Digestive and Liver Disease
Volume 42, Issue 6 , Pages 409-418 , June 2010

Bile salts and cholestasis

  • Lucas Maillette de Buy Wenniger
    • ,
  • Ulrich Beuers

      Affiliations

    • Corresponding Author InformationCorresponding author at: Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, G4-213, University of Amsterdam, The Netherlands. Tel.: +31 20 5662422.

Received 13 March 2010 ,Accepted 13 March 2010.

References 

  1. Hofmann AF, Eckmann L. How bile acids confer gut mucosal protection against bacteria. Proc Natl Acad Sci USA. 2006;103:4333–4334
  2. Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29:625–651
  3. Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008;65:2461–2483
  4. Hylemon PB, Zhou H, Pandak WM, et al. Bile acids as regulatory molecules. J Lipid Res. 2009;50:1509–1520
  5. Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol. 2009;156:7–27
  6. Schmucker DL, Ohta M, Kanai S, et al. Hepatic injury induced by bile salts: correlation between biochemical and morphological events. Hepatology. 1990;12:1216–1221
  7. Hofmann AF, Roda A. Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. J Lipid Res. 1984;25:1477–1489
  8. Griffiths WJ, Sjovall J. Bile acids: analysis in biological fluids and tissues. J Lipid Res. 2009;
  9. Hofmann AF, Hagey LR, Krasowski MD. Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res. 2009;
  10. Monte MJ, Marin JJ, Antelo A, Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol. 2009;15:804–816
  11. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15:1677–1689
  12. Roda A, Grigolo B, Minutello A, et al. Physicochemical and biological properties of natural and synthetic C-22 and C-23 hydroxylated bile acids. J Lipid Res. 1990;31:289–298
  13. Hofmann AF, Mysels KJ. Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions. J Lipid Res. 1992;33:617–626
  14. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:318–328
  15. Hagey LR, Crombie DL, Espinosa E, et al. Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores. J Lipid Res. 1993;34:1911–1917
  16. Sola S, Garshelis DL, Amaral JD, et al. Plasma levels of ursodeoxycholic acid in black bears, Ursus americanus: seasonal changes. Comp Biochem Physiol C Toxicol Pharmacol. 2006;143:204–208
  17. Poupon RE, Chretien Y, Poupon R, Paumgartner G. Serum bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid therapy. Hepatology. 1993;17:599–604
  18. Reddy S, Sanders TA, Owen RW, Thompson MH. Faecal pH, bile acid and sterol concentrations in premenopausal Indian and white vegetarians compared with white omnivores. Br J Nutr. 1998;79:495–500
  19. van Faassen A, Hazen MJ, van den Brandt PA, et al. Bile acids and pH values in total feces and in fecal water from habitually omnivorous and vegetarian subjects. Am J Clin Nutr. 1993;58:917–922
  20. Bisschop PH, Bandsma RH, Stellaard F, et al. Low-fat, high-carbohydrate and high-fat, low-carbohydrate diets decrease primary bile acid synthesis in humans. Am J Clin Nutr. 2004;79:570–576
  21. Asakura H, Suzuki K, Kitahora T, Morizane T. Is there a link between food and intestinal microbes and the occurrence of Crohn's disease and ulcerative colitis?. J Gastroenterol Hepatol. 2008;23:1794–1801
  22. Meier PJ, Stieger B. Bile salt transporters. Annu Rev Physiol. 2002;64:635–661
  23. Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998;20:233–238
  24. Duarte IF, Legido-Quigley C, Parker DA, et al. Identification of metabolites in human hepatic bile using 800MHz 1H NMR spectroscopy. HPLC-NMR/MS and UPLC–MS. Mol Biosyst. 2009;5:180–190
  25. Chari RS, Schutz SM, Haebig JE, et al. Adenosine nucleotides in bile. Am J Physiol. 1996;270:G246–G252
  26. Chen B, Dong JQ, Chen YJ, et al. Two-dimensional electrophoresis for comparative proteomic analysis of human bile. Hepatobiliary Pancreat Dis Int. 2007;6:402–406
  27. Farina A, Dumonceau JM, Frossard JL, et al. Proteomic analysis of human bile from malignant biliary stenosis induced by pancreatic cancer. J Proteome Res. 2009;8:159–169
  28. Kristiansen TZ, Bunkenborg J, Gronborg M, et al. A proteomic analysis of human bile. Mol Cell Proteomics. 2004;3:715–728
