Primer

Autoimmune hepatitis

  • Nature Reviews Disease Primers volume 4, Article number: 18017 (2018)
  • doi:10.1038/nrdp.2018.17
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Abstract

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.

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References

  1. 1.

    , , , & Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19, 1513–1520 (1994).

  2. 2.

    , & Autoimmune hepatitis — update 2015. J. Hepatol. 62, S100–S111 (2015).

  3. 3.

    , & Diego and Giorgina Vergani: the two hearts of translational autoimmunity. J. Autoimmun. 66, 1–6 (2016).

  4. 4.

    Liver, blood proteins and food proteins [German]. Dtsch. Z. Verdau. Stoffwechselkr. 12, 113–121 (1952).

  5. 5.

    , & Lupoid hepatitis. Lancet 268, 1323–1326 (1956).

  6. 6.

    et al. Diagnosis and management of autoimmune hepatitis. Hepatology 51, 2193–2213 (2010). These evidence-based guidelines for the diagnosis and management of AIH were issued by the American Association for the Study of Liver Diseases.

  7. 7.

    , & Antibody to smooth muscle in patients with liver disease. Lancet 2, 878–879 (1965).

  8. 8.

    et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis. Hepatology 7, 1333–1339 (1987).

  9. 9.

    et al. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology 8, 1662–1666 (1988).

  10. 10.

    et al. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology 111, 1576–1586 (1996).

  11. 11.

    , , , & Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1, 292–294 (1987).

  12. 12.

    , & Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis. Hepatology 18, 1–9 (1993).

  13. 13.

    et al. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 355, 1510–1515 (2000).

  14. 14.

    et al. Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype. Aliment. Pharmacol. Ther. 41, 1281–1287 (2015).

  15. 15.

    , , , & Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 21, 78–83 (1980).

  16. 16.

    European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J. Hepatol. 63, 971–1004 (2015). These 2015 guidelines for the diagnosis and management of AIH were issued by the European Association for the Study of the Liver.

  17. 17.

    et al. Autoimmune hepatitis in Italy: the Bologna experience. J. Hepatol. 50, 1210–1218 (2009).

  18. 18.

    , , , & Application of the 2010 American Association for the study of liver diseases criteria of remission to a cohort of Italian patients with autoimmune hepatitis. Hepatology 52, 1857 (2010).

  19. 19.

    Wilderness at Dawn: The Settling of the North American Continent. (Simon & Schuster, 1993).

  20. 20.

    , & The Autoimmune Diseases (Elsevier Academic Press, 2014).

  21. 21.

    et al. in Autoimmune Liver Diseases 2nd edn (eds Krawitt, E., Wiesner, R. & Nishioka, M.) 413–424 (Elsevier BV, 1998).

  22. 22.

    et al. Incidence and prevalence of autoimmune hepatitis in the area of the Hospital de Sagunto (Spain) [Spanish]. Gastroenterol. Hepatol. 27, 239–243 (2004).

  23. 23.

    et al. Cutting edge issues in autoimmune hepatitis. J. Autoimmun. 75, 6–19 (2016).

  24. 24.

    et al. Autoimmune liver diseases in the Asia-Pacific region: proceedings of APASL symposium on AIH and PBC 2016. Hepatol. Int. 10, 909–915 (2016).

  25. 25.

    et al. Clinical features of autoimmune hepatitis and comparison of two diagnostic criteria in Korea: a nationwide, multicenter study. J. Gastroenterol. Hepatol. 28, 128–134 (2013).

  26. 26.

    et al. Present status of autoimmune hepatitis in Japan: a nationwide survey. J. Gastroenterol. 46, 1136–1141 (2011).

  27. 27.

    et al. Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients. J. Hepatol. 54, 340–347 (2011).

  28. 28.

    , & Autoimmune hepatitis in India: single tertiary referral centre experience. Trop. Gastroenterol. 36, 36–45.

  29. 29.

    et al. Clinical profile and HLA typing of autoimmune hepatitis from Pakistan. Hepat. Mon. 13, e13598 (2013).

  30. 30.

    et al. Type 1 autoimmune hepatitis in Taiwan: diagnosis using the revised criteria of the International Autoimmune Hepatitis Group. Dig. Dis. Sci. 51, 1978–1984 (2006).

