Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether “high dose” UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC.
Similar content being viewed by others
References
LaRusso NF, Shneider BL, Black D et al (2006) Primary sclerosing cholangitis: summary of a workshop. Hepatology 44(3):746–764
O’Mahony CA, Vierling JM (2006) Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis 26(1):3–21
Worthington J, Cullen S, Chapman R (2005) Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol 28(2):93–103
Adams DH, Eksteen B (2006) Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat Rev Immunol 6(3):244–251
Trauner M, Meier PJ, Boyer JL (1998) Molecular pathogenesis of cholestasis. N Engl J Med 339(17):1217–1227
Paumgartner G (2006) Medical treatment of cholestatic liver diseases: from pathobiology to pharmacological targets. World J Gastroenterol 12(28):4445–4451
Fischer S, Beuers U, Spengler U, Zwiebel FM, Koebe HG (1996) Hepatic levels of bile acids in end-stage chronic cholestatic liver disease. Clin Chim Acta 251(2):173–186
Beuers U, Boyer JL, Paumgartner G (1998) Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology 28(6):1449–1453
Trauner M, Boyer JL (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83(2):633–671
Boyer JL (2007) New perspectives for the treatment of cholestasis: lessons from basic science applied clinically. J Hepatol 46(3):365–371
Stedman CA, Liddle C, Coulter SA et al (2005) Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci U S A 102(6):2063–2068
Zollner G, Marschall HU, Wagner M, Trauner M (2006) Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 3(3):231–251
Bergquist A, Ekbom A, Olsson R et al (2002) Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 36(3):321–327
Melum E, Karlsen TH, Schrumpf E et al (2008) Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology 47(1):90–96
Karlsen TH, Schrumpf E, Boberg KM (2007) Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol 13(41):5421–5431
Broome U, Lofberg R, Veress B, Eriksson LS (1995) Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 22(5):1404–1408
Vera A, Gunson BK, Ussatoff V et al (2003) Colorectal cancer in patients with inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation 75(12):1983–1988
Loftus EV Jr, Aguilar HI, Sandborn WJ et al (1998) Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 27(3):685–690
Narumi S, Roberts JP, Emond JC, Lake J, Ascher NL (1995) Liver transplantation for sclerosing cholangitis. Hepatology 22(2):451–457
Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO (2002) Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 56(1):48–54
Lindberg BU, Broome U, Persson B (2001) Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 44(1):77–85
Loftus EV Jr, Harewood GC, Loftus CG et al (2005) PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 54(1):91–96
Cullen SN, Chapman RW (2006) The medical management of primary sclerosing cholangitis. Semin Liver Dis 26(1):52–61
Beuers U, Spengler U, Kruis W et al (1992) Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial. Hepatology 16(3):707–714
Stiehl A, Walker S, Stiehl L, Rudolph G, Hofmann WJ, Theilmann L (1994) Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period. J Hepatol 20(1):57–64
Lindor KD (1997) Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med 336(10):691–695
Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW (2001) A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 121(4):900–907
Olsson R, Boberg KM, de Muckadell OS et al (2005) High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 129(5):1464–1472
Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman R (2008) High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol 48(5):792–800
Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD (2001) High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol 96(5):1558–1562
Brandsaeter B, Isoniemi H, Broome U et al (2004) Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol 40(5):815–822
Pardi DS, Loftus EV Jr., Kremers WK, Keach J, Lindor KD (2003) Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 124(4):889–893
Tung BY, Emond MJ, Haggitt RC et al (2001) Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 134(2):89–95
Beuers U (2006) Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nature Clin Pract Gastroenterol Hepatol 3(6):318–328
Paumgartner G, Beuers U (2002) Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36(3):525–531
Lazaridis KN, Gores GJ, Lindor KD (2001) Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol 35(1):134–146
Karlsen TH, Lie BA, Frey Froslie K et al (2006) Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 131(3):781–787
Hruz P, Zimmermann C, Gutmann H et al (2006) Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis. Gut 55(3):395–402
Stiehl A, Rudolph G, Sauer P, Theilmann L (1995) Biliary secretion of bile acids and lipids in primary sclerosing cholangitis. Influence of cholestasis and effect of ursodeoxycholic acid treatment. J Hepatol 23(3):283–289
Serfaty L, De Leusse A, Rosmorduc O et al (2003) Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study. Hepatology 38(1):203–209
