Autoimmune hepatitis

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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Figure 1: Possible pathways of autoimmune attack of hepatocytes in AIH.
Figure 2: Histopathology of AIH.
Figure 3: Management of AIH in adults.
Figure 4: Follow-up of adults with AIH following remission.
Figure 5: Treatment decision-making in children with autoimmune liver disease.

References

  1. 1

    Desmet, V. J., Gerber, M., Hoofnagle, J. H., Manns, M. & Scheuer, P. J. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19, 1513–1520 (1994).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Manns, M. P., Lohse, A. W. & Vergani, D. Autoimmune hepatitis — update 2015. J. Hepatol. 62, S100–S111 (2015).

    PubMed  Article  Google Scholar 

  3. 3

    Liberal, R., Selmi, C. & Gershwin, M. E. Diego and Giorgina Vergani: the two hearts of translational autoimmunity. J. Autoimmun. 66, 1–6 (2016).

    PubMed  Article  Google Scholar 

  4. 4

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

    CAS  PubMed  Google Scholar 

  5. 5

    Mackay, I., Taft, L. I. & Cowling, D. C. Lupoid hepatitis. Lancet 268, 1323–1326 (1956).

    Article  Google Scholar 

  6. 6

    Manns, M. P. 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.

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Johnson, G. D., Holborow, E. J. & Glynn, L. E. Antibody to smooth muscle in patients with liver disease. Lancet 2, 878–879 (1965).

    CAS  PubMed  Article  Google Scholar 

  8. 8

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

    CAS  PubMed  Article  Google Scholar 

  9. 9

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

    CAS  PubMed  Article  Google Scholar 

  10. 10

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

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Manns, M., Gerken, G., Kyriatsoulis, A., Staritz, M. & Meyer zum Büschenfelde, K. H. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1, 292–294 (1987).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Stechemesser, E., Klein, R. & Berg, P. A. Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis. Hepatology 18, 1–9 (1993).

    CAS  PubMed  Article  Google Scholar 

  13. 13

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

    CAS  PubMed  Article  Google Scholar 

  14. 14

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

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Kirk, A. P., Jain, S., Pocock, S., Thomas, H. C. & Sherlock, S. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    Article  Google Scholar 

  17. 17

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

    PubMed  Article  Google Scholar 

  18. 18

    Muratori, L., Muratori, P., Lanzoni, G., Ferri, S. & Lenzi, M. 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).

    PubMed  Article  Google Scholar 

  19. 19

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

    Google Scholar 

  20. 20

    Vergani, D., Mckay, I. & Mieli-Vergani, G. The Autoimmune Diseases (Elsevier Academic Press, 2014).

    Google Scholar 

  21. 21

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

    Google Scholar 

  22. 22

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

    CAS  PubMed  Article  Google Scholar 

  23. 23

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

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Tanaka, A. 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).

    PubMed  Article  Google Scholar 

  25. 25

    Kim, B. H. 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).

    CAS  PubMed  Article  Google Scholar 

  26. 26

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

    CAS  PubMed  Article  Google Scholar 

  27. 27

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

    PubMed  Article  Google Scholar 

  28. 28

    Amarapurkar, D., Dharod, M. & Amarapurkar, A. Autoimmune hepatitis in India: single tertiary referral centre experience. Trop. Gastroenterol. 36, 36–45.

  29. 29

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

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Koay, L.-B. 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).

    CAS  PubMed  Article  Google Scholar 

  31. 31

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

    PubMed  Article  Google Scholar 

  32. 32

    Boberg, K. M. 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).

    CAS  PubMed  Article  Google Scholar 

  33. 33

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

    PubMed  Google Scholar 

  34. 34

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

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Grønbæk, L., Vilstrup, H. & Jepsen, P. 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.

    PubMed  Article  Google Scholar 

  36. 36

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

    PubMed  Article  Google Scholar 

  37. 37

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

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Danielsson Borssén, Å. 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).

