Journal of Hepatology
Volume 48 , Pages S38-S57 , 2008

The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy

References 

  1. Bargen J. Complications and sequelae of chronic ulcerative colitis. Ann Intern Med. 1929;3:335–352
  2. Kimmelstiel P, Large HL, Verner HD. Liver damage in ulcerative colitis. Am J Pathol. 1952;28:259–289
  3. Schrumpf E, Boberg KM. Epidemiology of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2001;15:553–562
  4. Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33:99–103
  5. Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol. 2007;102:1042–1049
  6. Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. 2003;125:1364–1369
  7. Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology. 2004;126:1929–1930
  8. Escorsell A, Pares A, Rodes J, Solis-Herruzo JA, Miras M, de la Morena E. Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver. J Hepatol. 1994;21:787–791
  9. Ang TL, Fock KM, Ng TM, Teo EK, Chua TS, Tan JY. Clinical profile of primary sclerosing cholangitis in Singapore. J Gastroenterol Hepatol. 2002;17:908–913
  10. Takikawa H, Takamori Y, Tanaka A, Kurihara H, Nakanuma Y. Analysis of 388 cases of primary sclerosing cholangitis in Japan; presence of a subgroup without pancreatic involvement in older patients. Hepatol Res. 2004;29:153–159
  11. Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV. Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol. 2002;97:2402–2407
  12. Olsson R, Danielsson A, Jarnerot G, Lindstrom E, Loof L, Rolny P, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology. 1991;100:1319–1323
  13. Mitchell SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW. Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut. 2002;51:567–573
  14. Loftus EV, Sandborn WJ, Tremaine WJ, Mahoney DW, Zinsmeister AR, Offord KP, et al. Primary sclerosing cholangitis is associated with nonsmoking: a case-control study. Gastroenterology. 1996;110:1496–1502
  15. Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321–327
  16. Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–615
  17. Tischendorf JJ, Hecker H, Kruger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol. 2007;102:107–114
  18. O’Mahony CA, Vierling JM. Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis. 2006;26:3–21
  19. Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol. 2005;28:93–103
  20. Saarinen S, Olerup O, Broome U. Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2000;95:3195–3199
  21. Bergquist A, Lindberg G, Saarinen S, Broome U. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol. 2005;42:252–256
  22. Donaldson PT. Genetics of liver disease: immunogenetics and disease pathogenesis. Gut. 2004;53:599–608
  23. Norris S, Kondeatis E, Collins R, Satsangi J, Clare M, Chapman R, et al. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology. 2001;120:1475–1482
  24. Donaldson PT, Norris S. Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity. 2002;35:555–564
  25. Spurkland A, Saarinen S, Boberg KM, Mitchell S, Broome U, Caballeria L, et al. HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens. 1999;53:459–469
  26. Henckaerts L, Fevery J, Van Steenbergen W, Verslype C, Yap P, Nevens F, et al. CC-type chemokine receptor 5-Delta32 mutation protects against primary sclerosing cholangitis. Inflamm Bowel Dis. 2006;12:272–277
  27. Eri R, Jonsson JR, Pandeya N, Purdie DM, Clouston AD, Martin N, et al. CCR5-Delta32 mutation is strongly associated with primary sclerosing cholangitis. Genes Immun. 2004;5:444–450
  28. Yang X, Cullen SN, Li JH, Chapman RW, Jewell DP. Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1. J Hepatol. 2004;40:375–379
  29. Bowlus CL, Karlsen TH, Broome U, Thorsby E, Vatn M, Schrumpf E, et al. Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis. J Hepatol. 2006;45:704–710
  30. Mitchell SA, Grove J, Spurkland A, Boberg KM, Fleming KA, Day CP, et al. Association of the tumour necrosis factor alpha-308 but not the interleukin 10-627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis. Gut. 2001;49:288–294
