Risk Factors for Primary Sclerosing Cholangitis

Kirsten Boonstra; Elisabeth M. G. de Vries; Nan van Geloven; Karel J. van Erpecum; Marcel Spanier; Alexander C. Poen; Carin M. van Nieuwkerk; Ben J. Witteman; Hans A. Tuynman; Anton H. Naber; Paul J. Kingma; Ulrich Beuers; Cyriel Y. Ponsioen


Liver International. 2016;36(1):84-91. 

In This Article

Abstract and Introduction


Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease of unknown cause, but strongly associated with inflammatory bowel disease (IBD). Potential risk factors triggering PSC have never been studied on a population level. The aim of this study was to evaluate smoking, appendectomy, family history and geographical distribution in a population-based cohort of PSC patients, as compared to IBD control patients and healthy controls (HC).

Methods: For this case–control study 343 PSC patients, 370 IBD controls and 232 HC's living in a geographically defined area in the Netherlands filled-out a questionnaire concerning smoking, appendectomy and family history of IBD and autoimmune liver diseases.

Results: Smoking was associated with a lower risk of developing PSC in PSC-ulcerative colitis (UC) patients (adjusted OR 0.21; 95% CI 0.12–0.34; P < 0.001). Comparable results were found for PSC-Crohn's disease (CD) patients (16% former smokers) compared to CD patients (55% former smokers) (adjusted OR 0.17; 95% CI 0.08–0.39; P < 0.001). Frequency of appendectomy did not differ between PSC and HC, but PSC-UC patients had undergone appendectomy more often than UC patients (13% vs. 6%) (adjusted OR 2.51; 95%CI 1.04–6.07; P = 0.041). We found no association between family history of IBD or autoimmune liver disease and risk of PSC. Degree of urbanization was not associated with PSC incidence.

Conclusion: In this large population-based case–control study we confirm that smoking is associated with a lower risk of developing PSC, independent of its protective effect for developing UC. Appendectomy is not associated with the risk of developing PSC.


Primary sclerosing cholangitis (PSC) is a puzzling cholestatic liver disease affecting the intra- and extrahepatic bile ducts. PSC is more common in men than in women (2:1) and can occur at any age with a peak incidence around 40 years.[1] Disease course is highly variable and there is no treatment available with proven efficacy in halting disease progression other than liver transplantation (LTx). PSC is strongly associated with inflammatory bowel disease (IBD) and patients are at increased risk for developing colorectal and biliary malignancies.[1–3] Although the strong association between PSC and IBD is well established, the underlying pathogenesis is not known. IBD in PSC patients represents a distinct phenotype in that pancolitis is observed in 94% of PSC-ulcerative colitis (UC) and colitis in 96% of PSC-Crohn's disease (CD) patients.[4] PSC and IBD are considered to be complex genetic diseases, caused by a combination of genetic and environmental factors. In IBD, 163 risk loci have been identified so far and some of these risk loci have also been associated with PSC.[5] However, the number of patients included in genetic studies in IBD is 10-fold higher than in PSC.[6] First-degree relatives of PSC patients run an increased risk of PSC and UC.[7] Besides limited knowledge of the genetic risk factors, little is known about environmental factors triggering disease. Current smoking and previous appendectomy have been shown to protect against developing UC.[8–20] However, studies on smoking behaviour and appendectomy and the risk of developing PSC are many fold smaller, warranting larger studies.[21–24]

The aim of this case–control study was to evaluate smoking behaviour, history of appendectomy, family history of IBD and autoimmune liver disease and geographical distribution in a large group of PSC patients compared to IBD disease controls and healthy controls.