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Annual Review of Pharmacology and Toxicology

Volume 60, 2020

Drug Therapies for Chronic Cholestatic Liver Diseases

Abstract

Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.

Keyword(s): obeticholic acid, primary biliary cholangitis, primary sclerosing cholangitis, ursodeoxycholic acid
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/content/journals/10.1146/annurev-pharmtox-010818-021059
2020-01-06
2024-04-20
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Literature Cited

  1. 1. 
    Jansen PL, Ghallab A, Vartak N, Reif R, Schaap FG et al. 2017. The ascending pathophysiology of cholestatic liver disease. Hepatology 65:722–38
     [Google Scholar]
  2. 2. 
    Lazaridis KN, Gores GJ, Lindor KD 2001. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders. .’ J. Hepatol. 35:134–46
     [Google Scholar]
  3. 3. 
    Beuers U. 2006. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3:318–28
     [Google Scholar]
  4. 4. 
    Pares A, Caballeria L, Rodes J 2006. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 130:715–20
     [Google Scholar]
  5. 5. 
    Harms MH, Lammers WJ, Thorburn D, Corpechot C, Invernizzi P et al. 2018. Major hepatic complications in ursodeoxycholic acid–treated patients with primary biliary cholangitis: risk factors and time trends in incidence and outcome. Am. J. Gastroenterol. 113:254–64
     [Google Scholar]
  6. 6. 
    Selmi C, Bowlus CL, Gershwin ME, Coppel RL 2011. Primary biliary cirrhosis. Lancet 377:1600–9
     [Google Scholar]
  7. 7. 
    Eur. Assoc. Study Liver 2017. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J. Hepatol 67:145–72
     [Google Scholar]
  8. 8. 
    Corpechot C, Carrat F, Poupon R, Poupon RE 2002. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology 122:652–8
     [Google Scholar]
  9. 9. 
    Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P et al. 2014. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 147:1338–49e5
     [Google Scholar]
  10. 10. 
    Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL et al. 2013. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 144:560–69.e7
     [Google Scholar]
  11. 11. 
    Goet JC, Harms MH, Carbone M, Hansen BE 2018. Risk stratification and prognostic modelling in primary biliary cholangitis. Best Pract. Res. Clin. Gastroenterol. 34–35:95–106
     [Google Scholar]
  12. 12. 
    Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M et al. 2007. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 45:118–27
     [Google Scholar]
  13. 13. 
    Cristoferi L, Nardi A, Ronca V, Invernizzi P, Mells G, Carbone M 2018. Prognostic models in primary biliary cholangitis. J. Autoimmun. 95:171–78
     [Google Scholar]
  14. 14. 
    Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K et al. 2016. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 63:930–50
     [Google Scholar]
  15. 15. 
    Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD et al. 2015. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 149:1804–12.e4
     [Google Scholar]
  16. 16. 
    Carbone M, Nardi A, Flack S, Carpino G, Varvaropoulou N et al. 2018. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score. Lancet Gastroenterol. Hepatol. 3:626–34
     [Google Scholar]
  17. 17. 
    Corpechot C, Carrat F, Poujol-Robert A, Gaouar F, Wendum D et al. 2012. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology 56:198–208
     [Google Scholar]
  18. 18. 
    Eaton JE, Vesterhus M, McCauley BM, Atkinson EJ, Schlicht EM et al. 2019. Primary Sclerosing Cholangitis Risk Estimate Tool (PREsTo) predicts outcomes of the disease: a derivation and validation study using machine learning. Hepatology In press. https://doi.org/10.1002/hep.30085
    [Crossref] [Google Scholar]
  19. 19. 
    Gulamhusein AF, Hirschfield GM. 2018. Pathophysiology of primary biliary cholangitis. Best Pract. Res. Clin. Gastroenterol. 34–35:17–25
     [Google Scholar]
  20. 20. 
    Dyson JK, Hirschfield GM, Adams DH, Beuers U, Mann DA et al. 2015. Novel therapeutic targets in primary biliary cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 12:147–58
     [Google Scholar]
  21. 21. 
    Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U 1996. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J. Hepatol. 25:49–57
     [Google Scholar]
  22. 22. 
    Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF 1989. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology 10:420–29
     [Google Scholar]
  23. 23. 
    Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA et al. 2005. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 42:1184–93
     [Google Scholar]
  24. 24. 
    Gong Y, Christensen E, Gluud C 2007. Azathioprine for primary biliary cirrhosis. Cochrane Database Syst. Rev. 3:CD006000
     [Google Scholar]
  25. 25. 
    Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP et al. 1990. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N. Engl. J. Med. 322:1419–24
     [Google Scholar]
  26. 26. 
    Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD 2005. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J. Clin. Gastroenterol. 39:168–71
     [Google Scholar]
  27. 27. 
    Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW 2013. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am. J. Gastroenterol. 108:933–41
     [Google Scholar]
  28. 28. 
    Tsuda M, Moritoki Y, Lian ZX, Zhang W, Yoshida K et al. 2012. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 55:512–21
     [Google Scholar]
  29. 29. 
    Hirschfield GM, Liu X, Xu C, Lu Y, Xie G et al. 2009. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N. Engl. J. Med. 360:2544–55
     [Google Scholar]
  30. 30. 
    Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y et al. 2010. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat. Genet. 42:658–60
     [Google Scholar]
  31. 31. 
    Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS et al. 2011. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43:329–32
     [Google Scholar]
  32. 32. 
    Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y 2009. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin. Exp. Immunol. 157:261–70
     [Google Scholar]
  33. 33. 
    Rong G, Zhou Y, Xiong Y, Zhou L, Geng H et al. 2009. Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population. Clin. Exp. Immunol. 156:217–25
     [Google Scholar]
  34. 34. 
    Hirschfield GM, Gershwin ME, Strauss R, Mayo MJ, Levy C et al. 2016. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: a proof-of-concept study. Hepatology 64:189–99
     [Google Scholar]
  35. 35. 
    Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y et al. 2008. Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells. Hepatology 47:958–65
     [Google Scholar]
  36. 36. 
    Popp F, Semela D, von Kempis J, Mueller RB 2018. Improvement of primary biliary cholangitis (PBC) under treatment with sulfasalazine and abatacept. BMJ Case Rep 2018.bcr–2018-224205
     [Google Scholar]
  37. 37. 
    Bowlus CL, Yang GX, Liu CH, Johnson CR, Dhaliwal SS et al. 2019. Therapeutic trials of biologics in primary biliary cholangitis: an open label study of abatacept and review of the literature. J. Autoimmun. 101:26–34
     [Google Scholar]
  38. 38. 
    Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R 2005. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 128:297–303
     [Google Scholar]
  39. 39. 
    Harms MH, van Buuren HR, van der Meer AJ 2018. Improving prognosis in primary biliary cholangitis—therapeutic options and strategy. Best Pract. Res. Clin. Gastroenterol. 34–35:85–94
     [Google Scholar]
  40. 40. 
    Wagner M, Trauner M. 2016. Recent advances in understanding and managing cholestasis. F1000Research 5:705
     [Google Scholar]
  41. 41. 
    Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G et al. 2002. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45:3569–72
     [Google Scholar]
  42. 42. 
    Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C et al. 2016. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N. Engl. J. Med. 375:631–43
     [Google Scholar]
  43. 43. 
    Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R et al. 2018. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 67:1890–902
     [Google Scholar]
  44. 44. 
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML et al. 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–65
     [Google Scholar]
  45. 45. 
    Owen BM, Mangelsdorf DJ, Kliewer SA 2015. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 26:22–9
     [Google Scholar]
  46. 46. 
    Krones E, Wagner M. 2016. Fibroblast growth factor 19 meets mammalian target of rapamycin: a mitogenic tete-a-tete under consideration. Hepatology 64:1028–30
     [Google Scholar]
  47. 47. 
    Mayo MJ, Wigg AJ, Leggett BA, Arnold H, Thompson AJ et al. 2018. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol. Commun. 2:1037–50
     [Google Scholar]
  48. 48. 
    Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Habersetzer F et al. 2018. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N. Engl. J. Med. 378:2171–81
     [Google Scholar]
  49. 49. 