    PubMed  Article  CAS  Google Scholar 

  39. 39

    Arinaga-Hino, T. 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).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Yeoman, A. D. 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).

    PubMed  Article  Google Scholar 

  41. 41

    Wong, R. J., Gish, R., Frederick, T., Bzowej, N. & Frenette, C. Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series. Dig. Dis. Sci. 56, 578–585 (2011).

    PubMed  Article  Google Scholar 

  42. 42

    Tansel, A. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43

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

    PubMed  Article  Google Scholar 

  44. 44

    de Boer, Y. S. 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.

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Alvarez, F. 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.

    CAS  PubMed  Article  Google Scholar 

  46. 46

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

    CAS  PubMed  Article  Google Scholar 

  47. 47

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

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

    CAS  PubMed  Article  Google Scholar 

  49. 49

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

    CAS  PubMed  Article  Google Scholar 

  50. 50

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51

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

    CAS  PubMed  Article  Google Scholar 

  52. 52

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

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Fainboim, L. 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).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Mann, D. A. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

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

    CAS  PubMed  Article  Google Scholar 

  56. 56

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

    Article  Google Scholar 

  57. 57

    Simmonds, M. J. & Gough, S. C. L. Genetic insights into disease mechanisms of autoimmunity. Br. Med. Bull. 71, 93–113 (2004).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Liston, A., Lesage, S., Gray, D. H. D., Boyd, R. L. & Goodnow, C. C. Genetic lesions in T-cell tolerance and thresholds for autoimmunity. Immunol. Rev. 204, 87–101 (2005).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    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. 322, 1829–1836 (1990).

    CAS  PubMed  Article  Google Scholar 

  60. 60

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

    CAS  PubMed  Article  Google Scholar 

  61. 61

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

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Muratori, P., Fabbri, A., Lalanne, C., Lenzi, M. & Muratori, L. Autoimmune liver disease and concomitant extrahepatic autoimmune disease. Eur. J. Gastroenterol. Hepatol. 27, 1175–1179 (2015).

    CAS  PubMed  Article  Google Scholar 

  63. 63

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Lin, R., Zhou, L., Zhang, J. & Wang, B. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

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

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Vergani, D., Choudhuri, K., Bogdanos, D. P. & Mieli-Vergani, G. Pathogenesis of autoimmune hepatitis. Clin. Liver Dis. 6, 727–737 (2002).

    PubMed  Article  Google Scholar 

  67. 67

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

    CAS  PubMed  Article  Google Scholar 

  68. 68

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

    Article  Google Scholar 

  69. 69

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

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Miyakawa, H. 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).

    CAS  PubMed  Article  Google Scholar 

  71. 71

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

    CAS  PubMed  Article  Google Scholar 

  72. 72

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

    CAS  PubMed  Article  Google Scholar 

  73. 73

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Hintermann, E. 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).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Choudhuri, K., Gregorio, G. V., Mieli-Vergani, G. & Vergani, D. Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis. Hepatology 28, 1177–1181 (1998).

    CAS  PubMed  Article  Google Scholar 

  76. 76

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

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Ebrahimkhani, M. R., Mohar, I. & Crispe, I. N. Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 54, 1379–1387 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78

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

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Lobo-Yeo, A. 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).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Senaldi, G., Lobo-Yeo, A., Mowat, A. P., 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. 44, 107–114 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

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

    PubMed  Article  CAS  Google Scholar 

  82. 82

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

    PubMed  Article  CAS  Google Scholar 

  83. 83

    Jensen, D. M., McFarlane, I. G., Portmann, B. S., Eddleston, A. L. W. F. & Williams, R. 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).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    McFarlane, B. M., McSorley, C. G., Vergani, D., McFarlane, I. G. & Williams, R. Serum autoantibodies reacting with the hepatic asialoglycoprotein receptor protein (hepatic lectin) in acute and chronic liver disorders. J. Hepatol. 3, 196–205 (1986).