  31. Gallegos-Orozco JF, Yurk CE, Wang N, Rakela J, Charlton MR, Cutting GR, et al. Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis. Am J Gastroenterol. 2005;100:874–878
  32. Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, et al. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet. 2003;113:286–292
  33. Angulo P, Peter JB, Gershwin ME, DeSotel CK, Shoenfeld Y, Ahmed AE, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol. 2000;32:182–187
  34. Mulder AH, Horst G, Haagsma EB, Limburg PC, Kleibeuker JH, Kallenberg CG. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology. 1993;17:411–417
  35. Bansi DS, Fleming KA, Chapman RW. Importance of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and ulcerative colitis: prevalence, titre, and IgG subclass. Gut. 1996;38:384–389
  36. Terjung B, Spengler U. Role of auto-antibodies for the diagnosis of chronic cholestatic liver diseases. Clin Rev Allergy Immunol. 2005;28:115–133
  37. Terjung B, Spengler U, Sauerbruch T, Worman HJ. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines. Gastroenterology. 2000;119:310–322
  38. Bodenheimer HC, LaRusso NF, Thayer WR, Charland C, Staples PJ, Ludwig J. Elevated circulating immune complexes in primary sclerosing cholangitis. Hepatology. 1983;3:150–154
  39. Senaldi G, Donaldson PT, Magrin S, Farrant JM, Alexander GJ, Vergani D, et al. Activation of the complement system in primary sclerosing cholangitis. Gastroenterology. 1989;97:1430–1434
  40. Bo X, Broome U, Remberger M, Sumitran-Holgersson S. Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis. Gut. 2001;49:131–141
  41. Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet. 2002;359:150–157
  42. Eksteen B, Miles AE, Grant AJ, Adams DH. Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease. Clin Med. 2004;4:173–180
  43. Salmi M, Jalkanen S. Endothelial ligands and homing of mucosal leukocytes in extraintestinal manifestations of IBD. Inflamm Bowel Dis. 1998;4:149–156
  44. Grant AJ, Lalor PF, Hubscher SG, Briskin M, Adams DH. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology. 2001;33:1065–1072
  45. Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med. 2004;200:1511–1517
  46. Palmer KR, Duerden BI, Holdsworth CD. Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery. Gut. 1980;21:851–854
  47. Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology. 1981;1:632–640
  48. Lichtman SN, Sartor RB, Keku J, Schwab JH. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth. Gastroenterology. 1990;98:414–423
  49. Bjornsson E, Cederborg A, Akvist A, Simren M, Stotzer PO, Bjarnason I. Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2005;40:1090–1094
  50. Nilsson HO, Taneera J, Castedal M, Glatz E, Olsson R, Wadstrom T. Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis. J Clin Microbiol. 2000;38:1072–1076
  51. Boomkens SY, de Rave S, Pot RG, Egberink HF, Penning LC, Rothuizen J, et al. The role of Helicobacter spp. in the pathogenesis of primary biliary cirrhosis and primary sclerosing cholangitis. FEMS Immunol Med Microbiol. 2005;44:221–225
  52. Krasinskas AM, Yao Y, Randhawa P, Dore MP, Sepulveda AR. Helicobacter pylori may play a contributory role in the pathogenesis of primary sclerosing cholangitis. Dig Dis Sci. 2007;52:2265–2270
  53. Mehal WZ, Hattersley AT, Chapman RW, Fleming KA. A survey of cytomegalovirus (CMV) DNA in primary sclerosing cholangitis (PSC) liver tissues using a sensitive polymerase chain reaction (PCR) based assay. J Hepatol. 1992;15:396–399
  54. Minuk GY, Rascanin N, Paul RW, Lee PW, Buchan K, Kelly JK. Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 1987;5:8–13
  55. Pohl J, Ring A, Stremmel W, Stiehl A. The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol. 2006;18:69–74
  56. Bjornsson ES, Kilander AF, Olsson RG. Bile duct bacterial isolates in primary sclerosing cholangitis and certain other forms of cholestasis – a study of bile cultures from ERCP. Hepatogastroenterology. 2000;47:1504–1508