Fickert P, Wagner M, Marschall HU et al (2006) 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130(2):465–481
Hofmann AF, Zakko SF, Lira M et al (2005) Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 42(6):1391–1398
Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284(5418):1362–1365
Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284(5418):1365–1368
Paumgartner G, Pusl T (2008) Medical treatment of cholestatic liver disease. Clin Liver Dis 12(1):53–80
Eloranta JJ, Jung D, Kullak-Ublick GA (2006) The human Na + -taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol 20(1):65–79
Jung D, Kullak-Ublick GA (2003) Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression. Hepatology 37(3):622–631
Eloranta JJ, Kullak-Ublick GA (2005) Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 433(2):397–412
Barbier O, Torra IP, Sirvent A et al (2003) FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Gastroenterology 124(7):1926–1940
Gnerre C, Blattler S, Kaufmann MR, Looser R, Meyer UA (2004) Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene. Pharmacogenetics 14(10):635–645
Grober J, Zaghini I, Fujii H et al (1999) Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem 274(42):29749–29754
Cariou B, Staels B (2006) The expanding role of the bile acid receptor FXR in the small intestine. J Hepatol 44(6):1213–1215
Landrier JF, Eloranta JJ, Vavricka SR, Kullak-Ublick GA (2006) The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol 290(3):G476–485
Neimark E, Chen F, Li X, Shneider BL (2004) Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology 40(1):149–156
Pellicciari R, Fiorucci S, Camaioni E et al (2002) 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 45(17):3569–3572
Fiorucci S, Clerici C, Antonelli E et al (2005) Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 313(2):604–612
Goodwin B, Jones SA, Price RR et al (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6(3):517–526
Liu Y, Binz J, Numerick MJ et al (2003) Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112(11):1678–1687
Fiorucci S, Antonelli E, Rizzo G et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127(5):1497–1512
Wagner M, Fickert P, Zollner G et al (2003) Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 125(3):825–838
Stedman C, Liddle C, Coulter S et al (2006) Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A 103(30):11323–11328
Kliewer SA, Willson TM (2002) Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor. J Lipid Res 43(3):359–364
Bertilsson G, Heidrich J, Svensson K et al (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95(21):12208–12213
Staudinger JL, Goodwin B, Jones SA et al (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 98(6):3369–3374
Fang HL, Strom SC, Ellis E et al (2007) Positive and negative regulation of human hepatic hydroxysteroid sulfotransferase (SULT2A1) gene transcription by rifampicin: roles of hepatocyte nuclear factor 4alpha and pregnane X receptor. J Pharmacol Exp Ther 323(2):586–598
Gardner-Stephen D, Heydel JM, Goyal A et al (2004) Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression. Drug Metab Dispos 32(3):340–347
Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276(18):14581–14587
Kast HR, Goodwin B, Tarr PT et al (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 277(4):2908–2915
Teng S, Jekerle V, Piquette-Miller M (2003) Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab Dispos 31(11):1296–1299
Teng S, Piquette-Miller M (2007) Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis. Br J Pharmacol 151(3):367–376
Bachs L, Pares A, Elena M, Piera C, Rodes J (1989) Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet 1(8638):574–576
Bachs L, Pares A, Elena M, Piera C, Rodes J (1992) Effects of long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology 102(6):2077–2080
Marschall HU, Wagner M, Zollner G et al (2005) Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129(2):476–485
Dilger K, Denk A, Heeg MH, Beuers U (2005) No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology 41(3):595–602
Khurana S, Singh P (2006) Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int 26(8):943–948
Wagner M, Halilbasic E, Marschall HU et al (2005) CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 42(2):420–430
Stojakovic T, Putz-Bankuti C, Fauler G et al (2007) Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology 46(3):776–784
Boberg KM, Egeland T, Schrumpf E (2003) Long-term effect of corticosteroid treatment in primary sclerosing cholangitis patients. Scand J Gastroenterol 38(9):991–995
Maier A, Zimmermann C, Beglinger C, Drewe J, Gutmann H (2007) Effects of budesonide on P-glycoprotein expression in intestinal cell lines. Br J Pharmacol 150(3):361–368
Sandborn WJ, Feagan BG, Lichtenstein GR (2007) Medical management of mild to moderate Crohn’s disease: evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther 26(7):987–1003
Wiegand J, Schuler A, Kanzler S et al (2005) Budesonide in previously untreated autoimmune hepatitis. Liver Int 25(5):927–934