    CAS  PubMed  Article  Google Scholar 

  85. 85

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Thomas-Dupont, P. 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

    Ma, C. S. & Deenick, E. K. Human T follicular helper (Tfh) cells and disease. Immunol. Cell Biol. 92, 64–71 (2013).

    PubMed  Article  CAS  Google Scholar 

  89. 89

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90

    Kimura, N. 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).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Wen, L., Peakman, M., Mieli-Vergani, G. & Vergani, D. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

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

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Grønbaek, H. 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).

    PubMed  Article  CAS  Google Scholar 

  94. 94

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

    CAS  PubMed  Article  Google Scholar 

  95. 95

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

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Longhi, M. S., Ma, Y., Mieli-Vergani, G. & Vergani, D. Regulatory T cells in autoimmune hepatitis. J. Hepatol. 57, 932–933 (2012).

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Longhi, M. S. 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).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Liberal, R. 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).

    CAS  PubMed  Article  Google Scholar 

  99. 99

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

    CAS  PubMed  Article  Google Scholar 

  100. 100

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

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Grant, C. R. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102

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

    CAS  PubMed  Google Scholar 

  103. 103

    Diestelhorst, J. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104

    Taubert, R. 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).

    CAS  PubMed  Article  Google Scholar 

  105. 105

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

    Google Scholar 

  106. 106

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107

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

    Article  Google Scholar 

  108. 108

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

    CAS  PubMed  Article  Google Scholar 

  109. 109

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

    PubMed  Article  Google Scholar 

  110. 110

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

    PubMed  Article  CAS  Google Scholar 

  111. 111

    Liberal, R., Grant, C. R., Longhi, M. S., Mieli-Vergani, G. & Vergani, D. Diagnostic criteria of autoimmune hepatitis. Autoimmun. Rev. 13, 435–440 (2014).

    CAS  PubMed  Article  Google Scholar 

  112. 112

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

    PubMed  Article  CAS  Google Scholar 

  113. 113

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

    PubMed  Article  CAS  Google Scholar 

  114. 114

    Vergani, D. 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.

    PubMed  Article  Google Scholar 

  115. 115

    Zhang, W.-C., Zhao, F.-R., Chen, J. & Chen, W.-X. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. 116

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117

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

    PubMed  Article  Google Scholar 

  118. 118

    Te, H. S., Koukoulis, G. & Ganger, D. R. Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis. Gut 41, 269–271 (1997).

    CAS  PubMed  Article  Google Scholar 

  119. 119

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120

    Verdonk, R. C., Lozano, M. F., van den Berg, A. P. & Gouw, A. S. H. Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis. Liver Int. 36, 1362–1369 (2016).

    PubMed  Article  Google Scholar 

  121. 121

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

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122

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

    PubMed  Article  Google Scholar 

  123. 123

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

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Mieli-Vergani, G. 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.

    PubMed  Article  Google Scholar 

  125. 125

    Hennes, E. M. 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.

    PubMed  Article  Google Scholar 

  126. 126

    Gatselis, N. K. 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).

    PubMed  Article  Google Scholar 

  127. 127

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

    PubMed  Article  Google Scholar 

  128. 128

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

    PubMed  PubMed Central  Google Scholar 

  129. 129

    Scott, J., Gollan, J. L., Samourian, S. & Sherlock, S. Wilson's disease, presenting as chronic active hepatitis. Gastroenterology 74, 645–651 (1978).

    CAS  PubMed  Article  Google Scholar 

  130. 130

    Santos, R. G., Alissa, F., Reyes, J., Teot, L. & Ameen, N. Fulminant hepatic failure: Wilson's disease or autoimmune hepatitis? Implications for transplantation. Pediatr. Transplant. 9, 112–116 (2005).

    CAS  PubMed  Article  Google Scholar 

  131. 131

    Milkiewicz, P., Saksena, S., Hubscher, S. G. & Elias, E. Wilson's disease with superimposed autoimmune features: report of two cases and review. J. Gastroenterol. Hepatol. 15, 570–574 (2000).