  57. Kulaksiz H, Rudolph G, Kloeters-Plachky P, Sauer P, Geiss H, Stiehl A. Biliary Candida infections in primary sclerosing cholangitis. J Hepatol. 2006;45:711–716
  58. Tietz PS, Larusso NF. Cholangiocyte biology. Curr Opin Gastroenterol. 2006;22:279–287
  59. Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology. 2004;127:1565–1577
  60. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. 1998;339:1217–1227
  61. Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G, Tsybrovskyy O, 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
  62. Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology. 2002;123:1238–1251
  63. Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2004;39:779–791
  64. Das KM, Vecchi M, Sakamaki S. A shared and unique epitope(s) on human colon, skin, and biliary epithelium detected by a monoclonal antibody. Gastroenterology. 1990;98:464–469
  65. Mandal A, Dasgupta A, Jeffers L, Squillante L, Hyder S, Reddy R, et al. Autoantibodies in sclerosing cholangitis against a shared peptide in biliary and colon epithelium. Gastroenterology. 1994;106:185–192
  66. Xu B, Broome U, Ericzon BG, Sumitran-Holgersson S. High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6. Gut. 2002;51:120–127
  67. Karrar A, Broome U, Sodergren T, Jaksch M, Bergquist A, Bjornstedt M, et al. Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis. Gastroenterology. 2007;132:1504–1514
  68. Spirli C, Nathanson MH, Fiorotto R, Duner E, Denson LA, Sanz JM, et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology. 2001;121:156–169
  69. Spirli C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology. 2003;124:737–753
  70. Fevery J, Verslype C, Lai G, Aerts R, Van Steenbergen W. Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci. 2007;52:3123–3135
  71. Komichi D, Tazuma S, Nishioka T, Hyogo H, Chayama K. Glycochenodeoxycholate plays a carcinogenic role in immortalized mouse cholangiocytes via oxidative DNA damage. Free Radic Biol Med. 2005;39:1418–1427
  72. Meng F, Yamagiwa Y, Ueno Y, Patel T. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol. 2006;44:1055–1065
  73. Ahrendt SA, Rashid A, Chow JT, Eisenberger CF, Pitt HA, Sidransky D. p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. J Hepatobiliary Pancreat Surg. 2000;7:426–431
  74. Boberg KM, Schrumpf E, Bergquist A, Broome U, Pares A, Remotti H, et al. Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development. J Hepatol. 2000;32:374–380
  75. Taniai M, Higuchi H, Burgart LJ, Gores GJ. p16INK4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and PSC-associated cholangiocarcinoma. Gastroenterology. 2002;123:1090–1098
  76. Ahrendt SA, Eisenberger CF, Yip L, Rashid A, Chow JT, Pitt HA, et al. Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma. J Surg Res. 1999;84:88–93
  77. Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology. 1989;10:430–436
  78. Bergquist A, Said K, Broome U. Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden. Scand J Gastroenterol. 2007;42:88–93
  79. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm Bowel Dis. 2005;11:62–72
  80. Zein CO, Lindor KD, Angulo P. Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis. Hepatology. 2004;39:204–210
  81. Bjornsson E, Simren M, Olsson R, Chapman RW. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2004;39:961–968
  82. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology. 1998;27:311–316
  83. Hay JE, Lindor KD, Wiesner RH, Dickson ER, Krom RA, LaRusso NF. The metabolic bone disease of primary sclerosing cholangitis. Hepatology. 1991;14:257–261
  84. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332:924–933
  85. Majoie CB, Reeders JW, Sanders JB, Huibregtse K, Jansen PL. Primary sclerosing cholangitis: a modified classification of cholangiographic findings. AJR Am J Roentgenol. 1991;157:495–497
  86. Rajaram R, Ponsioen CY, Majoie CB, Reeders JW, Lameris JS. Evaluation of a modified cholangiographic classification system for primary sclerosing cholangitis. Abdom Imaging. 2001;26:43–47
  87. Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts?. Ann Intern Med. 1985;102:581–587
