In paediatrics, there are 2 liver disorders in which liver damage most likely stems from an autoimmune attack: ‘classical' autoimmune hepatitis (AIH) and the AIH/sclerosing cholangitis overlap syndrome (also known as autoimmune sclerosing cholangitis, ASC). The presentation of childhood autoimmune liver disease (AILD) is non-specific and can mimic most other liver disorders. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil; if this fails then calcineurin inhibitors can be tried. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure at diagnosis, will require liver transplantation. ASC responds to the same immunosuppressive treatment used for AIH when treatment is initiated early. Abnormal liver function tests often resolve within a few months of treatment, although medium- to long-term prognosis is worse than that of AIH because bile duct disease continues to progress despite treatment in approximately 50% of patients. Ursodeoxycholic acid is usually added to conventional treatment regimen in ASC, but whether this actually helps arrest the progression of bile duct disease remains to be established. The pathogenesis of paediatric-onset AILD is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4pos T-cells. While Th1 effector cells are associated with hepatocyte damage in both AIH and ASC, Th17 immune responses predominate in the latter where they correlate with biochemical indices of cholestasis, indicating that IL-17 is involved in the bile duct damage characteristic of this condition. Since a substantial difference between these 2 pathologies is the frequent association of ASC with inflammatory bowel disease, it can be speculated that lymphocytes of intestinal origin are present in patients with a diagnosis of ASC rather than in those with AIH. Animal models faithfully representing the human conditions are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AILD is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.

Mieli-Vergani G, Vergani D: Autoimmune hepatitis. Nat Rev Gastroenterol Hepatol 2011;8:320-329.
Mieli-Vergani G, Vergani D: Autoimmune liver diseases in children - what is different from adulthood? Best Pract Res Clin Gastroenterol 2011;25:783-795.
Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, Mowat AP, et al: Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 1997;25:541-547.
Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, Mieli-Vergani G: Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544-553.
Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, Nishioka M, et al: Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the international autoimmune hepatitis group. J Hepatol 2004;41:677-683.
Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H: Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33:99-103.
Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV: Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol 2002;97:2402-2407.
Ngu JH, Bechly K, Chapman BA, Burt MJ, Barclay ML, Gearry RB, Stedman CA: Population-based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroenterol Hepatol 2010;25:1681-1686.
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM, et al: Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193-2213.
Krawitt EL: Clinical features and management of autoimmune hepatitis. World J Gastroenterol 2008;14:3301-3305.
Krawitt EL: Autoimmune hepatitis. N Engl J Med 2006;354:54-66.
Lohse AW, Mieli-Vergani G: Autoimmune hepatitis. J Hepatol 2011;55:171-182.
Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J: Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829-1836.
Johnson PJ, McFarlane IG: Meeting report: international autoimmune hepatitis group. Hepatology 1993;18:998-1005.
Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, et al: International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929-938.
Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, et al: Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169-176.
Manns M, Gerken G, Kyriatsoulis A, Staritz M, Meyer zum Büschenfelde KH: Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1987;1:292-294.
Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, Underhill J, et al: Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002;35:658-664.
Gassert DJ, Garcia H, Tanaka K, Reinus JF: Corticosteroid-responsive cryptogenic chronic hepatitis: evidence for seronegative autoimmune hepatitis. Dig Dis Sci 2007;52:2433-2437.
el-Shabrawi M, Wilkinson ML, Portmann B, Mieli-Vergani G, Chong SK, Williams R, Mowat AP: Primary sclerosing cholangitis in childhood. Gastroenterology 1987;92:1226-1235.
Wurbs D, Klein R, Terracciano LM, Berg PA, Bianchi L: A 28-year-old woman with a combined hepatitic/cholestatic syndrome. Hepatology 1995;22:1598-1605.
Gohlke F, Lohse AW, Dienes HP, Löhr H, Märker-Hermann E, Gerken G, Meyer zum Büschenfelde KH: Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis. J Hepatol 1996;24:699-705.
McNair AN, Moloney M, Portmann BC, Williams R, McFarlane IG: Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases. Am J Gastroenterol 1998;93:777-784.
Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E; International Autoimmune Hepatitis G: Overlap syndromes: the international autoimmune hepatitis group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54:374-385.
Hirschfield GM, Karlsen TH, Lindor KD, Adams DH: Primary sclerosing cholangitis. Lancet 2013;382:1587-1599.