    CAS  PubMed  Article  Google Scholar 

  132. 132

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

    PubMed  Article  Google Scholar 

  133. 133

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

    Google Scholar 

  134. 134

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

    CAS  PubMed  Article  Google Scholar 

  135. 135

    De Luca-Johnson, J., Wangensteen, K. J., Hanson, J., Krawitt, E. & Wilcox, R. Natural history of patients presenting with autoimmune hepatitis and coincident nonalcoholic fatty liver disease. Dig. Dis. Sci. 61, 2710–2720 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136

    Lohse, A. W. & Mieli-Vergani, G. Autoimmune hepatitis. J. Hepatol. 55, 171–182 (2011).

    CAS  PubMed  Article  Google Scholar 

  137. 137

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

    CAS  PubMed  Article  Google Scholar 

  138. 138

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

    CAS  PubMed  Article  Google Scholar 

  139. 139

    Peiseler, M. 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).

    CAS  PubMed  Article  Google Scholar 

  140. 140

    Kanzler, S., Löhr, H., Gerken, G., Galle, P. R. & Lohse, A. W. Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience. Z. Gastroenterol. 39, 339–348 (2001).

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Hübener, S. 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).

    PubMed  Article  CAS  Google Scholar 

  142. 142

    Heneghan, M. A., Allan, M. L., Bornstein, J. D., Muir, A. J. & Tendler, D. A. 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).

    CAS  PubMed  Article  Google Scholar 

  143. 143

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

    CAS  PubMed  Article  Google Scholar 

  144. 144

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

    CAS  PubMed  Article  Google Scholar 

  145. 145

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

    CAS  PubMed  Article  Google Scholar 

  146. 146

    Hartl, J. 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).

    CAS  PubMed  Article  Google Scholar 

  147. 147

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

    CAS  PubMed  Article  Google Scholar 

  148. 148

    Than, N. N. 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).

    PubMed  Article  CAS  Google Scholar 

  149. 149

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

    CAS  PubMed  Article  Google Scholar 

  150. 150

    Burak, K. W. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  151. 151

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

    PubMed  Article  Google Scholar 

  152. 152

    Mieli-Vergani, G., Bargiota, K., Samyn, M. & Vergani, D. in Autoimmune Liver Diseases-Falk Symposium Dordrecht (eds Dienes, H. P. et al.) 278–282 (Springer, 2005).

    Google Scholar 

  153. 153

    Gregorio, G. V., McFarlane, B., Bracken, P., Vergani, D. & Mieli-Vergani, G. 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).

    CAS  PubMed  Article  Google Scholar 

  154. 154

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

    CAS  PubMed  Article  Google Scholar 

  155. 155

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

    PubMed  Article  Google Scholar 

  156. 156

    Liberal, R., Grant, C. R., Mieli-Vergani, G. & Vergani, D. Autoimmune hepatitis: a comprehensive review. J. Autoimmun. 41, 126–139 (2013).

    CAS  PubMed  Article  Google Scholar 

  157. 157

    Strassburg, C. P. & Manns, M. P. Treatment of autoimmune hepatitis. Semin. Liver Dis. 29, 273–285 (2009).

    CAS  PubMed  Article  Google Scholar 

  158. 158

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

    PubMed  PubMed Central  Article  Google Scholar 

  159. 159

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

    CAS  PubMed  Article  Google Scholar 

  160. 160

    Liberal, R., Zen, Y., Mieli-Vergani, G. & Vergani, D. Liver transplantation and autoimmune liver diseases. Liver Transplant. 19, 1065–1077 (2013).

    Google Scholar 

  161. 161

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

    CAS  PubMed  Article  Google Scholar 

  162. 162

    Liberal, R., Vergani, D. & Mieli-Vergani, G. Recurrence of autoimmune liver disease and inflammatory bowel disease after pediatric liver transplantation. Liver Transplant. 22, 1275–1283 (2016).