  88. Trauner M, Boyer JL. Cholestatic syndromes. Curr Opin Gastroenterol. 2004;20:220–230
  89. Engler S, Elsing C, Flechtenmacher C, Theilmann L, Stremmel W, Stiehl A. Progressive sclerosing cholangitis after septic shock: a new variant of vanishing bile duct disorders. Gut. 2003;52:688–693
  90. Gelbmann CM, Rummele P, Wimmer M, Hofstadter F, Gohlmann B, Endlicher E, et al. Ischemic-like cholangiopathy with secondary sclerosing cholangitis in critically ill patients. Am J Gastroenterol. 2007;102:1221–1229
  91. Byrne MF, Chong HI, O’Donovan D, Sheehan KM, Leader MB, Kay E, et al. Idiopathic cholangiopathy in a biliary cast syndrome necessitating liver transplantation following head trauma. Eur J Gastroenterol Hepatol. 2003;15:415–417
  92. van Milligen de Wit AW, van Bracht J, Rauws EA, Jones EA, Tytgat GN, Huibregtse K. Endoscopic stent therapy for dominant extrahepatic bile duct strictures in primary sclerosing cholangitis. Gastrointest Endosc. 1996;44:293–299
  93. Stiehl A, Rudolph G, Kloeters-Plachky P, Sauer P, Walker S. Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment. J Hepatol. 2002;36:151–156
  94. van Milligen de Wit AW, Rauws EA, van Bracht J, Mulder CJ, Jones EA, Tytgat GN, et al. Lack of complications following short-term stent therapy for extrahepatic bile duct strictures in primary sclerosing cholangitis. Gastrointest Endosc. 1997;46:344–347
  95. Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335:909–918
  96. Loperfido S, Angelini G, Benedetti G, Chilovi F, Costan F, De Berardinis F, et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc. 1998;48:1–10
  97. Masci E, Toti G, Mariani A, Curioni S, Lomazzi A, Dinelli M, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96:417–423
  98. Ernst O, Asselah T, Sergent G, Calvo M, Talbodec N, Paris JC, et al. MR cholangiography in primary sclerosing cholangitis. AJR Am J Roentgenol. 1998;171:1027–1030
  99. Fulcher AS, Turner MA, Franklin KJ, Shiffman ML, Sterling RK, Luketic VA, et al. Primary sclerosing cholangitis: evaluation with MR cholangiography – a case-control study. Radiology. 2000;215:71–80
  100. Angulo P, Pearce DH, Johnson CD, Henry JJ, LaRusso NF, Petersen BT, et al. Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis. J Hepatol. 2000;33:520–527
  101. Moff SL, Kamel IR, Eustace J, Lawler LP, Kantsevoy S, Kalloo AN, et al. Diagnosis of primary sclerosing cholangitis: a blinded comparative study using magnetic resonance cholangiography and endoscopic retrograde cholangiography. Gastrointest Endosc. 2006;64:219–223
  102. Berstad AE, Aabakken L, Smith HJ, Aasen S, Boberg KM, Schrumpf E. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2006;4:514–520
  103. Textor HJ, Flacke S, Pauleit D, Keller E, Neubrand M, Terjung B, et al. Three-dimensional magnetic resonance cholangiopancreatography with respiratory triggering in the diagnosis of primary sclerosing cholangitis: comparison with endoscopic retrograde cholangiography. Endoscopy. 2002;34:984–990
  104. Olsson R, Hagerstrand I, Broome U, Danielsson A, Jarnerot G, Loof L, et al. Sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis. J Clin Pathol. 1995;48:933–935
  105. Burak KW, Angulo P, Lindor KD. Is there a role for liver biopsy in primary sclerosing cholangitis?. Am J Gastroenterol. 2003;98:1155–1158
  106. Kim WR, Therneau TM, Wiesner RH, Poterucha JJ, Benson JT, Malinchoc M, et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000;75:688–694
  107. Kim WR, Ludwig J, Lindor KD. Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol. 2000;95:1130–1138
  108. Bjornsson E, Boberg KM, Cullen S, Fleming K, Clausen OP, Fausa O, et al. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut. 2002;51:731–735
  109. Broome U, Glaumann H, Lindstom E, Loof L, Almer S, Prytz H, et al. Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC). J Hepatol. 2002;36:586–589
  110. Angulo P, Maor-Kendler Y, Lindor KD. Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology. 2002;35:1494–1500
