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This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the Association. 1. Preamble Clinical practice guidelines are defined as ''systematically developed statements to assist practitioner and patient decisions about appropriate heath care for specific clinical circumstances.'' 1 (All references are available in the Supporting Information.) These guidelines on autoimmune hepatitis provide a data-supported approach to the diagnosis and management of this disease. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic [Medline search]; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines; 2 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines; 3 and (4) the experience of the authors in the specified topic. These recommendations, intended for use by physicians, suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting the recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation. 4 The grading system applied to the recommendations has been adapted from the American College of Cardiology and the American Heart Association Practice Guidelines, and it is given below (Table 1).

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8+ cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation.These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

between the ages of 10 and 20 and 45 and 70 years and has To determine the clinical, biochemical, and histologia relatively benign course at least in adults, 3 whereas LKMcal features, and outcome of childhood autoimmune 1 positive patients have a more severe disease with progreshepatitis (AIH), we reviewed the medical records of 52 sion to cirrhosis despite immunosuppressive treatment. gest that ANA/SMA positive AIH has two peaks of incidence median age: 10.5, range 2.3-14.9 years). At presentation, four children were positive for ANA alone (titer range: 1:80-1:320), 10 for SMA alone (titer range: 1:40-1:2560) and 14 for both ANA (titer range: 1:20-1:5120) and SMA (titer range: 1:40-1:1280). In two paAbbreviations: AIH, autoimmune hepatitis; ANA/SMA, nuclear and/or smooth muscle

To investigate whether sclerosing cholangitis with an autoimmune serology characteristic of autoimmune hepatitis (AIH) and AIH are distinct entities, we studied 55 consecutive children with clinical and/or biochemical evidence of liver disease and circulating antinuclear (ANA), anti-smooth muscle (SMA), and/or liver-kidney-microsomal type 1 (LKM1) autoantibodies. They underwent liver biopsy, direct cholangiography, sigmoidoscopy, and rectal biopsy at presentation. Twenty-eight were diagnosed as AIH in the absence and 27 autoimmune sclerosing cholangitis (ASC) in the presence of radiological features of cholangiopathy. Twenty-six ASC and 20 AIH had ANA and/or SMA; 1 ASC and 8 AIH LKM1 autoantibody. Similarities between the 2 conditions included most clinical and biochemical parameters and a lower frequency of HLA DR4. Inflammatory bowel disease and histological biliary changes were more common in ASC; coagulopathy, hypoalbuminemia, lymphocytic periportal hepatitis, and HLA DR3 were more common in AIH. Histological biliary changes were observed in 65% of ASC and 31% of AIH patients. Eighty-nine percent responded to immunosuppression. Follow-up liver biopsies from 17 ASC and 18 AIH patients had similarly reduced inflammatory activity and no progression to cirrhosis. Sixteen follow-up cholangiograms from AIH patients and 9 from ASC patients were unchanged, while 8 ASC patients showed a progressive cholangiopathy. One child with AIH and ulcerative colitis developed sclerosing cholangitis 8 years after presentation. At 2 to 16 years (median, 7 years) from presentation, all patients are alive, including 4 ASC patients who underwent liver transplantation. In conclusion, ASC and AIH are similarly prevalent in childhood; cholangiography is often needed to distinguish between these 2 entities, which are likely to lie within the same disease process. (HEPATOLOGY 2001;33:544-553.)

Paediatric autoimmune liver disease is characterised by inflammatory liver histology, circulating autoantibodies and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. Two types of paediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (anti-LKM-1/anti-LC-1; AIH-2).Pertinent issues addressing the diagnosis, treatment and long term follow up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate and Mendeley databases over the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.

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Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.