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Biliary Disease pp 129–182Cite as

Primary Biliary Cholangitis: Its Science and Practice

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Abstract

Primary biliary cholangitis (PBC) is an autoimmune liver disorder characterized by progressive destruction of intrahepatic bile ducts, leading to cholestasis, cirrhosis, and liver failure. The etiology of PBC is unknown; however a complex interaction between genetic, environmental, and autoimmune factors is believed to play a role. The major hallmark of PBC is the presence of antimitochondrial antibodies (AMA), with sensitivity and specificity for PBC >90–95%. The immunodominant epitopes recognized by AMA are all mapped within the lipoyl domains of the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2). In addition to autoantibodies, PBC is characterized by an enrichment of autoreactive CD4+ and CD8+ T cells, by enhanced natural killer (NK) cell activity and monocyte responses and accumulation of Th17 cells around damaged bile ducts. Controversial findings regarding numbers and function of regulatory T cells have been reported. The development of several animal models has aided the study and understanding of different aspects of PBC pathogenesis; however no “perfect model” has been developed to date. Novel therapeutic avenues targeting bile acids, nuclear receptors, immune cell receptors, and cytokines have been developed with promising results.

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References

  1. Ahrens Jr EH, Payne MA, Kunkel HG, Eisenmenger WJ, Blondheim SH. Primary biliary cirrhosis. Medicine (Baltimore). 1950;29:299–364.

    Article  Google Scholar 

  2. Griffiths L, Dyson JK, Jones DE. The new epidemiology of primary biliary cirrhosis. Semin Liver Dis. 2014;34:318–28.

    Article  PubMed  Google Scholar 

  3. Triger DR, Berg PA, Rodes J. Epidemiology of primary biliary cirrhosis. Liver. 1984;4:195–200.

    Article  CAS  PubMed  Google Scholar 

  4. Lofgren J, Jarnerot G, Danielsson D, Hemdal I. Incidence and prevalence of primary biliary cirrhosis in a defined population in Sweden. Scand J Gastroenterol. 1985;20:647–50.

    Article  CAS  PubMed  Google Scholar 

  5. Liu H, Liu Y, Wang L, Xu D, Lin B, Zhong R, Gong S, et al. Prevalence of primary biliary cirrhosis in adults referring hospital for annual health check-up in Southern China. BMC Gastroenterol. 2010;10:100.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56:1181–8.

    Article  PubMed  Google Scholar 

  7. OF J, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV. Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology. 1999;30:390–4.

    Article  Google Scholar 

  8. Myers RP, Shaheen AA, Fong A, Burak KW, Wan A, Swain MG, Hilsden RJ, et al. Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: a population-based study. Hepatology. 2009;50:1884–92.

    Article  PubMed  Google Scholar 

  9. Liu H, Norman GL, Shums Z, Worman HJ, Krawitt EL, Bizzaro N, Vergani D, et al. PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. J Autoimmun. 2010;35:436–42.

    Article  CAS  PubMed  Google Scholar 

  10. Turchany JM, Uibo R, Kivik T, Van de Water J, Prindiville T, Coppel RL, Gershwin ME. A study of antimitochondrial antibodies in a random population in Estonia. Am J Gastroenterol. 1997;92:124–6.

    CAS  PubMed  Google Scholar 

  11. Mattalia A, Quaranta S, Leung PS, Bauducci M, Van de Water J, Calvo PL, Danielle F, et al. Characterization of antimitochondrial antibodies in health adults. Hepatology. 1998;27:656–61.

    Article  CAS  PubMed  Google Scholar 

  12. Lazaridis KN, Juran BD, Boe GM, Slusser JP, de Andrade M, Homburger HA, Ghosh K, et al. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology. 2007;46:785–92.

    Article  PubMed  Google Scholar 

  13. Shibata M, Onozuka Y, Morizane T, Koizumi H, Kawaguchi N, Miyakawa H, Kako M, et al. Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture. J Gastroenterol. 2004;39:255–9.

    Article  PubMed  Google Scholar 

  14. Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OF. Natural history of early primary biliary cirrhosis. Lancet. 1996;348:1399–402.

    Article  CAS  PubMed  Google Scholar 

  15. Sherlock S. Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterology. 1959;37:574–86.

    CAS  PubMed  Google Scholar 

  16. Tornay Jr AS. Primary biliary cirrhosis: natural history. Am J Gastroenterol. 1980;73:223–6.

    PubMed  Google Scholar 

  17. Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011;377:1600–9.

    Article  CAS  PubMed  Google Scholar 

  18. Mayo MJ. Natural history of primary biliary cirrhosis. Clin Liver Dis. 2008;12:277–88. viii

    Article  PubMed  Google Scholar 

  19. Pares A, Rodes J. Natural history of primary biliary cirrhosis. Clin Liver Dis. 2003;7:779–94.

    Article  PubMed  Google Scholar 

  20. Beswick DR, Klatskin G, Boyer JL. Asymptomatic primary biliary cirrhosis. A progress report on long-term follow-up and natural history. Gastroenterology. 1985;89:267–71.

    Article  CAS  PubMed  Google Scholar 

  21. Balasubramaniam K, Grambsch PM, Wiesner RH, Lindor KD, Dickson ER. Diminished survival in asymptomatic primary biliary cirrhosis. A prospective study. Gastroenterology. 1990;98:1567–71.

    Article  CAS  PubMed  Google Scholar 

  22. Mitchison HC, Lucey MR, Kelly PJ, Neuberger JM, Williams R, OF J. Symptom development and prognosis in primary biliary cirrhosis: a study in two centers. Gastroenterology. 1990;99:778–84.

    Article  CAS  PubMed  Google Scholar 

  23. Nyberg A, Loof L. Primary biliary cirrhosis: clinical features and outcome, with special reference to asymptomatic disease. Scand J Gastroenterol. 1989;24:57–64.

    Article  CAS  PubMed  Google Scholar 

  24. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, American Association for Study of Liver D. Primary biliary cirrhosis. Hepatology. 2009;50:291–308.

    Article  PubMed  Google Scholar 

  25. Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, Chazouilleres O, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–7.

    Article  CAS  PubMed  Google Scholar 

  26. Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, Houben MH, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136:1281–7.

    Article  CAS  PubMed  Google Scholar 

  27. Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006;130:715–20.

    Article  CAS  PubMed  Google Scholar 

  28. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5:1313–5.

    Article  PubMed  Google Scholar 

  29. Kuiper EM, Hansen BE, Adang RP, van Nieuwkerk CM, Timmer R, Drenth JP, Spoelstra P, et al. Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid. Eur J Gastroenterol Hepatol. 2010;22:1495–502.

    CAS  PubMed  Google Scholar 

  30. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73.

    Article  CAS  PubMed  Google Scholar 

  31. Kitic I, Boskovic A, Stankovic I, Prokic D. Twelve-year-old girl with primary biliary cirrhosis. Case Rep Pediatr. 2012;2012:937150.

    PubMed  PubMed Central  Google Scholar 

  32. Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL, Heneghan MA, Neuberger JM, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013;144:560–569 e567. ; quiz e513-564

    Article  CAS  PubMed  Google Scholar 

  33. Rubel LR, Rabin L, Seeff LB, Licht H, Cuccherini BA. Does primary biliary cirrhosis in men differ from primary biliary cirrhosis in women? Hepatology. 1984;4:671–7.

    Article  CAS  PubMed  Google Scholar 

  34. Nalbandian G, Van de Water J, Gish R, Manns M, Coppel RL, Rudich SM, Prindiville T, et al. Is there a serological difference between men and women with primary biliary cirrhosis? Am J Gastroenterol. 1999;94:2482–6.

    Article  CAS  PubMed  Google Scholar 

  35. Lohse AW, Weiler-Normann C. Not all PBC is the same! Gastroenterology. 2013;144:494–7.

    Article  PubMed  Google Scholar 

  36. Owens GM. Gender differences in health care expenditures, resource utilization, and quality of care. J Manag Care Pharm. 2008;14:2–6.

    PubMed  Google Scholar 

  37. Oksuzyan A, Juel K, Vaupel JW, Christensen K. Men: good health and high mortality. Sex differences in health and aging. Aging Clin Exp Res. 2008;20:91–102.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Floreani A, Franceschet I, Cazzagon N. Primary biliary cirrhosis: overlaps with other autoimmune disorders. Semin Liver Dis. 2014;34:352–60.

    Article  PubMed  Google Scholar 

  39. Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E, International Autoimmune Hepatitis G. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54:374–85.

    Article  PubMed  Google Scholar 

  40. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology. 1998;28:296–301.

    Article  CAS  PubMed  Google Scholar 

  41. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, Bittencourt PL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76.

    Article  PubMed  Google Scholar 

  42. Kuiper EM, Zondervan PE, van Buuren HR. Paris criteria are effective in diagnosis of primary biliary cirrhosis and autoimmune hepatitis overlap syndrome. Clin Gastroenterol Hepatol. 2010;8:530–4.