  29. Glickerman DJ, Kim MH, Malik R, Lee SP. The gallbladder also secretes. Dig Dis Sci. 1997;42:489–491
  30. von Ritter C, Eder MI, Stieber P, et al. Biliary mucin secreted by cultured human gallbladder epithelial cells carries the epitope of CA 19-9. Anticancer Res. 1997;17:2931–2934
  31. Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci. 2009;14:2584–2598
  32. Hruz P, Zimmermann C, Gutmann H, et al. Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis. Gut. 2006;55:395–402
  33. Ballatori N, Fang F, Christian WV, et al. Ostalpha-Ostbeta is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol. 2008;295:G179–G186
  34. Ballatori N, Li N, Fang F, Boyer JL, et al. OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci. 2009;14:2829–2844
  35. Ma K, Xiao R, Tseng HT, et al. Circadian dysregulation disrupts bile acid homeostasis. PLoS One. 2009;4:e6843
  36. Alpini G, Glaser S, Baiocchi L, et al. Secretin activation of the apical Na+-dependent bile acid transporter is associated with cholehepatic shunting in rats. Hepatology. 2005;41:1037–1045
  37. Xia X, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes. World J Gastroenterol. 2006;12:3553–3563
  38. Fickert P, Wagner M, Marschall HU, et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2006;130:465–481
  39. Glaser SS, Alpini G. Activation of the cholehepatic shunt as a potential therapy for primary sclerosing cholangitis. Hepatology. 2009;49:1795–1797
  40. Shindo K, Machida M, Fukumura M, Koide K, Yamazaki R. Omeprazole induces altered bile acid metabolism. Gut. 1998;42:266–271
  41. Beuers U, Fischer S, Spengler U, Paumgartner G. Formation of iso-ursodeoxycholic acid during administration of ursodeoxycholic acid in man. J Hepatol. 1991;13:97–103
  42. Toda T, Ohi K, Kudo T, et al. Ciprofloxacin suppresses Cyp3a in mouse liver by reducing lithocholic acid-producing intestinal flora. Drug Metab Pharmacokinet. 2009;24:201–208
  43. Lepercq P, Hermier D, David O, et al. Increasing ursodeoxycholic acid in the enterohepatic circulation of pigs through the administration of living bacteria. Br J Nutr. 2005;93:457–469
  44. Handschin C, Meyer UA. Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys. 2005;433:387–396
  45. Tietz PS, Marinelli RA, Chen XM, et al. Agonist-induced coordinated trafficking of functionally related transport proteins for water and ions in cholangiocytes. J Biol Chem. 2003;278:20413–20419
  46. Lam IP, Lee LT, Choi HS, et al. Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP). Am J Physiol Gastrointest Liver Physiol. 2009;297:G90–G97
  47. Pande C, Kumar A, Sarin SK. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment Pharmacol Ther. 2009;29:1273–1281
  48. Gunnarsdottir SA, Sadik R, Shev S, et al. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol. 2003;98:1362–1370
  49. Slocum MM, Sittig KM, Specian RD, Deitch EA. Absence of intestinal bile promotes bacterial translocation. Am Surg. 1992;58:305–310
  50. Kurdi P, Kawanishi K, Mizutani K, Yokota A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J Bacteriol. 2006;188:1979–1986
  51. Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA. 2006;103:3920–3925
  52. D’Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology. 2009;136:1435–1443
  53. Stange EF. For bugs in bile: the times they are a-changin. Gastroenterology. 2009;136:1164–1167
  54. Ding JW, Andersson R, Soltesz V, et al. The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur Surg Res. 1993;25:11–19
  55. Beuers U. Effects of bile acids on hepatocellular signaling and secretion. Yale J Biol Med. 1997;70:341–346
  56. Anwer MS. Cellular regulation of hepatic bile acid transport in health and cholestasis. Hepatology. 2004;39:581–590
  57. Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm. 2006;3:231–251
  58. Anwer MS, Engelking LR, Nolan K, et al. Hepatotoxic bile acids increase cytosolic Ca++ activity of isolated rat hepatocytes. Hepatology. 1988;8:887–891
  59. Beuers U, Nathanson MH, Boyer JL. Effects of tauroursodeoxycholic acid on cytosolic Ca2+ signals in isolated rat hepatocytes. Gastroenterology. 1993;104:604–612