Hayee B, Samyn M, Shawcross D, Heneghan M, Bjarnason I: Autoimmune sclerosing cholangitis is associated with small bowel ulceration on capsule enteroscopy. J Crohns Colitis 2014;8:S46.
de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, et al: Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014;147:443-452.e5.
Djilali-Saiah I, Fakhfakh A, Louafi H, Caillat-Zucman S, Debray D, Alvarez F: HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis. J Hepatol 2006;45:844-850.
Ma Y, Bogdanos DP, Hussain MJ, Underhill J, Bansal S, Longhi MS, Cheeseman P, et al: Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology 2006;130:868-882.
Senaldi G, Portmann B, Mowat AP, Mieli-Vergani G, Vergani D: Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis. Arch Dis Child 1992;67:1447-1453.
Lobo-Yeo A, Senaldi G, Portmann B, Mowat AP, Mieli-Vergani G, Vergani D: Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease. Hepatology 1990;12:224-232.
Senaldi G, Lobo-Yeo A, Mowat AP, Mieli-Vergani G, Vergani D: Class I and class II major histocompatibility complex antigens on hepatocytes: importance of the method of detection and expression in histologically normal and diseased livers. J Clin Pathol 1991;44:107-114.
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, et al: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-238.
Miossec P, Korn T, Kuchroo VK: Interleukin-17 and type 17 helper T cells. N Engl J Med 2009;361:888-898.
Zhao L, Tang Y, You Z, Wang Q, Liang S, Han X, Qiu D, et al: Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One 2011;6:e18909.
Liberal R, Grant CR, Ma Y, Heneghan M, Mieli-Vergani G, Vergani D, Longhi MS: Th17 effector cells may be involved in the bile duct damage characteristic of autoimmune sclerosing cholangitis. J Hepatol 2014;60:S196-S197.
Longhi MS, Ma Y, Mieli-Vergani G, Vergani D: Aetiopathogenesis of autoimmune hepatitis. J Autoimmun 2010;34:7-14.
Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D: Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41:31-37.
Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M, Cheeseman P, Mieli-Vergani G, et al: Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun 2005;25:63-71.
Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, Hussain MJ, et al: A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 2010;52:999-1007.
Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, Ma Y: Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006;176:4484-4491.
Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, Baron U, et al: FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 2012;57:125-132.
Liberal R, Grant CR, Holder BS, Ma Y, Mieli-Vergani G, Vergani D, Longhi MS: The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology 2012;56:677-686.
Longhi MS, Mitry RR, Samyn M, Scalori A, Hussain MJ, Quaglia A, Mieli-Vergani G, et al: Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology 2009;50:130-142.
Grant CR, Liberal R, Holder BS, Cardone J, Ma Y, Robson SC, Mieli-Vergani G, et al: Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology 2014;59:1007-1015.
Vergani D, Mieli-Vergani G: Pharmacological management of autoimmune hepatitis. Expert Opin Pharmacother 2011;12:607-613.
Kerkar N, Annunziato RA, Foley L, Schmeidler J, Rumbo C, Emre S, Shneider B, et al: Prospective analysis of nonadherence in autoimmune hepatitis: a common problem. J Pediatr Gastroenterol Nutr 2006;43:629-634.
Alvarez F, Ciocca M, Canero-Velasco C, Ramonet M, de Davila MT, Cuarterolo M, Gonzalez T, et al: Short-term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol 1999;30:222-227.
Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, Bahr MJ, et al: Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010;139:1198-1206.
Woynarowski M, Nemeth A, Baruch Y, Koletzko S, Melter M, Rodeck B, Strassburg CP, et al: Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr 2013;163:1347-1353.e1.
Longhi MS, Hussain MJ, Kwok WW, Mieli-Vergani G, Ma Y, Vergani D: Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology 2011;53:536-547.
Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli-Vergani G: Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up. J Hepatol 2009;51:156-160.
Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW: A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001;121:900-907.
Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, Harnois D, et al: High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808-814.
Liberal R, Longhi MS, Grant CR, Mieli-Vergani G, Vergani D: Autoimmune hepatitis after liver transplantation. Clin Gastroenterol Hepatol 2012;10:346-353.
Scalori A Heneghan M, Hadzic N, Vergani D, Mieli-Vergani G: Outcome and survival in childhood onset autoimmune sclerosing cholangitis and autoimmune hepatitis: a 13-year follow up study. Hepatology 2007;46(suppl):555A.
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