  31. 31.

    et al. Incidence and prevalence of autoimmune hepatitis in the Ueda area. Japan. Hepatol. Res. 46, 878–883 (2016).

  32. 32.

    et al. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand. J. Gastroenterol. 33, 99–103 (1998).

  33. 33.

    et al. Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis. Scand. J. Gastroenterol. 52, 1022–1028 (2017).

  34. 34.

    et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand. J. Gastroenterol. 49, 1245–1254 (2014).

  35. 35.

    , & Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J. Hepatol. 60, 612–617 (2014). This nationwide population-based epidemiological study in Denmark exemplifies the studies that are necessary to understand the changing incidence, clinical phenotype and outcome of AIH in different countries and ethnicities, as it describes a rising incidence and high mortality, especially in the first year after diagnosis.

  36. 36.

    et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics 136, e1237–e1248 (2015).

  37. 37.

    et al. Hepatic and extrahepatic malignancies in autoimmune hepatitis. A long-term follow-up in 473 Swedish patients. J. Hepatol. 50, 388–393 (2009).

  38. 38.

    et al. Hepatocellular and extrahepatic cancer in patients with autoimmune hepatitis — a long-term follow-up study in 634 Swedish patients. Scand. J. Gastroenterol. 50, 217–223 (2015).

  39. 39.

    et al. Risk of malignancies in autoimmune hepatitis type 1 patients with a long-term follow-up in Japan. Hepatol. Res. 48, E222–E231 (2018).

  40. 40.

    et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. Hepatology 48, 863–870 (2008).

  41. 41.

    , , , & Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series. Dig. Dis. Sci. 56, 578–585 (2011).

  42. 42.

    et al. Incidence and determinants of hepatocellular carcinoma in autoimmune hepatitis: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 15, 1207–1217.e4 (2017).

  43. 43.

    et al. Hepatocellular carcinoma associated with noncirrhotic autoimmune hepatitis. Clin. J. Gastroenterol. 3, 111–115 (2010).

  44. 44.

    et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 147, 443–452.e5 (2014). This study confirms the key role of the HLA genes in predisposing to AIH and identifies a variant of SH2B3 that may enhance disease severity; the study demonstrates the potential of genome-wide association studies to implicate gene products that may in turn become targets of molecular interventions.

  45. 45.

    et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J. Hepatol. 31, 929–938 (1999). This paper describes the comprehensive diagnostic criteria (established by an expert panel) of the International Autoimmune Hepatitis Group that enable the diagnosis of AIH with high sensitivity and specificity in comparative studies and for all types of presentation.

  46. 46.

    Genetics in autoimmune hepatitis. Semin. Liver Dis. 22, 353–364 (2002).

  47. 47.

    Genetics of liver disease: immunogenetics and disease pathogenesis. Gut 53, 599–608 (2004).

  48. 48.

    & Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol. Rev. 174, 250–259 (2000).

  49. 49.

    et al. Autoimmune hepatitis in childhood: A 20-year experience. Hepatology 25, 541–547 (1997).

  50. 50.

    , , & HLA-DRB1 as a risk factor in children with autoimmune hepatitis and its relation to hepatitis A infection. Ital. J. Pediatr. 36, 73 (2010).

  51. 51.

    et al. Autoimmune hepatitis, HLA and extended haplotypes. Autoimmun. Rev. 10, 189–193 (2011).

  52. 52.

    et al. Pediatric and adult forms of type I autoimmune hepatitis in argentina: Evidence for differential genetic predisposition. Hepatology 30, 1374–1380 (1999).

  53. 53.

    et al. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis. Hepatology 33, 1512–1517 (2001).

  54. 54.

    Epigenetics in liver disease. Hepatology 60, 1418–1425 (2014). This is a comprehensive review that indicates the mechanisms that alter gene performance without altering DNA sequence, providing the background necessary to encourage future investigations in AIH.

  55. 55.

    et al. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology 130, 868–882 (2006).

  56. 56.

    et al. Different immunogenetic background in autoimmune hepatitis type 1, type 2 and autoimmune sclerosing cholangitis. J. Hepatol. 36, 156 (2002).

  57. 57.

    & Genetic insights into disease mechanisms of autoimmunity. Br. Med. Bull. 71, 93–113 (2004).

  58. 58.

    , , , & Genetic lesions in T-cell tolerance and thresholds for autoimmunity. Immunol. Rev. 204, 87–101 (2005).

