Skip to main content
Log in

Primary biliary cholangitis: a comprehensive overview

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90–95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Modified from [52]

Similar content being viewed by others

References

  1. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. Hepatology. 2015;62(5):1620–2. doi:10.1002/hep.28140 (PubMed PMID: 26372460).

    Article  PubMed  Google Scholar 

  2. Sherlock S. Primary billiary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterology. 1959;37:574–86 (PubMed PMID: 14445875).

    CAS  PubMed  Google Scholar 

  3. Walker JG, Doniach D, Roitt IM, Sherlock S. Serological tests in diagnosis of primary biliary cirrhosis. Lancet. 1965;39:827–31 (PubMed PMID: 14263538).

    Article  Google Scholar 

  4. 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(10):3525–31 (PubMed PMID: 3571977).

    CAS  PubMed  Google Scholar 

  5. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56(5):1181–8. doi:10.1016/j.jhep.2011.10.025 (PubMed PMID: 22245904).

    Article  PubMed  Google Scholar 

  6. Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. 2000;119(6):1631–6 (PubMed PMID: 11113084).

    Article  CAS  PubMed  Google Scholar 

  7. 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(4):830–6 (PubMed PMID: 9279616).

    Article  CAS  PubMed  Google Scholar 

  8. Koulentaki M, Mantaka A, Sifaki-Pistolla D, Thalassinos E, Tzanakis N, Kouroumalis E. Geoepidemiology and space-time analysis of primary biliary cirrhosis in Crete, Greece. Liver Int. 2014;34(7):e200–7. doi:10.1111/liv.12479 (PubMed PMID: 24502439).

    Article  CAS  PubMed  Google Scholar 

  9. 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(6):927–30 (PubMed PMID: 7615286; PubMed Central PMCID: PMCPMC1382635).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Witt-Sullivan H, Heathcote J, Cauch K, Blendis L, Ghent C, Katz A, et al. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology. 1990;12(1):98–105 (PubMed PMID: 2197212).

    Article  CAS  PubMed  Google Scholar 

  11. Chong VH, Telisinghe PU, Jalihal A. Primary biliary cirrhosis in Brunei Darussalam. Hepatobiliary Pancreat Dis Int. 2010;9(6):622–8 (PubMed PMID: 21134832).

    PubMed  Google Scholar 

  12. Lleo A, Jepsen P, Morenghi E, Carbone M, Moroni L, Battezzati PM, et al. Evolving trends in female to male incidence and male mortality of primary biliary cholangitis. Sci Rep. 2016;6:25906. doi:10.1038/srep25906 (PubMed PMID: 27192935; PubMed Central PMCID: PMCPMC4872151).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kisand KE, Metskula K, Kisand KV, Kivik T, Gershwin ME, Uibo R. The follow-up of asymptomatic persons with antibodies to pyruvate dehydrogenase in adult population samples. J Gastroenterol. 2001;36(4):248–54 (PubMed PMID: 11324728).

    Article  CAS  PubMed  Google Scholar 

  14. Marzorati S, Invernizzi P, Lleo A. Making sense of autoantibodies in cholestatic liver diseases. Clin Liver Dis. 2016;20(1):33–46. doi:10.1016/j.cld.2015.08.003 (PubMed PMID: 26593289).

    Article  PubMed  Google Scholar 

  15. Invernizzi P, Podda M, Battezzati PM, Crosignani A, Zuin M, Hitchman E, et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol. 2001;34(3):366–72 (PubMed PMID: 11322196).

    Article  CAS  PubMed  Google Scholar 

  16. 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(3):961–7 (PubMed PMID: 2167346; PubMed Central PMCID: PMC2188537).

    Article  CAS  PubMed  Google Scholar 

  17. Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology. 1996;110(3):840–7 (PubMed PMID: 8608894).

    Article  CAS  PubMed  Google Scholar 

  18. Inoue K, Hirohara J, Nakano T, Seki T, Sasaki H, Higuchi K, et al. Prediction of prognosis of primary biliary cirrhosis in Japan. Liver. 1995;15(2):70–7 (PubMed PMID: 7791541).