  60. Beuers U, Throckmorton DC, Anderson MS, et al. Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology. 1996;110:1553–1563
  61. Bouscarel B, Kroll SD, Fromm H. Signal transduction and hepatocellular bile acid transport: cross talk between bile acids and second messengers. Gastroenterology. 1999;117:433–452
  62. Rao YP, Stravitz RT, Vlahcevic ZR, et al. Activation of protein kinase C alpha and delta by bile acids: correlation with bile acid structure and diacylglycerol formation. J Lipid Res. 1997;38:2446–2454
  63. Beuers U, Nathanson MH, Isales CM, Boyer JL. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J Clin Invest. 1993;92:2984–2993
  64. Misra S, Ujhazy P, Gatmaitan Z, et al. The role of phosphoinositide 3-kinase in taurocholate-induced trafficking of ATP-dependent canalicular transporters in rat liver. J Biol Chem. 1998;273:26638–26644
  65. Misra S, Ujhazy P, Varticovski L, Arias IM. Phosphoinositide 3-kinase lipid products regulate ATP-dependent transport by sister of P-glycoprotein and multidrug resistance associated protein 2 in bile canalicular membrane vesicles. Proc Natl Acad Sci USA. 1999;96:5814–5819
  66. Beuers U, Denk GU, Soroka CJ, et al. Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol 3-kinase-dependent mechanisms in perfused rat livers and rat hepatocyte couplets. J Biol Chem. 2003;278:17810–17818
  67. Haussinger D, Kurz AK, Wettstein M, et al. Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis. Gastroenterology. 2003;124:1476–1487
  68. Dent P, Fang Y, Gupta S, et al. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology. 2005;42:1291–1299
  69. Nguyen A, Bouscarel B. Bile acids and signal transduction: role in glucose homeostasis. Cell Signal. 2008;20:2180–2197
  70. Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–191
  71. Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA. 2006;103:1006–1011
  72. Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. EMBO J. 2006;25:1419–1425
  73. Keitel V, Kubitz R, Haussinger D. Endocrine and paracrine role of bile acids. World J Gastroenterol. 2008;14:5620–5629
  74. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–489
  75. Ikemoto S, Takahashi M, Tsunoda N, et al. Cholate inhibits high-fat diet-induced hyperglycemia and obesity with acyl-CoA synthetase mRNA decrease. Am J Physiol. 1997;273:E37–45
  76. Makishima M, Lu TT, Xie W, et al. Vitamin D receptor as an intestinal bile acid sensor. Science. 2002;296:1313–1316
  77. Ishizawa M, Matsunawa M, Adachi R, et al. Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia. J Lipid Res. 2008;49:763–772
  78. Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278:9435–9440
  79. Yamazaki K, Gleich GJ, Kita H. Bile acids induce eosinophil degranulation by two different mechanisms. Hepatology. 2001;33:582–590
  80. Bergamini A, Dini L, Baiocchi L, et al. Bile acids with differing hydrophilic-hydrophobic properties do not influence cytokine production by human monocytes and murine Kupffer cells. Hepatology. 1997;25:927–933
  81. Oumi M, Yamamoto T. A scanning electron microscope study on the effects of different bile salts on the epithelial lining of jejunal mucosa. Med Electron Microsc. 2000;33:11–15
  82. Benedetti A, Alvaro D, Bassotti C, et al. Cytotoxicity of bile salts against biliary epithelium: a study in isolated bile ductule fragments and isolated perfused rat liver. Hepatology. 1997;26:9–21
  83. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159:2647–2658
  84. Palmeira CM, Rolo AP. Mitochondrially-mediated toxicity of bile acids. Toxicology. 2004;203:1–15
  85. Sokol RJ, McKim JM, Goff MC, et al. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology. 1998;114:164–174
  86. Schubert R, Schmidt KH. Structural changes in vesicle membranes and mixed micelles of various lipid compositions after binding of different bile salts. Biochemistry. 1988;27:8787–8794
  87. Lemasters JJ. The mitochondrial permeability transition: from biochemical curiosity to pathophysiological mechanism. Gastroenterology. 1998;115:783–786
  88. Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta. 1998;1366:177–196
  89. Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL. Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta. 2009;1787:1395–1401