    Article  Google Scholar 

  163. 163

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

    PubMed  Article  Google Scholar 

  164. 164

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

    CAS  PubMed  Article  Google Scholar 

  165. 165

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

    PubMed  Article  Google Scholar 

  166. 166

    Dyson, J. K. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167

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

    PubMed  Article  Google Scholar 

  168. 168

    Mells, G. 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).

    Google Scholar 

  169. 169

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. 170

    Younossi, Z. M. 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).

    CAS  PubMed  Article  Google Scholar 

  171. 171

    Younossi, Z. M. 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).

    PubMed  Article  Google Scholar 

  172. 172

    Golabi, P. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  173. 173

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

    PubMed  Article  Google Scholar 

  174. 174

    Seela, S., Sheela, H. & Boyer, J. L. Autoimmune hepatitis type 1: safety and efficacy of prolonged medical therapy. Liver Int. 25, 734–739 (2005).

    CAS  PubMed  Article  Google Scholar 

  175. 175

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

    PubMed  Article  Google Scholar 

  176. 176

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

    PubMed  Article  Google Scholar 

  177. 177

    Younossi, Z. M., Guyatt, G., Kiwi, M., Boparai, N. & King, D. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 45, 295–300 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178

    Alt, Y. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  179. 179

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

    PubMed  PubMed Central  Article  Google Scholar 

  180. 180

    Sockalingam, S., Blank, D., Abdelhamid, N., Abbey, S. E. & Hirschfield, G. M. Identifying opportunities to improve management of autoimmune hepatitis: evaluation of drug adherence and psychosocial factors. J. Hepatol. 57, 1299–1304 (2012).

    PubMed  Article  Google Scholar 

  181. 181

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

    CAS  PubMed  Article  Google Scholar 

  182. 182

    Fried, R. G. & Wechsler, A. Psychological problems in the acne patient. Dermatol. Ther. 19, 237–240 (2006).

    PubMed  Article  Google Scholar 

  183. 183

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

    CAS  PubMed  Article  Google Scholar 

  184. 184

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

    CAS  PubMed  Article  Google Scholar 

  185. 185

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

    CAS  PubMed  Article  Google Scholar 

  186. 186

    Czaja, A. J. Epigenetic changes and their implications in autoimmune hepatitis. Eur. J. Clin. Invest.https://doi.org/10.1111/eci.12899 (2018).

    Article  CAS  Google Scholar 

  187. 187

    Migita, K. 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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  188. 188

    Kuchroo, V. K., Meyers, J. H., Umetsu, D. T. & DeKruyff, R. H. TIM family of genes in immunity and tolerance. Adv. Immunol. 91, 227–249 (2006).

    CAS  PubMed  Article  Google Scholar 

  189. 189

    Golden-Mason, L. & Rosen, H. R. Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology 66, 271–279 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. 190

    Zamani, M. R., Aslani, S., Salmaninejad, A., Javan, M. R. & Rezaei, N. PD-1/PD-L and autoimmunity: a growing relationship. Cell. Immunol. 310, 27–41 (2016).

    CAS  PubMed  Article  Google Scholar 

  191. 191

    McKinney, E. F., Lee, J. C., Jayne, D. R. W., Lyons, P. A. & Smith, K. G. C. T-Cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. 192

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193

    Zhang, W. 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).

    PubMed  Google Scholar 

  194. 194

    Markle, J. G. M., Frank, D. N., Adeli, K., von Bergen, M. & Danska, J. S. Microbiome manipulation modifies sex-specific risk for autoimmunity. Gut Microbes 5, 485–493 (2014).

    PubMed  Article  Google Scholar 

  195. 195

    Markle, J. G. M. 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.

    CAS  PubMed  Article  Google Scholar 

  196. 196

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

    CAS  PubMed  Article  Google Scholar 

  197. 197

    Efe, C. 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).