    Article  CAS  PubMed  Google Scholar 

  19. Ahrens EH Jr, Payne MA, Kunkel HG, Eisenmenger WJ, Blondheim SH. Primary biliary cirrhosis. Medicine (Baltimore). 1950;29(4):299–364 (PubMed PMID: 14796348).

    Article  Google Scholar 

  20. Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL, Heneghan MA, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013;144(3):560e7–569e7. doi:10.1053/j.gastro.2012.12.005 (quiz e13-4; PubMed PMID: 23246637).

    Article  CAS  Google Scholar 

  21. Longo M, Crosignani A, Battezzati PM, Squarcia Giussani C, Invernizzi P, Zuin M, et al. Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut. 2002;51(2):265–9 (PubMed PMID: 12117892).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Talwalkar JA, Lindor KD. Primary biliary cirrhosis. Lancet. 2003;362(9377):53–61 (PubMed PMID: 12853201).

    Article  CAS  PubMed  Google Scholar 

  23. Findor J, He XS, Sord J, Terg R, Gershwin ME. Primary biliary cirrhosis and hepatocellular carcinoma. Autoimmun Rev. 2002;1(4):220–5 (PubMed PMID: 12848999).

    Article  PubMed  Google Scholar 

  24. Trivedi PJ, Lammers WJ, van Buuren HR, Pares A, Floreani A, Janssen HL, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2016;65(2):321–9. doi:10.1136/gutjnl-2014-308351 (PubMed PMID: 25567117).

    Article  PubMed  Google Scholar 

  25. Hewagama A. Role of X-chromosome encoded miRNAs in autoimmunity: suppressing the suppressor and female predisposition. Rheumatol Curr Res. 2013;3(1):1000118.

    Google Scholar 

  26. 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(2):485–92 (PubMed PMID: 15300581).

    Article  PubMed  Google Scholar 

  27. Invernizzi P, Ransom M, Raychaudhuri S, Kosoy R, Lleo A, Shigeta R, et al. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis. Genes Immunity. 2012;13(6):461–8. doi:10.1038/gene.2012.17 (PubMed PMID: 22573116; PubMed Central PMCID: PMC3423484).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2012;44(10):1137–41. doi:10.1038/ng.2395 (PubMed PMID: 22961000; PubMed Central PMCID: PMC3459817).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Selmi C, De Santis M, Cavaciocchi F, Gershwin ME. Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. Dis Markers. 2010;29(6):287–99. doi:10.3233/DMA-2010-0746 (PubMed PMID: 21297248; PubMed Central PMCID: PMC3835616).

    Article  PubMed  Google Scholar 

  30. Selmi C, Cavaciocchi F, Lleo A, Cheroni C, De Francesco R, Lombardi SA, et al. Genome-wide analysis of DNA methylation, copy number variation, and gene expression in monozygotic twins discordant for primary biliary cirrhosis. Front Immunol. 2014;5:128. doi:10.3389/fimmu.2014.00128 (PubMed PMID: 24734033; PubMed Central PMCID: PMC3975093).

    PubMed  PubMed Central  Google Scholar 

  31. Lleo A, Liao J, Invernizzi P, Zhao M, Bernuzzi F, Ma L, et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology. 2012;55(1):153–60. doi:10.1002/hep.24630 (PubMed PMID: 21898485; PubMed Central PMCID: PMC3245335).

    Article  CAS  PubMed  Google Scholar 

  32. Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M. Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun. 2009;33(1):12–6. doi:10.1016/j.jaut.2009.03.005 (PubMed PMID: 19356902).

    Article  CAS  PubMed  Google Scholar 

  33. 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(9408):533–5 (PubMed PMID: 14975617).

    Article  PubMed  Google Scholar 

  34. Prothero KE, Stahl JM, Carrel L. Dosage compensation and gene expression on the mammalian X chromosome: one plus one does not always equal two. Chromosome Res. 2009;17(5):637–48. doi:10.1007/s10577-009-9063-9 (PubMed PMID: 19802704; PubMed Central PMCID: PMC4941101).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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(2):456–62. doi:10.1002/hep.21696 (PubMed PMID: 17659578).

