Journal of Hepatology
Volume 52, Issue 5 , Pages 745-758 , May 2010

Primary biliary cirrhosis: A 2010 update

  • Raoul Poupon

      Affiliations

    • Corresponding Author InformationAddress: Service d’Hépatologie, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. Tel.: +33 1 49 28 23 78; fax: +33 1 49 28 21 07.

Received 14 October 2009 ,Revised 27 November 2009 ,Accepted 30 November 2009.

References 

  1. Addison T, Gull W. On a certain affection of the skin ,vitiligoidea – a. plana, b. tuberosa. Guys Hosp Rep. 1851;7:265–276
  2. Dauphinee JA, Sinclair JC. Primary biliary cirrhosis. Can J Gastroenterol. 1949;61:1–6
  3. Ahrens EH, Payne MA, Kunkel HG, Eisenmenger WJ, Blondheim SH. Primary biliary cirrhosis. Medicine (Baltimore). 1950;29:299–364
  4. Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis. Chronic non-suppurative destructive cholangitis. Am J Pathol. 1965;46:387–407
  5. Walker JG, Doniach D, Roitt IM, Sherlock S. Serological tests in diagnosis of primary biliary cirrhosis. Lancet. 1965;1:827–831
  6. Berg PA, Klein R, Lindenborn-Fotinos J, Kloppel W. ATPase-associated antigen (M2): marker antigen for serological diagnosis of primary biliary cirrhosis. Lancet. 1982;2:1423–1426
  7. Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification and specificity of a cDNA encoding the 70kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol. 1987;138:3525–3531
  8. Yeaman SJ, Fussey SP, Danner DJ, James OF, Mutimer DJ, Bassendine MF. Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet. 1988;1:1067–1070
  9. Tzakis AG, Carcassonne C, Todo S, Makowka L, Starzl TE. Liver transplantation for primary biliary cirrhosis. Semin Immunol. 1989;9:144–148
  10. Poupon RE, Balkau B, Eschwege E, Poupon R UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med. 1991;324:1548–1554
  11. Prince MI, James OF. The epidemiology of primary biliary cirrhosis. Clin Liver Dis. 2003;7:795–819
  12. Corpechot C, Gaouar F, Salle AV, Diemert B, Carrat F, Johanet C, et al. Epidemiology of primary biliary cirrhosis: results of a prospective study performed on the overall metropolitan French population. Hepatology. 2008;48:602A
  13. Mattalia A, Quaranta S, Leung PS, Bauducci M, Van de Water J, Calvo PL, et al. Characterization of antimitochondrial antibodies in health adults. Hepatology. 1998;27:656–661
  14. Ohba K, Omagari K, Kinoshita H, Soda H, Masuda J, Hazama H, et al. Primary biliary cirrhosis among atomic bomb survivors in Nagasaki, Japan. J Clin Epidemiol. 2001;54:845–850
  15. James OF, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV. Primary biliary cirrhosis once rare, now common in the United Kingdom?. Hepatology. 1999;30:390–394
  16. Metcalf JV, Bhopal RS, Gray J, Howel D, James OF. Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England. Int J Epidemiol. 1997;26:830–836
  17. Kim WR, Lindor KD, Locke GR, Therneau TM, Homburger HA, Batts KP, et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. 2000;119:1631–1636
  18. Watson RG, Angus PW, Dewar M, Goss B, Sewell RB, Smallwood RA. Low prevalence of primary biliary cirrhosis in Victoria, Australia. Melbourne Liver Group. Gut. 1995;36:927–930
  19. Sood S, Gow PJ, Christie JM, Angus PW. Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations. Gastroenterology. 2004;127:470–475
  20. Remmel T, Remmel H, Uibo R, Salupere V. Primary biliary cirrhosis in Estonia. With special reference to incidence, prevalence, clinical features, and outcome. Scand J Gastroenterol. 1995;30:367–371
  21. Danielsson A, Boqvist L, Uddenfeldt P. Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden. Hepatology. 1990;11:458–464
  22. Prince MI, Chetwynd A, Diggle P, Jarner M, Metcalf JV, James OF. The geographical distribution of primary biliary cirrhosis in a well-defined cohort. Hepatology. 2001;34:1083–1088
  23. Ala A, Stanca CM, Bu-Ghanim M, Ahmado I, Branch AD, Schiano TD, et al. Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites. Hepatology. 2006;43:525–531
  24. Abu-Mouch S, Selmi C, Benson GD, Kenny TP, Invernizzi P, Zuin M, et al. Geographic clusters of primary biliary cirrhosis. Clin Dev Immunol. 2003;10:127–131
  25. Arbour L, Field L, Ross P, Erikson A, Yoshida E. The mystery of primary biliary cirrhosis in British Columbia’s First Nations people. Int J Circumpolar Health. 2004;63:185–188