  59. 59.

    , , & Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N. Engl. J. Med. 322, 1829–1836 (1990).

  60. 60.

    et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J. Clin. Endocrinol. Metab. 97, 1114–1124 (2012).

  61. 61.

    Autoimmune hepatitis. N. Engl. J. Med. 354, 54–66 (2006).

  62. 62.

    , , , & Autoimmune liver disease and concomitant extrahepatic autoimmune disease. Eur. J. Gastroenterol. Hepatol. 27, 1175–1179 (2015).

  63. 63.

    et al. A novel ‘humanized mouse’ model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 62, 1536–1550 (2015).

  64. 64.

    , , & Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis. Int. J. Clin. Exp. Pathol. 8, 5153–5160 (2015). This report describes how dysbiosis, circulating lipopolysaccharide and reduced expression of proteins that maintain tight junctions in the intestinal mucosa implicate involvement of the intestinal microbiota in patients with AIH.

  65. 65.

    , & The incidence of inflammatory bowel disease in Denmark 1980-2013: a nationwide cohort study. Aliment. Pharmacol. Ther. 45, 961–972 (2017).

  66. 66.

    , , & Pathogenesis of autoimmune hepatitis. Clin. Liver Dis. 6, 727–737 (2002).

  67. 67.

    et al. Primary and secondary liver/kidney microsomal autoantibody response following infection with hepatitis C virus. Gastroenterology 106, 1672–1675 (1994).

  68. 68.

    et al. P0295 virus-self crossreactivity inducing de novo autoimmune hepatitis eight-years after liver transplantation. J. Pediatr. Gastroenterol. Nutr. 39, S169 (2004).

  69. 69.

    et al. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet 335, 258–259 (1990).

  70. 70.

    et al. Immunoreactivity to various human cytochrome P450 proteins of sera from patients with autoimmune hepatitis, chronic hepatitis B, and chronic hepatitis C. Autoimmunity 33, 23–32 (2000).

  71. 71.

    et al. Anti-GOR and hepatitis C virus in autoimmune liver diseases. Lancet 339, 267–269 (1992).

  72. 72.

    et al. Liver/kidney microsome antibody type 1 and hepatitis C virus infection. Hepatology 16, 630–636 (1992).

  73. 73.

    et al. Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection. J. Exp. Med. 205, 1409–1422 (2008).

  74. 74.

    et al. Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J. Autoimmun. 37, 242–253 (2011).

  75. 75.

    , , & Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis. Hepatology 28, 1177–1181 (1998).

  76. 76.

    Liver antigen-presenting cells. J. Hepatol. 54, 357–365 (2011).

  77. 77.

    , & Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 54, 1379–1387 (2011).

  78. 78.

    et al. T cell immunity in autoimmune hepatitis. Autoimmun. Rev. 4, 315–321 (2005).

  79. 79.

    et al. Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease. Hepatology 12, 224–232 (1990).

  80. 80.

    , , , & 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. 44, 107–114 (1991).

  81. 81.

    Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood 101, 143–150 (2002).

  82. 82.

    Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2003).

  83. 83.

    , , , & Detection of antibodies directed against a liver-specific membrane lipoprotein in patients with acute and chronic active hepatitis. N. Engl. J. Med. 299, 1–7 (1978).

  84. 84.

    , , , & Serum autoantibodies reacting with the hepatic asialoglycoprotein receptor protein (hepatic lectin) in acute and chronic liver disorders. J. Hepatol. 3, 196–205 (1986).

  85. 85.

    Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane. Gut 46, 553–561 (2000).

  86. 86.

    et al. Interleukin-17 Contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS ONE 6, e18909 (2011).

  87. 87.

    et al. Elevated circulating levels of IL-21 and IL-22 define a cytokine signature profile in type 2 autoimmune hepatitis patients. Ann. Hepatol. 15, 550–558.

  88. 88.

    & Human T follicular helper (Tfh) cells and disease. Immunol. Cell Biol. 92, 64–71 (2013).

  89. 89.

    et al. Interleukin-21 plays a critical role in the pathogenesis and severity of type I autoimmune hepatitis. Springerplus 5, 777 (2016).

  90. 90.

    et al. Possible involvement of CCR7-PD-1+ follicular helper T cell subset in the pathogenesis of autoimmune hepatitis. J. Gastroenterol. Hepatol. 33, 298–306 (2018).

