Digestive Diseases and Sciences

, Volume 58, Issue 11, pp 3079–3087 | Cite as

Ursodiol and Colorectal Cancer or Dysplasia Risk in Primary Sclerosing Cholangitis and Inflammatory Bowel Disease: A Meta-Analysis

Review

Abstract

Background

Patients with primary sclerosing cholangitis (PSC) and colonic inflammatory bowel disease (IBD) demonstrate increased risk of colorectal cancer. Prior studies have yielded conflicting information on the relationship between ursodiol (UDCA) and the risk of colorectal cancer or dysplasia in this group.

Aims

To examine the impact of UDCA on risk of colorectal cancer or dysplasia in adult PSC and IBD patients.

Methods

A systematic review and meta-analysis of case–control and cohort studies was performed. Subgroup analysis compared the effects of “low-to-medium” (<25 mg/kg/day) versus “high” dose (≥25 mg/kg/day) UDCA exposures.

Results

Inclusion and exclusion criteria, as well as all variables, were determined a priori. Seven papers, with 707 participants and greater than 5,751 person-years of follow-up time, met the criteria for final analysis. The overall pooled relative risk using a random effects model was not statistically significant (RR = 0.87, 95 % CI 0.51–1.49, p = 0.62). Subgroup analysis by UDCA dose category in a random effects model was not statistically significant (RR = 0.64, 95 % CI 0.38–1.07, p = 0.09), but suggested a possible trend in risk reduction at low-to-medium-dose exposures that may warrant further investigation.

Conclusion

UDCA use was not associated with risk of colorectal cancer or dysplasia in adult PSC and IBD patients, but UDCA dose was a source of heterogeneity across studies. Subgroup analysis suggests a possible trend toward decreased colorectal cancer risk in low-to-medium-dose exposures. Additional study of UDCA treatments at low doses in PSC and IBD patients may be warranted.

Keywords

Ursodeoxycholic acid Inflammatory bowel disease Colonic neoplasia Primary sclerosing cholangitis 

References

  1. 1.
    Chapman RW, Arborgh BA, Rhodes JM, et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut. 1980;21:870–877.PubMedCrossRefGoogle Scholar
  2. 2.
    Sivak MV Jr, Farmer RG, Lalli AF. Sclerosing cholangitis: its increasing frequency of recognition and association with inflammatory bowel disease. J Clin Gastroenterol. 1981;3:261–266.PubMedCrossRefGoogle Scholar
  3. 3.
    Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332:924–933.PubMedCrossRefGoogle Scholar
  4. 4.
    Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology (Baltimore, MD). 2009;50:808–814.CrossRefGoogle Scholar
  5. 5.
    Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology (Baltimore, MD). 2010;51:660–678.CrossRefGoogle Scholar
  6. 6.
    Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer. 2001;91:854–862.PubMedCrossRefGoogle Scholar
  7. 7.
    Lewis JD, Deren JJ, Lichtenstein GR. Cancer risk in patients with inflammatory bowel disease. Gastroenterol Clin N Am. 1999;28:459–477.CrossRefGoogle Scholar
  8. 8.
    Silveira MG, Lindor KD. Primary sclerosing cholangitis. Can J Gastroenterol. 2008;22:689–698.PubMedGoogle Scholar
  9. 9.
    Eaton JE, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011;106:1638–1645.PubMedCrossRefGoogle Scholar
  10. 10.
    Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002;56:48–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Braden B, Halliday J, Aryasingha S, et al. Risk for colorectal neoplasia in patients with colonic Crohn’s disease and concomitant primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2012;10:303–308.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    Narisawa T, Fukaura Y, Terada K, Sekiguchi H. Prevention of N-methylnitrosourea-induced colon tumorigenesis by ursodeoxycholic acid in F344 rats. Jpn J Cancer Res. 1998;89:1009–1013.PubMedCrossRefGoogle Scholar
  15. 15.
    Earnest DL, Holubec H, Wali RK, et al. Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid. Cancer Res. 1994;54:5071–5074.PubMedGoogle Scholar
  16. 16.
    Pardi DS, Loftus EV Jr, 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Rudolph G, Gotthardt DN, Kloeters-Plachky P, Kulaksiz H, Schirmacher P, Stiehl A. In PSC with colitis treated with UDCA, most colonic carcinomas develop in the first years after the start of treatment. Dig Dis Sci. 2011;56:3624–3630.PubMedCrossRefGoogle Scholar
  18. 18.
    Lindstrom L, Boberg KM, Wikman O, et al. High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia. Aliment Pharmacol Ther. 2012;35:451–457.PubMedCrossRefGoogle Scholar
  19. 19.
    Navaneethan U, Kochhar G, Venkatesh PG, et al. Duration and severity of primary sclerosing cholangitis is not associated with risk of neoplastic changes in the colon in patients with ulcerative colitis. Gastrointest Endosc. 2012;75:1045–1054 e1.PubMedCrossRefGoogle Scholar
  20. 20.
    Ashraf I, Choudhary A, Arif M, et al. Ursodeoxycholic acid in patients with ulcerative colitis and primary sclerosing cholangitis for prevention of colon cancer: a meta-analysis. Indian J Gastroenterol. 2012.Google Scholar
  21. 21.
    Wells Ga, Shea B, O’Donnell D. The Newcastle–Ottawa Score (NOS) for assessing the quality of nonrandomised studies in meta-analyses, 2008. Available at: http://www.medicine.mcgill.ca/rtamblyn/Readings%5CThe%20Newcastle%20-%20Scale%20for%20assessing%20the%20quality%20of%20nonrandomised%20studies%20in%20meta-analyses.pdf. Accessed March 25, 2012.
  22. 22.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials. 1986;7:177–188.PubMedCrossRefGoogle Scholar
  23. 23.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed.). 2003;327:557–560.CrossRefGoogle Scholar
  24. 24.
    Egger M, Smith GD, Altman DG. Systematic reviews in healthcare. London: British Medical Journal Publishing Group; 2001.CrossRefGoogle Scholar
  25. 25.
    Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Sinakos E, Marschall HU, Kowdley KV, Befeler A, Keach J, Lindor K. Bile acid changes after hid dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: relation to disease progression. Hepatology. 2010;52:197–203.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jonathan D. Hansen
    • 1
  • Sonal Kumar
    • 1
    • 2
  • Wai-Kit Lo
    • 1
    • 2
  • David M. Poulsen
    • 1
  • Umme-Aiman Halai
    • 1
  • Kathy C. Tater
    • 1
  1. 1.Harvard School of Public HealthBostonUSA
  2. 2.Division of GastroenterologyBrigham and Women’s HospitalBostonUSA

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