  26. Bach N, Schaffner F. Familial primary biliary cirrhosis. J Hepatol. 1994;20:698–701
  27. Tsuji K, Watanabe Y, Van De Water J, Nakanishi T, Kajiyama G, Parikh-Patel A, et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun. 1999;13:171–178
  28. Jones DE, Watt FE, Metcalf JV, Bassendine MF, James OF. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol. 1999;30:402–407
  29. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127:485–492
  30. Jones DE, Donaldson PT. Genetic factors in the pathogenesis of primary biliary cirrhosis. Clin Liver Dis. 2003;7:841–864
  31. Juran BD, Lazaridis KN. Genetics and genomics of primary biliary cirrhosis. Clin Liver Dis. 2008;12:349–365ix
  32. Tanaka A, Nezu S, Uegaki S, Kikuchi K, Shibuya A, Miyakawa H, et al. Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations. J Hepatol. 2009;50:1202–1209
  33. Poupon R, Ping C, Chretien Y, Corpechot C, Chazouilleres O, Simon T, et al. Genetic factors of susceptibility and of severity in primary biliary cirrhosis. J Hepatol. 2008;49:1038–1045
  34. Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Gu X, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360:2544–2555
  35. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol. 2006;18:347–361
  36. Walker EJ, Hirschfield GM, Xu C, Lu Y, Liu X, Coltescu C, et al. CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population. Arthritis Rheum. 2009;60:931–937
  37. Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Lazaridis KN. Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene. Gastroenterology. 2008;135:1200–1206
  38. Donaldson P, Veeramani S, Baragiotta A, Floreani A, Venturi C, Pearce S, et al. Cytotoxic T-lymphocyte-associated antigen-4 single nucleotide polymorphisms and haplotypes in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5:755–760
  39. d’Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology. 2009;136:1435–1443
  40. Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I, et al. Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology. 2008;134:1482–1493
  41. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42:1194–1202
  42. James O, Ducker S, Prince M. Case control studies support the association of environmental and genetic risk factors with primary biliary cirrhosis. Hepatology. 2005;42:299A
  43. Corpechot C, Chrétien Y, Chazouillères O, Poupon R. Results of the French study of risk factors for primary biliary cirrhosis. Hepatology. 2007;46:547A
  44. Howel D, Fischbacher CM, Bhopal RS, Gray J, Metcalf JV, James OF. An exploratory population-based case–control study of primary biliary cirrhosis. Hepatology. 2000;31:1055–1060
  45. Eliasson E, Gardner I, Hume-Smith H, de Waziers I, Beaune P, Kenna JG. Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis. Chem Biol Interact. 1998;116:123–141
  46. Lakehal F, Dansette PM, Becquemont L, Lasnier E, Delelo R, Balladur P, et al. Indirect cytotoxicity of flucloxacillin toward human biliary epithelium via metabolite formation in hepatocytes. Chem Res Toxicol. 2001;14:694–701
  47. Walden HR, Kirby JA, Yeaman SJ, Gray J, Jones DE, Palmer JM. Xenobiotic incorporation into pyruvate dehydrogenase complex can occur via the exogenous lipoylation pathway. Hepatology. 2008;48:1874–1884
  48. Leung PS, Park O, Tsuneyama K, Kurth MJ, Lam KS, Ansari AA, et al. Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol. 2007;179:2651–2657
  49. Long SA, Quan C, Van de Water J, Nantz MH, Kurth MJ, Barsky D, et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol. 2001;167:2956–2963
  50. Rieger R, Leung PS, Jeddeloh MR, Kurth MJ, Nantz MH, Lam KS, et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun. 2006;27:7–16
  51. Wakabayashi K, Yoshida K, Leung PS, Moritoki Y, Yang GX, Tsuneyama K, et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol. 2009;155:577–586
  52. Wakabayashi K, Lian ZX, Leung PS, Moritoki Y, Tsuneyama K, Kurth MJ, 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;48:531–540
  53. Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology. 2003;38:1250–1257
  54. Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008;3:304–315
  55. Sadamoto T, Joplin R, Keogh A, Mason A, Carman W, Neuberger J. Expression of pyruvate-dehydrogenase complex PDC-E2 on biliary epithelial cells induced by lymph nodes from primary biliary cirrhosis. Lancet. 1998;352:1595–1596