  111. Charatcharoenwitthaya P, Angulo P, Enders FB, Lindor KD. Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis. Hepatology. 2008;47:133–142
  112. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938
  113. van Buuren HR, van Hoogstraten HJE, Terkivatan T, Schalm SW, Vleggaar FP. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol. 2000;33:543–548
  114. Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol. 2000;33:537–542
  115. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–553
  116. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, et al. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005;100:1516–1522
  117. Kawa S, Hamano H, Umemura T, Kiyosawa K, Uehara T. Sclerosing cholangitis associated with autoimmune pancreatitis. Hepatol Res. 2007;37:S487–S495
  118. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37:S478–S486
  119. Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?. Am J Surg Pathol. 2004;28:1193–1203
  120. Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006;101:2070–2075
  121. Dickson ER, Murtaugh PA, Wiesner RH, Grambsch PM, Fleming TR, Ludwig J, et al. Primary sclerosing cholangitis: refinement and validation of survival models. Gastroenterology. 1992;103:1893–1901
  122. Nyblom H, Nordlinder H, Olsson R. High aspartate to alanine aminotransferase ratio is an indicator of cirrhosis and poor outcome in patients with primary sclerosing cholangitis. Liver Int. 2007;27:694–699
  123. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–526
  124. Tischendorf JJ, Meier PN, Strassburg CP, Klempnauer J, Hecker H, Manns MP, et al. Characterization and clinical course of hepatobiliary carcinoma in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2006;41:1227–1234
  125. Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. 2000;31:7–11
  126. Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, Hansen B, et al. Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol. 2004;40:815–822
  127. Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U, et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol. 2002;37:1205–1211
  128. Leidenius M, Hockersted K, Broome U, Ericzon BG, Friman S, Olausson M, et al. Hepatobiliary carcinoma in primary sclerosing cholangitis: a case control study. J Hepatol. 2001;34:792–798
  129. Ramage JK, Donaghy A, Farrant JM, Iorns R, Williams R. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995;108:865–869
  130. Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005;50:1734–1740
  131. Bjornsson E, Kilander A, Olsson R. CA 19-9 and CEA are unreliable markers for cholangiocarcinoma in patients with primary sclerosing cholangitis. Liver. 1999;19:501–508
  132. Petersen-Benz C, Stiehl A. Impact of dominant stenoses on the serum level of the tumor marker CA19-9 in patients with primary sclerosing cholangitis. Z Gastroenterol. 2005;43:587–590
  133. Lempinen M, Isoniemi H, Makisalo H, Nordin A, Halme L, Arola J, et al. Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures. J Hepatol. 2007;47:677–683
  134. Campbell WL, Ferris JV, Holbert BL, Thaete FL, Baron RL. Biliary tract carcinoma complicating primary sclerosing cholangitis: evaluation with CT, cholangiography, US, and MR imaging. Radiology. 1998;207:41–50
  135. Prytz H, Keiding S, Bjornsson E, Broome U, Almer S, Castedal M, et al. Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology. 2006;44:1572–1580
  136. Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ. In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol. 2002;97:1138–1142
  137. Bergquist A, Broome U. Hepatobiliary and extra-hepatic malignancies in primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2001;15:643–656
  138. Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol. 2006;45:568–574
  139. Ponsioen CY, Vrouenraets SM, van Milligen de Wit AW, Sturm P, Tascilar M, Offerhaus GJ, et al. Value of brush cytology for dominant strictures in primary sclerosing cholangitis. Endoscopy. 1999;31:305–309