    Article  PubMed  Google Scholar 

  43. European Association for the Study of the L. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–67.

    Article  Google Scholar 

  44. Culp KS, Fleming CR, Duffy J, Baldus WP, Dickson ER. Autoimmune associations in primary biliary cirrhosis. Mayo Clin Proc. 1982;57:365–70.

    CAS  PubMed  Google Scholar 

  45. Crowe JP, Christensen E, Butler J, Wheeler P, Doniach D, Keenan J, Williams R. Primary biliary cirrhosis: the prevalence of hypothyroidism and its relationship to thyroid autoantibodies and sicca syndrome. Gastroenterology. 1980;78:1437–41.

    CAS  PubMed  Google Scholar 

  46. Mang FW, Michieletti P, O’Rourke K, Cauch-Dudek K, Diamant N, Bookman A, Heathcote J. Primary biliary cirrhosis, sicca complex, and dysphagia. Dysphagia. 1997;12:167–70.

    Article  CAS  PubMed  Google Scholar 

  47. Watt FE, James OF, Jones DE. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM. 2004;97:397–406.

    Article  CAS  PubMed  Google Scholar 

  48. Inoue K, Hirohara J, Nakano T, Seki T, Sasaki H, Higuchi K, Ohta Y, et al. Prediction of prognosis of primary biliary cirrhosis in Japan. Liver. 1995;15:70–7.

    Article  CAS  PubMed  Google Scholar 

  49. Marasini B, Gagetta M, Rossi V, Ferrari P. Rheumatic disorders and primary biliary cirrhosis: an appraisal of 170 Italian patients. Ann Rheum Dis. 2001;60:1046–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Matsumoto T, Kobayashi S, Shimizu H, Nakajima M, Watanabe S, Kitami N, Sato N, et al. The liver in collagen diseases: pathologic study of 160 cases with particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune hepatitis and nodular regenerative hyperplasia of the liver. Liver. 2000;20:366–73.

    Article  CAS  PubMed  Google Scholar 

  51. Dickey W, McMillan SA, Callender ME. High prevalence of celiac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol. 1997;25:328–9.

    Article  CAS  PubMed  Google Scholar 

  52. Bardella MT, Quatrini M, Zuin M, Podda M, Cesarini L, Velio P, Bianchi P, et al. Screening patients with celiac disease for primary biliary cirrhosis and vice versa. Am J Gastroenterol. 1997;92:1524–6.

    CAS  PubMed  Google Scholar 

  53. Volta U, Rodrigo L, Granito A, Petrolini N, Muratori P, Muratori L, Linares A, et al. Celiac disease in autoimmune cholestatic liver disorders. Am J Gastroenterol. 2002;97:2609–13.

    Article  PubMed  Google Scholar 

  54. Deutsch M, Papatheodoridis GV, Tzakou A, Hadziyannis SJ. Risk of hepatocellular carcinoma and extrahepatic malignancies in primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2008;20:5–9.

    Article  PubMed  Google Scholar 

  55. Jackson H, Solaymani-Dodaran M, Card TR, Aithal GP, Logan R, West J. Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology. 2007;46:1131–7.

    Article  CAS  PubMed  Google Scholar 

  56. Jones DE, Metcalf JV, Collier JD, Bassendine MF, OF J. Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology. 1997;26:1138–42.

    Article  CAS  PubMed  Google Scholar 

  57. Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis. Hepatology. 1999;29:644–7.

    Article  CAS  PubMed  Google Scholar 

  58. Harada K, Hirohara J, Ueno Y, Nakano T, Kakuda Y, Tsubouchi H, Ichida T, et al. Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan. Hepatology. 2013;57:1942–9.

    Article  PubMed  Google Scholar 

  59. Rong G, Wang H, Bowlus CL, Wang C, Lu Y, Zeng Z, Qu J, et al. Incidence and risk factors for hepatocellular carcinoma in primary biliary cirrhosis. Clin Rev Allergy Immunol. 2015;48:132–41.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang XX, Wang LF, Jin L, Li YY, Hao SL, Shi YC, Zeng QL, et al. Primary biliary cirrhosis-associated hepatocellular carcinoma in Chinese patients: incidence and risk factors. World J Gastroenterol. 2015;21:3554–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Floreani A, Baragiotta A, Baldo V, Menegon T, Farinati F, Naccarato R. Hepatic and extrahepatic malignancies in primary biliary cirrhosis. Hepatology. 1999;29:1425–8.

    Article  CAS  PubMed  Google Scholar 

  62. Piscaglia F, Sagrini E. Malignancies in primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2008;20:1–4.

    Article  PubMed  Google Scholar 

  63. Liang Y, Yang Z, Zhong R. Smoking, family history and urinary tract infection are associated with primary biliary cirrhosis: a meta-analysis. Hepatol Res. 2011;41:572–8.

    Article  PubMed  Google Scholar 

  64. Wolke AM, Schaffner F, Kapelman B, Sacks HS. Malignancy in primary biliary cirrhosis. High incidence of breast cancer in affected women. Am J Med. 1984;76:1075–8.

    Article  CAS  PubMed  Google Scholar 

  65. Goudie BM, Burt AD, Boyle P, Macfarlane G, Birnie GG, Mills PR, Gillis CR, et al. Breast cancer in women with primary biliary cirrhosis. Br Med J (Clin Res Ed). 1985;291:1597–8.

    Article  CAS  Google Scholar 

  66. Floreani A, Spinazze A, Caballeria L, Reig A, Cazzagon N, Franceschet I, Buja A, et al. Extrahepatic malignancies in primary biliary cirrhosis: a comparative study at two European centers. Clin Rev Allergy Immunol. 2015;48:254–62.

    Article  PubMed  Google Scholar 

  67. Liang Y, Yang Z, Zhong R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology. 2012;56:1409–17.

    Article  PubMed  Google Scholar 

  68. Trivedi PJ, Kumagi T, Al-Harthy N, Coltescu C, Ward S, Cheung A, Hirschfield GM. Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2014;12:1179–85. e1171

    Article  PubMed  Google Scholar 

  69. Stellon AJ, Williams R. Increased incidence of menstrual abnormalities and hysterectomy preceding primary biliary cirrhosis. Br Med J (Clin Res Ed). 1986;293:297–8.

    Article  CAS  Google Scholar 

  70. Nir A, Sorokin Y, Abramovici H, Theodor E. Pregnancy and primary biliary cirrhosis. Int J Gynaecol Obstet. 1989;28:279–82.

    Article  CAS  PubMed  Google Scholar 

  71. Olsson R, Loof L, Wallerstedt S. Pregnancy in patients with primary biliary cirrhosis--a case for dissuasion? The Swedish Internal Medicine Liver Club. Liver. 1993;13:316–8.

    Article  CAS  PubMed  Google Scholar 

  72. Ji H, Haring P, Kirkinen P, Saarikoski S. Glucocorticoid treatment of primary biliary cirrhosis in a pregnant woman. Acta Obstet Gynecol Scand. 1995;74:654–6.

    Article  CAS  PubMed  Google Scholar 

  73. Rabinovitz M, Appasamy R, Finkelstein S. Primary biliary cirrhosis diagnosed during pregnancy. Does it have a different outcome? Dig Dis Sci. 1995;40:571–4.

    Article  CAS  PubMed  Google Scholar 

  74. Rudi J, Schonig T, Stremmel W. Therapy with ursodeoxycholic acid in primary biliary cirrhosis in pregnancy. Z Gastroenterol. 1996;34:188–91.

    CAS  PubMed  Google Scholar 

  75. Goh SK, Gull SE, Alexander GJ. Pregnancy in primary biliary cirrhosis complicated by portal hypertension: report of a case and review of the literature. BJOG. 2001;108:760–2.

    CAS  PubMed  Google Scholar 

  76. Floreani A, Paternoster D, Mega A, Farinati F, Plebani M, Baldo V, Grella. Sex hormone profile and endometrial cancer risk in primary biliary cirrhosis: a case-control study. Eur J Obstet Gynecol Reprod Biol. 2002;103:154–7.

    Article  CAS  PubMed  Google Scholar 

  77. Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol. 2012;36(Suppl 1):S3–12.

    Article  CAS  PubMed  Google Scholar 

  78. Parikh-Patel A, Gold E, Utts J, Gershwin ME. The association between gravidity and primary biliary cirrhosis. Ann Epidemiol. 2002;12:264–72.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Floreani A, Infantolino C, Franceschet I, Tene IM, Cazzagon N, Buja A, Baldo V, et al. Pregnancy and primary biliary cirrhosis: a case-control study. Clin Rev Allergy Immunol. 2015;48:236–42.

    Article  PubMed  Google Scholar 

  80. Efe C, Kahramanoglu-Aksoy E, Yilmaz B, Ozseker B, Takci S, Roach EC, Purnak T, et al. Pregnancy in women with primary biliary cirrhosis. Autoimmun Rev. 2014;13:931–5.

    Article  PubMed  Google Scholar 

  81. de Buy Wenniger LJ M, Hohenester S, Maroni L, SJ v V, RP OE, Beuers U. The cholangiocyte glycocalyx stabilizes the ‘Biliary HCO3 Umbrella’: an integrated line of defense against toxic bile acids. Dig Dis. 2015;33:397–407.