  91. 91.

    , , & Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease. Clin. Exp. Immunol. 89, 78–82 (1992).

  92. 92.

    et al. A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 52, 999–1007 (2010).

  93. 93.

    et al. Single-centre experience of the macrophage activation marker soluble (s)CD163 - associations with disease activity and treatment response in patients with autoimmune hepatitis. Aliment. Pharmacol. Ther. 44, 1062–1070 (2016).

  94. 94.

    Regulatory T cells. Cell 101, 455–458 (2000).

  95. 95.

    et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J. Hepatol. 57, 125–132 (2012).

  96. 96.

    , , & Regulatory T cells in autoimmune hepatitis. J. Hepatol. 57, 932–933 (2012).

  97. 97.

    et al. Effect of CD4+CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J. Autoimmun. 25, 63–71 (2005).

  98. 98.

    et al. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression. Hepatology 62, 863–875 (2015).

  99. 99.

    et al. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J. Hepatol. 41, 31–37 (2004).

  100. 100.

    et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology 56, 677–686 (2012).

  101. 101.

    et al. Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology 59, 1007–1015 (2014).

  102. 102.

    et al. Assessment of intrahepatic regulatory T cells in children with autoimmune hepatitis. Ann. Hepatol. 15, 682–690 (2016).

  103. 103.

    et al. Pediatric autoimmune hepatitis shows a disproportionate decline of regulatory T cells in the liver and of IL-2 in the blood of patients undergoing therapy. PLoS ONE 12, e0181107 (2017).

  104. 104.

    et al. Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J. Hepatol. 61, 1106–1114 (2014).

  105. 105.

    et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Hepatology 44, 357–365 (2014).

  106. 106.

    et al. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J. Clin. Invest. 123, 3510–3524 (2013).

  107. 107.

    et al. Treg conditioning endows activated Teff with suppressor function in juvenile autoimmune liver disease. J. Hepatol. 66, S554 (2017).

  108. 108.

    et al. Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2. J. Autoimmun. 53, 26–32 (2014).

  109. 109.

    Autoimmune hepatitis and overlap syndromes: diagnosis and management. Clin. Gastroenterol. Hepatol. 13, 2088–2108 (2015).

  110. 110.

    et al. Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis. Hepatology 59, 592–600 (2013).

  111. 111.

    , , , & Diagnostic criteria of autoimmune hepatitis. Autoimmun. Rev. 13, 435–440 (2014).

  112. 112.

    Autoantibody-Negative Autoimmune Hepatitis. Dig. Dis. Sci. 57, 610–624 (2011).

  113. 113.

    Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig. Dis. Sci. 56, 545–554 (2010).

  114. 114.

    et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J. Hepatol. 41, 677–683 (2004). This report describes the directions issued by the International Autoimmune Hepatitis Group on how to test for and interpret liver autoimmune serology.

  115. 115.

    , , & Meta-analysis: diagnostic accuracy of antinuclear antibodies, smooth muscle antibodies and antibodies to a soluble liver antigen/liver pancreas in autoimmune hepatitis. PLoS ONE 9, e92267 (2014).

  116. 116.

    et al. Autoimmune acute liver failure: Proposed clinical and histological criteria. Hepatology 53, 517–526 (2011).

  117. 117.

    Histology of autoimmune hepatitis and its variants. Clin. Liver Dis. 14, 577–590 (2010).

  118. 118.

    , & Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis. Gut 41, 269–271 (1997).

  119. 119.

    Centrilobular necrosis in autoimmune hepatitis: a histological feature associated with acute clinical presentation. J. Clin. Pathol. 59, 246–249 (2006).

  120. 120.

    , , & Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis. Liver Int. 36, 1362–1369 (2016).

  121. 121.

    Diagnosis and management of the overlap syndromes of autoimmune hepatitis. Can. J. Gastroenterol. 27, 417–423 (2013).

  122. 122.

    et al. Overlap syndromes: The International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J. Hepatol. 54, 374–385 (2011).

  123. 123.

    Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: A 16-year prospective study. Hepatology 33, 544–553 (2001).

  124. 124.

    et al. Diagnosis and management of paediatric autoimmune liver disease: ESPGHAN Hepatology Committee position statement. J. Pediatr. Gastroenterol. Nutr. 66, 345–360 (2018). This is a position statement for the diagnosis and management of AIH in children.

