The IBD and PSC Phenotypes of PSC-IBD
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Purpose of review
To review the characteristics of IBD and PSC that occur in association, as well as their reciprocal influences on disease evolution, in adult and pediatric populations.
IBD co-existing with PSC is genetically and clinically distinct from IBD alone. It is frequently characterized by pancolitis, rectal sparing, and possibly backwash ileitis, as well as a threefold increased risk of colorectal dysplasia. Adults and children with colitis and PSC appear to be at increased risk of active endoscopic and histologic disease in the absence of symptoms compared to individuals without PSC. PSC occurring with Crohn’s disease has been observed to be less severe than PSC co-existing with ulcerative colitis, independent of its association with small duct disease. Recent studies suggest that colectomy is associated with a decreased risk of recurrent PSC after liver transplantation, challenging the traditional teaching that PSC and IBD evolve independently.
While much about the gut-liver axis in PSC-IBD remains poorly understood, the IBD associated with PSC has a unique phenotype, of which subclinical inflammation is an important component. Additional research is needed to characterize further the potentially protective role of colectomy against recurrent PSC post-liver transplantation and to investigate the influence of IBD control and/or colectomy on PSC progression.
KeywordsColectomy Inflammatory bowel disease (IBD) Liver transplantation Phenotype Primary sclerosing cholangitis (PSC) PSC-IBD
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Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 9.•• de Vries AB, Janse M, Blokzijl H, Weersma RK. Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. World J Gastroenterol: WJG. 2015;21(6):1956–71. https://doi.org/10.3748/wjg.v21.i6.1956. Systematic review of studies investigating the IBD phenotype of PSC-IBD in adults.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Palmela C, Peerani F, Castaneda D, Torres J, Itzkowitz SH. Inflammatory bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features. Gut Liver. 2017 https://doi.org/10.5009/gnl16510.
- 13.Fraga M, Fournier N, Safroneeva E, Pittet V, Godat S, Straumann A, et al. Primary sclerosing cholangitis in the Swiss inflammatory bowel disease cohort study: prevalence, risk factors, and long-term follow-up. Eur J Gastroenterol Hepatol. 2017;29(1):91–7. https://doi.org/10.1097/meg.0000000000000747.CrossRefPubMedGoogle Scholar
- 14.• Lunder AK, Hov JR, Borthne A, Gleditsch J, Johannesen G, Tveit K, et al. Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease. Gastroenterology. 2016;151(4):660–9.e4. https://doi.org/10.1053/j.gastro.2016.06.021. Recent study in which MRCP screening of IBD patients revealed a higher than previously appreciated prevalence of PSC. CrossRefPubMedGoogle Scholar
- 17.Liu K, Strasser SI, Koorey DJ, Leong RW, Solomon M, McCaughan GW. Interactions between primary sclerosing cholangitis and inflammatory bowel disease: implications in the adult liver transplant setting. Expert Rev Gastroenterol Hepatol. 2017;11(10):949–60. https://doi.org/10.1080/17474124.2017.1343666.CrossRefPubMedGoogle Scholar
- 19.•• Weismuller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology. 2017; https://doi.org/10.1053/j.gastro.2017.02.038. The largest clinical PSC study to date (>7000 patients). PSC-CD and no IBD were associated with better PSC outcomes than PSC-UC when analyzing IBD as a time-dependent covariate.
- 22.• Deneau M, Jensen MK, Holmen J, Williams MS, Book LS, Guthery SL. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology (Baltimore, Md). 2013;58(4):1392–400. https://doi.org/10.1002/hep.26454. The largest clinical pediatric PSC study to date, providing natural history data on >700 children. CrossRefGoogle Scholar
- 24.Deneau MR, El-Matary W, Valentino PL, Abdou R, Alqoaer K, Amin M, et al. The natural history of primary sclerosing cholangitis in 781 children: a multicenter, international collaboration. Hepatology (Baltimore, Md). 2017; https://doi.org/10.1002/hep.29204.