    Article  Google Scholar 

  82. Dilger K, Hohenester S, Winkler-Budenhofer U, Bastiaansen BA, Schaap FG, Rust C, Beuers U. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. J Hepatol. 2012;57:133–40.

    Article  CAS  PubMed  Google Scholar 

  83. Hohenester S, de Buy Wenniger L M, DM J, RP OE, Beuers U. Biliary bicarbonate secretion constitutes a protective mechanism against bile acid-induced injury in man. Dig Dis. 2011;29:62–5.

    Article  PubMed  CAS  Google Scholar 

  84. Moteki S, Leung PS, Coppel RL, Dickson ER, Kaplan MM, Munoz S, Gershwin ME. Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies. Hepatology. 1996;24:97–103.

    Article  CAS  PubMed  Google Scholar 

  85. Howard MJ, Fuller C, Broadhurst RW, Perham RN, Tang JG, Quinn J, Diamond AG, et al. Three-dimensional structure of the major autoantigen in primary biliary cirrhosis. Gastroenterology. 1998;115:139–46.

    Article  CAS  PubMed  Google Scholar 

  86. Amano K, Leung PS, Rieger R, Quan C, Wang X, Marik J, Suen YF, et al. Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol. 2005;174:5874–83.

    Article  CAS  PubMed  Google Scholar 

  87. Naiyanetr P, Butler JD, Meng L, Pfeiff J, Kenny TP, Guggenheim KG, Reiger R, et al. Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. J Autoimmun. 2011;37:209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rieger R, Leung PS, Jeddeloh MR, Kurth MJ, Nantz MH, Lam KS, Barsky D, et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun. 2006;27:7–16.

    Article  CAS  PubMed  Google Scholar 

  89. Leung PS, Park O, Tsuneyama K, Kurth MJ, Lam KS, Ansari AA, Coppel RL, et al. Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol. 2007;179:2651–7.

    Article  CAS  PubMed  Google Scholar 

  90. Leung PS, Quan C, Park O, Van de Water J, Kurth MJ, Nantz MH, Ansari AA, et al. Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies. J Immunol. 2003;170:5326–32.

    Article  CAS  PubMed  Google Scholar 

  91. Leung PS, Wang J, Naiyanetr P, Kenny TP, Lam KS, Kurth MJ, Gershwin ME. Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun. 2013;41:79–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wakabayashi K, Lian ZX, Leung PS, Moritoki Y, Tsuneyama K, Kurth MJ, Lam KS, et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology. 2008;48:531–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wakabayashi K, Yoshida K, Leung PS, Moritoki Y, Yang GX, Tsuneyama K, Lian ZX, et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol. 2009;155:577–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shimoda S, Miyakawa H, Nakamura M, Ishibashi H, Kikuchi K, Kita H, Niiro H, et al. CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis. J Autoimmun. 2008;31:110–5.

    Article  CAS  PubMed  Google Scholar 

  95. Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology. 2006;43:729–37.

    Article  PubMed  Google Scholar 

  96. Kikuchi K, Lian ZX, Yang GX, Ansari AA, Ikehara S, Kaplan M, Miyakawa H, et al. Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology. 2005;128:304–12.

    Article  CAS  PubMed  Google Scholar 

  97. Chuang YH, Lian ZX, Tsuneyama K, Chiang BL, Ansari AA, Coppel RL, Gershwin ME. Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun. 2006;26:232–40.

    Article  CAS  PubMed  Google Scholar 

  98. Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, Koning F, et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology. 2002;123:1031–43.

    Article  CAS  PubMed  Google Scholar 

  99. Mao TK, Lian ZX, Selmi C, Ichiki Y, Ashwood P, Ansari AA, Coppel RL, et al. Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology. 2005;42:802–8.

    Article  CAS  PubMed  Google Scholar 

  100. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest. 2001;108:223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, Gores GJ, et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology. 2009;49:871–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lleo A, Zhang W, McDonald WH, Seeley EH, Leung PS, Coppel RL, Ansari AA, et al. Shotgun proteomics: identification of unique protein profiles of apoptotic bodies from biliary epithelial cells. Hepatology. 2014;60:1314–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rong GH, Yang GX, Ando Y, Zhang W, He XS, Leung PS, Coppel RL, et al. Human intrahepatic biliary epithelial cells engulf blebs from their apoptotic peers. Clin Exp Immunol. 2013;172:95–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Rong G, Zhong R, Lleo A, Leung PS, Bowlus CL, Yang GX, Yang CY, et al. Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis. Hepatology. 2011;54:196–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lleo A, Bowlus CL, Yang GX, Invernizzi P, Podda M, Van de Water J, Ansari AA, et al. Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology. 2010;52:987–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127:485–92.

    Article  PubMed  Google Scholar 

  107. Invernizzi P. Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving. Hepatology. 2011;54:714–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Donaldson P, Agarwal K, Craggs A, Craig W, James O, Jones D. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility. Gut. 2001;48:397–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Invernizzi P, Ransom M, Raychaudhuri S, Kosoy R, Lleo A, Shigeta R, Franke A, et al. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis. Genes Immun. 2012;13:461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Umemura T, Joshita S, Ichijo T, Yoshizawa K, Katsuyama Y, Tanaka E, Ota M, et al. Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis. Hepatology. 2012;55:506–11.

    Article  CAS  PubMed  Google Scholar 

  111. Zhao DT, Liao HY, Zhang X, Liu YM, Zhao Y, Zhang HP, Sun LM, et al. Human leucocyte antigen alleles and haplotypes and their associations with antinuclear antibodies features in Chinese patients with primary biliary cirrhosis. Liver Int. 2014;34:220–6.

    Article  CAS  PubMed  Google Scholar 

  112. Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360:2544–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Nakamura M, Nishida N, Kawashima M, Aiba Y, Tanaka A, Yasunami M, Nakamura H, et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet. 2012;91:721–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, Podda M, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42:658–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, Heneghan MA, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011;43:329–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, Ducker SJ, et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2012;44:1137–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mells GF, Kaser A, Karlsen TH. Novel insights into autoimmune liver diseases provided by genome-wide association studies. J Autoimmun. 2013;46:41–54.

    Article  CAS  PubMed  Google Scholar 

  118. Lleo A, Liao J, Invernizzi P, Zhao M, Bernuzzi F, Ma L, Lanzi G, et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology. 2012;55:153–60.

    Article  CAS  PubMed  Google Scholar 

  119. Amur S, Parekh A, Mummaneni. Sex differences and genomics in autoimmune diseases. J Autoimmun. 2012;38:J254–65.

    Article  CAS  PubMed  Google Scholar 

  120. Mitchell MM, Lleo A, Zammataro L, Mayo MJ, Invernizzi P, Bach N, Shimoda S, et al. Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis. Epigenetics. 2011;6:95–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. O’Hara SP, Gradilone SA, Masyuk TV, Tabibian JH, LaRusso NF. MicroRNAs in Cholangiopathies. Curr Pathobiol Rep. 2014;2:133–42.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Juran BD, Lazaridis KN. Environmental factors in primary biliary cirrhosis. Semin Liver Dis. 2014;34:265–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Burroughs AK, Rosenstein IJ, Epstein O, Hamilton-Miller JM, Brumfitt W, Sherlock S. Bacteriuria and primary biliary cirrhosis. Gut. 1984;25:133–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Varyani FK, West J, Card TR. An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterol. 2011;11:95.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008;3:304–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, Leung PS, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology. 2003;38:1250–7.

    Article  CAS  PubMed  Google Scholar 

  127. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, Coppel RL, et al. Analysis of TCR antagonism and molecular mimicry of an HLA-A0201-restricted CTL epitope in primary biliary cirrhosis. Hepatology. 2002;36:918–26.

    Article  CAS  PubMed  Google Scholar 

  128. Fujiwara K, Yokosuka O. Frequent detection of immunoglobulin M anti-herpes simplex viral antibody in patients with primary biliary cirrhosis. Hepatology. 2012;56:395.

    Article  PubMed  Google Scholar 

  129. Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, O’Donnell B, et al. Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci U S A. 2003;100:8454–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Selmi C, Ross SR, Ansari AA, Invernizzi P, Podda M, Coppel RL, Gershwin ME. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology. 2004;127:493–501.

    Article  CAS  PubMed  Google Scholar 

  131. Morshed SA, Nishioka M, Saito I, Komiyama K, Moro I. Increased expression of Epstein-Barr virus in primary biliary cirrhosis patients. Gastroenterol Jpn. 1992;27:751–8.

    CAS  PubMed  Google Scholar 

  132. Uzoegwu PN, Baum H, Williamson J. The occurrence and localization in trypanosomes and other endo-parasites of an antigen cross-reacting with mitochondrial antibodies of primary biliary cirrhosis. Comp Biochem Physiol B. 1987;88:1181–9.