  90. Sokol RJ, Dahl R, Devereaux MW, et al. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J Pediatr Gastroenterol Nutr. 2005;41:235–243
  91. Rolo AP, Palmeira CM, Wallace KB. Mitochondrially mediated synergistic cell killing by bile acids. Biochim Biophys Acta. 2003;1637:127–132
  92. Sokol RJ, Winklhofer-Roob BM, Devereaux MW, McKim JM. Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids. Gastroenterology. 1995;109:1249–1256
  93. Gumpricht E, Devereaux MW, Dahl R, et al. Resistance of young rat hepatic mitochondria to bile acid-induced permeability transition: potential role of alpha-tocopherol. Pediatr Res. 2008;64:498–504
  94. Yerushalmi B, Dahl R, Devereaux MW, et al. Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology. 2001;33:616–626
  95. Prince MI, Mitchison HC, Ashley D, et al. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Aliment Pharmacol Ther. 2003;17:137–143
  96. Reinehr R, Graf D, Haussinger D. Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation. Gastroenterology. 2003;125:839–853
  97. Reinehr R, Becker S, Keitel V, et al. Bile salt-induced apoptosis involves NADPH oxidase isoform activation. Gastroenterology. 2005;129:2009–2031
  98. Rust C, Wild N, Bernt C, et al. Bile acid-induced apoptosis in hepatocytes is caspase-6-dependent. J Biol Chem. 2009;284:2908–2916
  99. Schoemaker MH, Conde de la Rosa L, Buist-Homan M, et al. Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways. Hepatology. 2004;39:1563–1573
  100. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7:1013–1030
  101. Kaplowitz N, Than TA, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Semin Liver Dis. 2007;27:367–377
  102. Iizaka T, Tsuji M, Oyamada H, et al. Interaction between caspase-8 activation and endoplasmic reticulum stress in glycochenodeoxycholic acid-induced apoptotic HepG2 cells. Toxicology. 2007;241:146–156
  103. Hitomi J, Katayama T, Eguchi Y, et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol. 2004;165:347–356
  104. Bochkis IM, Rubins NE, White P, et al. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med. 2008;14:828–836
  105. Kitani K, Ohta M, Kanai S. Tauroursodeoxycholate prevents biliary protein excretion induced by other bile salts in the rat. Am J Physiol. 1985;248:G407–G417
  106. Wimmer R, Hohenester S, Pusl T, et al. Tauroursodeoxycholic acid exerts anticholestatic effects by a cooperative cPKC alpha-/PKA-dependent mechanism in rat liver. Gut. 2008;57:1448–1454
  107. Marzioni M, Francis H, Benedetti A, et al. Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts. Am J Pathol. 2006;168:398–409
  108. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36:525–531
  109. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol. 2001;35:134–146
  110. Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology. 1998;28:1449–1453
  111. Dombrowski F, Stieger B, Beuers U. Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab Invest. 2006;86:166–174
  112. Beuers U, Bilzer M, Chittattu A, et al. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology. 2001;33:1206–1216
  113. Fiorotto R, Spirli C, Fabris L, et al. Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion. Gastroenterology. 2007;133:1603–1613
  114. Minagawa N, Nagata J, Shibao K, et al. Cyclic AMP regulates bicarbonate secretion in cholangiocytes through release of ATP into bile. Gastroenterology. 2007;133:1592–1602
  115. Nathanson MH, Burgstahler AD, Masyuk A, Larusso NF. Stimulation of ATP secretion in the liver by therapeutic bile acids. Biochem J. 2001;358:1–5
  116. Rodrigues CM, Fan G, Ma X, et al. A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest. 1998;101:2790–2799
  117. Serviddio G, Pereda J, Pallardo FV, et al. Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress. Hepatology. 2004;39:711–720
  118. Rodrigues CM, Steer CJ. The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent. Expert Opin Investig Drugs. 2001;10:1243–1253
  119. Mitsuyoshi H, Nakashima T, Sumida Y, et al. Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochem Biophys Res Commun. 1999;263:537–542
