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Bile Acids and Cholestatic Liver Disease 1: Primary Biliary Cholangitis (PBC)

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Bile Acids in Gastroenterology

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Abstract

Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis and recently the name was changed with keeping the abbreviation “PBC” along with a global consensus, is a chronic cholestatic liver disease, potentially resulting in liver failure. While the aspect of autoimmune disease of PBC was formally emphasized and immune reactions with lymphocytes against autoantigens were extensively investigated, the interactions between bile acids and cholangiocytes have been well clarified in this decade. Cytotoxic hydrophobic bile acids play an important role in pathogenesis of PBC via defect in the biliary HCO3 − “umbrella.” This biliary HCO3 − “umbrella” is maintained by Cl−/HCO3 − exchanger (anion exchanger 2 (AE2)) located at apical surface of cholangiocytes, and accumulating evidences have indicated that lack or reduction of AE2 activities is closely associated with PBC. Treatment is targeted to cytotoxicity of hydrophobic bile acids; ursodeoxycholic acid (UDCA) exerts its effect through reduction of cytotoxicity of hydrophobic bile acids and stabilizing biliary HCO3 − umbrella. Both bezafibrate and obeticholic acids are also capable of reducing cytotoxicity of hydrophobic bile acids. The alternative treatment is strongly awaited for patients with PBC refractory to UDCA, and targeting cytotoxicity of hydrophobic bile acids, as well as immune-based therapies, is expected to be a promising approach for new pharmacotherapy.

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References

  1. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ et al. Primary biliary cirrhosis. Hepatology. 2009;50(1):291–308. doi:10.1002/hep.22906 [doi].

    Google Scholar 

  2. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353(12):1261–73.

    Article  CAS  PubMed  Google Scholar 

  3. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–67. doi:S0168-8278(09)003092 [pii]10.1016/j.jhep.2009.04.009 [doi].

    Google Scholar 

  4. Working Subgroup for Clinical Practice Guidelines for Primary Biliary C. Guidelines for the management of primary biliary cirrhosis: the Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res. 2014;44 Suppl S1:71–90. doi:10.1111/hepr.12270 [doi].

    Google Scholar 

  5. Shimoda S, Tanaka A. It is time to change PBC: new nomenclature from “cirrhosis” to “cholangitis”, and upcoming treatment based on unveiling pathology. Hepatol Res. 2015; doi:10.1111/hepr.12615.

    Google Scholar 

  6. Dauphinee JA, Sinclair JC. Primary biliary cirrhosis. Can Med Assoc J. 1949;61(1):1–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. J Hepatol. 2015; doi:10.1016/j.jhep.2015.06.031.

    PubMed Central  Google Scholar 

  8. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, et al. Changing nomenclature for PBC: from ‘Cirrhosis’ to ‘Cholangitis’. Gastroenterology. 2015; doi:10.1053/j.gastro.2015.08.031.

    PubMed  Google Scholar 

  9. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. Hepatology. 2015; doi:10.1002/hep.28140.

    Google Scholar 

  10. Muratori L, Granito A, Muratori P, Pappas G, Bianchi FB. Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clin Liver Dis 2008;12(2):261–276; vii. doi:S1089-3261(08)00025-1 [pii].

    Google Scholar 

  11. Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis. Chronic non-suppurative destructive cholangitis. Am J Pathol. 1965;46:387–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kikuchi K, Lian ZX, Yang GX, Ansari AA, Ikehara S, Kaplan M, et al. Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology. 2005;128(2):304–12. . doi:S0016508504020013 [pii]

    Article  CAS  PubMed  Google Scholar 

  13. Mao T, Lian Z, Selmi C, Ichiki Y, Ashwood P, Ansari A, et al. Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis. Hepatology. 2005;42(4):802–8.

    Article  CAS  PubMed  Google Scholar 

  14. Moritoki Y, Lian Z, Wulff H, Yang G, Chuang Y, Lan R, et al. AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology. 2007;45(2):314–22.

    Article  CAS  PubMed  Google Scholar 

  15. Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology. 2002;123(4):1031–43. . doi:S0016508502002081 [pii]

    Article  CAS  PubMed  Google Scholar 

  16. Shimoda S, Hisamoto S, Harada K, Iwasaka S, Chong Y, Nakamura M, et al. Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. Hepatology. 2015; doi:10.1002/hep.28122.

    PubMed  PubMed Central  Google Scholar 

  17. Carbone M, Lleo A, Sandford RN, Invernizzi P. Implications of genome-wide association studies in novel therapeutics in primary biliary cirrhosis. Eur J Immunol 2014. doi:10.1002/eji.201344270 [doi].

    Google Scholar 

  18. Aiba Y, Yamazaki K, Nishida N, Kawashima M, Hitomi Y, Nakamura H, et al. Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population. J Hum Genet. 2015; doi:10.1038/jhg.2015.59.

    PubMed  Google Scholar 

  19. Dvorak K, Payne CM, Chavarria M, Ramsey L, Dvorakova B, Bernstein H, et al. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett’s oesophagus. Gut. 2007;56(6):763–71. doi:10.1136/gut.2006.103697.

    Article  CAS  PubMed  Google Scholar 

  20. Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP. The biliary HCO(3)(−) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology. 2010;52(4):1489–96. doi:10.1002/hep.23810.

    Article  CAS  PubMed  Google Scholar 

  21. Hohenester S, Wenniger LM, Paulusma CC, van Vliet SJ, Jefferson DM, Elferink RP, et al. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 2012;55(1):173–83. doi:10.1002/hep.24691.