    Dubois V, Eeckhoute J, Lefebvre P, Staels B 2017. Distinct but complementary contributions of PPAR isotypes to energy homeostasis. J. Clin. Investig. 127:1202–14
     [Google Scholar]
  50. 50. 
    Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J et al. 2013. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 57:1931–41
     [Google Scholar]
  51. 51. 
    Kok T, Bloks VW, Wolters H, Havinga R, Jansen PL et al. 2003. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Biochem. J. 369:539–47
     [Google Scholar]
  52. 52. 
    Shoda J, Inada Y, Tsuji A, Kusama H, Ueda T et al. 2004. Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARα-mediated redistribution of ABCB4. J. Lipid Res. 45:1813–25
     [Google Scholar]
  53. 53. 
    Wagner M, Zollner G, Trauner M 2011. Nuclear receptors in liver disease. Hepatology 53:1023–34
     [Google Scholar]
  54. 54. 
    Reig A, Sese P, Pares A 2018. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am. J. Gastroenterol. 113:49–55
     [Google Scholar]
  55. 55. 
    Kremer AE, Le Cleac'h A, Lemoinne S, Wolf K, De Chaisemartin L et al. 2019. Antipruritic effect of bezafibrate and serum autotaxin measures in patients with primary biliary cholangitis. Gut 68:1902–3
     [Google Scholar]
  56. 56. 
    Hosonuma K, Sato K, Yamazaki Y, Yanagisawa M, Hashizume H et al. 2015. 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. 110:423–31
     [Google Scholar]
  57. 57. 
    Levy C, Peter JA, Nelson DR, Keach J, Petz J et al. 2011. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment. Pharmacol. Ther. 33:235–42
     [Google Scholar]
  58. 58. 
    Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR et al. 2017. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol. Hepatol. 2:716–26
     [Google Scholar]
  59. 59. 
    Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P et al. 2016. Elafibranor, an agonist of the peroxisome proliferator–activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150:1147–59.e5
     [Google Scholar]
  60. 60. 
    Wettstein G, Luccarini JM, Poekes L, Faye P, Kupkowski F et al. 2017. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol. Commun. 1:524–37
     [Google Scholar]
  61. 61. 
    Arenas F, Hervias I, Uriz M, Joplin R, Prieto J, Medina JF 2008. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J. Clin. Investig. 118:695–709
     [Google Scholar]
  62. 62. 
    Poupon R, Ping C, Chretien Y, Corpechot C, Chazouilleres O et al. 2008. Genetic factors of susceptibility and of severity in primary biliary cirrhosis. J. Hepatol. 49:1038–45
     [Google Scholar]
  63. 63. 
    Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G et al. 1999. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 117:918–25
     [Google Scholar]
  64. 64. 
    Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P et al. 2005. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 41:747–52
     [Google Scholar]
  65. 65. 
    Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD 2000. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 31:318–23
     [Google Scholar]
  66. 66. 
    Muir AJ, Levy C, Janssen HLA, Montano-Loza AJ, Shiffman ML et al. 2019. Simtuzumab for primary sclerosing cholangitis: phase 2 study results with insights on the natural history of the disease. Hepatology 69:684–98
     [Google Scholar]
  67. 67. 
    Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM et al. 2018. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 155:1140–53
     [Google Scholar]
  68. 68. 
    Fickert P. 2019. Is this the last requiem for simtuzumab?. Hepatology 69:476–79
     [Google Scholar]
  69. 69. 
    Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F et al. 2012. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56:2316–27
     [Google Scholar]
  70. 70. 
    Lan T, Kisseleva T, Brenner DA 2015. Deficiency of NOX1 or NOX4 prevents liver inflammation and fibrosis in mice through inhibition of hepatic stellate cell activation. PLOS ONE 10:e0129743
     [Google Scholar]
  71. 71. 
    Mortezaee K. 2018. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and liver fibrosis: a review. Cell Biochem. Funct. 36:292–302
     [Google Scholar]
  72. 72. 
    Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A et al. 2004. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–512
     [Google Scholar]
  73. 73. 
    Zardi EM, Navarini L, Sambataro G, Piccinni P, Sambataro FM et al. 2013. Hepatic PPARs: their role in liver physiology, fibrosis and treatment. Curr. Med. Chem. 20:3370–96
     [Google Scholar]
  74. 74. 
