Pathogenesis Of Primary Sclerosing Cholangitis Research Articles

Small Duct Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a well documented disease of the biliary tract associated with inflammatory bowel diseases (IBD), especially ulcerative colitis.1 Small-duct PSC, a variant of PSC, also has an association with inflammatory bowel disease.1 The exact pathogenesis of PSC is not well understood, but thought to be due to a combination of a genetic predisposition and gut structure.1 A 34 year-old male with a history significant for rheumatoid arthritis, portal vein thrombosis and ulcerative colitis presented to the hepatology clinic for evaluation of abnormal liver enzymes. He was diagnosed with ulcerative colitis at age 24 and over the years treated with Mesalamine, steroids, Azathioprine, Cyclosporine, and Infliximab. However, he was unresponsive to therapy and underwent total colectomy 2 years after diagnosis. The liver enzymes of concern had a mixed cholestatic and hepatocellular pattern with ALT 203, AST 104, Tbili 1.7, Dbili 0.6, and ALP 339. Hence, the differential was initially broad including possible autoimmune causes, vascular with the portal vein thromboses history, drug induced or primary sclerosing cholangitis (PSC) or primary biliary cirrhosis. A viral hepatitis screen was negative. Autoimmune testing revealed a positive anti-nuclear antibody titer. Magnetic resonance cholangiopancreatography (MRCP) revealed hypoattenuations correlating with his history of portal vein thromboses. Liver biopsy revealed small duct PSC. He is scheuled for imaging every 6 months to observe for cholangitis. A retrospective analysis of patients with PSC from 1980 to 2010 at 37 centers in Europe, North America, and Australia was completed by the International PSC Study Group.2 Of the 7121 patients, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point.2 Small-duct PSC was associated with a lower risk of liver transplant, death or malignancy compared with classic PSC.2 Small-duct PSC characterized a low-risk phenotype in both sexes.2 This suggests that small duct PSC is usually seen in younger individuals, in early stage disease, and suggests better outcomes.

Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?

In primary sclerosing cholangitis (PSC), annular fibrosis around intrahepatic and extrahepatic bile ducts leads to progressive liver disease for which there is no effective therapy except liver transplantation.1 The concentric...

Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases.

Autoimmune cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are manifested as an impairment of normal bile flow and excessive accumulation of potentially toxic bile acids. Endogenous bile acids are involved in the pathogenesis and progression of cholestasis. Consequently, chronic cholestasis affects the expression of bile acid transporters and nuclear receptors, and results in liver injury. Several lines of evidence suggest that intestinal microbiota plays an important role in the etiopathogenesis of cholestatic liver diseases by regulating metabolism and immune responses. However, progression of the disease may also affect the composition of gut microbiota, which in turn exacerbates the progression of cholestasis. In addition, the interaction between intestinal microbiota and bile acids is not unidirectional. Bile acids can shape the gut microbiota community, and in turn, intestinal microbes are able to alter bile acid pool. In general, gut microbiota actively communicates with bile acids, and together play an important role in the pathogenesis of PBC and PSC. Targeting the link between bile acids and intestinal microbiota offers exciting new perspectives for the treatment of those cholestatic liver diseases. This review highlights current understanding of the interactions between bile acids and intestinal microbiota and their roles in autoimmune cholestatic liver diseases. Further, we postulate a bile acids-intestinal microbiota-cholestasis triangle in the pathogenesis of autoimmune cholestatic liver diseases and potential therapeutic strategies by targeting this triangle.

Genetics of primary sclerosing cholangitis and pathophysiological implications.

Primary sclerosing cholangitis (PSC) is a chronic disease leading to fibrotic scarring of the intrahepatic and extrahepatic bile ducts, causing considerable morbidity and mortality via the development of cholestatic liver cirrhosis, concurrent IBD and a high risk of bile duct cancer. Expectations have been high that genetic studies would determine key factors in PSC pathogenesis to support the development of effective medical therapies. Through the application of genome-wide association studies, a large number of disease susceptibility genes have been identified. The overall genetic architecture of PSC shares features with both autoimmune diseases and IBD. Strong human leukocyte antigen gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in disease pathogenesis, and position PSC as an autoimmune disease. In this Review, we survey the developments that have led to these gene discoveries. We also elaborate relevant interpretations of individual gene findings in the context of established disease models in PSC, and propose relevant translational research efforts to pursue novel insights.

Management of cholestatic disease in 2017.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent chronic cholestatic liver diseases and serve as model diseases to discuss the management of cholestasis in 2017 in the lecture that is summarized in this report. PBC and PSC are characterized by inflammation and fibrosis of small intrahepatic (PBC) or larger intra- and/or extrahepatic (PSC) bile ducts. Bile duct damage leads to cholestasis and can progress to liver fibrosis and even cirrhosis. Various genetic, environmental and endogenous factors may contribute to the development of chronic cholestatic liver diseases, but the exact pathogenesis of PBC and PSC has not been clarified. Ursodeoxycholic acid (UDCA) is the standard treatment of PBC and is used also for other cholestatic conditions including PSC, and it exerts anticholestatic effects at adequate doses. Novel anticholestatic therapeutic options for patients not adequately responding to UDCA are under development or have, like obeticholic acid, already been proven to have efficacy when combined with UDCA in the treatment of PBC. The future role of immunomodulating/immunosuppressive drug regimens must be critically reviewed.