    CAS  PubMed  Google Scholar 

  133. Sakly W, Jeddi M, Ghedira I. Anti-Saccharomyces cerevisiae antibodies in primary biliary cirrhosis. Dig Dis Sci. 2008;53:1983–7.

    Article  CAS  PubMed  Google Scholar 

  134. Leung PS, Rossaro L, Davis PA, Park O, Tanaka A, Kikuchi K, Miyakawa H, et al. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology. 2007;46:1436–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. McLean MH, Dieguez Jr D, Miller LM, Young HA. Does the microbiota play a role in the pathogenesis of autoimmune diseases? Gut. 2015;64:332–41.

    Article  CAS  PubMed  Google Scholar 

  136. Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol. 1987;138:3525–31.

    CAS  PubMed  Google Scholar 

  137. Wang L, Wang FS, Chang C, Gershwin ME. Breach of tolerance: primary biliary cirrhosis. Semin Liver Dis. 2014;34:297–317.

    Article  PubMed  CAS  Google Scholar 

  138. Bjorkland A, Loof L, Mendel-Hartvig I, Totterman TH. Primary biliary cirrhosis. High proportions of B cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes. J Immunol. 1994;153:2750–7.

    CAS  PubMed  Google Scholar 

  139. Nakamura M, Ishibashi H, Matsui M, Shimoda S, Hayashida K, Koike K, Niho Y. Peripheral B lymphocyte repertoire to mitochondrial antigen in primary biliary cirrhosis--positive correlation between the disease activity and the frequency of circulating B lymphocytes specific for pyruvate dehydrogenase complex. Autoimmunity. 1995;21:253–62.

    Article  CAS  PubMed  Google Scholar 

  140. Moritoki Y, Lian ZX, Ohsugi Y, Ueno Y, Gershwin ME. B cells and autoimmune liver diseases. Autoimmun Rev. 2006;5:449–57.

    Article  CAS  PubMed  Google Scholar 

  141. Zhang J, Zhang W, Leung PS, Bowlus CL, Dhaliwal S, Coppel RL, Ansari AA, et al. Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis. Hepatology. 2014;60:1708–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med. 1995;181:1835–45.

    Article  CAS  PubMed  Google Scholar 

  143. Shimoda S, Ishikawa F, Kamihira T, Komori A, Niiro H, Baba E, Harada K, et al. Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory. Gastroenterology. 2006;131:606–18.

    Article  CAS  PubMed  Google Scholar 

  144. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, Coppel RL, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest. 2002;109:1231–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Harada K, Van de Water J, Leung PS, Coppel RL, Ansari A, Nakanuma Y, Gershwin ME. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset. Hepatology. 1997;25:791–6.

    Article  CAS  PubMed  Google Scholar 

  146. Nagano T, Yamamoto K, Matsumoto S, Okamoto R, Tagashira M, Ibuki N, Matsumura S, et al. Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol. 1999;19:422–7.

    Article  CAS  PubMed  Google Scholar 

  147. Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, Ridgway WM, et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol. 2006;177:1655–60.

    Article  CAS  PubMed  Google Scholar 

  148. Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH, Yang GX, et al. IL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Hepatology. 2006;44:1240–9.

    Article  CAS  PubMed  Google Scholar 

  149. Zhang W, Sharma R, Ju ST, He XS, Tao Y, Tsuneyama K, Tian Z, et al. Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology. 2009;49:545–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, Moritoki Y, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun. 2009;32:43–51.

    Article  CAS  PubMed  Google Scholar 

  151. Wang L, Sun Y, Zhang Z, Jia Y, Zou Z, Ding J, Li Y, et al. CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis. Hepatology. 2015;61:627–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tobe K. Electron microscopy of liver lesions in primary biliary cirrhosis. II. A bile duct with chronic non-suppurative destructive cholangitis. Acta Pathol Jpn. 1982;32:345–57.

    CAS  PubMed  Google Scholar 

  153. Takii Y, Nakamura M, Ito M, Yokoyama T, Komori A, Shimizu-Yoshida Y, Nakao R, et al. Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis. Lab Invest. 2005;85:908–20.

    Article  CAS  PubMed  Google Scholar 

  154. Honda Y, Yamagiwa S, Matsuda Y, Takamura M, Ichida T, Aoyagi Y. Altered expression of TLR homolog RP105 on monocytes hypersensitive to LPS in patients with primary biliary cirrhosis. J Hepatol. 2007;47:404–11.

    Article  CAS  PubMed  Google Scholar 

  155. Demetris AJ, Sever C, Kakizoe S, Oguma S, Starzl TE, Jaffe R. S100 protein positive dendritic cells in primary biliary cirrhosis and other chronic inflammatory liver diseases. Relevance to pathogenesis? Am J Pathol. 1989;134:741–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Tanimoto K, Akbar SM, Michitaka K, Onji M. Immunohistochemical localization of antigen presenting cells in liver from patients with primary biliary cirrhosis; highly restricted distribution of CD83-positive activated dendritic cells. Pathol Res Pract. 1999;195:157–62.

    Article  CAS  PubMed  Google Scholar 

  157. Akbar SM, Yamamoto K, Miyakawa H, Ninomiya T, Abe M, Hiasa Y, Masumoto T, et al. Peripheral blood T-cell responses to pyruvate dehydrogenase complex in primary biliary cirrhosis: role of antigen-presenting dendritic cells. Eur J Clin Invest. 2001;31:639–46.

    Article  CAS  PubMed  Google Scholar 

  158. Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, Luketic V, et al. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med. 2002;195:113–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hiasa Y, Akbar SM, Abe M, Michitaka K, Horiike N, Onji M. Dendritic cell subtypes in autoimmune liver diseases; decreased expression of HLA DR and CD123 on type 2 dendritic cells. Hepatol Res. 2002;22:241–9.

    Article  CAS  PubMed  Google Scholar 

  160. Harada K, Shimoda S, Ikeda H, Chiba M, Hsu M, Sato Y, Kobayashi M, et al. Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3alpha in the pathogenesis of primary biliary cirrhosis. Liver Int. 2011;31:245–53.

    Article  CAS  PubMed  Google Scholar 

  161. Panasiuk A, Prokopowicz D, Zak J. Peripheral blood T, B lymphocytes and NK cells in primary biliary cirrhosis. Rocz Akad Med Bialymst. 2001;46:231–9.

    CAS  PubMed  Google Scholar 

  162. Hudspeth K, Pontarini E, Tentorio P, Cimino M, Donadon M, Torzilli G, Lugli E, et al. The role of natural killer cells in autoimmune liver disease: a comprehensive review. J Autoimmun. 2013;46:55–65.

    Article  CAS  PubMed  Google Scholar 

  163. Chuang YH, Lian ZX, Yang GX, Shu SA, Moritoki Y, Ridgway WM, Ansari AA, et al. Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology. 2008;47:571–80.

    Article  CAS  PubMed  Google Scholar 

  164. Wu SJ, Yang YH, Tsuneyama K, Leung PS, Illarionov P, Gershwin ME, Chuang YH. Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology. 2011;53:915–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Aso-Ishimoto Y, Yamagiwa S, Ichida T, Miyakawa R, Tomiyama C, Sato Y, Watanabe H, et al. Increased activated natural killer T cells in the liver of patients with advanced stage primary biliary cirrhosis. Biomed Res. 2014;35:161–9.

    Article  CAS  PubMed  Google Scholar 

  166. Shimoda S, Tsuneyama K, Kikuchi K, Harada K, Nakanuma Y, Nakamura M, Ishibashi H, et al. The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis. Clin Exp Immunol. 2012;168:279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Trivedi PJ, Adams DH. Mucosal immunity in liver autoimmunity: a comprehensive review. J Autoimmun. 2013;46:97–111.

    Article  CAS  PubMed  Google Scholar 

  168. Li Y, Wang W, Tang L, He X, Yan X, Zhang X, Zhu Y, et al. Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis. Hepatology. 2015;61:1998–2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Tanaka A, Nezu S, Uegaki S, Mikami M, Okuyama S, Kawamura N, Aiso M, et al. The clinical significance of IgA antimitochondrial antibodies in sera and saliva in primary biliary cirrhosis. Ann N Y Acad Sci. 2007;1107:259–70.

    Article  CAS  PubMed  Google Scholar 

  170. Takahashi T, Miura T, Nakamura J, Yamada S, Miura T, Yanagi M, Matsuda Y, et al. Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis. Hepatology. 2012;55:846–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wang J, Yang GX, Tsuneyama K, Gershwin ME, Ridgway WM, Leung PS. Animal models of primary biliary cirrhosis. Semin Liver Dis. 2014;34:285–96.

    Article  CAS  PubMed  Google Scholar 

  172. Koarada S, Wu Y, Fertig N, Sass DA, Nalesnik M, Todd JA, Lyons PA, et al. Genetic control of autoimmunity: protection from diabetes, but spontaneous autoimmune biliary disease in a nonobese diabetic congenic strain. J Immunol. 2004;173:2315–23.

    Article  CAS  PubMed  Google Scholar 

  173. Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, Peterson LB, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med. 2006;203:1209–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I, Oude Elferink RP, et al. Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology. 2008;134:1482–93.