  125. 125.

    et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48, 169–176 (2008). The simplified International Autoimmune Hepatitis Group diagnostic criteria described in this paper are suitable for a rapid diagnosis in the clinical setting but are less useful than the revised criteria of the same group in the setting of acute presentation.

  126. 126.

    et al. Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: A new or a complementary diagnostic score? Dig. Liver Dis. 42, 807–812 (2010).

  127. 127.

    Comparability of probable and definite autoimmune hepatitis by international diagnostic scoring criteria. Gastroenterology 140, 1472–1480 (2011).

  128. 128.

    , & Evaluation of the revised versus the simplified scoring system in patients with autoimmune hepatitis. Exp. Ther. Med. 7, 131–136 (2013).

  129. 129.

    , , & Wilson's disease, presenting as chronic active hepatitis. Gastroenterology 74, 645–651 (1978).

  130. 130.

    , , , & Fulminant hepatic failure: Wilson's disease or autoimmune hepatitis? Implications for transplantation. Pediatr. Transplant. 9, 112–116 (2005).

  131. 131.

    , , & Wilson's disease with superimposed autoimmune features: report of two cases and review. J. Gastroenterol. Hepatol. 15, 570–574 (2000).

  132. 132.

    et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 25, 541–547 (1997).

  133. 133.

    et al. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight 1, e88782 (2016).

  134. 134.

    Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 35, 658–664 (2002).

  135. 135.

    , , , & Natural history of patients presenting with autoimmune hepatitis and coincident nonalcoholic fatty liver disease. Dig. Dis. Sci. 61, 2710–2720 (2016).

  136. 136.

    & Autoimmune hepatitis. J. Hepatol. 55, 171–182 (2011).

  137. 137.

    et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 139, 1198–1206 (2010).

  138. 138.

    et al. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J. Pediatr. 163, 1347–1353.e1 (2013).

  139. 139.

    et al. Efficacy and limitations of budesonide as a second-line treatment for patients with autoimmune hepatitis. Clin. Gastroenterol. Hepatol. 16, 260–267.e1 (2018).

  140. 140.

    , , , & Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience. Z. Gastroenterol. 39, 339–348 (2001).

  141. 141.

    et al. Efficacy of 6-mercaptopurine as second-line treatment for patients with autoimmune hepatitis and azathioprine intolerance. Clin. Gastroenterol. Hepatol. 14, 445–453 (2016).

  142. 142.

    , , , & Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. J. Hepatol. 45, 584–591 (2006).

  143. 143.

    et al. Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis. Hepatology 56, 1401–1408 (2012).

  144. 144.

    et al. Duration of immunosuppressive therapy in autoimmune hepatitis. J. Hepatol. 34, 354–355 (2001).

  145. 145.

    et al. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J. Hepatol. 58, 141–147 (2013).

  146. 146.

    et al. Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis. J. Hepatol. 62, 642–646 (2015).

  147. 147.

    et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am. J. Gastroenterol. 103, 3063–3070 (2008).

  148. 148.

    et al. Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on Tacrolimus therapy. Scand. J. Gastroenterol. 51, 329–336 (2015).

  149. 149.

    et al. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J. Hepatol. 58, 529–534 (2013).

  150. 150.

    et al. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. Can. J. Gastroenterol. 27, 273–280 (2013).

  151. 151.

    et al. Prospective analysis of nonadherence in autoimmune hepatitis: a common problem. J. Pediatr. Gastroenterol. Nutr. 43, 629–634 (2006).

  152. 152.

    , , & in Autoimmune Liver Diseases-Falk Symposium Dordrecht (eds et al.) 278–282 (Springer, 2005).

  153. 153.

    , , , & Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. Autoimmunity 35, 515–519 (2002).

  154. 154.

    et al. Follow-up of children with autoimmune hepatitis treated with cyclosporine. J. Pediatr. Gastroenterol. Nutr. 43, 635–639 (2006).

  155. 155.

    & Budesonide for juvenile autoimmune hepatitis? Not yet. J. Pediatr. 163, 1246–1248 (2013).

  156. 156.

    , , & Autoimmune hepatitis: a comprehensive review. J. Autoimmun. 41, 126–139 (2013).

  157. 157.

    & Treatment of autoimmune hepatitis. Semin. Liver Dis. 29, 273–285 (2009).

