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)

Previous studies showed that following acute carbon tetrachloride (CCl(4)) treatment, interleukin-6 null (IL-6-/-) mice develop increased hepatocellular injury, defective regeneration, delayed wound healing, and increased hepatocyte apoptosis. Pretreatment with IL-6 prior to CCl(4) reduces injury, hepatocyte apoptosis, and accelerates regeneration in both IL-6-/- and +/+ livers. To demonstrate whether IL-6 can prevent liver injury that involves direct stimulation of hepatocyte apoptosis, IL-6-/- and +/+ mice were treated with the Fas agonist, Jo-2 mAb. At low Fas agonist doses, IL-6+/+ mice developed mild hepatic injury and survived, whereas IL-6-/- mice developed severe apoptotic hepatitis within 12 h and died. Pretreatment with IL-6 improved survival in IL-6-/- mice and reduced injury in both IL-6-/- and +/+ livers. The direct anti-apoptotic effects of IL-6 were demonstrated in vitro as IL-6 decreased Fas-mediated apoptosis in both IL-6-/- and +/+ primary hepatocyte cultures, and suggested that IL-6-/- hepatocytes have a pre-existing defect in anti-apoptotic pathways. After Fas activation, IL-6-/- livers demonstrated evidence of both proximal and distal alterations in the apoptotic pathways including elevated caspase 8 and 3 activation-associated fragments, and loss of cytochrome c staining. IL-6-/- livers had reduced pre-existing protein expression of the anti-apoptotic factors Bcl-2 and Bcl-xL as well as more rapid degradation of FLIP following Fas treatment that appeared to be post-transcriptionally regulated. FLIP is a crucial proximal inhibitor of caspase 8 activation in Fas, tumor necrosis factor, and DR3/DR4-mediated apoptosis, and Bcl-2 and Bcl-xL more downstream anti-apoptotic regulators. IL-6 may function as a critical anti-apoptotic factor in the liver by its ability to establish and maintain an adequate level of FLIP and downstream anti-apoptotic factors.
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PMID:Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. 1134 25

Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by hypergammaglobulinaemia, non-organ and liver-related autoantibodies, association with HLA-DR3 or DR4 and a favourable response to immunosuppression. The current classification of AIH and the several autoantibodies/target autoantigens found in this disease are reported. The importance of these markers in the differential diagnosis and the study of pathogenesis of AIH is also given. AIH is subdivided into two major types: AIH type 1 (AIH-1) and AIH type 2 (AIH-2). AIH-1 is characterised by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Antineutrophil cytoplasmic autoantibodies (ANCA), in most cases of perinuclear pattern (p-ANCA), by the indirect immunofluorescence assay, antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of individuals who are seronegative for ANA/SMA. AIH-2 is characterised by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). For these reasons, the distinction between AIH and chronic viral hepatitis is of particular importance. Cytochrome P450 2D6 (CYP2D6) is the major target autoantigen of anti-LKM-1 autoantibodies in both conditions (AIH-2 and HCV infection). Recent data have demonstrated the expression of CYP2D6 on the surface of hepatocytes, suggesting a pathogenetic role of anti-LKM-1 autoantibodies in liver injury. Family 1 of UDP-glycuronosyltransferases has been identified as the target autoantigen of anti-LKM-3. The molecular target of anti-SLA/LP autoantibodies has been identified recently as a 50 kDa protein with unknown structure and function. A liver-specific enzyme, the formiminotransferase cyclodeaminase, was identified as the target autoantigen of anti-LC1 autoantibodies. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate better with the severity of AIH and the response to treatment. The latter may suggest a pathogenic role of these autoantibodies in the hepatocellular damage in AIH. In general, however, autoantibodies should not be used to monitor treatment or to predict AIH activity or outcome. Finally, current knowledge concerning a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyglandular syndrome type-1 (APS-1), is also discussed. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies found in AIH as a disease component of APS-1. However, anti-LM autoantibodies have also been described in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target autoantigen of anti-LM autoantibodies in both disease entities.
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PMID:Autoantibodies and defined target autoantigens in autoimmune hepatitis: an overview. 1214 8