  56. Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, et al. Does a betaretrovirus infection trigger primary biliary cirrhosis?. Proc Natl Acad Sci USA. 2003;100:8454–8459
  57. Selmi C, Ross SR, Ansari AA, Invernizzi P, Podda M, Coppel RL, et al. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology. 2004;127:493–501
  58. Johal H, Scott GM, Jones R, Camaris C, Riordan S, Rawlinson WD. Mouse mammary tumour virus-like virus (MMTV-LV) is present within the liver in a wide range of hepatic disorders and unrelated to nuclear p53 expression or hepatocarcinogenesis. J Hepatol. 2009;50:548–554
  59. Mason AL, Lindor KD, Bacon BR, Vincent C, Neuberger JM, Wasilenko ST. Clinical trial: randomized controlled trial of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol. Aliment Pharmacol Ther. 2008;
  60. Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med. 2006;203:1209–1219
  61. Chen M, Graham D, Zhang G, Wasilenko S, McDougall C, Kneteman M, et al. Biliary infection with mouse mammary tumor virus in the nod.C3C4 mouse and other mouse models of primary biliary cirrhosis. Hepatology. 2007;46:551A
  62. Subsin B, Chen M, Girgis S, Mason AL. Mouse mammary tumor virus triggers viral cholangitis in the nod.c3c4 mouse model of primary biliary cirrhosis. Hepatology. 2009;50:998A
  63. Chuang YH, Ridgway WM, Ueno Y, Gershwin ME. Animal models of primary biliary cirrhosis. Clin Liver Dis. 2008;12:333–347ix
  64. Yoshida K, Yang GX, Zhang W, Tsuda M, Tsuneyama K, Moritoki Y, et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology. 2009;50:1494–1500
  65. Beuers U, Oude-Elferink RP. New light on anion exchangers in primary biliary cirrhosis. J Hepatol. 2008;49:881–883
  66. Tanaka A, Lindor K, Gish R, Batts K, Shiratori Y, Omata M, et al. Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis. Hepatology. 1999;30:833–838
  67. Corpechot C, Barbu V, Chazouilleres O, Poupon R. Fetal microchimerism in primary biliary cirrhosis. J Hepatol. 2000;33:696–700
  68. Fanning PA, Jonsson JR, Clouston AD, Edwards-Smith C, Balderson GA, Macdonald GA, et al. Detection of male DNA in the liver of female patients with primary biliary cirrhosis. J Hepatol. 2000;33:690–695
  69. Rubbia-Brandt L, Philippeaux MM, Chavez S, Mentha G, Borisch B, Hadengue A. FISH for Y chromosome in women with primary biliary cirrhosis: lack of evidence for leukocyte microchimerism. Hepatology. 1999;30:821–822
  70. Invernizzi P, De Andreis C, Sirchia SM, Battezzati PM, Zuin M, Rossella F, et al. Blood fetal microchimerism in primary biliary cirrhosis. Clin Exp Immunol. 2000;122:418–422
  71. Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR, Simoni G, et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet. 2004;363:533–535
  72. Invernizzi P, Miozzo M, Oertelt-Prigione S, Meroni PL, Persani L, Selmi C, et al. X monosomy in female systemic lupus erythematosus. Ann NY Acad Sci. 2007;1110:84–91
  73. Miozzo M, Selmi C, Gentilin B, Grati FR, Sirchia S, Oertelt S, et al. Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology. 2007;46:456–462
  74. Joplin R, Lindsay JG, Hubscher SG, Johnson GD, Shaw JC, Strain AJ, et al. Distribution of dihydrolipoamide acetyltransferase (E2) in the liver and portal lymph nodes of patients with primary biliary cirrhosis: an immunohistochemical study. Hepatology. 1991;14:442–447
  75. Joplin R, Lindsay JG, Johnson GD, Strain A, Neuberger J. Membrane dihydrolipoamide acetyltransferase (E2) on human biliary epithelial cells in primary biliary cirrhosis. Lancet. 1992;339:93–94
  76. Van de Water J, Turchany J, Leung PS, Lake J, Munoz S, Surh CD, et al. Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2. J Clin Invest. 1993;91:2653–2664
  77. Tsuneyama K, Van de Water J, Leung PS, Cha S, Nakanuma Y, Kaplan M, et al. Abnormal expression of the E2 component of the pyruvate dehydrogenase complex on the luminal surface of biliary epithelium occurs before major histocompatibility complex class II and BB1/B7 expression. Hepatology. 1995;21:1031–1037
  78. Van de Water J, Gerson LB, Ferrell LD, Lake JR, Coppel RL, Batts KP, et al. Immunohistochemical evidence of disease recurrence after liver transplantation for primary biliary cirrhosis. Hepatology. 1996;24:1079–1084
  79. Neuberger J. Liver allograft rejection – current concepts on diagnosis and treatment. J Hepatol. 1995;23:54–61