  158. 158.

    & Transplantation in autoimmune liver diseases. World J. Gastroenterol. 14, 3388–3395 (2008).

  159. 159.

    et al. Liver transplantation for autoimmune hepatitis. Hepatology 32, 693–700 (2000).

  160. 160.

    , , & Liver transplantation and autoimmune liver diseases. Liver Transplant. 19, 1065–1077 (2013).

  161. 161.

    et al. Recurrence of primary sclerosing cholangitis following liver transplantation. Hepatology 29, 1050–1056 (1999).

  162. 162.

    , & Recurrence of autoimmune liver disease and inflammatory bowel disease after pediatric liver transplantation. Liver Transplant. 22, 1275–1283 (2016).

  163. 163.

    & ‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: a comprehensive review. J. Autoimmun. 66, 17–24 (2016).

  164. 164.

    et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 351, 409–413 (1998).

  165. 165.

    et al. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am. J. Transplant. 5, 1085–1089 (2005).

  166. 166.

    et al. The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis. Aliment. Pharmacol. Ther. 44, 1039–1050 (2016).

  167. 167.

    et al. Factors that reduce health-related quality of life in patients with primary sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 10, 769–775.e2 (2012).

  168. 168.

    et al. The impact of primary biliary cirrhosis (PBC) on perceived quality of lIFE (QoL): the UK-PBC National study [abstract]. J. Hepatol. 58 (Suppl. 1), 952 (2013).

  169. 169.

    et al. Superiority of interferon-free regimens for chronic hepatitis C. Medicine 96, e5914 (2017).

  170. 170.

    et al. Minimal impact of sofosbuvir and ribavirin on health related quality of life in Chronic Hepatitis C (CH-C). J. Hepatol. 60, 741–747 (2014).

  171. 171.

    et al. A disease-specific quality of life instrument for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: CLDQ-NAFLD. Liver Int. 37, 1209–1218 (2017).

  172. 172.

    et al. Non-alcoholic Fatty Liver Disease (NAFLD) is associated with impairment of Health Related Quality of Life (HRQOL). Health Qual. Life Outcomes 14, 18 (2016).

  173. 173.

    et al. Health-related quality of life, depression, and anxiety in patients with autoimmune hepatitis. J. Hepatol. 60, 618–624 (2014).

  174. 174.

    , & Autoimmune hepatitis type 1: safety and efficacy of prolonged medical therapy. Liver Int. 25, 734–739 (2005).

  175. 175.

    & Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer. J. Neuroimmune Pharmacol. 1, 421–427 (2006).

  176. 176.

    et al. Hostile marital interactions, proinflammatory cytokine production, and wound healing. Arch. Gen. Psychiatry 62, 1377–1384 (2005).

  177. 177.

    , , , & Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 45, 295–300 (1999).

  178. 178.

    et al. The impact of liver cell injury on health-related quality of life in patients with chronic liver disease. PLoS ONE 11, e0151200 (2016).

  179. 179.

    & Psychological stress is associated with relapse in type 1 autoimmune hepatitis. Liver Int. 30, 1439–1447 (2010).

  180. 180.

    , , , & Identifying opportunities to improve management of autoimmune hepatitis: evaluation of drug adherence and psychosocial factors. J. Hepatol. 57, 1299–1304 (2012).

  181. 181.

    et al. Health-related quality of life in children with autoimmune liver disease. J. Pediatr. Gastroenterol. Nutr. 57, 444–450 (2013).

  182. 182.

    & Psychological problems in the acne patient. Dermatol. Ther. 19, 237–240 (2006).

  183. 183.

    Exogenous corticosteroids and major depression in the general population. J. Psychosom. Res. 49, 447–449 (2000).

  184. 184.

    Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis. Aliment. Pharmacol. Ther. 46, 920–937 (2017).

  185. 185.

    & Using GWAS to identify genetic predisposition in hepatic autoimmunity. J. Autoimmun. 66, 25–39 (2016).

  186. 186.

    Epigenetic changes and their implications in autoimmune hepatitis. Eur. J. Clin. Invest. (2018).

  187. 187.

    et al. Circulating microRNA profiles in patients with type-1 autoimmune hepatitis. PLoS ONE 10, e0136908 (2015). This paper shows that circulating levels of miR-21 and miR-122 are increased in AIH, correlate with serum alanine transaminase levels and histological grades of inflammation and are reduced in cirrhosis, thereby implicating epigenetic changes as biomarkers of inflammatory activity and possible pathogenetic factors in AIH.