  140. Lindberg B, Arnelo U, Bergquist A, Thorne A, Hjerpe A, Granqvist S, et al. Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis. Endoscopy. 2002;34:909–916
  141. Ponchon T, Gagnon P, Berger F, Labadie M, Liaras A, Chavaillon A, et al. Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc. 1995;42:565–572
  142. Tischendorf JJ, Kruger M, Trautwein C, Duckstein N, Schneider A, Manns MP, et al. Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy. 2006;38:665–669
  143. Chen YK, Pleskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with video). Gastrointest Endosc. 2007;65:832–841
  144. Tischendorf JJ, Meier PN, Schneider A, Manns MP, Kruger M. Transpapillary intraductal ultrasound in the evaluation of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2007;42:1011–1017
  145. Kubicka S, Kuhnel F, Flemming P, Hain B, Kezmic N, Rudolph KL, et al. K-ras mutations in the bile of patients with primary sclerosing cholangitis. Gut. 2001;48:403–408
  146. Alvaro D, Macarri G, Mancino MG, Marzioni M, Bragazzi M, Onori P, et al. Serum and biliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007;147:451–459
  147. Ponsioen CY, Vrouenraets SM, Prawirodirdjo W, Rajaram R, Rauws EA, Mulder CJ, et al. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut. 2002;51:562–566
  148. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990;323:1228–1233
  149. Aadland E, Schrumpf E, Fausa O, Elgjo K, Heilo A, Aakhus T, et al. Primary sclerosing cholangitis: a long-term follow-up study. Scand J Gastroenterol. 1987;22:655–664
  150. Brentnall TA, Haggitt RC, Rabinovitch PS, Kimmey MB, Bronner MP, Levine DS, et al. Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology. 1996;110:331–338
  151. Broome U, Lindberg G, Lofberg R. Primary sclerosing cholangitis in ulcerative colitis – a risk factor for the development of dysplasia and DNA aneuploidy?. Gastroenterology. 1992;102:1877–1880
  152. Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut. 1997;41:522–525
  153. Shetty K, Rybicki L, Brzezinski A, Carey WD, Lashner BA. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol. 1999;94:1643–1649
  154. Broome U, Lofberg R, Veress B, Eriksson LS. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology. 1995;22:1404–1408
  155. Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology. 2003;124:880–888
  156. Hurlstone DP, McAlindon ME, Sanders DS, Koegh R, Lobo AJ, Cross SS. Further validation of high-magnification chromoscopic-colonoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology. 2004;126:376–378
  157. LaRusso NF, Shneider BL, Black D, Gores GJ, James SP, Doo E, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764
  158. Okolicsanyi L, Fabris L, Viaggi S, Carulli N, Podda M, Ricci G. Primary sclerosing cholangitis: clinical presentation, natural history and prognostic variables: an Italian multicentre study. The Italian PSC Study Group. Eur J Gastroenterol Hepatol. 1996;8:685–691
  159. Farrant JM, Hayllar KM, Wilkinson ML, Karani J, Portmann BC, Westaby D, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100:1710–1717
  160. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology. 2001;121:900–907
  161. Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD. High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol. 2001;96:1558–1562
  162. 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
  163. Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129:1464–1472
  164. Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–893
  165. Tung BY, Emond MJ, Haggitt RC, Bronner MP, Kimmey MB, Kowdley KV, 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
  166. van Hoogstraten HJ, Vleggaar FP, Boland GJ, van Steenbergen W, Griffioen P, Hop WC, et al. 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. 2000;95:2015–2022
  167. Boberg KM, Fausa O, Haaland T, Holter E, Mellbye OJ, Spurkland A, et al. Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology. 1996;23:1369–1376
  168. Beuers U, Rust C. Overlap syndromes. Semin Liver Dis. 2005;25:311–320
  169. Stiehl A. Primary sclerosing cholangitis: the role of endoscopic therapy. Semin Liver Dis. 2006;26:62–68