- 26.• Bramuzzo M, Martelossi S, Torre G, Cardile S, Arrigo S, Vignola S, et al. Clinical features and risk factors of autoimmune liver involvement in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2016;63(2):259–64. https://doi.org/10.1097/mpg.0000000000001078. The largest study to date describing the IBD phenotype of PSC-IBD in children.CrossRefPubMedGoogle Scholar
- 30.Bazerbachi F, Furuya KN, Abdou R, Alqoaer K, Amin M, Amir A, et al. PS-138—recurrence of primary sclerosing cholangitis after liver transplantation in children: data from the Pediatric PSC Consortium. J Hepatol. 2017;66(1, Supplement):S76. https://doi.org/10.1016/S0168-8278(17)30414-2.CrossRefGoogle Scholar
- 32.Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T, et al. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology (Baltimore, Md). 2013;58(3):1074–83. https://doi.org/10.1002/hep.25977.CrossRefGoogle Scholar
- 33.Janse M, Lamberts LE, Franke L, Raychaudhuri S, Ellinghaus E, Muri Boberg K, et al. Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. Hepatology (Baltimore, Md). 2011;53(6):1977–85. https://doi.org/10.1002/hep.24307.CrossRefGoogle Scholar
- 34.Folseraas T, Melum E, Rausch P, Juran BD, Ellinghaus E, Shiryaev A, et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J Hepatol. 2012;57(2):366–75. https://doi.org/10.1016/j.jhep.2012.03.031.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.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(11):1511–7. https://doi.org/10.1084/jem.20041035.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.• Ji SG, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2017;49(2):269–73. https://doi.org/10.1038/ng.3745. A genome-wide association study of PSC that showed relatively little genetic overlap between PSC and IBD. CrossRefPubMedGoogle Scholar
- 41.Mueller T, Beutler C, Pico AH, Shibolet O, Pratt DS, Pascher A, et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int. 2011;31(10):1574–88. https://doi.org/10.1111/j.1478-3231.2011.02635.x.CrossRefPubMedGoogle Scholar
- 42.Tabibian JH, O'Hara SP, Trussoni CE, Tietz PS, Splinter PL, Mounajjed T, et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology (Baltimore, Md). 2016;63(1):185–96. https://doi.org/10.1002/hep.27927.CrossRefGoogle Scholar
- 45.Kummen M, Holm K, Anmarkrud JA, Nygard S, Vesterhus M, Hoivik ML, et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut. 2016;66:611–9. https://doi.org/10.1136/gutjnl-2015-310500.CrossRefPubMedGoogle Scholar
- 47.Rossen NG, Fuentes S, Boonstra K, D'Haens GR, Heilig HG, Zoetendal EG, et al. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J Crohns Colitis. 2015;9(4):342–8. https://doi.org/10.1093/ecco-jcc/jju023.CrossRefPubMedGoogle Scholar
- 51.Bajer L, Kverka M, Kostovcik M, Macinga P, Dvorak J, Stehlikova Z, et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J Gastroenterol: WJG. 2017;23(25):4548–58. https://doi.org/10.3748/wjg.v23.i25.4548.CrossRefPubMedPubMedCentralGoogle Scholar
- 63.Jorgensen KK, Grzyb K, Lundin KE, Clausen OP, Aamodt G, Schrumpf E, et al. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm Bowel Dis. 2012;18(3):536–45. https://doi.org/10.1002/ibd.21699.CrossRefPubMedGoogle Scholar
- 66.Schaeffer DF, Win LL, Hafezi-Bakhtiari S, Cino M, Hirschfield GM, El-Zimaity H. The phenotypic expression of inflammatory bowel disease in patients with primary sclerosing cholangitis differs in the distribution of colitis. Dig Dis Sci. 2013;58(9):2608–14. https://doi.org/10.1007/s10620-013-2697-7.CrossRefPubMedGoogle Scholar
- 68.Sorensen JO, Nielsen OH, Andersson M, Ainsworth MA, Ytting H, Belard E, et al. Inflammatory bowel disease with primary sclerosing cholangitis: a Danish population-based cohort study 1977-2011. Liver Int. 2017; https://doi.org/10.1111/liv.13548.
- 69.• Cleveland NK, Rubin DT, Hart J, Weber CR, Meckel K, Tran AL, et al. Patients with ulcerative colitis and primary sclerosing cholangitis frequently have subclinical inflammation in the proximal colon. Clin Gastroenterol Hepatol. 2017; https://doi.org/10.1016/j.cgh.2017.07.023. Found that adult UC patients in clinical remission with PSC were more likely than those without PSC to have ongoing endoscopic and histologic disease in the right colon.