    Article  CAS  PubMed  Google Scholar 

  175. Wang JJ, Yang GX, Zhang WC, Lu L, Tsuneyama K, Kronenberg M, Vela JL, et al. Escherichia coli infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice. Clin Exp Immunol. 2014;175:192–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Katsumi T, Tomita K, Leung PS, Yang GX, Gershwin ME, Ueno Y. Animal models of primary biliary cirrhosis. Clin Rev Allergy Immunol. 2015;48:142–53.

    Article  PubMed  Google Scholar 

  177. Nakagome Y, Ueno Y, Kogure T, Fukushima K, Moritoki Y, Ridgway WM, Eric Gershwin M, et al. Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency. J Autoimmun. 2007;29:20–29

    Google Scholar 

  178. Kawata K, Tsuda M, Yang GX, Zhang W, Tanaka H, Tsuneyama K, Leung P, et al. Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis. PLoS One. 2013;8:e74225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Dhirapong A, Lleo A, Yang GX, Tsuneyama K, Dunn R, Kehry M, Packard TA, et al. B cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology. 2011;53:527–35.

    Article  CAS  PubMed  Google Scholar 

  180. Dhirapong A, Yang GX, Nadler S, Zhang W, Tsuneyama K, Leung P, Knechtle S, et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology. 2013;57:708–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bogdanos DP, Baum H, Grasso A, Okamoto M, Butler P, Ma Y, Rigopoulou E, et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol. 2004;40:31–9.

    Article  CAS  PubMed  Google Scholar 

  182. Padgett KA, Selmi C, Kenny TP, Leung PS, Balkwill DL, Ansari AA, Coppel RL, et al. Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun. 2005;24:209–19.

    Article  CAS  PubMed  Google Scholar 

  183. AW T. Review of the activation of TGF-beta in immunity. J Leukoc Biol. 2009;85:29–33.

    Google Scholar 

  184. Kawata K, Yang GX, Ando Y, Tanaka H, Zhang W, Kobayashi Y, Tsuneyama K, et al. Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFbetaRII mice. Hepatology. 2013;58:1094–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Leung PS, Yang GX, Dhirapong A, Tsuneyama K, Ridgway WM, Gershwin ME. Animal models of primary biliary cirrhosis: materials and methods. Methods Mol Biol. 2012;900:291–316.

    Article  CAS  PubMed  Google Scholar 

  186. Moritoki Y, Lian ZX, Lindor K, Tuscano J, Tsuneyama K, Zhang W, Ueno Y, et al. B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology. 2009;50:1893–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Yoshida K, Yang GX, Zhang W, Tsuda M, Tsuneyama K, Moritoki Y, Ansari AA, et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology. 2009;50:1494–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ando Y, Yang GX, Tsuda M, Kawata K, Zhang W, Nakajima T, Tsuneyama K, et al. The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice. Hepatology. 2012;56:1418–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Tsuda M, Zhang W, Yang GX, Tsuneyama K, Ando Y, Kawata K, Park O, et al. Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFbeta receptor type II mice. Hepatology. 2013;57:806–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Mackay IR. Primary biliary cirrhosis showing a high titer of autoantibody; report of a case. N Engl J Med. 1958;258:185–8.

    Article  CAS  PubMed  Google Scholar 

  191. Nakamura M. Clinical significance of autoantibodies in primary biliary cirrhosis. Semin Liver Dis. 2014;34:334–40.

    Article  CAS  PubMed  Google Scholar 

  192. Bandin O, Courvalin JC, Poupon R, Dubel L, Homberg JC, Johanet C. Specificity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis. Hepatology. 1996;23:1020–4.

    Article  CAS  PubMed  Google Scholar 

  193. Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, Daikoku M, et al. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol. 2005;42:386–92.

    Article  CAS  PubMed  Google Scholar 

  194. Invernizzi P, Podda M, Battezzati PM, Crosignani A, Zuin M, Hitchman E, Maggioni M, et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol. 2001;34:366–72.

    Article  CAS  PubMed  Google Scholar 

  195. Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology. 1996;110:840–7.

    Article  CAS  PubMed  Google Scholar 

  196. Davis LI, Blobel G. Nuclear pore complex contains a family of glycoproteins that includes p62: glycosylation through a previously unidentified cellular pathway. Proc Natl Acad Sci U S A. 1987;84:7552–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Lin F, Noyer CM, Ye Q, Courvalin JC, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR. Hepatology. 1996;23:57–61.

    Article  CAS  PubMed  Google Scholar 

  198. Courvalin JC, Lassoued K, Worman HJ, Blobel G. Identification and characterization of autoantibodies against the nuclear envelope lamin B receptor from patients with primary biliary cirrhosis. J Exp Med. 1990;172:961–7.

    Article  CAS  PubMed  Google Scholar 

  199. Zuchner D, Sternsdorf T, Szostecki C, Heathcote EJ, Cauch-Dudek K, Will H. Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis. Hepatology. 1997;26:1123–30.

    CAS  PubMed  Google Scholar 

  200. Mytilinaiou MG, Meyer W, Scheper T, Rigopoulou EI, Probst C, Koutsoumpas AL, Abeles D, et al. Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis. Clin Chim Acta. 2012;413:1211–6.

    Article  CAS  PubMed  Google Scholar 

  201. Szostecki C, Krippner H, Penner E, Bautz FA. Autoimmune sera recognize a 100 kD nuclear protein antigen (sp-100). Clin Exp Immunol. 1987;68:108–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Rigopoulou EI, Davies ET, Pares A, Zachou K, Liaskos C, Bogdanos DP, Rodes J, et al. Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis. Gut. 2005;54:528–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Granito A, Yang WH, Muratori L, Lim MJ, Nakajima A, Ferri S, Pappas G, et al. PML nuclear body component Sp140 is a novel autoantigen in primary biliary cirrhosis. Am J Gastroenterol. 2010;105:125–31.

    Article  CAS  PubMed  Google Scholar 

  204. Janka C, Selmi C, Gershwin ME, Will H, Sternsdorf T. Small ubiquitin-related modifiers: a novel and independent class of autoantigens in primary biliary cirrhosis. Hepatology. 2005;41:609–16.

    Article  CAS  PubMed  Google Scholar 

  205. Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, Takii Y, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2007;45:118–27.

    Article  CAS  PubMed  Google Scholar 

  206. Akbarali Y, Matousek-Ronck J, Hunt L, Staudt L, Reichlin M, Guthridge JM, James JA. Fine specificity mapping of autoantigens targeted by anti-centromere autoantibodies. J Autoimmun. 2006;27:272–80.

    Article  CAS  PubMed  Google Scholar 

  207. Walker JG, Doniach D, Roitt IM, Sherlock S. Serological tests in diagnosis of primary biliary cirrhosis. Lancet. 1965;1:827–31.

    Article  CAS  PubMed  Google Scholar 

  208. Fussey SP, Guest JR, James OF, Bassendine MF, Yeaman SJ. Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci U S A. 1988;85:8654–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Oertelt S, Rieger R, Selmi C, Invernizzi P, Ansari AA, Coppel RL, Podda M, et al. A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis. Hepatology. 2007;45:659–65.

    Article  CAS  PubMed  Google Scholar 

  210. Dahnrich C, Pares A, Caballeria L, Rosemann A, Schlumberger W, Probst C, Mytilinaiou M, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009;55:978–85.

    Article  PubMed  CAS  Google Scholar 

  211. Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010;55:2144–61.

    Article  CAS  PubMed  Google Scholar 

  212. Hu CJ, Zhang FC, Li YZ, Zhang X. Primary biliary cirrhosis: what do autoantibodies tell us? World J Gastroenterol. 2010;16:3616–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Liberal R, Grant CR, Sakkas L, Bizzaro N, Bogdanos DP. Diagnostic and clinical significance of anti-centromere antibodies in primary biliary cirrhosis. Clin Res Hepatol Gastroenterol. 2013;37:572–85.

    Article  CAS  PubMed  Google Scholar 

  214. Bizzaro N, Covini G, Rosina F, Muratori P, Tonutti E, Villalta D, Pesente F, et al. Overcoming a "probable" diagnosis in antimitochondrial antibody negative primary biliary cirrhosis: study of 100 sera and review of the literature. Clin Rev Allergy Immunol. 2012;42:288–97.

    Article  CAS  PubMed  Google Scholar 

  215. Benson GD, Kikuchi K, Miyakawa H, Tanaka A, Watnik MR, Gershwin ME. Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis. Clin Dev Immunol. 2004;11:129–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Courvalin JC, Worman HJ. Nuclear envelope protein autoantibodies in primary biliary cirrhosis. Semin Liver Dis. 1997;17:79–90.

    Article  CAS  PubMed  Google Scholar 

  217. Itoh S, Ichida T, Yoshida T, Hayakawa A, Uchida M, Tashiro-Itoh T, Matsuda Y, et al. Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 1998;13:257–65.

    Article  CAS  PubMed  Google Scholar 

  218. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, Rodrigo L, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol. 2003;98:431–7.