Autoimmune Hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent acute and chronic inflammatory liver diseases in which immune reactions against host antigens are found to be the major pathological mechanism. Only for AIH there is evidence of an autoimmune etiology and humoral and cellular immune reactions are found directed against various liver cell antigens. By diverse autoantibodies several subgroups of autoimmune hepatitis can be distinguished. A very important disease promoting factor seems to be the genetically determined background for autoimmunity characterized by the HLA haplotype A1, B8 and DR3, respectively DR4. Although the histopathology of AIH shows no pathognomonic features distinguishing this type of hepatitis from virus induced chronic hepatitis there are some distinct characteristic morphological lesions. If untreated the prognosis of AIH is unfavourable but the benefit from immunosuppressive therapy with prednisolone and azathioprin is well established. In the last years there was increasing evidence for an overlap syndrome between AIH and PBC and rarely AIH and PSC. These patients are characterized by PBC characteristic bileduct lesions and oftenly antimitochondrial antibodies (AMA). They also show AIH typical inflammatory hepatic lesions in the periportal areas and portal tracts and oftenly the typical genetical background, the HLA haplotype A1, B8, DR3 or DR4. Most of these patients respond probably to a combination therapy containing prednisolon, azathioprine and ursodesoxycholic acid that leads to the reduction of the inflammatory activity.
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PMID:[Autoimmune hepatitis and overlap syndrome: therapy]. 1223 65

Atorvastatin and other members of the statin family are widely used for the treatment of hypercholesterolaemia in order to reduce the risk of atherosclerosis and cardiovascular disease. Atorvastatin-induced adverse events are mostly mild and only a few cases of lupus-like syndrome or severe acute hepatitis have been documented. In this case report we describe a patient who developed an atorvastatin-induced severe autoimmune hepatitis. In addition, this patient presented with a concomitant systemic lupus-like syndrome which has been already described for statins but not in association with severe liver disease. Although the drug was immediately withdrawn the disease persisted and even deteriorated to a fulminant disease with evidence of acute hepatic failure. The patient failed to respond to conventional immunosuppression with corticosteroids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery of the patient. Interestingly, the patient was HLA DR3- and HLA DR4-positive, which are well-known genetic factors associated with autoimmune diseases. This case is the first report of a drug-induced lupus-likesyndrome concomitant with a severe autoimmune hepatitis in a genetically predisposed patient.
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PMID:Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis. 1276 6

Hepatic fibrosis and cirrhosis are possible consequences of corticosteroid-treated autoimmune hepatitis. Our aims were to determine the frequency of progressive fibrosis and the factors associated with this progression. Two hundred seventy-seven liver tissue specimens that had been obtained from 73 patients were interpreted in batch under code by a single pathologist. Fibrosis scores and histological activity indices were determined using the Ishak scoring system, and worsening fibrosis scores were correlated with clinical features, laboratory findings, and treatment responses. Fibrosis scores increased (2.3 +/- 0.4 points to 4.2 +/- 0.4 points; P <.0001) in 18 patients (25%) during 79 +/- 13 months. Only five patients (7%) developed cirrhosis, and 55 patients (75%) had stable (16 patients) or decreased (39 patients) fibrosis scores. Human leukocyte antigen (HLA) DR3/DR4 occurred more frequently in patients with progressive fibrosis than others (23% vs. 2%; P =.03). Patients with progressive fibrosis had higher histological activity indices at last follow-up than patients with stable or reduced fibrosis (3.2 +/- 0.7 vs. 1.7 +/- 0.2; P =.01), and these indices worsened more commonly during therapy (17% vs. 2%, P =.04). Relapse, treatment failure, and incomplete response did not affect progression of fibrosis. In conclusion, fibrosis progresses in only a minority of patients during corticosteroid therapy. Progression is associated with HLA DR3/DR4 and worsening histological activity. Exacerbations or persistence of disease activity does not increase disease progression after treatment has been instituted.
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PMID:Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. 1518 4