    Article  CAS  PubMed  Google Scholar 

  36. Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology. 2009;49(3):871–9. doi:10.1002/hep.22736 (PubMed PMID: 19185000; PubMed Central PMCID: PMC2665925).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Leung PS, Rossaro L, Davis PA, Park O, Tanaka A, Kikuchi K, et al. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology. 2007;46(5):1436–42. doi:10.1002/hep.21828 (PubMed PMID: 17657817; PubMed Central PMCID: PMC3731127).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Youinou P. B cell conducts the lymphocyte orchestra. J Autoimmun. 2007;28(2–3):143–51. doi:10.1016/j.jaut.2007.02.011 (PubMed PMID: 17363215).

    Article  CAS  PubMed  Google Scholar 

  39. Lleo AIP, Mackay IR, Prince H, Zhong R-Q, Gershwin ME. Etiopathogenesis of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3328–37. doi:10.3748/wjg.14.3328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chuanga Y-H, Lian Z-X, Tsuneyamab K, Chiangc B-L, Ansarid AA, Coppele RL, Gershwin ME. Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun. 2006;26(4):232–40. doi:10.1016/j.jaut.2006.04.001 (PubMed PMID: 16730427).

    Article  CAS  Google Scholar 

  41. Mao TK, Lian Z-X, Selmi C, Ichiki Y, Ashwood P, Ansari AA, Coppel RL, Shimoda S, Ishibashi H, Gershwin ME. Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology. 2005;42:802–8.

    Article  CAS  PubMed  Google Scholar 

  42. Fava GGS, Francis H, Alpini G. The immunophysiology of biliary epithelium. Semin Liver Dis. 2005;25(3):251–64.

    Article  PubMed  Google Scholar 

  43. Harada K, Kono N, Tsuneyama K, Nakanuma Y. Cell-kinetic study of proliferating bile ductules in various hepatobiliary diseases. Liver. 1998;18(4):277–84.

    Article  CAS  PubMed  Google Scholar 

  44. Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology. 2008;47(2):737–45. doi:10.1002/hep.22042 (PubMed PMID: 18098322).

    Article  PubMed  Google Scholar 

  45. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol. 2001;35(1):134–46 (PubMed PMID: 11495032).

    Article  CAS  PubMed  Google Scholar 

  46. European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–67. doi:10.1016/j.jhep.2009.04.009 (PubMed PMID: 19501929).

    Article  Google Scholar 

  47. Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, 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(6):1338e5–1349e5. doi:10.1053/j.gastro.2014.08.029 (quiz e15; PubMed PMID: 25160979).

    Article  CAS  Google Scholar 

  48. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–43. doi:10.1056/NEJMoa1509840 (PubMed PMID: 27532829).

    Article  CAS  PubMed  Google Scholar 

  49. Oo YH, Neuberger J. Options for treatment of primary biliary cirrhosis. Drugs. 2004;64(20):2261–71 (PubMed PMID: 15456326).

    Article  CAS  PubMed  Google Scholar 

  50. Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013;57(5):1931–41. doi:10.1002/hep.26018 (PubMed PMID: 22911624).

    Article  CAS  PubMed  Google Scholar 

  51. Duclos-Vallee JC, Sebagh M. Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation. Liver Transpl. 2009;15(Suppl 2):S25–34. doi:10.1002/lt.21916 (PubMed PMID: 19876939).

    Article  PubMed  Google Scholar 

  52. Carbone M, Ronca V, Bruno S, Invernizzi P, Mells GF. Toward precision medicine in primary biliary cholangitis. Dig Liver Dis. 2016;48(8):843–50. doi:10.1016/j.dld.2016.05.023 (PubMed PMID: 27324985).

    Article  PubMed  Google Scholar 

  53. Tanaka A, Gershwin ME. Finding the cure for primary biliary cholangitis - Still waiting. Liver Int. 2017;37(4):500–2. doi:10.1111/liv.13344 (PubMed PMID: 28371099).