  170. Stiehl A, Rost D. Endoscopic treatment of dominant stenoses in patients with primary sclerosing cholangitis. Clin Rev Allergy Immunol. 2005;28:159–165
  171. Bjornsson E, Lindqvist-Ottosson J, Asztely M, Olsson R. Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:502–508
  172. Johnson GK, Geenen JE, Venu RP, Schmalz MJ, Hogan WJ. Endoscopic treatment of biliary tract strictures in sclerosing cholangitis: a larger series and recommendations for treatment. Gastrointest Endosc. 1991;37:38–43
  173. Lombard M, Farrant M, Karani J, Westaby D, Williams R. Improving biliary-enteric drainage in primary sclerosing cholangitis: experience with endoscopic methods. Gut. 1991;32:1364–1368
  174. Linder S, Soderlund C. Endoscopic therapy in primary sclerosing cholangitis: outcome of treatment and risk of cancer. Hepatogastroenterology. 2001;48:387–392
  175. Baluyut AR, Sherman S, Lehman GA, Hoen H, Chalasani N. Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis. Gastrointest Endosc. 2001;53:308–312
  176. Wagner S, Gebel M, Meier P, Trautwein C, Bleck J, Nashan B, et al. Endoscopic management of biliary tract strictures in primary sclerosing cholangitis. Endoscopy. 1996;28:546–551
  177. Allison MC, Burroughs AK, Noone P, Summerfield JA. Biliary lavage with corticosteroids in primary sclerosing cholangitis. A clinical, cholangiographic and bacteriological study. J Hepatol. 1986;3:118–122
  178. Awadallah NS, Chen YK, Piraka C, Antillon MR, Shah RJ. Is there a role for cholangioscopy in patients with primary sclerosing cholangitis?. Am J Gastroenterol. 2006;101:284–291
  179. Wiesner RH, Porayko MK, Dickson ER, Gores GJ, LaRusso NF, Hay JE, et al. Selection and timing of liver transplantation in primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 1992;16:1290–1299
  180. Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242:451–458
  181. Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B, McCashland T, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002;2:774–779
  182. Graziadei IW, Wiesner RH, Marotta PJ, Porayko MK, Hay JE, Charlton MR, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology. 1999;30:1121–1127
  183. Graziadei IW, Wiesner RH, Batts KP, Marotta PJ, LaRusso NF, Porayko MK, et al. Recurrence of primary sclerosing cholangitis following liver transplantation. Hepatology. 1999;29:1050–1056
  184. Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11:1488–1496
  185. Jonas S, Benckert C, Thelen A, Lopez-Hanninen E, Rosch T, Neuhaus P. Radical surgery for hilar cholangiocarcinoma. Eur J Surg Oncol. 2007;23
  186. Mantel HT, Rosen CB, Heimbach JK, Nyberg SL, Ishitani MB, Andrews JC, et al. Vascular complications after orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl. 2007;13:1372–1381
  187. Ortner ME, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003;125:1355–1363
  188. Crescenzi E, Chiaviello A, Canti G, Reddi E, Veneziani BM, Palumbo G. Low doses of cisplatin or gemcitabine plus photofrin/photodynamic therapy: disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non-small cell lung cancer cells (H1299). Mol Cancer Ther. 2006;5:776–785
  189. Malek NP, Greten T, Kubicka S. Systemic treatment of liver and biliary tumors. Internist (Berl). 2007;48:46–49

 The Authors T.J. Weismüller, J. Wedemeyer, C.P. Strassburg and S. Kubicka state that they have nothing to declare regarding conflict of interest and funding with respect to this manuscript. M.P. Manns is an investigator/consultant/speaker at Novartis, Roche, Schering-Plough, Gilead Sciences Inc., Tibotec, Vertex, GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Idenix and Merck. M.P. Manns received meeting support and lecture fees from the Falk Foundation, Freiburg, Germany. M.P. Manns received funding from Deutsche Forschungsgemeinschaft (KF0119, SFB 621, SFB738), DFG Cluster of Excellence “Rebirth” and Transplantation centre.

PII: S0168-8278(08)00059-7

doi: 10.1016/j.jhep.2008.01.020

Journal of Hepatology
Volume 48 , Pages S38-S57 , 2008