    CAS  PubMed  Article  Google Scholar 

  198. 198

    Ramagopalan, S. V. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199

    Aarslev, K. 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).

    PubMed  Article  CAS  Google Scholar 

  200. 200

    Matsumoto, K. 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).

    Article  CAS  Google Scholar 

  201. 201

    Miyake, Y. 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).

    CAS  PubMed  Article  Google Scholar 

  202. 202

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  203. 203

    Assis, D. N. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  205. 205

    Muratori, P., Lalanne, C., Bianchi, G., Lenzi, M. & Muratori, L. Predictive factors of poor response to therapy in autoimmune hepatitis. Dig. Liver Dis. 48, 1078–1081 (2016).

    PubMed  Article  Google Scholar 

  206. 206

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

    PubMed  Article  Google Scholar 

  207. 207

    Montano-Loza, A. J., Carpenter, H. A. & Czaja, A. J. 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).

    CAS  PubMed  Article  Google Scholar 

  208. 208

    Montano-Loza, A. J., Carpenter, H. A. & Czaja, A. J. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am. J. Gastroenterol. 103, 1944–1951 (2008).

    CAS  PubMed  Article  Google Scholar 

  209. 209

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

    CAS  PubMed  Article  Google Scholar 

  210. 210

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

    PubMed  PubMed Central  Article  Google Scholar 

  211. 211

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

    PubMed  Article  Google Scholar 

  212. 212

    Hartl, J. et al. Usefulness of biochemical remission and transient elastography in monitoring disease course in autoimmune hepatitis. J. Hepatol.https://doi.org/10.1016/j.jhep.2017.11.020 (2017).

    PubMed  Article  Google Scholar 

  213. 213

    Colmenero, J. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  214. 214

    Meissner, E. G. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215

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

    CAS  PubMed  Article  Google Scholar 

  216. 216

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  217. 217

    Nishikawa, H. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218

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

    CAS  PubMed  Article  Google Scholar 

  219. 219

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

    CAS  PubMed  Article  Google Scholar 

  220. 220

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  222. 222

    Puengel, T. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  223. 223

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224

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

    PubMed Central  Article  PubMed  Google Scholar 

  225. 225

    Friedman, S. L. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatologyhttps://doi.org/10.1002/hep.29477 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  226. 226

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

    CAS  PubMed  Article  Google Scholar 

  227. 227

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  228. 228

    Jiang, J. X. 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).

    CAS  Google Scholar 

  229. 229

    Laping, N. J. 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).

    CAS  PubMed  Article  Google Scholar 

  230. 230

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

    CAS  PubMed  Article  Google Scholar 

  231. 231

    Lapierre, P., Béland, K., Yang, R. & Alvarez, F. 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.

    CAS  PubMed  Article  Google Scholar 

  232. 232

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  233. 233

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

    PubMed  Article  Google Scholar 

  234. 234

    Lee, Y. M., Teo, E. K., Ng, T. M., Khor, C. & Fock, K. M. Autoimmune hepatitis in Singapore: a rare syndrome affecting middle-aged women. J. Gastroenterol. Hepatol. 16, 1384–1389 (2001).

    CAS  PubMed  Article  Google Scholar 

  235. 235

    Gupta, R., Agarwal, S. R., Jain, M., Malhotra, V. & Sarin, S. K. Autoimmune hepatitis in the Indian subcontinent: 7 years experience. J. Gastroenterol. Hepatol. 16, 1144–1148 (2001).

    CAS  PubMed  Article  Google Scholar 

  236. 236

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

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

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

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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.).

Corresponding authors

Correspondence to Giorgina Mieli-Vergani or Diego Vergani.

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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.

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Mieli-Vergani, G., Vergani, D., Czaja, A. et al. Autoimmune hepatitis. Nat Rev Dis Primers 4, 18017 (2018). https://doi.org/10.1038/nrdp.2018.17

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