    Article  PubMed  Google Scholar 

  54. Tanaka T, Zhang W, Sun Y, Shuai Z, Chida AS, Kenny TP, et al. Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics. Hepatology. 2017;. doi:10.1002/hep.29245 (PubMed PMID: 28470667).

    Google Scholar 

  55. Generali E, Ceribelli A, Stazi MA, Selmi C. Lessons learned from twins in autoimmune and chronic inflammatory diseases. J Autoimmun. 2017;. doi:10.1016/j.jaut.2017.04.005 (PubMed PMID: 28431796).

    PubMed  Google Scholar 

  56. Marzorati S, Lleo A, Carbone M, Gershwin ME, Invernizzi P. The epigenetics of PBC: the link between genetic susceptibility and environment. Clin Res Hepatol Gastroenterol. 2016;40(6):650–9. doi:10.1016/j.clinre.2016.05.011 (PubMed PMID: 27341761).

    Article  CAS  PubMed  Google Scholar 

  57. Xiang Z, Yang Y, Chang C, Lu Q. The epigenetic mechanism for discordance of autoimmunity in monozygotic twins. J Autoimmun. 2017;. doi:10.1016/j.jaut.2017.04.003 (PubMed PMID: 28412046).

    Google Scholar 

  58. He XS, Gershwin ME, Ansari AA. Checkpoint-based immunotherapy for autoimmune diseases—opportunities and challenges. J Autoimmun. 2017;79:1–3. doi:10.1016/j.jaut.2017.02.004 (PubMed PMID: 28256368).

    Article  CAS  PubMed  Google Scholar 

  59. Tang R, Wei Y, Li Y, Chen W, Chen H, Wang Q, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 2017;. doi:10.1136/gutjnl-2016-313332 (PubMed PMID: 28213609).

    Google Scholar 

  60. Shuai Z, Wang J, Badamagunta M, Choi J, Yang G, Zhang W, et al. The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis. Hepatology. 2017;65(5):1670–82. doi:10.1002/hep.29059 (PubMed PMID: 28100006; PubMed Central PMCID: PMCPMC5397331).

    Article  CAS  PubMed  Google Scholar 

  61. Doria A, Gershwin ME, Selmi C. From old concerns to new advances and personalized medicine in lupus: the end of the tunnel is approaching. J Autoimmun. 2016;74:1–5. doi:10.1016/j.jaut.2016.08.007 (PubMed PMID: 27592380).

    Article  PubMed  Google Scholar 

  62. Long H, Yin H, Wang L, Gershwin ME, Lu Q. The critical role of epigenetics in systemic lupus erythematosus and autoimmunity. J Autoimmun. 2016;74:118–38. doi:10.1016/j.jaut.2016.06.020 (PubMed PMID: 27396525).

    Article  CAS  PubMed  Google Scholar 

  63. Hisamoto S, Shimoda S, Harada K, Iwasaka S, Onohara S, Chong Y, et al. Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis. J Autoimmun. 2016;75:150–60. doi:10.1016/j.jaut.2016.08.006 (PubMed PMID: 27592379).

    Article  CAS  PubMed  Google Scholar 

  64. Uchida K, Tanaka T, Gershwin ME, Okazaki K. The geoepidemiology and clinical aspects of IgG4-related disease. Semin Liver Dis. 2016;36(3):187–99. doi:10.1055/s-0036-1584323 (PubMed PMID: 27466790).

    Article  CAS  PubMed  Google Scholar 

  65. Bae HR, Leung PS, Tsuneyama K, Valencia JC, Hodge DL, Kim S, et al. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology. 2016;64(4):1189–201. doi:10.1002/hep.28641 (PubMed PMID: 27178326; PubMed Central PMCID: PMCPMC5033675).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jang M, Kim H, Kim Y, Choi J, Jeon J, Hwang Y, et al. The crucial role of IL-22 and its receptor in thymus and activation regulated chemokine production and T-cell migration by house dust mite extract. Exp Dermatol. 2016;25(8):598–603. doi:10.1111/exd.12988 (PubMed PMID: 26914146).