  80. 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;108:223–232
  81. Allina J, Hu B, Sullivan DM, Fiel MI, Thung SN, Bronk SF, et al. T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun. 2006;27:232–241
  82. Allina J, Stanca CM, Garber J, Hu B, Sautes-Fridman C, Bach N, et al. Anti-CD16 autoantibodies and delayed phagocytosis of apoptotic cells in primary biliary cirrhosis. J Autoimmun. 2008;30:238–245
  83. Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ, et al. Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. Hepatology. 2004;39:1415–1422
  84. Charlotte F, L’Hermine A, Martin N, Geleyn Y, Nollet M, Gaulard P, et al. Immunohistochemical detection of bcl-2 protein in normal and pathological human liver. Am J Pathol. 1994;144:460–465
  85. Celli A, Que FG. Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma. Semin Liver Dis. 1998;18:177–185
  86. Celli A, Que FG, Gores GJ, LaRusso NF. Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes. Am J Physiol. 1998;275:G749–G757
  87. Harada K, Nakanuma Y. Molecular mechanisms of cholangiopathy in primary biliary cirrhosis. Med Mol Morphol. 2006;39:55–61
  88. Koga H, Sakisaka S, Ohishi M, Sata M, Tanikawa K. Nuclear DNA fragmentation and expression of Bcl-2 in primary biliary cirrhosis. Hepatology. 1997;25:1077–1084
  89. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology. 1999;29:1007–1012
  90. Kuroki T, Seki S, Kawakita N, Nakatani K, Hisa T, Kitada T, et al. Expression of antigens related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis. Virchows Arch. 1996;429:119–129
  91. Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, et al. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol. 2004;41:905–912
  92. Onori P, Alvaro D, Floreani AR, Mancino MG, Franchitto A, Guido M, et al. Activation of the IGF1 system characterizes cholangiocyte survival during progression of primary biliary cirrhosis. J Histochem Cytochem. 2007;55:327–334
  93. Isse K, Harada K, Zen Y, Kamihira T, Shimoda S, Harada M, et al. Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. Hepatology. 2005;41:506–516
  94. Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A, et al. Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells. Hepatology. 2008;47:958–965
  95. Borchers AT, Shimoda S, Bowlus C, Keen CL, Gershwin ME. Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis. Semin Immunopathol. 2009;31:309–322
  96. Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol. 2009;157:261–270
  97. Shimoda S, Harada K, Niiro H, Taketomi A, Maehara Y, Tsuneyama K, et al. CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis. Hepatology. 2009;
  98. Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, et al. Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun. 2009;32:43–51
  99. Afford SC, Ahmed-Choudhury J, Randhawa S, Russell C, Youster J, Crosby HA, et al. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells. FASEB J. 2001;15:2345–2354
  100. Alvaro D, Mancino MG, Glaser S, Gaudio E, Marzioni M, Francis H, et al. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology. 2007;132:415–431
  101. Alvaro D, Mancino MG. New insights on the molecular and cell biology of human cholangiopathies. Mol Aspects Med. 2008;29:50–57
  102. Popper H, Paronetto F, Schaffner F. Immune processes in the pathogenesis of liver disease. Ann NY Acad Sci. 1965;124:781–799
  103. Portmann B, Popper H, Neuberger J, Williams R. Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients. Gastroenterology. 1985;88:1777–1790
  104. Nakanuma Y, Saito K, Unoura M. Semiquantitative assessment of cholestasis and lymphocytic piecemeal necrosis in primary biliary cirrhosis: a histologic and immunohistochemical study. J Clin Pathol. 1990;12:357–362
  105. Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology. 2002;122:652–658
  106. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007;117:539–548
  107. Kinnman N, Hultcrantz R, Barbu V, Rey C, Wendum D, Poupon R, et al. PDGF-mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury. Lab Invest. 2000;80:697–707
  108. Kinnman N, Francoz C, Barbu V, Wendum D, Rey C, Hultcrantz R, et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest. 2003;83:163–173