  120. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–267
  121. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991;324:1548–1554
  122. Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994;19:1149–1156
  123. Lindor KD, Dickson ER, Baldus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994;106:1284–1290
  124. Combes B, Carithers RL, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1995;22:759–766
  125. Pares A, Caballeria L, Rodes J, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol. 2000;32:561–566
  126. Corpechot C, Carrat F, Bonnand AM, et al. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000;32:1196–1199
  127. 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
  128. Goulis J, Leandro G, Burroughs A. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet. 1999;354:1053–1060
  129. Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses. Am J Gastroenterol. 2007;102:1799–1807
  130. Shi J, Wu C, Lin Y, et al. Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006;101:1529–1538
  131. Lindor KD, Poupon R, Heathcote EJ, Therneau T. Ursodeoxycholic acid for primary biliary cirrhosis. Lancet. 2000;355:657–658
  132. Corpechot C, Carrat F, Bahr A, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005;128:297–303
  133. 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
  134. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–877
  135. Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136:1281–1287
  136. Chazouilleres O, Poupon R, Capron JP, et al. Ursodeoxycholic acid for primary sclerosing cholangitis. J Hepatol. 1990;11:120–123
  137. O’Brien CB, Senior JR, Arora-Mirchandani R, et al. Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study. Hepatology. 1991;14:838–847
  138. Beuers U, Spengler U, Kruis W, et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial. Hepatology. 1992;16:707–714
  139. Stiehl A. Ursodeoxycholic acid therapy in treatment of primary sclerosing cholangitis. Scand J Gastroenterol Suppl. 1994;204:59–61
  140. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997;336:691–695
  141. Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A. Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology. 2004;40:693–698
  142. Mitchell SA, Bansi DS, Hunt N, et al. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology. 2001;121:900–907
  143. Harnois DM, Angulo P, Jorgensen RA, et al. High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol. 2001;96:1558–1562
  144. Cullen SN, Rust C, Fleming K, et al. High dose ursodeoxycholic acid for the treatment of primary sclerosig cholangitis is safe and effective. J Hepatol. 2008;48:792–800
  145. Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129:1464–1472
  146. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808–814
  147. Lindor KD, Enders FB, Schmoll JA, et al. Randomized, double-blind controlled trial of high-dose ursodeoxycholic acid for primary sclerosing cholangitis. Hepatology. 2008;48:378A
  148. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321–327
  149. Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med. 2001;134:89–95
  150. Wolf JM, Rybicki LA, Lashner BA. The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis. Aliment Pharmacol Ther. 2005;22:783–788
  151. Pardi DS, Loftus EV, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–893
  152. Rudolph G, Kloeters-Plachky P, Rost D, Stiehl A. The incidence of cholangiocarcinoma in primary sclerosing cholangitis after long-time treatment with ursodeoxycholic acid. Eur J Gastroenterol Hepatol. 2007;19:487–491
  153. Lazaridis KN, Gores GJ. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver Dis. 2006;26:42–51
  154. Brandsaeter B, Isoniemi H, Broome U, et al. Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol. 2004;40:815–822
  155. Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol. 1997;27:1022–1028
  156. Williamson C, Hems LM, Goulis DG, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG. 2004;111:676–681
  157. Roncaglia N, Locatelli A, Arreghini A, et al. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG. 2004;111:17–21
  158. Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology. 2005;42:1399–1405