    Article  CAS  PubMed  Google Scholar 

  67. Choi J, Selmi C, Leung PS, Kenny TP, Roskams T, Gershwin ME. Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis. Expert Rev Clin Immunol. 2016;12(6):661–72. doi:10.1586/1744666X.2016.1147956 (PubMed PMID: 26821815; PubMed Central PMCID: PMCPMC4935758).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hirschfield GM, Gershwin ME, Strauss R, Mayo MJ, Levy C, Zou B, et al. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: a proof-of-concept study. Hepatology. 2016;64(1):189–99. doi:10.1002/hep.28359 (PubMed PMID: 26597786).

    Article  PubMed  Google Scholar 

  69. Hsueh YH, Chang YN, Loh CE, Gershwin ME, Chuang YH. AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis. J Autoimmun. 2016;66:89–97. doi:10.1016/j.jaut.2015.10.005 (PubMed PMID: 26537567; PubMed Central PMCID: PMCPMC4718765).

    Article  CAS  PubMed  Google Scholar 

  70. Yang JB, Wang YH, Yang W, Lu FT, Ma HD, Zhao ZB, et al. Successful treatment of murine autoimmune cholangitis by parabiosis: implications for hematopoietic therapy. J Autoimmun. 2016;66:108–17. doi:10.1016/j.jaut.2015.09.002 (PubMed PMID: 26432598; PubMed Central PMCID: PMCPMC4829433).

    Article  CAS  PubMed  Google Scholar 

  71. Yang F, Wang Q, Wang Z, Miao Q, Xiao X, Tang R, et al. The natural history and prognosis of primary biliary cirrhosis with clinical features of autoimmune hepatitis. Clin Rev Allergy Immunol. 2016;50(1):114–23. doi:10.1007/s12016-015-8516-5 (PubMed PMID: 26411425).

    Article  CAS  PubMed  Google Scholar 

  72. Yang GX, Sun Y, Tsuneyama K, Zhang W, Leung PS, He XS, et al. Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice. Clin Exp Immunol. 2016;185(2):154–64. doi:10.1111/cei.12806 (PubMed PMID: 27148790; PubMed Central PMCID: PMCPMC4955007).

    Article  CAS  PubMed  Google Scholar 

  73. Cordell HJ, Han Y, Mells GF, Li Y, Hirschfield GM, Greene CS, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 2015;6:8019. doi:10.1038/ncomms9019 (PubMed PMID: 26394269; PubMed Central PMCID: PMCPMC4580981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Triger DR, Berg PA, Rodes J. Epidemiology of primary biliary cirrhosis. Liver. 1984;4(3):195–200 (PubMed PMID: 6748874).

    Article  CAS  PubMed  Google Scholar 

  75. 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(5):647–50 (PubMed PMID: 4023628).

    Article  CAS  PubMed  Google Scholar 

  76. Myszor M, James OF. The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease? Q J Med. 1990;75(276):377–85 (PubMed PMID: 2385742).

    CAS  PubMed  Google Scholar 

  77. 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(4):367–71 (PubMed PMID: 7610354).

    Article  CAS  PubMed  Google Scholar 

  78. Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33(1):99–103 (PubMed PMID: 9489916).

    Article  CAS  PubMed  Google Scholar 

  79. 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(6):1083–8. doi:10.1053/jhep.2001.29760 (PubMed PMID: 11731995).

    Article  CAS  PubMed  Google Scholar 

  80. Sood S, Gow PJ, Christie JM, Angus PW. Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations. Gastroenterology. 2004;127(2):470–5 (PubMed PMID: 15300579).

    Article  PubMed  Google Scholar 

  81. Sakauchi F, Mori M, Zeniya M, Toda G. A cross-sectional study of primary biliary cirrhosis in Japan: utilization of clinical data when patients applied to receive public financial aid. J Epidemiol. 2005;15(1):24–8 (PubMed PMID: 15678923).