  109. Jhandier MN, Kruglov EA, Lavoie EG, Sevigny J, Dranoff JA. Portal fibroblasts regulate the proliferation of bile duct epithelia via expression of NTPDase2. J Biol Chem. 2005;280:22986–22992
  110. Kruglov EA, Nathanson RA, Nguyen T, Dranoff JA. Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am J Physiol Gastrointest Liver Physiol. 2006;290:G765–G771
  111. Jung Y, McCall SJ, Li YX, Diehl AM. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology. 2007;45:1091–1096
  112. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, et al. Hedgehog signaling regulates epithelial–mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest. 2008;118:3331–3342
  113. Omenetti A, Syn WK, Jung Y, Francis H, Porrello A, Witek RP, et al. Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology. 2009;50:518–527
  114. Levine RA, Hall RC. Cyclic AMP in secretin choleresis. Evidence for a regulatory role in man and baboons but not in dogs. Gastroenterology. 1976;70:537–544
  115. Alpini G, Baiocchi L, Glaser S, Ueno Y, Marzioni M, Francis H, et al. Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha. Hepatology. 2002;35:1041–1052
  116. Fitz JG. Regulation of cholangiocyte secretion. Semin Liver Dis. 2002;22:241–249
  117. Fiorotto R, Spirli C, Fabris L, Cadamuro M, Okolicsanyi L, Strazzabosco M. Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion. Gastroenterology. 2007;133:1603–1613
  118. Medina JF, Martinez A, Vazquez JJ, Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology. 1997;25:12–17
  119. Melero S, Spirli C, Zsembery A, Medina JF, Joplin RE, Duner E, et al. Defective regulation of cholangiocyte Cl−/HCO3(−) and Na+/H+ exchanger activities in primary biliary cirrhosis. Hepatology. 2002;35:1513–1521
  120. Shibao K, Hirata K, Robert ME, Nathanson MH. Loss of inositol 1,4,5-trisphosphate receptors from bile duct epithelia is a common event in cholestasis. Gastroenterology. 2003;125:117511–117587
  121. Spirli C, Nathanson MH, Fiorotto R, Duner E, Denson LA, Sanz JM, et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology. 2001;121:156–169
  122. Sakisaka S, Kawaguchi T, Taniguchi E, Hanada S, Sasatomi K, Koga H, et al. Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2001;33:1460–1468
  123. Spirli C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology. 2003;124:737–753
  124. Prieto J, Garcia N, Marti-Climent JM, Penuelas I, Richter JA, Medina JF. Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology. 1999;117:167–172
  125. Wong JH, Xia L, Ng TB. A review of defensins of diverse origins. Curr Gastroenterol Rep. 2007;8:446–459
  126. Tuin A, Huizinga-Van der Vlag A, van Loenen-Weemaes AM, Meijer DK, Poelstra K. On the role and fate of LPS-dephosphorylating activity in the rat liver. Am J Physiol Gastrointest Liver Physiol. 2006;290:G377–G385
  127. Sasatomi K, Noguchi K, Sakisaka S, Sata M, Tanikawa K. Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 1998;29:409–416
  128. Ballot E, Bandin O, Chazouilleres O, Johanet C, Poupon R. Immune response to lipopolysaccharide in primary biliary cirrhosis and autoimmune diseases. J Autoimmun. 2004;22:153–158
  129. Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, et al. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007;27:920–929
  130. Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003;38:717–727
  131. Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology. 2001;33:633–646
  132. Shapiro JM, Smith H, Schaffner F. Serum bilirubin: a prognostic factor in primary biliary cirrhosis. Gut. 1979;20:137–140
  133. Christensen E, Crowe J, Doniach D, Popper H, Ranek L, Rodes J, et al. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients. Gastroenterology. 1980;78:236–246
  134. Prince M, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002;123:1044–1051
  135. Locke GR, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology. 1996;23:52–56
  136. 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;32:1196–1199
  137. Gores GJ, Wiesner RH, Dickson ER, Zinsmeister AR, Jorgensen RA, Langworthy A. Prospective evaluation of esophageal varices in primary biliary cirrhosis: development, natural history, and influence on survival. Gastroenterology. 1989;96:1552–1559
  138. 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;29:644–647
  139. Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER. Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis. Mayo Clin Proc. 1997;72:1137–1140