    Article  CAS  PubMed  Google Scholar 

  22. 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(5):1482–1493. doi:S0016-5085(08)00253-9 [pii] 1053/j.gastro.2008.02.020 [doi].

    Google Scholar 

  23. 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(1):12–7. doi:10.1002/hep.510250104.

    Article  CAS  PubMed  Google Scholar 

  24. 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(6):1513–1521. doi:S0270913902912619 [pii] 1053/jhep.2002.33634 [doi].

    Google Scholar 

  25. 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(6):1038–1045. doi:S0168-8278(08)00602-8 [pii]10.1016/j.jhep.2008.07.027 [doi].

    Google Scholar 

  26. Banales JM, Saez E, Uriz M, Sarvide S, Urribarri AD, Splinter P et al. Up-regulation of microRNA 506 leads to decreased Cl(−) /HCO(3) (−) anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology. 2012;56(2):687–697. doi:10.1002/hep.25691 [doi].

    Google Scholar 

  27. T Wada, R Kohziro, K Tanikawa. The effect of long-term administration of ursodeoxycholic acid in patients with primary biliary cirrhosis. Tokyo Tanabe Q. 1989: 39–46. [in Japanese]

    Google Scholar 

  28. European Association for the Study of the L. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51(2):237–267. doi:S0168-8278(09)00309-2 [pii] 1016/j.jhep.2009.04.009 [doi].

    Google Scholar 

  29. Arenas F, Hervias I, Uriz M, Joplin R, Prieto J, Medina JF. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J Clin Invest. 2008;118(2):695–709. doi:10.1172/JCI33156.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet. 2015; doi:10.1016/s0140-6736(15)00154-3.

    PubMed Central  Google Scholar 

  31. Mousa HS, Lleo A, Invernizzi P, Bowlus CL, Gershwin ME. Advances in pharmacotherapy for primary biliary cirrhosis. Expert Opin Pharmacother. 2015;16(5):633–43. doi:10.1517/14656566.2015.998650.

    Article  CAS  PubMed  Google Scholar 

  32. Azemoto N, Abe M, Murata Y, Hiasa Y, Hamada M, Matsuura B, et al. Early biochemical response to ursodeoxycholic acid predicts symptom development in patients with asymptomatic primary biliary cirrhosis. J Gastroenterol. 2009;44(6):630–4. doi:10.1007/s00535-009-0051-9.

    Article  CAS  PubMed  Google Scholar 

  33. 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(3):871–7. doi:10.1002/hep.22428.

    Article  CAS  PubMed  Google Scholar 

  34. Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011;55(6):1361–1367. doi:S0168-8278(11)00282-0 [pii] 1016/j.jhep.2011.02.031 [doi].

    Google Scholar 

  35. 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(4):1281–1287. doi:S0016-5085(09)00007-9 [pii] 1053/j.gastro.2009.01.003 [doi].

    Google Scholar 

  36. Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2010;105(10):2186–2194. doi: ajg2010216 [pii] 1038/ajg.2010.216 [doi].

    Google Scholar 

  37. 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(3):715–20.

    Article  CAS  PubMed  Google Scholar 

  38. Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, 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. 2015; doi:10.1002/hep.28017.

    PubMed  Google Scholar 

  39. Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015; doi:10.1053/j.gastro.2015.07.061.

    Google Scholar 

  40. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010;52(5):745–758. doi:S0168-8278(10)00027-9 [pii] 1016/j.jhep.2009.11.027 [doi].

    Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. Iwasaki S, Tsuda K, Ueta H, Aono R, Ono M, Saibara T et al. Bezafibrate may have a beneficial effect in pre-cirrhotic primary biliary cirrhosis. Hepatol Res. 1999;16(1):12–18. doi:http://dx.doi.org/10.1016/S1386-6346(99)00033-9.

    Google Scholar 

  43. Hosonuma K, Sato K, Yamazaki Y, Yanagisawa M, Hashizume H, Horiguchi N, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol. 2015;110(3):423–31. doi:10.1038/ajg.2015.20.

    Article  CAS  PubMed  Google Scholar 

  44. Tanaka A, Hirohara J, Nakanuma Y, Tsubouchi H, Takikawa H. Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA. J Gastroenterol. 2015;50(6):675–82. doi:10.1007/s00535-014-0998-z.

    Article  CAS  PubMed  Google Scholar 

  45. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(4):751–61. e8 doi:10.1053/j.gastro.2014.12.005.

    Article  CAS  PubMed  Google Scholar 

  46. Uegaki S, Mikami M, Morisawa Y, Negoro S, Goto H, Fukami M, et al. A study on dividing doses of ursodeoxycholic acid (UDCA) for patients with chronic hepatitis C. Kanzo. 2007;48:559–61.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Atsushi Tanaka

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  1. Atsushi Tanaka
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Correspondence to Atsushi Tanaka .

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Editors and Affiliations

  1. Department of General Medicine, Hiroshima University Hospital, Hiroshima, Japan

    Susumu Tazuma

  2. Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan

    Hajime Takikawa

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Tanaka, A. (2017). Bile Acids and Cholestatic Liver Disease 1: Primary Biliary Cholangitis (PBC). In: Tazuma, S., Takikawa, H. (eds) Bile Acids in Gastroenterology. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56062-3_7

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  • DOI: https://doi.org/10.1007/978-4-431-56062-3_7

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