    Article  PubMed  Google Scholar 

  82. Myers RP, Shaheen AA, Fong A, Burak KW, Wan A, Swain MG, et al. Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: a population-based study. Hepatology. 2009;50(6):1884–92. doi:10.1002/hep.23210 (PubMed PMID: 19821525).

    Article  PubMed  Google Scholar 

  83. Liu H, Liu Y, Wang L, Xu D, Lin B, Zhong R, et al. Prevalence of primary biliary cirrhosis in adults referring hospital for annual health check-up in Southern China. BMC Gastroenterol. 2010;10:100. doi:10.1186/1471-230X-10-100 (PubMed PMID: 20815889; PubMed Central PMCID: PMCPMC2944334).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Cheung KS, Seto WK, Fung J, Lai CL, Yuen MF. Epidemiology and natural history of primary biliary cholangitis in the Chinese: a territory-based study in Hong Kong between 2000 and 2015. Clin Transl Gastroenterol. 2017;8(8):e116. doi:10.1038/ctg.2017.43 (PubMed PMID: 28858291).

    Article  PubMed  Google Scholar 

  85. Tsianos EV, Hoofnagle JH, Fox PC, Alspaugh M, Jones EA, Schafer DF, et al. Sjögren’s syndrome in patients with primary biliary cirrhosis. Hepatology. 1990;11(5):730–4 (PubMed PMID: 2347546).

    Article  CAS  PubMed  Google Scholar 

  86. Pares A, Rimola A, Bruguera M, Mas E, Rodes J. Renal tubular acidosis in primary biliary cirrhosis. Gastroenterology. 1981;80(4):681–6 (PubMed PMID: 7202940).

    CAS  PubMed  Google Scholar 

  87. Costa C, Sambataro A, Baldi S, Modena V, Todros L, Libertucci D, et al. Primary biliary cirrhosis: lung involvement. Liver. 1995;15(4):196–201 (PubMed PMID: 8544642).

    Article  CAS  PubMed  Google Scholar 

  88. 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(11):1046–9 (PubMed PMID: 11602476).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Elta GH, Sepersky RA, Goldberg MJ, Connors CM, Miller KB, Kaplan MM. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci. 1983;28(11):971–5 (PubMed PMID: 6628157).

    Article  CAS  PubMed  Google Scholar 

  90. Kingham JG, Parker DR. The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences. Gut. 1998;42(1):120–2 (PubMed PMID: 9518232).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gulamhusein AF, Juran BD, Lazaridis KN. Genome-wide association studies in primary biliary cirrhosis. Semin Liver Dis. 2015;35(4):392–401. doi:10.1055/s-0035-1567831 (PubMed PMID: 26676814; PubMed Central PMCID: PMCPMC4683605).

    Article  PubMed  PubMed Central  Google Scholar 

  92. 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(24):2544–55. doi:10.1056/NEJMoa0810440 (PubMed PMID: 19458352; PubMed Central PMCID: PMC2857316).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Liu X, Invernizzi P, Lu Y, Kosoy R, Bianchi I, Podda M, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42(8):658–60. doi:10.1038/ng.627 (PubMed PMID: 20639880; PubMed Central PMCID: PMC3150510).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011;43(4):329–32. doi:10.1038/ng.789 (PubMed PMID: 21399635; PubMed Central PMCID: PMCPMC3071550).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nakamura M, Nishida N, Kawashima M, Aiba Y, Tanaka A, Yasunami M, 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(4):721–8. doi:10.1016/j.ajhg.2012.08.010 (PubMed PMID: 23000144; PubMed Central PMCID: PMC3484650).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, et al. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet. 2012;21(23):5209–21. doi:10.1093/hmg/dds359 (PubMed PMID: 22936693; PubMed Central PMCID: PMC3490520).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li Z, White P, Tuteja G, Rubins N, Sackett S, Kaestner KH. Foxa1 and Foxa2 regulate bile duct development in mice. J Clin Investig. 2009;119(6):1537–45. doi:10.1172/JCI38201 (PubMed PMID: 19436110; PubMed Central PMCID: PMC2689124).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fu S, Fei Q, Jiang H, Chuai S, Shi S, Xiong W, et al. Involvement of histone acetylation of Sox17 and Foxa2 promoters during mouse definitive endoderm differentiation revealed by microRNA profiling. PLoS One. 2011;6(11):e27965. doi:10.1371/journal.pone.0027965 (PubMed PMID: 22132182; PubMed Central PMCID: PMC3223193).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. McDaniel K, Meng F, Wu N, Sato K, Venter J, Bernuzzi F, et al. Forkhead box A2 regulated biliary heterogeneity and senescence during cholestatic liver injury. Hepatology. 2016;. doi:10.1002/hep.28831 (PubMed PMID: 27639079).

