Autoimmune hepatitis (AIH) is a chronic immunologic disorder in which the immune system targets the liver. The disease has a genetic basis and this accounts for the epidemiologic variation observed in serologic testing and clinical presentation across different populations. The incidence of AIH increases with age into the 70s and seems to be increasing in prevalence. Most patients test positive for antinuclear antibody, ASMA, or anti-LKM but about 20% of patients do not have these serologic markers. At clinical presentation, patients may be asymptomatic, symptomatic, have acute liver failure, or decompensated cirrhosis.

Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.

Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression.

To review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH.

Published studies on AIH extracted mainly from PubMed during the last 15 years.

Autoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients - particularly children, elderly and acute cases - IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal.

Autoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.

Autoimmune hepatitis (AIH) is a unique form of immune-mediated disease that attacks the liver through a variety of immune mechanisms. The outcomes of AIH are either acute liver disease, which can be fatal, or, more commonly, chronic progressive liver disease, which can lead to decompensated liver cirrhosis if left untreated. AIH has characteristic immunological, and pathological, features that are important for the establishment of the diagnosis. More importantly, most patients with AIH have a favorable response to treatment with prednisolone and azathioprine, although some patients with refractory AIH or more aggressive disease require more potent immune-suppressant agents, such as cyclosporine or Mycophenolate Mofetil. In this paper, we discuss the immunological, pathological and clinical features of AIH, as well as the standard and alternative treatments for AIH.

The spectrum of autoimmune liver diseases (AILD) includes primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. The immunological mechanisms triggering the initiation and perpetuation of AILD remains unknown, while autoantigens are now recognized in most cases, and are generally nontraditional in their widespread distribution. Sensitive and specific methods for the detection of serum autoantibodies in patients affected by AILD represent a challenge for researchers and clinicians who desire to obtain an early and certain diagnosis as well as markers of disease control. To this regard, the use and interpretation of serum autoantibodies in AILD may be seen as paradigmatic for the large gaps in our knowledge based on the lack of true population-based studies. The present review article will critically discuss the available evidence on the use of autoantibody findings in the diagnosis or management of autoimmune liver disease.

Certain autoantibodies in autoimmune liver disease have prognostic implications that are under-utilized and under-developed. The goals of this review are to indicate progress in characterizing the autoantibodies with prognostic connotations and to indicate the feasibility and importance of discovering other markers. Prime source and review articles in English were selected by a Medline search through 2010. Antibodies to soluble liver antigen, actin, liver cytosol type 1, asialoglycoprotein receptor, chromatin, cyclic citrullinated peptide, and uridine glucuronosyltransferases have been associated with the occurrence, severity, and progression of autoimmune hepatitis, and antibodies to Sp100, gp210, and centromere have had similar implications in primary biliary cirrhosis. Antibodies to soluble liver antigen have shown the most promise in autoimmune hepatitis as they have been associated with severe histological changes, long durations of treatment, relapse after drug withdrawal, and high frequency of liver failure. Antibodies to the nuclear rim pore protein, gp210, have shown the most promise in primary biliary cirrhosis as they have been associated with severe interface hepatitis, lobular inflammation, and progression to liver failure. The major limitations of the autoantibodies have been their lack of standardized assays, low negative predictabilities, and fluctuating levels. Performance parameters will improve as critical pathogenic pathways, comprehensive testing batteries, and standardized assays through international exchange workshops are developed. Progress has been made in identifying the serological markers of prognosis in autoimmune liver disease, and they promise to reflect critical disease mechanisms and enhance patient management.

The widespread use of serum autoantibodies in the practice of clinical hepatology has led to novel challenges in the interpretation of results obtained with routine techniques, such as indirect immunofluorescence (IIF) or with recombinant antigens. In fact, the laboratory methods are often overlooked factors in the interpretation of data by the bedside clinician despite being critical in the interpretation of data. Importantly, the sensitivity and specificity of these serum hallmarks are not defined in all cases. Taken altogether, these observations point towards the need for a systematic discussion of autoimmune serology in the clinical setting of everyday practice. The target of this review article is therefore, to illustrate the current knowledge and available experimental evidence to guide the diagnostic and prognostic decision making in autoimmune and viral chronic liver diseases.

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.