  188. 188.

    , , & TIM family of genes in immunity and tolerance. Adv. Immunol. 91, 227–249 (2006).

  189. 189.

    & Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology 66, 271–279 (2017).

  190. 190.

    , , , & PD-1/PD-L and autoimmunity: a growing relationship. Cell. Immunol. 310, 27–41 (2016).

  191. 191.

    , , , & T-Cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).

  192. 192.

    Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J. Gastroenterol. 22, 9257–9278 (2016).

  193. 193.

    et al. Intestinal flora imbalance results in altered bacterial translocation and liver function in rats with experimental cirrhosis. Eur. J. Gastroenterol. Hepatol. 22, 1481–1486 (2010).

  194. 194.

    , , , & Microbiome manipulation modifies sex-specific risk for autoimmunity. Gut Microbes 5, 485–493 (2014).

  195. 195.

    et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013). This study demonstrates that the transfer of intestinal microbiota from adult male non-obese diabetic mice to immature female mice alters the microflora, raises serum testosterone levels, reduces antibody production and protects the recipients from developing type 1 diabetes mellitus, indicating that susceptibility to immune-mediated disease is influenced by sex-specific intestinal microbiota.

  196. 196.

    et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013).

  197. 197.

    et al. Low serum vitamin D levels are associated with severe histological features and poor response to therapy in patients with autoimmune hepatitis. Dig. Dis. Sci. 59, 3035–3042 (2014).

  198. 198.

    et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 20, 1352–1360 (2010).

  199. 199.

    et al. Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis. Scand. J. Gastroenterol. 52, 93–99 (2016).

  200. 200.

    et al. Anti-programmed cell death-1 antibody as a new serological marker for type 1 autoimmune hepatitis. J. Gastroenterol. Hepatol. 29, 110–115 (2013).

  201. 201.

    et al. Multicenter validation study of anti-programmed cell death-1 antibody as a serological marker for type 1 autoimmune hepatitis. Hepatol. Res. 44, 1299–1307 (2014).

  202. 202.

    et al. The role of macrophage migration inhibitory factor in autoimmune liver disease. Hepatology 59, 580–591 (2013).

  203. 203.

    et al. A macrophage migration inhibitory factor polymorphism is associated with autoimmune hepatitis severity in US and Japanese patients. Dig. Dis. Sci. 61, 3506–3512 (2016).

  204. 204.

    et al. Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis. PLoS ONE 12, e0179074 (2017).

  205. 205.

    , , , & Predictive factors of poor response to therapy in autoimmune hepatitis. Dig. Liver Dis. 48, 1078–1081 (2016).

  206. 206.

    et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 53, 926–934 (2011).

  207. 207.

    , & Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 46, 1138–1145 (2007).

  208. 208.

    , & Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am. J. Gastroenterol. 103, 1944–1951 (2008).

  209. 209.

    Hepatocellular carcinoma and other malignancies in autoimmune hepatitis. Dig. Dis. Sci. 58, 1459–1476 (2013).

  210. 210.

    et al. Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis. World J. Gastroenterol. 23, 859–868 (2017).

  211. 211.

    et al. Transient elastography in autoimmune hepatitis: timing determines the impact of inflammation and fibrosis. J. Hepatol. 65, 769–775 (2016).

  212. 212.

    et al. Usefulness of biochemical remission and transient elastography in monitoring disease course in autoimmune hepatitis. J. Hepatol. (2017).

  213. 213.

    et al. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G726–734 (2009).

  214. 214.

    et al. Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int. 36, 1783–1792 (2016).

  215. 215.

    Evolving paradigm of treatment for autoimmune hepatitis. Expert Rev. Clin. Immunol. 13, 781–798 (2017).

  216. 216.

    et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 57, 708–715 (2013).

  217. 217.

    et al. B-Cell activating factor belonging to the tumor necrosis factor family and interferon-γ-inducible protein-10 in autoimmune hepatitis. Medicine 95, e3194 (2016).

  218. 218.

    et al. Elevated serum BAFF levels in patients with autoimmune hepatitis. Hum. Immunol. 68, 586–591 (2007).

  219. 219.