    PubMed  Google Scholar 

  100. Sawalha AH. Epigenetics and T-cell immunity. Autoimmunity. 2008;41(4):245–52. doi:10.1080/08916930802024145 (PubMed PMID: 18432405).

    Article  CAS  PubMed  Google Scholar 

  101. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259–73 (PubMed PMID: 19109157; PubMed Central PMCID: PMC3731994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kont V, Murumagi A, Tykocinski LO, Kinkel SA, Webster KE, Kisand K, et al. DNA methylation signatures of the AIRE promoter in thymic epithelial cells, thymomas and normal tissues. Mol Immunol. 2011;49(3):518–26. doi:10.1016/j.molimm.2011.09.022 (PubMed PMID: 22036612).

    Article  CAS  PubMed  Google Scholar 

  103. Wu H, Zhao M, Chang C, Lu Q. The real culprit in systemic lupus erythematosus: abnormal epigenetic regulation. Int J Mol Sci. 2015;16(5):11013–33. doi:10.3390/ijms160511013 (PubMed PMID: 25988383; PubMed Central PMCID: PMC4463688).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mitchell MM, Lleo A, Zammataro L, Mayo MJ, Invernizzi P, Bach N, et al. Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis. Epigenetics. 2011;6(1):95–102. doi:10.4161/epi.6.1.13405 (PubMed PMID: 20864813; PubMed Central PMCID: PMC3029486).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lee JT. Epigenetic regulation by long noncoding RNAs. Science. 2012;338(6113):1435–9. doi:10.1126/science.1231776 (PubMed PMID: 23239728).

    Article  CAS  PubMed  Google Scholar 

  106. Ricano-Ponce I, Wijmenga C. Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet. 2013;14:325–53. doi:10.1146/annurev-genom-091212-153450 (PubMed PMID: 23834318).

    Article  CAS  PubMed  Google Scholar 

  107. Ninomiya M, Kondo Y, Funayama R, Nagashima T, Kogure T, Kakazu E, et al. Distinct microRNAs expression profile in primary biliary cirrhosis and evaluation of miR 505-3p and miR197-3p as novel biomarkers. PLoS One. 2013;8(6):e66086. doi:10.1371/journal.pone.0066086 (PubMed PMID: 23776611; PubMed Central PMCID: PMC3680413).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, et al. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood. 2008;112(10):4202–12. doi:10.1182/blood-2008-03-147645 (PubMed PMID: 18713946).

    Article  CAS  PubMed  Google Scholar 

  109. Padgett KA, Lan RY, Leung PC, Lleo A, Dawson K, Pfeiff J, et al. Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun. 2009;32(3–4):246–53. doi:10.1016/j.jaut.2009.02.022 (PubMed PMID: 19345069; PubMed Central PMCID: PMC2698796).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Eric Gershwin.

Ethics declarations

Conflict of interest

None.

Human and animal rights statement

Our article is a review paper, it therefore does not contain studies with human or animal subjects. Any of the cited articles performed by the authors, include procedures performed in accordance with the ethical standards of the responsible commitee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lleo, A., Marzorati, S., Anaya, JM. et al. Primary biliary cholangitis: a comprehensive overview. Hepatol Int 11, 485–499 (2017). https://doi.org/10.1007/s12072-017-9830-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-017-9830-1

Keywords

Navigation