Abstract
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.
Highlights
Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown etiology
Neither autoantibody titers at first diagnosis nor autoantibody behaviour in the time course of the disease are prognostic markers for AIH type 1 (AIH-1) [14,15,47]. These findings indicate that antinuclear antibodies (ANA) and smooth muscle autoantibodies (SMA) are not involved in the pathogenesis of AIH-1 and their determination is more of diagnostic than prognostic value [5,14,15,47]
In contrast to other patients with hepatitis C virus (HCV) infection, this patient further recognized a rarely detected epitope on the C-terminal third of the protein. These results suggest that determination and monitoring of Cytochrome P450 2D6 (CYP2D6) autoantibody titers by both indirect immunofluorescence (IIF) and the radioligand assay (RLA) in combination with epitope mapping of CYP2D6 in HCV/ anti-LKM positive patients before the initiation of interferon-alpha treatment, might be helpful in an attempt to identify those patients at risk of developing undesired autoimmune reactions [104]
Summary
Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown etiology. The estimated prevalence of AIH in Northern European countries is approximately 160–170 patients/106 inhabitants [1,2]. The presence of autoantibodies is one of the distinguishing features of AIH, there is no single autoantibody with the diagnostic significance and specificity that antimitochondrial autoantibodies (AMA) demonstrate for the diagnosis of primary biliary cirrhosis (PBC). Autoantibodies can not be employed as a single marker for the diagnosis of AIH It is rather a diagnosis reached by the exclusion of other factors leading to chronic hepatitis that include viral, toxic, genetic and metabolic causes [6]. Significant progress has been made in the characterization of liver-related targetautoantigens This has led to the notion that some of the major target-autoantigens in AIH are active enzymes of the human hepatic and non-hepatic microsomal xenobiotic metabolism [14,15,16]. This article will focus on the data that have evolved in the course of the characterization of autoantibody-autoantigen "system" in AIH by giving the current aspects on the role and significance of this "system" in the differential diagnosis and study of pathogenesis of AIH
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call