    Article  PubMed  Google Scholar 

  219. Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, Shibata M, et al. Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study. J Autoimmun. 2003;20:247–54.

    Article  CAS  PubMed  Google Scholar 

  220. Yang WH, Yu JH, Nakajima A, Neuberg D, Lindor K, Bloch DB. Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure? Clin Gastroenterol Hepatol. 2004;2:1116–22.

    Article  PubMed  Google Scholar 

  221. Wesierska-Gadek J, Penner E, Battezzati PM, Selmi C, Zuin M, Hitchman E, Worman HJ, et al. Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology. 2006;43:1135–44.

    Article  CAS  PubMed  Google Scholar 

  222. Szostecki C, Guldner HH, Will H. Autoantibodies against “nuclear dots” in primary biliary cirrhosis. Semin Liver Dis. 1997;17:71–8.

    Article  CAS  PubMed  Google Scholar 

  223. Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation. Hepatology. 2015;61:2080–90.

    Article  CAS  PubMed  Google Scholar 

  224. Paronetto F, Schaffner F, Popper H. Immunocytochemical and serologic observations in primary biliary cirrhosis. N Engl J Med. 1964;271:1123–8.

    Article  CAS  PubMed  Google Scholar 

  225. Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 1978;379:103–12.

    Article  CAS  PubMed  Google Scholar 

  226. Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology. 2002;122:652–8.

    Article  CAS  PubMed  Google Scholar 

  227. Kaplan MM. Primary biliary cirrhosis. N Engl J Med. 1996;335:1570–80.

    Article  CAS  PubMed  Google Scholar 

  228. Taal BG, Schalm SW, ten Kate FW, Hermans J, Geertzen RG, Feltkamp BE. Clinical diagnosis of primary biliary cirrhosis: a classification based on major and minor criteria. Hepatogastroenterology. 1983;30:178–82.

    CAS  PubMed  Google Scholar 

  229. Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000;31:1005–13.

    Article  CAS  PubMed  Google Scholar 

  230. Zein CO, Angulo P, Lindor KD. When is liver biopsy needed in the diagnosis of primary biliary cirrhosis? Clin Gastroenterol Hepatol. 2003;1:89–95.

    Article  PubMed  Google Scholar 

  231. Tan Y, Pan T, Ye Y, Ge G, Chen L, Wen D, Zou S. Serum microRNAs as potential biomarkers of primary biliary cirrhosis. PLoS One. 2014;9:e111424.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Norman GL, Yang CY, Ostendorff HP, Shums Z, Lim MJ, Wang J, Awad A, et al. Anti-kelch-like 12 and anti-hexokinase 1: novel autoantibodies in primary biliary cirrhosis. Liver Int. 2015;35:642–51.

    Article  CAS  PubMed  Google Scholar 

  233. Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin Immunopathol. 2009;31:283–307.

    Article  PubMed  PubMed Central  Google Scholar 

  234. Hagey LR, Crombie DL, Espinosa E, Carey MC, Igimi H, Hofmann AF. Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores. J Lipid Res. 1993;34:1911–7.

    CAS  PubMed  Google Scholar 

  235. Hofmann AF, Roda A. Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. J Lipid Res. 1984;25:1477–89.

    CAS  PubMed  Google Scholar 

  236. Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hubner K. Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci. 1985;30:642–9.

    Article  CAS  PubMed  Google Scholar 

  237. Guldutuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U. Molecular aspects of membrane stabilization by ursodeoxycholate. Gastroenterology. 1993;104:1736–44.

    Article  CAS  PubMed  Google Scholar 

  238. Heuman DM, Bajaj RS, Lin Q. Adsorption of mixtures of bile salt taurine conjugates to lecithin-cholesterol membranes: implications for bile salt toxicity and cytoprotection. J Lipid Res. 1996;37:562–73.

    CAS  PubMed  Google Scholar 

  239. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36:525–31.

    Article  CAS  PubMed  Google Scholar 

  240. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis. 2004;8:67–81. vi

    Article  PubMed  Google Scholar 

  241. Poupon R, Poupon RE. Treatment of primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol. 2000;14:615–28.

    Article  CAS  PubMed  Google Scholar 

  242. Medina JF, Martinez A, Vazquez JJ, Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology. 1997;25:12–7.

    Article  CAS  PubMed  Google Scholar 

  243. Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Pojer C, Zenz R, Lammert F, et al. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology. 2001;121:170–83.

    Article  CAS  PubMed  Google Scholar 

  244. Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, Silbert D, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 2005;129:476–85.

    Article  PubMed  Google Scholar 

  245. Beuers U, Bilzer M, Chittattu A, Kullak-Ublick GA, Keppler D, Paumgartner G, Dombrowski F. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology. 2001;33:1206–16.

    Article  CAS  PubMed  Google Scholar 

  246. Kurz AK, Graf D, Schmitt M, Vom Dahl S, Haussinger D. Tauroursodeoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats. Gastroenterology. 2001;121:407–19.

    Article  CAS  PubMed  Google Scholar 

  247. Dombrowski F, Stieger B, Beuers U. Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab Invest. 2006;86:166–74.

    Article  CAS  PubMed  Google Scholar 

  248. Kubitz R, Sutfels G, Kuhlkamp T, Kolling R, Haussinger D. Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology. 2004;126:541–53.

    Article  CAS  PubMed  Google Scholar 

  249. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(6):318–28.

    Article  CAS  PubMed  Google Scholar 

  250. Wimmer R, Hohenester S, Pusl T, Denk GU, Rust C, Beuers U. Tauroursodeoxycholic acid exerts anticholestatic effects by a cooperative cPKC{alpha}-/PKA-dependent mechanism in rat liver. Gut. 2008;57:1448–54.

    Article  CAS  PubMed  Google Scholar 

  251. Benz C, Angermuller S, Tox U, Kloters-Plachky P, Riedel HD, Sauer P, Stremmel W, et al. Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes. J Hepatol. 1998;28:99–106.

    Article  CAS  PubMed  Google Scholar 

  252. Rodrigues CM, Fan G, Wong PY, Kren BT, Steer CJ. Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med. 1998;4:165–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Benz C, Angermuller S, Otto G, Sauer P, Stremmel W, Stiehl A. Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes. Eur J Clin Invest. 2000;30:203–9.

    Article  CAS  PubMed  Google Scholar 

  254. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol. 2001;35:134–46.

    Article  CAS  PubMed  Google Scholar 

  255. Azzaroli F, Mehal W, Soroka CJ, Wang L, Lee J, Crispe IN, Boyer JL. Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. Hepatology. 2002;36:49–54.

    Article  CAS  PubMed  Google Scholar 

  256. Graf D, Kurz AK, Fischer R, Reinehr R, Haussinger D. Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner. Gastroenterology. 2002;122:1411–27.

    Article  CAS  PubMed  Google Scholar 

  257. Yoshikawa M, Tsujii T, Matsumura K, Yamao J, Matsumura Y, Kubo R, Fukui H, et al. Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology. 1992;16:358–64.

    Article  CAS  PubMed  Google Scholar 

  258. Calmus Y, Guechot J, Podevin P, Bonnefis MT, Giboudeau J, Poupon R. Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes. Hepatology. 1992;16:719–23.

    Article  CAS  PubMed  Google Scholar 

  259. Lacaille F, Paradis K. The immunosuppressive effect of ursodeoxycholic acid: a comparative in vitro study on human peripheral blood mononuclear cells. Hepatology. 1993;18:165–72.

    CAS  PubMed  Google Scholar 

  260. Calmus Y, Weill B, Ozier Y, Chereau C, Houssin D, Poupon R. Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic acids in the mouse. Gastroenterology. 1992;103:617–21.

    Article  CAS  PubMed  Google Scholar 

  261. Tanaka H, Makino Y, Miura T, Hirano F, Okamoto K, Komura K, Sato Y, et al. Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway. J Immunol. 1996;156:1601–8.

    CAS  PubMed  Google Scholar 

  262. Miura T, Ouchida R, Yoshikawa N, Okamoto K, Makino Y, Nakamura T, Morimoto C, et al. Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid. J Biol Chem. 2001;276:47371–8.

    Article  CAS  PubMed  Google Scholar 

  263. Weitzel C, Stark D, Kullmann F, Scholmerich J, Holstege A, Falk W. Ursodeoxycholic acid induced activation of the glucocorticoid receptor in primary rat hepatocytes. Eur J Gastroenterol Hepatol. 2005;17:169–77.

    Article  CAS  PubMed  Google Scholar 

  264. Poupon R, Chretien Y, Poupon RE, Ballet F, Calmus Y, Darnis F. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet. 1987;1:834–6.

    Article  CAS  PubMed  Google Scholar 

  265. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991;324:1548–54.

    Article  CAS  PubMed  Google Scholar 

  266. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, Michieletti P, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994;19:1149–56.

    Article  CAS  PubMed  Google Scholar 

  267. Combes B, Carithers Jr RL, Maddrey WC, Lin D, McDonald MF, Wheeler DE, Eigenbrodt EH, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1995;22:759–66.