    Lazaridis KN, LaRusso NF. 2016. Primary sclerosing cholangitis. N. Engl. J. Med. 375:1161–70
     [Google Scholar]
  75. 75. 
    Karlsen TH, Folseraas T, Thorburn D, Vesterhus M 2017. Primary sclerosing cholangitis—a comprehensive review. J. Hepatol. 67:1298–323
     [Google Scholar]
  76. 76. 
    Karlsen TH, Vesterhus M, Boberg KM 2014. Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 39:282–301
     [Google Scholar]
  77. 77. 
    Lindstrom L, Hultcrantz R, Boberg KM, Friis-Liby I, Bergquist A 2013. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 11:841–46
     [Google Scholar]
  78. 78. 
    Al Mamari S, Djordjevic J, Halliday JS, Chapman RW 2013. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J. Hepatol. 58:329–34
     [Google Scholar]
  79. 79. 
    Stanich PP, Bjornsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD 2011. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig. Liver Dis. 43:309–13
     [Google Scholar]
  80. 80. 
    Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T et al. 2009. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 50:808–14
     [Google Scholar]
  81. 81. 
    Eur. Assoc. Study Liver 2009. EASL clinical practice guidelines: management of cholestatic liver diseases. J. Hepatol 51:237–67
     [Google Scholar]
  82. 82. 
    Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM et al. 2010. Diagnosis and management of primary sclerosing cholangitis. Hepatology 51:660–78
     [Google Scholar]
  83. 83. 
    Lindor KD, Kowdley KV, Harrison ME, Am. Coll. Gastroenterol. 2015. ACG clinical guideline: primary sclerosing cholangitis. Am. J. Gastroenterol. 110:646–59
     [Google Scholar]
  84. 84. 
    Ponsioen CY. 2018. Endpoints in the design of clinical trials for primary sclerosing cholangitis. Biochim. Biophys. Acta Mol. Basis Dis. 1864:1410–14
     [Google Scholar]
  85. 85. 
    Ponsioen CY, Chapman RW, Chazouilleres O, Hirschfield GM, Karlsen TH et al. 2016. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process. Hepatology 63:1357–67
     [Google Scholar]
  86. 86. 
    Krones E, Marschall HU, Fickert P 2019. Future medical treatment of PSC. Curr. Hepatol. Rep. 18:96–106
     [Google Scholar]
  87. 87. 
    Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W et al. 2019. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat. Microbiol. 4:492–503
     [Google Scholar]
  88. 88. 
    Am. Assoc. Study Liver Dis 2017. Late-breaking abstracts—presented at the 68th annual meeting of the American Association for the Study of Liver Diseases: the liver meeting 2017. Hepatology 66:1254A–72A
     [Google Scholar]
  89. 89. 
    Fu T, Coulter S, Yoshihara E, Oh TG, Fang S et al. 2019. FXR regulates intestinal cancer stem cell proliferation. Cell Biochem. Funct. 176:1098–112.e18
     [Google Scholar]
  90. 90. 
    de Aguiar Vallim TQ, Tarling EJ, Edwards PA 2013. Pleiotropic roles of bile acids in metabolism. Cell Metab 17:657–69
     [Google Scholar]
  91. 91. 
    Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML et al. 2019. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis.. Hepatology 70:788–801
     [Google Scholar]
  92. 92. 
    Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C 2014. Knocking on FXR's door: the “hammerhead”-structure series of FXR agonists—amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr. Top. Med. Chem. 14:2143–58
     [Google Scholar]
  93. 93. 
    Hirschfield GM, Chazouilleres O, Drenth JP, Thorburn D, Harrison SA et al. 2018. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J. Hepatol. 70:3483–93
     [Google Scholar]
  94. 94. 
    Tabibian JH, Lindor KD. 2019. NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a nebulous matter. J. Hepatol. 70:348–50
     [Google Scholar]
  95. 95. 
    Gerussi A, Invernizzi P. 2019. Better end points needed in primary sclerosing cholangitis trials. Nat. Rev. Gastroenterol. Hepatol. 16:143–44
     [Google Scholar]
  96. 96. 
