Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD). While the association between PSC and IBD is well established, the reason for this association is unknown. Both PSC and IBD are thought to be complex genetic diseases, caused by a combination of genetic and environmental risk factors. Research focussing on the role of genetics in PSC has shown that some of the genetic risk loci found in IBD are also associated with PSC. Knowledge of the role of genetics in PSC is increasing, but still little is known about possible environmental triggering factors.

Studies in the IBD field have shown that smoking and previous appendectomy have a protective effect against developing ulcerative colitis (UC). It has also been demonstrated that first-degree relatives of PSC patients have an increased risk of developing PSC and UC. So far, there are no large studies that consider the effect of smoking behaviour and appendectomy and the risk of developing PSC.

The researchers of this study aimed to evaluate potential environmental risk factors for developing PSC in a large group of patients with PSC. The potential risk factors studied were smoking behaviour, history of appendectomy, family history of IBD and autoimmune liver disease, as well as geographic distribution. In order to examine these risk factors, the PSC patients recruited for this current study were compared to IBD controls as well as healthy controls (HC). By using these control groups, the researchers were able to compare how frequently the exposure to a risk factor was present in each group, and thereby to determine the relationship between the risk factor and the disease.

The participants were recruited from the Epi PSC PBC project, which is a large population-based cohort study of patients with PSC and primary biliary cholangitis (PBC) in the Netherlands, conducted from 1 January 2008 to 31 December 2011. Participants were invited to take part in the study, provide informed consent and fill out a 10-item questionnaire regarding their smoking status, previous appendectomy and whether they had first degree relatives with IBD and/or autoimmune liver disease.

In total, 343 patients with PSC agreed to participate and completed the questionnaire; 164 of these patients had concomitant UC and 50 had Crohn’s disease (CD). A total of 370 patients with IBD and 232 HC agreed to participate and completed the questionnaire. Demographic data showed the group of PSC patients in this study was representative of the PSC population in the Netherlands.  Their median age was 48 years and 65% of patients were male; in the IBD control group 40% were male and median age was 43 years. In the HC group the median age was 55 years, with 46% male.

PSC patients were divided based on the presence of concurrent IBD, into patients with UC, patients with CD and patients without concurrent IBD. None of the IBD control patients had any diagnosis of liver disease, and all routine liver tests were normal.

To discern the risk factors for the development of PSC from the risk factors for IBD, patients with PSC and IBD-controls were matched according to the type of IBD (either UC or CD): PSC-UC patients were compared with UC control patients, PSC-CD patients were compared with CD control patients. PSC patients without IBD were analysed separately and compared with HCs.

The potential risk factors of sex, age, smoking behaviour, appendectomy (surgical removal of the appendix), family history of IBD and autoimmune liver disease for the development of PSC were analysed by comparing relative frequencies (how often a risk factor was present in the PSC-IBD group versus IBD control group, and the PSC-no IBD group versus the HC).

The researchers outlined the following findings.


There were less smokers in the PSC group as a whole than in the HC group A similar trend was observed in the subgroup of PSC patients without IBD compared to HC. When comparing PSC-UC patients to UC controls, UC patients were more often smokers compared to PSC-UC patients. Similar results were seen for the PSC-CD and CD groups. Smoking was significantly associated with a lower risk for the development of PSC in both UC and CD patients. This study is the largest case-control study showing that smoking behaviour is independently associated with a lower risk of developing PSC, and is in agreement with previous studies. The researchers note that their study concurred with a recent study by Eaton et al., who also found that smoking protected against the development of PSC in PSC-IBD patients but not among PSC patients without IBD. The results could suggest that the association between smoking and PSC is driven by a specific genotype and corresponding PSC-IBD phenotype. How the underlying mechanisms of smoking affects the development (pathogenesis) of PSC or IBD is not yet known. There are more than 4000 chemicals in tobacco, with nicotine being the most studied. Nicotine aggravates specific receptors in the central nervous system and elsewhere in the body that may lead to sensitization of a certain anti-inflammatory pathway: the cholinergic anti-inflammatory pathway. While the effects of smoking on the progression of PSC have not been studied, in patients with PBC smoking has been associated with advanced disease at presentation. This could suggest that even though smoking is associated with a lower risk of developing PSC, it might accelerate disease progression once liver fibrosis is present.



