach liver failure or develop hepatocellular carcinoma. To improve the prognosis of these patients, persistent normalization of transaminase is required.
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PMID:Current status of autoimmune hepatitis in Japan. 1876 4

Autoimmune hepatitis has diverse clinical presentations which complicate its diagnosis and adverse outcomes which demand new treatments. The aims of this review are to indicate the progress that has been made in solving these problems and to illuminate the pathway for additional solutions. Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into a personal library spanning 31 years. Two diagnostic scoring systems with complementary virtues have been developed that are useful in evaluating patients with confusing features. Acute severe and fulminant presentations require prompt corticosteroid therapy, and coincidental bile duct changes and centrilobular zone 3 necrosis on histological examination do not discount the diagnosis. Cholangio-graphic changes may be present in children and adults with the disease, and antibodies to soluble liver antigen have prognostic value. Autoimmune hepatitis must be considered in patients without autoantibodies and with graft dysfunction after liver transplantation. Asymptomatic patients may not require immediate treatment, and the Model of End Stage Liver Disease identifies problematic patients early. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long-term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies, and budesonide with azathioprine can be used as frontline treatment in select patients. Progress has been made in the diagnosis and treatment of autoimmune hepatitis, but more work must be done. Multicenter clinical trials are essential before the incorporation of new drugs into the treatment algorithm.
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PMID:Progress in the diagnosis and treatment of autoimmune hepatitis. 1903 54

Diagnostic criteria have been codified by the International Autoimmune Hepatitis Group, and a scoring system can quantify the strength of the diagnosis and over-ride the impact of absent or inconsistent features. The absence of a definable etiologic agent and precise diagnostic test, implies that the diagnosis may be missed or misapplied. Centrilobular (zone 3) necrosis may be an early form of autoimmune hepatitis and this pattern can transform to the classical pattern of interface hepatitis. An acute severe or fulminant presentation is possible, and different ethnic groups may have different manifestations and outcomes. Asymptomatic patients at presentation commonly become symptomatic, and treatment decisions must be based on objective features of disease severity and not the presence or absence of symptoms. Concurrent autoimmune diseases are frequent, and they may constitute an autoimmune polyglandular syndrome associated with a single gene mutation. Emerging autoantibodies of possible prognostic value are antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1. HLA DRB1*03, *04, *03-*04, *07, *13 and DQB1*02 are associated with the occurrence, clinical phenotype and outcome of autoimmune hepatitis. Variant syndromes should be suspected if cholestatic features are prominent and conventional treatment is ineffective.
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PMID:Autoimmune hepatitis. Part B: diagnosis. 1907 41

Autoantibody detection assists in the diagnosis and allows differentiation of autoimmune hepatitis (AIH) type 1 (AIH-1), characterized by antinuclear antibody (ANA) and/or smooth muscle antibody (SMA), and type 2 (AIH-2), distinguished by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM1) and/or antibodies to liver cytosol type 1 (anti-LC1). Detection of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-soluble liver antigen (SLA) antibodies can act as an additional pointer toward the diagnosis of AIH, particularly in the absence of the conventional autoantibodies. Routine autoantibody testing by indirect immunofluorescence has been recently complemented by molecular assays based on purified or recombinant antigens. Although the AIH-1-specific ANA and SMA targets need better definition, those of anti-LKM1 and anti-LC1 in AIH-2 have been clearly identified; the fine specificity of antibody reactivity and its clinical relevance to disease pathogenesis are the focus of ongoing investigation. This article critically discusses the current knowledge of the diagnostic and clinical significance of AIH-related autoantibody reactivities, focusing on key issues that the physician needs to be aware of to be able to request the appropriate testing and to interpret correctly the laboratory results within the clinical context of the patient.
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PMID:Autoantibodies and their antigens in autoimmune hepatitis. 1967 97


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