  140. Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005;128:297–303
  141. Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130:715–720
  142. Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–877
  143. Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136:1281–1287
  144. Poupon R. Autoimmune overlapping syndromes. Clin Liver Dis. 2003;7:865–878
  145. Vleggaar FP, van Buuren HR, Zondervan PE, ten Kate FJ, Hop WC. Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant. Gut. 2001;49:276–281
  146. Bjornsson E, Simren M, Olsson R, Chapman RW. Fatigue is not a specific symptom in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2005;17:351–357
  147. Cauch-Dudek K, Abbey S, Stewart DE, Heathcote EJ. Fatigue in primary biliary cirrhosis. Gut. 1998;43:705–710
  148. Huet PM, Deslauriers J, Tran A, Faucher C, Charbonneau J. Impact of fatigue on the quality of life of patients with primary biliary cirrhosis. Am J Gastroenterol. 2000;95:760–767
  149. Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, et al. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 2005;54:1622–1629
  150. Poupon RE, Chretien Y, Chazouilleres O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cirrhosis. Hepatology. 2004;40:489–494
  151. Goldblatt J, Taylor PJ, Lipman T, Prince MI, Baragiotta A, Bassendine MF, et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology. 2002;122:1235–1241
  152. Newton JL. Fatigue in primary biliary cirrhosis. Clin Liver Dis. 2008;12:367–383ix
  153. van Os E, van den Broek WW, Mulder PG, ter Borg PC, Bruijn JA, van Buuren HR. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2007;46:1099–1103
  154. Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology. 2006;44:85–90
  155. Chang PY, Lu SC, Su TC, Chou SF, Huang WH, Morrisett JD, et al. Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation. J Lipid Res. 2004;45:2116–2122
  156. Poupon R, Chazouilleres O, Balkau B, Poupon RE. Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group. J Hepatol. 1999;30:408–412
  157. Corpechot C, Poujol-Robert A, Wendum D, Galotte M, Chretien Y, Poupon RE, et al. Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis. Liver Int. 2004;24:187–193
  158. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–267.
  159. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology. 2009;50:291–308
  160. Czaja AJ, Carpenter HA, Manns MP. Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology. 1993;105:1522–1528
  161. Yoshida T, Bonkovsky H, Ansari A, Danner D. Antibodies against mitochondrial dehydrogenase complexes in primary biliary cirrhosis. Gastroenterology. 1990;99:187–194
  162. O’Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology. 2008;48:550–556
  163. Czaja AJ, Carpenter HA. Autoimmune hepatitis with incidental histologic features of bile duct injury. Hepatology. 2001;34:659–665
  164. Gossard AA, Lindor KD. Development of autoimmune hepatitis in primary biliary cirrhosis. Liver Int. 2007;27:1086–1090
  165. 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
  166. Pares A, Guanabens N. Osteoporosis in primary biliary cirrhosis: pathogenesis and treatment. Clin Liver Dis. 2008;12:407–424x
  167. 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;113:884–890
  168. 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;29:1668–1671
  169. ter Borg PC, Schalm SW, Hansen BE, van Buuren HR. Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol. 2006;101:2044–2050
  170. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5:1313–1315
  171. Corpechot C, Poupon R. Geotherapeutics of primary biliary cirrhosis: bright and sunny around the Mediterranean but still cloudy and foggy in the United Kingdom. Hepatology. 2007;46:963–965
  172. Thomas C, Auwerx J, Schoonjans K. Bile acids and the membrane bile acid receptor TGR5 – connecting nutrition and metabolism. Thyroid. 2008;18:167–174
  173. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology. 1999;117:918–925
  174. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology. 2005;41:747–752
  175. Kaplan MM, Schmid C, Provenzale D, Sharma A, Dickstein G, McKusick A. A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis. Gastroenterology. 1999;117:1173–1180
  176. Babatin MA, Sanai FM, Swain MG. Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy. Aliment Pharmacol Ther. 2006;24:813–820