Appendectomy occurred equally among PSC patients and HCs, while more PSC-UC patients than UC controls had undergone appendectomy. Several studies have shown a protective effect of appendectomy on developing UC and the findings from this study support these results. However, no association between appendectomy and the development of PSC was found – this is in agreement with a large meta-analysis of four studies that demonstrated no association. The higher frequency of appendectomy in the PSC-UC group compared to the UC group indicates that appendectomy may be a risk factor for developing PSC in UC patients. The reason why appendectomy influences the risk of developing UC has been a focus of research for many years. A large study by Anderson et al., suggests that it is more probably that the endured inflammation of the appendix (reason why it was removed) causes the protective effect, than the absence of the appendix after appendectomy.

Family History:

Ten percent of PSC-UC patients and 17% of UC controls had a first-degree family member with IBD, however no difference was found between PSC-CD and CD controls. Family history of IBD was not an independent risk factor for PSC in either of the PSC-IBD subgroups. Autoimmune liver diseases were more prevalent in families of PSC-CD patients than in families of CD controls, however, numbers were very small.  Families of PSC-UC patients had a similar frequency of auto-immune liver disease compared with UC families.

Geographical distribution:

There was a balanced geographical spread of PSC patients throughout the area in which they lived, suggesting that the residential environment does not play a role in the development of PSC.


The researchers concluded that in a large population based PSC cohort, smoking is associated with a lower risk of developing PSC, independent of the protective effect of smoking in UC, while appendectomy is not an independent risk factor for PSC.



Case-control study: A study that compares patients who have a disease or outcome of interest with patients who do not have the disease or outcome, and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease.

Cohort: Is a group of subjects who have experienced a particular event or suffer from a particular disease over a specific time span

Genotype: Gene combination at one specific locus or any specified combination of loci

Loci: (pl) Locus: In genetics, the loci are the positions of particular genes on a chromosome that are more common in a disease compared to controls

Median: The middle value in a distribution, above and below which lie an equal number of values

Pathogenesis: The biological mechanism (or mechanisms) that lead to the diseased state

Phenotype: The expression of a specific trait based on genetic and environmental influences

Population-based: Traditionally used to describe a study that involved a defined “general population” for example a group of people with PSC.


The author of this lay version of the article is Dr Valmae Ypinazar (PhD), Senior Research Fellow, Griffith University, Southport, Queensland, Australia.

The original (English) version of the above article has been checked and approved by
Dr. E.M.G de Vries and Dr. K. Boonstra.

This version is based on the full article:

Risk factors for primary sclerosing cholangitis

 Article published in June 2016

Kirsten Boonstra1*, Elisabeth M. G. de Vries1*, Nan van Geloven 2, Karel J. van Erpecum 3, Marcel Spanier 4, Alexander C. Poen 5, Carin M. van Nieuwkerk 6, Ben J. Witteman 7, Hans A. Tuynman 8, Anton H. Naber 9, Paul J. Kingma 9, Ulrich Beuers 1 and Cyriel Y. Ponsioen 1 on behalf of the Epi PSC PBC Study Group

1 Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; 2 Clinical Research Unit, Academic Medical Center, Amsterdam, the Netherlands; 3 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands; 4 Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands; 5 Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, the Netherlands; 6 Department of Gastroenterology and Hepatology, VU Medical Center, Amsterdam, the Netherlands; 7 Department of Gastroenterology and Hepatology, Gelderse Vallei Hospital, Ede, the Netherlands; 8 Department of Gastroenterology and Hepatology, Medical Center Alkmaar, Alkmaar, the Netherlands; 9 Department of Gastroenterology and Hepatology, Tergooiziekenhuizen, Hilversum/Blaricum, the Netherlands

*These authors contributed equally to the article.

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