    Cai SY, He H, Nguyen T, Mennone A, Boyer JL 2010. Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms. J. Lipid Res. 51:2265–74
     [Google Scholar]
  97. 97. 
    Cai SY, Mennone A, Soroka CJ, Boyer JL 2014. All-trans-retinoic acid improves cholestasis in α-naphthylisothiocyanate-treated rats and Mdr2−/− mice. J. Pharmacol. Exp. Ther. 349:94–98
     [Google Scholar]
  98. 98. 
    He H, Mennone A, Boyer JL, Cai SY 2011. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct–ligated rats and human hepatic cells. Hepatology 53:548–57
     [Google Scholar]
  99. 99. 
    Assis DN, Abdelghany O, Cai SY, Gossard AA, Eaton JE et al. 2017. Combination therapy of all-trans retinoic acid with ursodeoxycholic acid in patients with primary sclerosing cholangitis: a human pilot study. J. Clin. Gastroenterol. 51:e11–16
     [Google Scholar]
  100. 100. 
    Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G et al. 2006. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130:465–81
     [Google Scholar]
  101. 101. 
    Fickert P, Hirschfield GM, Denk G, Marschall HU, Altorjay I et al. 2017. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J. Hepatol. 67:549–58
     [Google Scholar]
  102. 102. 
    Lemoinne S, Pares A, Reig A, Ben Belkacem K, Kemgang Fankem AD et al. 2018. Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience. Clin. Res. Hepatol. Gastroenterol. 42:521–28
     [Google Scholar]
  103. 103. 
    Mizuno S, Hirano K, Isayama H, Watanabe T, Yamamoto N et al. 2015. Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis. J. Hepatobiliary Pancreat. Sci. 22:766–70
     [Google Scholar]
  104. 104. 
    Mizuno S, Hirano K, Tada M, Yamamoto K, Yashima Y et al. 2010. Bezafibrate for the treatment of primary sclerosing cholangitis. J. Gastroenterol. 45:758–62
     [Google Scholar]
  105. 105. 
    Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM et al. 2015. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J. Clin. Investig. 125:501–20
     [Google Scholar]
  106. 106. 
    Arndtz K, Corrigan M, Rowe A, Kirkham A, Barton D et al. 2017. Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): a single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol. BMJ Open 7:e015081
     [Google Scholar]
  107. 107. 
    Guicciardi ME, Trussoni CE, Krishnan A, Bronk SF, Lorenzo Pisarello MJ et al. 2018. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J. Hepatol. 69:676–86
     [Google Scholar]
  108. 108. 
    Grant AJ, Lalor PF, Hubscher SG, Briskin M, Adams DH 2001. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33:1065–72
     [Google Scholar]
  109. 109. 
    Tse CS, Loftus EV Jr, Raffals LE, Gossard AA, Lightner AL 2018. Effects of vedolizumab, adalimumab and infliximab on biliary inflammation in individuals with primary sclerosing cholangitis and inflammatory bowel disease. Aliment. Pharmacol. Ther 48:190–95
     [Google Scholar]
  110. 110. 
    Dubinsky MC, Cross RK, Sandborn WJ, Long M, Song X et al. 2018. Extraintestinal manifestations in vedolizumab and anti-TNF-treated patients with inflammatory bowel disease. Inflamm. Bowel Dis. 24:1876–82
     [Google Scholar]
  111. 111. 
    Christensen B, Micic D, Gibson PR, Yarur A, Bellaguarda E et al. 2018. Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Aliment. Pharmacol. Ther. 47:753–62
     [Google Scholar]
  112. 112. 
    Lynch KD, Chapman RW, Keshav S, Montano-Loza AJ, Mason AL et al. 2019. Effects of vedolizumab in patients with primary sclerosing cholangitis and inflammatory bowel diseases. Clin. Gastroenterol. Hepatol. In press. https://doi.org/10.1016/j.cgh.2019.05.013
    [Crossref] [Google Scholar]
  113. 113. 