Autoimmune hepatitis (AIH) is a hepatocellular inflammation that is characterised by a wide range of histopathologic (periportal interface hepatitis with plasma cell infiltration and piecemeal necrosis), biochemical (hypertransaminasemia, hypergammaglobulinaemia) and autoimmune (several autoantibodies presence) features. This relatively rare disorder frequently affects middle-aged women. There is no pathognomonic marker for AIH diagnosis, therefore it requires a careful rule out of other causes of liver disease together with the detection of a suggestive pattern of clinical and laboratory abnormalities. Scoring system for AIH diagnosis proposed by International Autoimmune Hepatitis Group has been used as a tool in clinical practice but is not sufficiently exclusive in terms of defining prognosis or treatment. AIH has been classified in two subtypes according to autoantibodies detected: 1 and 2, but this classification results in poor clinical implications. Previously known as subtype 3 is at the present included in subtype 1 because no clinical significant differences has been found between them. Aetiology, and molecular mechanisms still remain to be elucitaded in this disease, although viruses, drugs and molecular mimicry act presumably as a trigger in genetically predisposed patients (associated with HLA-DR3 and DR4 haplotypes). On the other hand, immunosuppressive therapy (corticosteroid or azathioprine) generally offers favourable response. Our aim is to review this disease from different points of view, considering: clinical, histopathological, etiologic, genetic, biochemical, autoimmune, treatment and prognosis features.
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PMID:[Autoimmune hepatitis]. 1534 41

Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver characterized by hypergammaglobulinemia, characteristic autoantibodies, association with HLA DR3 or DR4 and a favorable response to immunosuppressive treatment. The etiology is unknown. The detection of non-organ and liver-related autoantibodies remains the hallmark for the diagnosis of the disease in the absence of viral, metabolic, genetic, and toxic etiology of chronic hepatitis or hepatic injury. The current classification of AIH and the several autoantibodies/target-autoantigens found in this disease are reported. Current aspects on the significance of these markers in the differential diagnosis and the study of pathogenesis of AIH are also stated. AIH is subdivided into two major types; AIH type 1 (AIH-1) and type 2 (AIH-2). AIH-1 is characterized by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Determination of antineutrophil cytoplasmic autoantibodies (ANCA), antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies against to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of patients who are seronegative for ANA/SMA. AIH-2 is characterized by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). Cytochrome P450 2D6 (CYP2D6) has been documented as the major target-autoantigen of anti-LKM-1 autoantibodies in both AIH-2 and HCV infection. Recent convincing data demonstrated the expression of CYP2D6 on the surface of hepatocytes suggesting a pathogenetic role of anti-LKM-1 autoantibodies for the liver damage. Family 1 of UDP-glycuronosyltransferases has been identified as the target-autoantigen of anti-LKM-3. For these reasons the distinction between AIH and chronic viral hepatitis (especially of HCV) is of particular importance. Recently, the molecular target of anti-SLA/LP and anti-LC1 autoantibodies were identified as a 50 kDa UGA-suppressor tRNA-associated protein and a liver specific enzyme, the formiminotransferase cyclodeaminase, respectively. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate closely with disease severity and response to treatment suggesting a pathogenetic role of these autoantibodies for the hepatocellular injury. In general however, autoantibodies should not be used to monitor treatment, predict AIH activity or outcome. Finally, the current aspects on a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) are also given. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies detected in AIH as a disease component of APECED but also in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target-autoantigen of anti-LM autoantibodies in both APECED-related AIH and dihydralazine-induced hepatitis. The latter may indicate that similar autoimmune pathogenetic mechanisms can lead to liver injury in susceptible individuals irrespective of the primary defect. Characterization of the autoantigen-autoantibody repertoire continues to be an attractive and important tool to get access to the correct diagnosis and to gain insight into the as yet unresolved mystery of how hepatic tolerance is given up and AIH ensues.
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PMID:Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. 1567 7

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 (AIH) is characterised histologically by interface hepatitis, and serologically by the presence of non-organ and liver specific autoantibodies and increased levels of immunoglobulin G. Its onset is often ill-defined, frequently mimicing acute hepatitis. AIH usually responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Two types of AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1 AIH) or liver kidney microsomal type 1 antibody (LKM1, type 2 AIH). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age and commonly have immunoglobulin A deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment and long-term prognosis are similar in the 2 groups. Susceptibility to AIH type 1 is conferred by possession of HLA DR3 and DR4, while to AIH type 2 by possession of HLA DR7. Liver damage is likely to derive from an immune reaction to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, where immune responses to external pathogens, e.g. viruses, become directed towards structurally similar self-components. In AIH this process would be perpetuated by impairment in immune regulation.
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PMID:Autoimmune hepatitis. 1572 81

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


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