  159. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology. 2005;129:894–901
  160. Binder T, Salaj P, Zima T, Vitek L. Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis of pregnancy. J Perinat Med. 2006;34:383–391
  161. Glantz A, Reilly SJ, Benthin L, et al. Intrahepatic cholestasis of pregnancy: amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology. 2008;47:544–551
  162. Colombo C, Battezzati PM, Podda M, et al. Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis. Hepatology. 1996;23:1484–1490
  163. van de Meeberg PC, Houwen RH, Sinaasappel M, et al. Low-dose versus high-dose ursodeoxycholic acid in cystic fibrosis-related cholestatic liver disease. Results of a randomized study with 1-year follow-up. Scand J Gastroenterol. 1997;32:369–373
  164. Lindblad A, Glaumann H, Strandvik B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology. 1998;27:166–174
  165. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4:1
  166. Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001;120:1448–1458
  167. Nathwani RA, Kaplowitz N. Drug hepatotoxicity. Clin Liver Dis. 2006;10:207–217vii
  168. Essell JH, Schroeder MT, Harman GS, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128:975–981
  169. Ohashi K, Tanabe J, Watanabe R, et al. The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. Am J Hematol. 2000;64:32–38
  170. Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood. 2002;100:1977–1983
  171. Tay J, Tinmouth A, Fergusson D, et al. Systematic review of controlled clinical trials on the use of ursodeoxycholic acid for the prevention of hepatic veno-occlusive disease in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:206–217
  172. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. Hepatology. 2009;49:1729–1764
  173. European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–242
  174. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–1374
  175. Pelletier G, Roulot D, Davion T, et al. A randomized controlled trial of ursodeoxycholic acid in patients with alcohol-induced cirrhosis and jaundice. Hepatology. 2003;37:887–892
  176. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778
  177. Mancinelli R, Onori P, Gaudio E, et al. Taurocholate feeding to bile duct ligated rats prevents caffeic acid-induced bile duct damage by changes in cholangiocyte VEGF expression. Exp Biol Med (Maywood). 2009;234:462–474
  178. Ueno Y, Francis H, Glaser S, et al. Taurocholic acid feeding prevents tumor necrosis factor-alpha-induced damage of cholangiocytes by a PI3K-mediated pathway. Exp Biol Med (Maywood). 2007;232:942–949
  179. Marzioni M, Ueno Y, Glaser S, et al. Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver. Liver Int. 2007;27:558–568
  180. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5:456–468
  181. Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. 2006;130:908–925
  182. Heubi JE, Setchell KD, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27:282–294
  183. Gonzales E, Gerhardt MF, Fabre M, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009;137:1310–20 e1–3
  184. Halilbasic E, Fiorotto R, Fickert P, et al. Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2−/− mice. Hepatology. 2009;49:1972–1981
  185. Hofmann AF, Zakko SF, Lira M, et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology. 2005;42:1391–1398
  186. Hofmann AF. Bile acids: trying to understand their chemistry and biology with the hope of helping patients. Hepatology. 2009;49:1403–1418
  187. Yoon YB, Hagey LR, Hofmann AF, et al. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology. 1986;90:837–852
  188. Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2009;
  189. Fiorucci S, Clerici C, Antonelli E, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther. 2005;313:604–612
  190. Wang XX, Jiang T, Shen Y, et al. Farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria. Am J Physiol Renal Physiol. 2009;

PII: S1590-8658(10)00106-4

doi: 10.1016/j.dld.2010.03.015

Digestive and Liver Disease
Volume 42, Issue 6 , Pages 409-418 , June 2010

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