    CAS  PubMed  Google Scholar 

  268. Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 1996;110:1515–8.

    Article  CAS  PubMed  Google Scholar 

  269. Eriksson LS, Olsson R, Glauman H, Prytz H, Befrits R, Ryden BO, Einarsson K, et al. Ursodeoxycholic acid treatment in patients with primary biliary cirrhosis. A Swedish multicentre, double-blind, randomized controlled study. Scand J Gastroenterol. 1997;32:179–86.

    Article  CAS  PubMed  Google Scholar 

  270. Leuschner U, Fischer H, Kurtz W, Guldutuna S, Hubner K, Hellstern A, Gatzen M, et al. Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology. 1989;97:1268–74.

    Article  CAS  PubMed  Google Scholar 

  271. Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, Harrison JM, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994;106:1284–90.

    Article  CAS  PubMed  Google Scholar 

  272. Angulo P, Dickson ER, Therneau TM, Jorgensen RA, Smith C, DeSotel CK, Lange SM, et al. Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. J Hepatol. 1999;30:830–5.

    Article  CAS  PubMed  Google Scholar 

  273. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000;32:1196–9.

    Article  CAS  PubMed  Google Scholar 

  274. Poupon RE, Lindor KD, Pares A, Chazouilleres O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol. 2003;39:12–6.

    Article  CAS  PubMed  Google Scholar 

  275. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med. 1994;330:1342–7.

    Article  CAS  PubMed  Google Scholar 

  276. Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet. 1999;354:1053–60.

    Article  CAS  PubMed  Google Scholar 

  277. Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses. Am J Gastroenterol. 2007;102:1799–807.

    Article  CAS  PubMed  Google Scholar 

  278. Gong Y, Huang ZB, Christensen E, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev. 2008;12:CD000551.

    Google Scholar 

  279. Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev. 2012;12:CD000551.

    PubMed  Google Scholar 

  280. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113:884–90.

    Article  CAS  PubMed  Google Scholar 

  281. Poupon RE, Bonnand AM, Chretien Y, Poupon R. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology. 1999;29:1668–71.

    Article  CAS  PubMed  Google Scholar 

  282. Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C, Heathcote EJ, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105:2186–94.

    Article  CAS  PubMed  Google Scholar 

  283. Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–7.

    Article  CAS  PubMed  Google Scholar 

  284. Zhang LN, Shi TY, Shi XH, Wang L, Yang YJ, Liu B, Gao LX, et al. Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study. Hepatology. 2013;58:264–72.

    Article  CAS  PubMed  Google Scholar 

  285. Azemoto N, Abe M, Murata Y, Hiasa Y, Hamada M, Matsuura B, Onji M. Early biochemical response to ursodeoxycholic acid predicts symptom development in patients with asymptomatic primary biliary cirrhosis. J Gastroenterol. 2009;44:630–4.

    Article  CAS  PubMed  Google Scholar 

  286. Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, Floreani A, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149:1804–1812.e4.

    Article  PubMed  Google Scholar 

  287. Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, Ponsioen CY, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147:1338–1349 e1335. ; quiz e1315

    Article  CAS  PubMed  Google Scholar 

  288. Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, Griffiths L, et al. The UK-PBC Risk Scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cirrhosis. Hepatology. 2016;63:930–50.

    Article  CAS  PubMed  Google Scholar 

  289. Trivedi PJ, Bruns T, Cheung A, Li KK, Kittler C, Kumagi T, Shah H, et al. Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response. J Hepatol. 2014;60:1249–58.

    Article  CAS  PubMed  Google Scholar 

  290. Raczynska J, Habior A, Paczek L, Foroncewicz B, Pawelas A, Mucha K. Primary biliary cirrhosis in the era of liver transplantation. Ann Transplant. 2014;19:488–93.

    Article  PubMed  Google Scholar 

  291. Neuberger J, Portmann B, Macdougall BR, Calne RY, Williams R. Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med. 1982;306:1–4.

    Article  CAS  PubMed  Google Scholar 

  292. Carbone M, Neuberger J. Liver transplantation in PBC and PSC: indications and disease recurrence. Clin Res Hepatol Gastroenterol. 2011;35:446–54.

    Article  PubMed  Google Scholar 

  293. Schreibman I, Regev A. Recurrent primary biliary cirrhosis after liver transplantation – the disease and its management. MedGenMed. 2006;8:30.

    PubMed  PubMed Central  Google Scholar 

  294. Neuberger J. Recurrent primary biliary cirrhosis. Liver Transpl. 2003;9:539–46.

    Article  PubMed  Google Scholar 

  295. Charatcharoenwitthaya P, Pimentel S, Talwalkar JA, Enders FT, Lindor KD, Krom RA, Wiesner RH. Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl. 2007;13:1236–45.

    Article  PubMed  Google Scholar 

  296. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center. Hepatology. 2001;33:22–7.

    Article  CAS  PubMed  Google Scholar 

  297. Morioka D, Egawa H, Kasahara M, Jo T, Sakamoto S, Ogura Y, Haga H, et al. Impact of human leukocyte antigen mismatching on outcomes of living donor liver transplantation for primary biliary cirrhosis. Liver Transpl. 2007;13:80–90.

    Article  PubMed  Google Scholar 

  298. Hashimoto T, Sugawara Y, Makuuchi M. Impact of human leukocyte antigen mismatching on outcomes of living donor liver transplantation for primary biliary cirrhosis. Liver Transpl. 2007;13:938–9.

    Article  PubMed  Google Scholar 

  299. Neuberger J, Gunson B, Hubscher S, Nightingale P. Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl. 2004;10:488–91.

    Article  PubMed  Google Scholar 

  300. Manousou P, Arvaniti V, Tsochatzis E, Isgro G, Jones K, Shirling G, Dhillon AP, et al. Primary biliary cirrhosis after liver transplantation: influence of immunosuppression and human leukocyte antigen locus disparity. Liver Transpl. 2010;16:64–73.

    Article  PubMed  Google Scholar 

  301. Grat M, Lewandowski Z, Patkowski W, Wronka KM, Grat K, Krasnodebski M, Ligocka J, et al. Relevance of male-to-female sex mismatch in liver transplantation for primary biliary cirrhosis. Ann Transplant. 2015;20:116–23.

    Article  PubMed  Google Scholar 

  302. Guy JE, Qian P, Lowell JA, Peters MG. Recurrent primary biliary cirrhosis: peritransplant factors and ursodeoxycholic acid treatment post-liver transplant. Liver Transpl. 2005;11:1252–7.

    Article  PubMed  PubMed Central  Google Scholar 

  303. Quarneti C, Muratori P, Lalanne C, Fabbri A, Menichella R, Granito A, Masi C, et al. Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis. Liver Int. 2015;35:636–41.

    Article  PubMed  Google Scholar 

  304. Al-Harthy N, Kumagi T, Coltescu C, Hirschfield GM. The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice. Hepatology. 2010;52:562–70.

    Article  PubMed  Google Scholar 

  305. Cauch-Dudek K, Abbey S, Stewart DE, Heathcote EJ. Fatigue in primary biliary cirrhosis. Gut. 1998;43:705–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Newton JL, Hudson M, Tachtatzis P, Sutcliffe K, Pairman J, Burt JA, Jones DE. Population prevalence and symptom associations of autonomic dysfunction in primary biliary cirrhosis. Hepatology. 2007;45:1496–505.

    Article  PubMed  Google Scholar 

  307. Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology. 2006;44:91–8.

    Article  PubMed  Google Scholar 

  308. Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18(Suppl 1):S79–83.

    Article  PubMed  Google Scholar 

  309. Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, Jones DE. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 2005;54:1622–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. Kaplan MM, Bonis PA. Modafinil for the treatment of fatigue in primary biliary cirrhosis. Ann Intern Med. 2005;143:546–7.

    Article  PubMed  Google Scholar 

  311. Ian Gan S, de Jongh M, Kaplan MM. Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience. Dig Dis Sci. 2009;54:2242–6.

    Article  CAS  PubMed  Google Scholar 

  312. Alemi F, Kwon E, Poole DP, Lieu T, Lyo V, Cattaruzza F, Cevikbas F, et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest. 2013;123:1513–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. Dawson PA, Karpen SJ. Bile acids reach out to the spinal cord: new insights to the pathogenesis of itch and analgesia in cholestatic liver disease. Hepatology. 2014;59:1638–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Beuers U, Kremer AE, Bolier R, Elferink RP. Pruritus in cholestasis: facts and fiction. Hepatology. 2014;60:399–407.

    Article  CAS  PubMed  Google Scholar 

  315. Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EM, Mettang T, Reiners KS, et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions. Hepatology. 2012;56:1391–400.

    Article  CAS  PubMed  Google Scholar 

  316. Garbutt JT, Kenney TJ. Effect of cholestyramine on bile acid metabolism in normal man. J Clin Invest. 1972;51:2781–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Javitt NB. Letter: timing of cholestyramine doses in cholestatic liver disease. N Engl J Med. 1974;290:1328–9.