- 73.• Zheng HH, Jiang XL. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis of 16 observational studies. Eur J Gastroenterol Hepatol. 2016;28(4):383–90. https://doi.org/10.1097/meg.0000000000000576. This large meta-analysis demonstrated that PSC-UC patients have a threefold higher risk of colorectal dysplasia and cancer than UC patients without PSC.PubMedGoogle Scholar
- 78.Shiau H, Ihekweazu FD, Amin M, Fofanova T, Miloh T, Kellermayer R. Unique inflammatory bowel disease phenotype of pediatric primary sclerosing cholangitis: a single-center study. J Pediatr Gastroenterol Nutr. 2017;65(4):404–9. https://doi.org/10.1097/mpg.0000000000001531.CrossRefPubMedGoogle Scholar
- 79.Torres J, Pineton de Chambrun G, Itzkowitz S, Sachar DB, Colombel JF. Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34(5):497–508. https://doi.org/10.1111/j.1365-2036.2011.04753.x.CrossRefPubMedGoogle Scholar
- 81.Torres J, Bao X, Iuga AC, Chen A, Harpaz N, Ullman T, et al. Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia. Inflamm Bowel Dis. 2013;19(2):275–82. https://doi.org/10.1097/MIB.0b013e318286ff2e.CrossRefPubMedGoogle Scholar
- 82.Rubin DT, Huo D, Kinnucan JA, Sedrak MS, McCullom NE, Bunnag AP, et al. Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study. Clin Gastroenterol Hepatol. 2013;11(12):1601–8.e1–4. https://doi.org/10.1016/j.cgh.2013.06.023.CrossRefPubMedGoogle Scholar
- 84.• Ricciuto A, Carman N, Fish J, Crowley E, Church PC, Muise A, et al. 234 symptoms underestimate endoscopic activity in PSC-IBD. J Pediatr Gastroenterol Nutr. 2017;65(supplement 2):S104. Found that children with colitis in clinical remission with PSC are more likely than children without PSC to have ongoing endoscopic and histologic inflammation throughout the colon. Google Scholar
- 85.Jorgensen KK, Lindstrom L, Cvancarova M, Karlsen TH, Castedal M, Friman S, et al. Immunosuppression after liver transplantation for primary sclerosing cholangitis influences activity of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(5):517–23. https://doi.org/10.1016/j.cgh.2012.12.027.CrossRefPubMedGoogle Scholar
- 86.Fattahi MR, Malek-Hosseini SA, Sivandzadeh GR, Safarpour AR, Bagheri Lankarani K, Taghavi AR, et al. Clinical course of ulcerative colitis after liver transplantation in patients with concomitant primary sclerosing cholangitis and ulcerative colitis. Inflamm Bowel Dis. 2017;23(7):1160–7. https://doi.org/10.1097/mib.0000000000001105.CrossRefPubMedGoogle Scholar
- 89.Jorgensen KK, Lindstrom L, Cvancarova M, Castedal M, Friman S, Schrumpf E, et al. Colorectal neoplasia in patients with primary sclerosing cholangitis undergoing liver transplantation: a Nordic multicenter study. Scand J Gastroenterol. 2012;47(8–9):1021–9. https://doi.org/10.3109/00365521.2012.685754.CrossRefPubMedGoogle Scholar
- 90.Verdonk RC, Dijkstra G, Haagsma EB, Shostrom VK, Van den Berg AP, Kleibeuker JH, et al. Inflammatory bowel disease after liver transplantation: risk factors for recurrence and de novo disease. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2006;6(6):1422–9. https://doi.org/10.1111/j.1600-6143.2006.01333.x.CrossRefGoogle Scholar
- 91.Navaneethan U, Choudhary M, Venkatesh PG, Lashner BA, Remzi FH, Shen B, et al. The effects of liver transplantation on the clinical course of colitis in ulcerative colitis patients with primary sclerosing cholangitis. Aliment Pharmacol Ther. 2012;35(9):1054–63. https://doi.org/10.1111/j.1365-2036.2012.05067.x.PubMedGoogle Scholar
- 95.Ricciuto A, Kamath BM, Abdou R, Alqoaer K, Amin M, Amir AZ, et al. 423—a comparison of primary sclerosing cholangitis with and without associated inflammatory bowel disease: data from the Pediatric PSC Consortium. Gastroenterology. 2017;152(5, Supplement 1):S1057. https://doi.org/10.1016/S0016-5085(17)33571-0.CrossRefGoogle Scholar
- 96.Franceschet I, Cazzagon N, Del Ross T, D'Inca R, Buja A, Floreani A. Primary sclerosing cholangitis associated with inflammatory bowel disease: an observational study in a Southern Europe population focusing on new therapeutic options. Eur J Gastroenterol Hepatol. 2016;28(5):508–13. https://doi.org/10.1097/meg.0000000000000596.CrossRefPubMedGoogle Scholar
- 97.• Fevery J, Van Steenbergen W, Van Pelt J, Laleman W, Hoffman I, Geboes K, et al. Patients with large-duct primary sclerosing cholangitis and Crohn’s disease have a better outcome than those with ulcerative colitis, or without IBD. Aliment Pharmacol Ther. 2016;43(5):612–20. https://doi.org/10.1111/apt.13516. Demonstrated that the improved PSC outcomes in PSC-CD are independent of its association with small duct disease. CrossRefPubMedGoogle Scholar
- 100.•• Lindstrom L, Jorgensen KK, Boberg KM, Castedal M, Rasmussen A, Rostved AA, et al. Risk factors and prognosis for recurrent primary sclerosing cholangitis after liver transplantation: a Nordic multicentre study. Scand J Gastroenterol. 2018:1–8. https://doi.org/10.1080/00365521.2017.1421705. Observed a significantly decreased risk of recurrent PSC after liver transplantation with colectomy pre- or peri-transplant.
- 101.•• Ravikumar R, Tsochatzis E, Jose S, Allison M, Athale A, Creamer F, et al. Risk factors for recurrent primary sclerosing cholangitis after liver transplantation. J Hepatol. 2015; https://doi.org/10.1016/j.jhep.2015.07.005. Found ulcerative colitis post-liver transplant (vs no UC or colectomy before transplant) to be a risk factor for recurrent PSC after transplantation.
- 105.Nordenvall C, Olén O, Nilsson PJ, von Seth E, Ekbom A, Bottai M et al. Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients. Aliment. Pharmacol. Ther. 2018;47(2):238–45. https://doi.org/10.1111/apt.14393.