Leuschner M, Maier KP, Schlichting J et al (1999) Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 117(4):918–925
Rautiainen H, Karkkainen P, Karvonen AL et al (2005) Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 41(4):747–752
Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T (2003) Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology 38(1):196–202
Jung D, Fantin AC, Scheurer U, Fried M, Kullak-Ublick GA (2004) Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor. Gut 53(1):78–84
van Hoogstraten HJ, Vleggaar FP, Boland GJ et al (2000) Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double-blind pilot study. Belgian–Dutch PSC Study Group. Am J Gastroenterol 95(8):2015–2022
Angulo P, Batts KP, Jorgensen RA, LaRusso NA, Lindor KD (2000) Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol 95(9):2333–2337
Lechner D, Kallay E, Cross HS (2007) 1alpha,25-dihydroxyvitamin D3 downregulates CYP27B1 and induces CYP24A1 in colon cells. Mol Cell Endocrinol 263(1–2):55–64
Kim MS, Fujiki R, Kitagawa H, Kato S (2007) 1alpha,25(OH)2D3-induced DNA methylation suppresses the human CYP27B1 gene. Mol Cell Endocrinol 265–266:168–173
Turunen MM, Dunlop TW, Carlberg C, Vaisanen S (2007) Selective use of multiple vitamin D response elements underlies the 1 alpha,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. Nucleic Acids Res 35(8):2734–2747
Wang TT, Tavera-Mendoza LE, Laperriere D et al (2005) Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19(11):2685–2695
Shneider BL (2001) Intestinal bile acid transport: biology, physiology, and pathophysiology. J Pediatr Gastroenterol Nutr 32(4):407–417
Craddock AL, Love MW, Daniel RW et al (1998) Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol 274(1 Pt 1):G157–169
Chen X, Chen F, Liu S et al (2006) Transactivation of rat apical sodium-dependent bile acid transporter and increased bile acid transport by 1alpha,25-dihydroxyvitamin D3 via the vitamin D receptor. Mol Pharmacol 69(6):1913–1923
McCarthy TC, Li X, Sinal CJ (2005) Vitamin D receptor-dependent regulation of colon multidrug resistance-associated protein 3 gene expression by bile acids. J Biol Chem 280(24):23232–23242
Kozoni V, Tsioulias G, Shiff S, Rigas B (2000) The effect of lithocholic acid on proliferation and apoptosis during the early stages of colon carcinogenesis: differential effect on apoptosis in the presence of a colon carcinogen. Carcinogenesis 21(5):999–1005
Miyata M, Matsuda Y, Tsuchiya H et al (2006) Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase. Drug Metab Pharmacokinet 21(4):315–323
Makishima M, Lu TT, Xie W et al (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296(5571):1313–1316
Song CS, Echchgadda I, Seo YK et al (2006) An essential role of the CAAT/enhancer binding protein-alpha in the vitamin D-induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1). Mol Endocrinol 20(4):795–808
Gascon-Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A (2003) The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 37(5):1034–1042
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20(5):649–688
Zandbergen F, Plutzky J (2007) PPARalpha in atherosclerosis and inflammation. Biochim Biophys Acta 1771(8):972–982
Itakura J, Izumi N, Nishimura Y et al (2004) Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res 29(4):216–222
Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K (2004) Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 10(6):894–898
Iwasaki S, Akisawa N, Saibara T, Onishi S (2007) Fibrate for treatment of primary biliary cirrhosis. Hepatol Res 37(Suppl 3):S515–S517
Kleemann R, Verschuren L, de Rooij BJ et al (2004) Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. Blood 103(11):4188–4194
Kleemann R, Gervois PP, Verschuren L, Staels B, Princen HM, Kooistra T (2003) Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. Blood 101(2):545–551
Panigrahy D, Kaipainen A, Huang S, et al (2008) PPAR{alpha} agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. PNAS 105:985–990
Jung D, Fried M, Kullak-Ublick GA (2002) Human apical sodium-dependent bile salt transporter (SLC10A2) gene is regulated by the peroxisome proliferator-activated receptor alpha. J Biol Chem 277(34):30559–30566
Heikkinen S, Auwerx J, Argmann CA (2007) PPARgamma in human and mouse physiology. Biochim Biophys Acta 1771(8):999–1013
Belfort R, Harrison SA, Brown K et al (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355(22):2297–2307
Harada K, Isse K, Kamihira T, Shimoda S, Nakanuma Y (2005) Th1 cytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis. Hepatology 41(6):1329–1338
Fickert P, Moustafa T, Trauner M (2007) Primary sclerosing cholangitis—the arteriosclerosis of the bile duct? Lipids Health Dis 6:3
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Beuers, U., Kullak-Ublick, G.A., Pusl, T. et al. Medical Treatment of Primary Sclerosing Cholangitis: A Role for Novel Bile Acids and other (post-)Transcriptional Modulators?. Clinic Rev Allerg Immunol 36, 52–61 (2009). https://doi.org/10.1007/s12016-008-8085-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12016-008-8085-y