    CAS  PubMed  Google Scholar 

  318. Rust C, Sauter GH, Oswald M, Buttner J, Kullak-Ublick GA, Paumgartner G, Beuers U. Effect of cholestyramine on bile acid pattern and synthesis during administration of ursodeoxycholic acid in man. Eur J Clin Invest. 2000;30:135–9.

    Article  CAS  PubMed  Google Scholar 

  319. Bachs L, Pares A, Elena M, Piera C, Rodes J. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet. 1989;1:574–6.

    Article  CAS  PubMed  Google Scholar 

  320. Tandon P, Rowe BH, Vandermeer B, Bain VG. The efficacy and safety of bile Acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol. 2007;102:1528–36.

    Article  CAS  PubMed  Google Scholar 

  321. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997;113:1264–9.

    Article  CAS  PubMed  Google Scholar 

  322. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol. 2002;37:717–22.

    Article  CAS  PubMed  Google Scholar 

  323. Browning J, Combes B, Mayo MJ. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol. 2003;98:2736–41.

    Article  CAS  PubMed  Google Scholar 

  324. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45:666–74.

    Article  CAS  PubMed  Google Scholar 

  325. Pares A. Old and novel therapies for primary biliary cirrhosis. Semin Liver Dis. 2014;34:341–51.

    Article  CAS  PubMed  Google Scholar 

  326. Raszeja-Wyszomirska J, Miazgowski T. Osteoporosis in primary biliary cirrhosis of the liver. Prz Gastroenterol. 2014;9:82–7.

    PubMed  PubMed Central  Google Scholar 

  327. Pares A, Guanabens N. Osteoporosis in primary biliary cirrhosis: pathogenesis and treatment. Clin Liver Dis. 2008;12:407–24. x

    Article  PubMed  Google Scholar 

  328. Treeprasertsuk S, Silveira MG, Petz JL, Lindor KD. Parenteral bisphosphonates for osteoporosis in patients with primary biliary cirrhosis. Am J Ther. 2011;18:375–81.

    Article  PubMed  Google Scholar 

  329. Hofmann AF, Zakko SF, Lira M, Clerici C, Hagey LR, Lambert KK, Steinbach JH, et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology. 2005;42:1391–8.

    Article  CAS  PubMed  Google Scholar 

  330. Yoon YB, Hagey LR, Hofmann AF, Gurantz D, Michelotti EL, Steinbach JH. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology. 1986;90:837–52.

    Article  CAS  PubMed  Google Scholar 

  331. Hofmann AF, Hagey LR. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J Lipid Res. 2014;55:1553–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  332. Trauner M, Fickert P, Halilbasic E, Moustafa T. Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. Wien Med Wochenschr. 2008;158:542–8.

    Article  PubMed  Google Scholar 

  333. Hohenester S, Wenniger LM, Paulusma CC, van Vliet SJ, Jefferson DM, Elferink RP, Beuers U. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 2012;55:173–83.

    Article  CAS  PubMed  Google Scholar 

  334. Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, Kratky D, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology. 2012;142:140–51. e112

    Article  CAS  PubMed  Google Scholar 

  335. Trauner M, Halilbasic E, Kazemi-Shirazi L, Kienbacher C, Staufer K, Traussnigg S, Hofer H. Therapeutic role of bile acids and nuclear receptor agonists in fibrosing cholangiopathies. Dig Dis. 2014;32:631–6.

    Article  PubMed  Google Scholar 

  336. Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015;62:S25–37.

    Article  CAS  PubMed  Google Scholar 

  337. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45:3569–72.

    Article  CAS  PubMed  Google Scholar 

  338. Matsumoto T, Miyazaki H, Nakahashi Y, Hirohara J, Seki T, Inoue K, Okazaki K. Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate. Hepatol Res. 2004;30:125–36.

    Article  CAS  PubMed  Google Scholar 

  339. Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, Saito Y, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013;57:1931–41.

    Article  CAS  PubMed  Google Scholar 

  340. Zhang Y, Chen K, Dai W, Xia Y, Wang F, Shen M, Cheng P, et al. Combination therapy of bezafibrate and ursodeoxycholic acid for primary biliary cirrhosis: a meta-analysis. Hepatol Res. 2015;45:48–58.

    Article  CAS  PubMed  Google Scholar 

  341. Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev. 2005;204:102–15.

    Article  CAS  PubMed  Google Scholar 

  342. Oertelt S, Kenny TP, Selmi C, Invernizzi P, Podda M, Gershwin ME. SNP analysis of genes implicated in T cell proliferation in primary biliary cirrhosis. Clin Dev Immunol. 2005;12:259–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  343. Tanaka H, Yang GX, Tomiyama T, Tsuneyama K, Zhang W, Leung PS, Coppel RL, et al. Immunological potential of cytotoxic T lymphocyte antigen 4 immunoglobulin in murine autoimmune cholangitis. Clin Exp Immunol. 2015;180:371–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  344. Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology. 1989;10:420–9.

    Article  CAS  PubMed  Google Scholar 

  345. Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol. 1992;15:336–44.

    Article  CAS  PubMed  Google Scholar 

  346. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, Farkkila M. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology. 2005;41:747–52.

    Article  CAS  PubMed  Google Scholar 

  347. Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology. 2000;31:318–23.

    Article  CAS  PubMed  Google Scholar 

  348. Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology. 2003;38:196–202.

    Article  CAS  PubMed  Google Scholar 

  349. Leung J, Bonis PA, Kaplan MM. Colchicine or methotrexate, with ursodiol, are effective after 20 years in a subset of patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2011;9:776–80.

    Article  CAS  PubMed  Google Scholar 

  350. Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, McCashland TM, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology. 2005;42:1184–93.

    Article  CAS  PubMed  Google Scholar 

  351. Afford SC, Ahmed-Choudhury J, Randhawa S, Russell C, Youster J, Crosby HA, Eliopoulos A, et al. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells. FASEB J. 2001;15:2345–54.

    Article  CAS  PubMed  Google Scholar 

  352. Oertelt S, Invernizzi P, Selmi C, Podda M, Gershwin ME. Soluble CD40L in plasma of patients with primary biliary cirrhosis. Ann N Y Acad Sci. 2005;1051:205–10.

    Article  CAS  PubMed  Google Scholar 

  353. Higuchi M, Horiuchi T, Kojima T, Nishizaka H, Ishibashi H, Hayashi K, Niho Y, et al. Analysis of CD40 ligand gene mutations in patients with primary biliary cirrhosis. Scand J Clin Lab Invest. 1998;58:429–32.

    Article  CAS  PubMed  Google Scholar 

  354. Tanaka H, Yang GX, Iwakoshi N, Knechtle SJ, Kawata K, Tsuneyama K, Leung P, et al. Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clin Exp Immunol. 2013;174:364–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  355. Tsuda M, Moritoki Y, Lian ZX, Zhang W, Yoshida K, Wakabayashi K, Yang GX, et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology. 2012;55:512–21.

    Article  CAS  PubMed  Google Scholar 

  356. Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013;108:933–41.

    Article  CAS  PubMed  Google Scholar 

  357. Figueroa FE, Carrion F, Villanueva S, Khoury M. Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol Res. 2012;45:269–77.

    Article  PubMed  CAS  Google Scholar 

  358. Wang D, Zhang H, Liang J, Gu Z, Ma X, Huang J, Lin J, et al. Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model. Clin Exp Med. 2011;11:25–32.

    Article  CAS  PubMed  Google Scholar 

  359. Wang L, Li J, Liu H, Li Y, Fu J, Sun Y, Xu R, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 2013;28(Suppl 1):85–92.

    Article  CAS  PubMed  Google Scholar 

  360. Wang L, Han Q, Chen H, Wang K, Shan GL, Kong F, Yang YJ, et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis. Stem Cells Dev. 2014;23:2482–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Professor Ulrich Beuers who produced four figures for this chapter.

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Authors and Affiliations

  1. Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China

    Lifeng Wang & Fu-Sheng Wang

  2. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA

    Christopher L. Bowlus & M. Eric Gershwin

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  1. Lifeng Wang
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  2. Christopher L. Bowlus
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  3. Fu-Sheng Wang
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  4. M. Eric Gershwin
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Correspondence to Fu-Sheng Wang or M. Eric Gershwin .

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  1. Centre for Liver Research NIHR Biomedical Research Unit, Institute of Immunology and Immunotherapy University of Birmingham, Birmingham, United Kingdom

    Gideon Hirschfield

  2. Centre for Liver Research NIHR Biomedical Research Unit, Institute of Immunology and Immunotherapy University of Birmingham, Birmingham, United Kingdom

    David Adams

  3. Centre for Liver Research NIHR Biomedical Research Unit, Institute of Immunology and Immunotherapy University of Birmingham, Birmingham, United Kingdom

    Evaggelia Liaskou

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Wang, L., Bowlus, C.L., Wang, FS., Gershwin, M.E. (2017). Primary Biliary Cholangitis: Its Science and Practice. In: Hirschfield, G., Adams, D., Liaskou, E. (eds) Biliary Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-50168-0_8

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