    Caron B, Peyrin-Biroulet L, Pariente B, Bouhnik Y, Seksik P et al. 2019. Vedolizumab therapy is ineffective for primary sclerosing cholangitis in patients with inflammatory bowel disease: a GETAID multicentre cohort study. J. Crohn's Colitis 13:1239–47
     [Google Scholar]
  114. 114. 
    Hov JR, Kummen M. 2017. Intestinal microbiota in primary sclerosing cholangitis. Curr. Opin. Gastroenterol. 33:85–92
     [Google Scholar]
  115. 115. 
    Damman JL, Rodriguez EA, Ali AH, Buness CW, Cox KL et al. 2018. Review article: the evidence that vancomycin is a therapeutic option for primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 47:886–95
     [Google Scholar]
  116. 116. 
    Tabibian JH, Gossard A, El-Youssef M, Eaton JE, Petz J et al. 2017. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am. J. Ther. 24:e56–63
     [Google Scholar]
  117. 117. 
    Jorgensen SF, Macpherson ME, Bjornetro T, Holm K, Kummen M et al. 2019. Rifaximin alters gut microbiota profile, but does not affect systemic inflammation—a randomized controlled trial in common variable immunodeficiency. Sci. Rep. 9:167
     [Google Scholar]
  118. 118. 
    Silveira MG, Torok NJ, Gossard AA, Keach JC, Jorgensen RA et al. 2009. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am. J. Gastroenterol. 104:83–88
     [Google Scholar]
  119. 119. 
    Allegretti JR, Kassam Z, Carrellas M, Mullish BH, Marchesi JR et al. 2019. Fecal microbiota transplantation in patients with primary sclerosing cholangitis: a pilot clinical trial. Am. J. Gastroenterol. 114:71071–79
     [Google Scholar]
  120. 120. 
    Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P et al. 2017. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 66:569–80
     [Google Scholar]
  121. 121. 
    Khanna A, Leighton J, Lee Wong L, Jones DE 2018. Symptoms of PBC—pathophysiology and management. Best Pract. Res. Clin. Gastroenterol. 34–35:41–47
     [Google Scholar]
  122. 122. 
    Zakharia K, Tabibian A, Lindor KD, Tabibian JH 2018. Complications, symptoms, quality of life and pregnancy in cholestatic liver disease. Liver Int 38:399–411
     [Google Scholar]
  123. 123. 
    Kuo A, Bowlus CL. 2016. Management of symptom complexes in primary biliary cholangitis. Curr. Opin. Gastroenterol. 32:204–9
     [Google Scholar]
  124. 124. 
    Poupon RE, Poupon R, Balkau B 1994. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N. Engl. J. Med. 330:1342–47
     [Google Scholar]
  125. 125. 
    Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J et al. 1994. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 106:1284–90
     [Google Scholar]
  126. 126. 
    Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM et al. 1994. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 19:1149–56
     [Google Scholar]
  127. 127. 
    Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF et al. 1995. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 22:759–66
     [Google Scholar]
  128. 128. 
    Goulis J, Leandro G, Burroughs AK 1999. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 354:1053–60
     [Google Scholar]
  129. 129. 
    Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C 2012. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst. Rev. 12:CD000551
     [Google Scholar]
  130. 130. 
    Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC et al. 2015. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148:751–61.e8
     [Google Scholar]
  131. 131. 
    Lens S, Leoz M, Nazal L, Bruguera M, Pares A 2014. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int 34:197–203
     [Google Scholar]
  132. 132. 
    Cheung AC, Lapointe-Shaw L, Kowgier M, Meza-Cardona J, Hirschfield GM et al. 2016. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment. Pharmacol. Ther. 43:283–93
     [Google Scholar]
  133. 133. 
    Hegade VS, Khanna A, Walker LJ, Wong LL, Dyson JK, Jones DEJ 2016. Long-term fenofibrate treatment in primary biliary cholangitis improves biochemistry but not the UK-PBC risk score. Dig. Dis. Sci. 61:3037–44
     [Google Scholar]
  134. 134. 
    Duan W, Ou X, Wang X, Wang Y, Zhao X et al. 2018. Efficacy and safety of fenofibrate add-on therapy for patients with primary biliary cholangitis and a suboptimal response to UDCA. Rev. Esp. Enferm. Dig. 110:557–63
     [Google Scholar]
  135. 135. 
    Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P et al. 2013. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58:1941–52
     [Google Scholar]
  136. 136. 
    Agrawal R. 2014. The first approved agent in the Glitazar's class: saroglitazar. Curr. Drug Targets 15:151–55
     [Google Scholar]
  137. 137. 
    Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A et al. 2017. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J. Med. Chem. 60:9960–73
     [Google Scholar]
  138. 138. 
    Erstad DJ, Farrar CT, Ghoshal S, Masia R, Ferreira DS et al. 2018. Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP-305, a novel farnesoid X receptor agonist. Hepatol. Commun. 2:821–35
     [Google Scholar]
  139. 139. 
    Khanna A, Jopson L, Howel D, Bryant A, Blamire A et al. 2019. Rituximab is ineffective for treatment of fatigue in primary biliary cholangitis: a phase 2 randomized controlled trial. Hepatology In press. https://doi.org/10.1002/hep.30099
    [Crossref] [Google Scholar]
  140. 140. 
    Tanaka H, Yang GX, Iwakoshi N, Knechtle SJ, Kawata K et al. 2013. Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clin. Exp. Immunol. 174:364–71
     [Google Scholar]
  141. 141. 
    Wang L, Han Q, Chen H, Wang K, Shan GL et al. 2014. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis. Stem Cells Dev 23:2482–89
     [Google Scholar]
  142. 142. 
    Wunsch E, Raszeja-Wyszomirska J, Barbier O, Milkiewicz M, Krawczyk M, Milkiewicz P 2018. Effect of S-adenosyl-L-methionine on liver biochemistry and quality of life in patients with primary biliary cholangitis treated with ursodeoxycholic acid. A prospective, open label pilot study. J. Gastrointest. Liver Dis. 27:273–79
     [Google Scholar]
  143. 143. 
    Askari F, Innis D, Dick RB, Hou G, Marrero J et al. 2010. Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial. Transl. Res. 155:123–30
     [Google Scholar]
  144. 144. 
    Sharon D, Mason AL. 2015. Role of novel retroviruses in chronic liver disease: assessing the link of human betaretrovirus with primary biliary cirrhosis. Curr. Infect. Dis. Rep. 17:4
     [Google Scholar]
  145. 145. 
    Slijepcevic D, Roscam Abbing RLP, Fuchs CD, Haazen LCM, Beuers U et al. 2018. Na+-taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice. Hepatology 68:1057–69
     [Google Scholar]
  146. 146. 
    Lindor KD. 1997. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N. Engl. J. Med. 336:691–95
     [Google Scholar]
  147. 147. 
    Triantos CK, Koukias NM, Nikolopoulou VN, Burroughs AK 2011. Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 34:901–10
     [Google Scholar]
  148. 148. 
    Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC et al. 2013. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis—a pilot study. Aliment. Pharmacol. Ther. 37:604–12
     [Google Scholar]
  149. 149. 
    Rahimpour S, Nasiri-Toosi M, Khalili H, Ebrahimi-Daryani N, Nouri-Taromlou MK, Azizi Z 2016. A triple blinded, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of oral vancomycin in primary sclerosing cholangitis: a pilot study. J. Gastrointest. Liver Dis. 25:457–64
     [Google Scholar]
  150. 150. 
    Vleggaar FP, Monkelbaan JF, van Erpecum KJ 2008. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur. J. Gastroenterol. Hepatol. 20:688–92
     [Google Scholar]
  151. 151. 
    Martin CR, Blanco PG, Keach JC, Petz JL, Zaman MM et al. 2012. The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis—a pilot study. Aliment. Pharmacol. Ther. 35:255–65
     [Google Scholar]
  152. 152. 
    Wagner M, Fickert P. 2018. Time for the dawn of multimodal therapies and the dusk for mono-therapeutic trials for cholestatic liver diseases?. Liver Int 38:991–94
     [Google Scholar]
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Drug Therapies for Chronic Cholestatic Liver Diseases
Annual Review of Pharmacology and Toxicology 60, 503 (2020); https://doi.org/10.1146/annurev-pharmtox-010818-021059
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