Clinics and Research in Hepatology and Gastroenterology
Mini reviewGenetics in primary sclerosing cholangitis
Introduction
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by inflammation and progressive obliterative fibrosis of the intra- and the extrahepatic biliary ducts, resulting in cirrhosis and ultimately liver failure [1]. Inflammatory bowel disease (IBD) is the most common accompanying condition, present in up to 80% of the patients of Northern European origin. Approximately 25% of the patients also suffer from other types of autoinflammatory conditions [2], [3]. Patients with PSC are at high risk of developing malignancies, in particular cholangiocarcinoma, but increased risk of hepatocellular carcinoma, gallbladder carcinoma, pancreatic cancer as well as colorectal carcinoma is also known [4], [5], [6].
The etiology and pathogenesis of PSC are still far from being understood. A genetic predisposition is suggested by familial clustering with up to 40–100 fold relative risk of PSC in siblings compared to the general population [7], [8]. Environmental influences likely play a role, but the only exogenous factor defined so far is smoking, which seems to be protective [9], [10], [11]. To what extent geographic differences in PSC prevalence are due to differences in genetic or environmental risk factors or IBD prevalence is not known [12], [13].
Several articles have summarized recent findings on the genetic susceptibility to PSC [14], [15]. In the present review, we aim to discuss these novel findings in the context of key molecular and cellular characteristics of PSC (Table 1). We show that the outcome of these genetic studies aligns with four mechanistic aspects of – inflammation, cholangiocytes activity, fibrosis and cancer – and propose that dedicated genetic studies may be performed taking into account characteristics of these four elements rather than the composite clinical “PSC phenotype” (Fig. 1).
Section snippets
Inflammation and genetics
The inflammatory infiltrate in PSC is largely comprised of T-cells, but also natural killer (NK) cells, B-cells, macrophages, dendritic cells (DCs) as well as biliary epithelial cells (BECs) are likely to play an important role in the “inflammatory phenotype” observed in PSC patients as discussed in this and the following sections [16], [17], [18]. Most of the associated genetic loci in PSC(Table 1) point to an involvement of inflammatory pathways in the pathogenesis of PSC, and the strongest
Cholangiocyte function and genetics
An active involvement of the biliary epithelium (cholangiocytes) in many forms of chronic liver disease and all cholangiopathies has been established [51]. In normal adult liver, cholangiocytes express a number of cell cycle related proteins keeping them mitotically inactive [52], [53]. However, under abnormal circumstances, biliary epithelium becomes activated and begins to proliferate [54]. Reactive cholangiocytes express adhesion molecules, growth factors, proinflammatory and profibrogenetic
Fibrosis in primary sclerosing cholangitis
The natural history of PSC is variable and difficult to predict [68]. However, PSC, in general, is a progressive disorder where fibrosis and cholestasis eventually leads to cirrhosis [69], [70], The characteristic histological finding in PSC is that of fibro-obliterative cholangitis or “onion-skin fibrosis” [71]. Thus, genetic factors that affect bile acid homeostasis or fibrosis may be important determinants of disease progression in PSC.
The multidrug resistance protein 3 (MDR3) is a
Cancer in primary sclerosing cholangitis
PSC patients are susceptible to cancer. Cholangiocarcinoma is the most common malignancy (160–1500 × increased risk), affecting up to 20% of the patients. The longitudinal growth of cholangiocarcinoma makes early diagnosis difficult, and the development of new molecular tools for diagnosis is an important priority [90], [91].
The malignant transformation of cholangiocytes into cholangiocarcinoma involves both genetic and epigenetic alterations (recently reviewed in [92]). Both inflammation and
Conclusions
In this review, we summarized recent genetic findings in the context of four pathogenetic aspects of PSC (Fig. 1). Further characterization of the genetic architecture of PSC requires larger studies with extensive international collaboration to increase the statistical power. The ongoing Immunochip Project, looking into the genetic overlap of several immune-mediated diseases, will potentially give valuable insight into the genetic similarity between PSC and other immune-mediated diseases.
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements
We thank Prof. Erik Schrumpf for critical reading of the manuscript.
Financial support: This study was supported by the Norwegian PSC research center (http://ous-research.no/nopsc/).
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