  177. Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology. 1995;22:1158–1162
  178. Gonzalez-Koch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol. 1997;27:143–149
  179. Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology. 2005;42:1184–1193
  180. Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology. 2004;39:915–923
  181. Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med. 1990;322:1419–1424
  182. Lombard M, Portmann B, Neuberger J, Williams R, Tygstrup N, Ranek L, et al. Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial. Gastroenterology. 1993;104:519–526
  183. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, et al. Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos. 2006;34:1575–1581
  184. Tsuboi K, Tazuma S, Ochi H, Chayama K. Hydrophilic bile salts have a cytoprotective effect against cyclosporine A-induced cholestasis through enhanced canalicular membrane fluidity and transporter activity. Hepatol Res. 2003;25:38–47
  185. Silveira MG, Lindor KD. Treatment of primary biliary cirrhosis: therapy with choleretic and immunosuppressive agents. Clin Liver Dis. 2008;12:425–443x–xi
  186. Vierling JM. Future treatment options in PBC. Semin Liver Dis. 2005;25:347–363
  187. Iwasaki S, Ohira H, Nishiguchi S, Zeniya M, Kaneko S, Onji M, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res. 2008;38:557–564
  188. Walker LJ, Newton J, Jones DE, Bassendine MF. Comment on biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2009;49:337–338[author reply 338]
  189. Chignard N, Poupon R. Targeting farnesoid x receptor in hepatic and biliary inflammatory diseases. Gastroenterology. 2009;137:734–735[discussion 736]
  190. Moritoki Y, Lian ZX, Lindor K, Tuscano J, Tsuneyama K, Zhang W, 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;[Epub ahead of print]
  191. Myers RP, Shaheen AA, Swain MG, Lee SS, Cole S, Coffey-Williamson S, et al. Rituximab for primary biliary cirrhosis (PBC) refractory to ursodeoxycholic acid (UDCA). Hepatology. 2007;46:550A
  192. Marzioni M, Alpini G, Saccomanno S, Candelaresi C, Venter J, Rychlicki C, et al. Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology. 2007;133:244–255
  193. Marzioni M, Alpini G, Saccomanno S, Candelaresi C, Venter J, Rychlicki C, et al. Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis. Gut. 2009;58:990–997
  194. MacQuillan GC, Neuberger J. Liver transplantation for primary biliary cirrhosis. Clin Liver Dis. 2003;7:941–956ix
  195. Schreuder TC, Hubscher SG, Neuberger J. Autoimmune liver diseases and recurrence after orthotopic liver transplantation: what have we learned so far?. Transpl Int. 2009;22:144–152
  196. Rust C, Sauter GH, Oswald M, Buttner J, Kullak-Ublick GA, Paumgartner G, et al. Effect of cholestyramine on bile acid pattern and synthesis during administration of ursodeoxycholic acid in man. Eur J Clin Invest. 2000;30:135–139
  197. Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int. 2006;26:943–948
  198. 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;102:1528–1536
  199. Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut. 2002;50:436–439
  200. Bergasa NV. Pruritus in primary biliary cirrhosis: pathogenesis and therapy. Clin Liver Dis. 2008;12:385–406x
  201. Kaplan MM, Bonis PA. Modafinil for the treatment of fatigue in primary biliary cirrhosis. Ann Intern Med. 2005;143:546–547
  202. Jones DE, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther. 2007;25:471–476
  203. Poupon RE, Ouguerram K, Chretien Y, Verneau C, Eschwege E, Magot T, et al. Cholesterol-lowering effect of ursodeoxycholic acid in patients with primary biliary cirrhosis. Hepatology. 1993;17:577–582
  204. Kurihara T, Akimoto M, Abe K, Ishiguro H, Niimi A, Maeda A, et al. Experimental use of pravastatin in patients with primary biliary cirrhosis associated with hypercholesterolemia. Clin Ther. 1993;15:890–898
  205. Stojakovic T, Claudel T, Putz-Bankuti C, Fauler G, Scharnagl H, Wagner M, et al. Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment. Atherosclerosis. 2009;
  206. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46:922–938

PII: S0168-8278(10)00027-9

doi: 10.1016/j.jhep.2009.11.027

Journal of Hepatology
Volume 52, Issue 5 , Pages 745-758 , May 2010

Article Tools

* Image Usage & Resolution