    Inhibition of B cell activating factor (BAFF) in the management of systemic lupus erythematosus (SLE). Expert Rev. Clin. Immunol. 13, 623–633 (2017).

  220. 220.

    et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J. Clin. Invest. 120, 4129–4140 (2010).

  221. 221.

    et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS ONE 11, e0158156 (2016).

  222. 222.

    et al. Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. PLoS ONE 12, e0184694 (2017).

  223. 223.

    et al. Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model. PLOS ONE 8, e53992 (2013).

  224. 224.

    et al. The effects of Maraviroc on liver fibrosis in HIV/HCV co-infected patients. J. Int. AIDS Soc. 17, 19643 (2014).

  225. 225.

    et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology (2018).

  226. 226.

    et al. Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol. Pharmacol. 84, 62–70 (2013).

  227. 227.

    et al. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91phox mediate hepatic fibrosis in mice. Hepatology 53, 1730–1741 (2011).

  228. 228.

    et al. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic. Biol. Med. 53, 289–296 (2012).

  229. 229.

    Inhibition of transforming growth factor (TGF)-beta 1-induced extracellular matrix with a novel inhibitor of the tgf-beta type I receptor kinase activity: SB-431542. Mol. Pharmacol. 62, 58–64 (2002).

  230. 230.

    et al. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50, 1421–1430 (2009).

  231. 231.

    , , & Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance. Hepatology 57, 217–227 (2013). This paper describes how the adoptive transfer of Treg cells, which had been expanded ex vivo and reinfused in mice with experimental AIH, induces peripheral tolerance to the autoantigen that triggered the disease (formiminotransferase cyclodeaminase) and reduces inflammatory activity.

  232. 232.

    et al. CD4+FoxP3+regulatory T cells confer infectious tolerance in a TGF-β–dependent manner. J. Exp. Med. 205, 1975–1981 (2008).

  233. 233.

    Global disparities and their implications in the occurrence and outcome of autoimmune hepatitis. Dig. Dis. Sci. 62, 2277–2292 (2017).

  234. 234.

    , , , & Autoimmune hepatitis in Singapore: a rare syndrome affecting middle-aged women. J. Gastroenterol. Hepatol. 16, 1384–1389 (2001).

  235. 235.

    , , , & Autoimmune hepatitis in the Indian subcontinent: 7 years experience. J. Gastroenterol. Hepatol. 16, 1144–1148 (2001).

  236. 236.

    et al. Access to primary care is associated with better autoimmune hepatitis outcomes in an urban county hospital. BMC Gastroenterol. 15, 91 (2015).

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Acknowledgements

The authors thank S. Dhingra for the contribution of Fig. 2.

Author information

Affiliations

  1. Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK.

    • Giorgina Mieli-Vergani
  2. Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK.

    • Diego Vergani
  3. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.

    • Albert J. Czaja
  4. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

    • Michael P. Manns
  5. Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.

    • Michael P. Manns
  6. Department of Medicine, University of Vermont, Burlington, VT, USA.

    • Edward L. Krawitt
  7. Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.

    • Edward L. Krawitt
  8. Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA.

    • John M. Vierling
  9. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

    • Ansgar W. Lohse
  10. Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.

    • Aldo J. Montano-Loza

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Contributions

Introduction (M.P.M.); Epidemiology (E.L.K.); Mechanisms/pathophysiology (D.V.); Diagnosis, screening and prevention (J.M.V. and G.M.-V.); Management (A.W.L. and G.M.-V.); Quality of life (A.J.M.-L.); Outlook (A.J.C.); Overview of Primer (D.V. and G.M.-V.).

Competing interests

M.P.M. received research grants and trial support from and serves as a consultant for Falk Foundation and Novartis Pharma. J.M.V. is a recipient of research grants from Gilead, Intercept, Novartis, Sundise and TaiwanJ and serves as a scientific adviser to BioIncept, Bristol-Myers Squibb, Gilead, Intercept, Novartis and Sundise. In addition, he is a co-author of “Immunosuppression in Liver Transplantation” for Up-to-Date. A.W.L. holds the patent on SLA/LP diagnostic testing, but all revenues from this patent go to the charitable YAEL foundation supporting patients and research in autoimmune liver diseases. G.M.-V., D.V., A.J.C., E.L.K. and A.J.M.-L. declare no competing interests.

Corresponding authors

Correspondence to Giorgina Mieli-Vergani or Diego Vergani.