Pathogenesis and clinical spectrum of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a disease of the biliary tract, which has been documented in the literature since 1867. This disease has a strong predilection for affecting men and can be seen in individuals as young as 2 years of age. PSC has a strong associated with inflammatory bowel disease, more commonly with ulcerative colitis, and is also part of the clinical spectrum of IgG4-related diseases. Small-duct PSC, a variant of PSC, also has an association with inflammatory bowel disease. The exact pathogenesis of PSC is not well understood at present, however, is likely a combination of a genetic predisposition with alteration of the molecular structure of the gut. Abnormal serum liver chemistry and presence of certain autoimmune markers are usually the first indicators leading to a diagnosis of PCS, however, these may often be normal in early stages of this disease. The diagnosis is made by cholangiography, which is now considered the gold standard. PSC is a known pre-malignant condition. Such patients have an increased risk of developing cholangiocarcinoma, gallbladder neoplasia, and colon cancer. Many new treatment modalities have emerged in the recent past, including anti-tumor necrosis factor- α and anti-integrins; however, liver transplantation is the only known cure for PSC. Despite past and present research, PSC remains an enigmatic biliary disease with few viable treatment options.

Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC).

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent the major clinical entities of chronic cholestatic liver diseases. Both disorders are characterized by portal inflammation and slowly progress to obliterative fibrosis and eventually liver cirrhosis. Although immune-pathogenic mechanisms have been implicated in the pathogenesis of PBC and PSC, neither disorder is considered to be a classical autoimmune disease, as PSC and PBC patients do not respond to immune-suppressants. Furthermore, the decreased bile flow resulting from the immune-mediated tissue assault and the subsequent accumulation of toxic bile products in PBC and PSC not only perpetuates biliary epithelial damage, but also alters the composition of the intestinal and biliary microbiota and its mutual interactions with the host. Consistent with the close association of PSC and inflammatory bowel disease (IBD), the polyclonal hyper IgM response in PBC and (auto-)antibodies which cross-react to microbial antigens in both diseases, an expansion of individual microbes leads to shifts in the composition of the intestinal or biliary microbiota and a subsequent altered integrity of epithelial layers, promoting microbial translocation. These changes have been implicated in the pathogenesis of both devastating disorders. Thus, we will discuss here these recent findings in the context of novel and alternative therapeutic options.

Basic Science Liver.

Basic Science Liver.

Stem Cell‐based Biliary Organoids and Gallbladder‐like Structures for Disease Modeling of Primary Sclerosing Cholangitis and Alagille Syndrome

Cholangiopathies such as primary sclerosing cholangitis (PSC), Alagille Syndrome (AS), polycystic liver disease and cholangiocarcinoma result in end‐stage liver disease. To understand the cell and molecular basis of these progressive disorders, a cell‐based interface would be very useful. Availability of human primary cholangiocytes is a limiting factor, and pluripotent stem cells provide an exciting option of generating unlimited quantity of cholangiocytes for in vitro disease modeling purposes. Our goal is to develop and in vitro platform using stem cell‐derived cholangiocytes to model the pathogenesis of PSC and AS. We established a three stage differentiation program to differentiate pluripotent stem cells to biliary epithelial cells. The first stage involves hepatoblast formation by definitive endoderm induction; a second phase entails biliary specification prompting cholangiocyte progenitors and the final third stage of cholangiocyte maturation. At 16 days post‐differentiation, the expression of biliary markers SOX9, CFTR, cytokeratin 7 (CK7) and CK19 were verified by RT‐qPCR and immunofluorescence assay. Marker expression was similar to that of human gallbladder tissue. Day 16 cells were induced to form organoids in 3D matrigel culture. The cells were organized to become branched tubular structures. The histology of these organoids showed the formation of duct‐like structures which are cytokeratin 19 and CK 8/18 positive with a defined collagen IV positive basement membrane. The tubules were surrounded by connective tissue‐like structures. By day 33, pear‐shaped gallbladder‐like cystic structures emerged. Immunohistochemistry of these tubular organoids showed polarized columnar cells lining the ductular structures. Zo‐1 tight junction proteins were localized to the apical side of the cells facing the lumen. In conclusion, we have developed a 3D in vitro platform to study the bile duct structure formation based on stem cell‐derived cholangiocytes. This system is currently being investigated for studying the effect of primary sclerosing cholangitis risk genes and the deregulation of NOTCH signaling pathway of Alagille Syndrome model.

New Therapeutic Strategies for Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade.

Biliary tree stem cells are involved in the pathogenesis of primary sclerosing cholangitis

Biliary tree stem cells (BTSCs) are multipotent stem cells located in peribiliary glands (PBGs) of extrahepatic and large intrahepatic bile ducts (1). Primary sclerosing cholangitis (PSC) is characterised by fibro-stenosing strictures involving extrahepatic and/or large intrahepatic bile ducts. Mechanisms leading to bile duct injury are poorly understood (2). Our aims are to study the role of BTSC in the pathogenesis of biliary fibrosis in PSC. Specimens containing extrahepatic or large intrahepatic bile ducts were obtained from normal liver (n=6), liver explants from patients with PSC (n=11), and primary biliary cirrhosis (n=6). Specimens were processed for histology, immunohistochemistry and immunofluorescence. In PSC samples, progressive hyperplasia and mucinous metaplasia of PBGs were observed in large ducts with fibrosis, but not in inflamed ducts without fibrosis. PBG hyperplasia was associated with progressive biliary fibrosis and the occurrence of dysplastic lesions. Hyperplasia of PBGs was determined by the expansion of biliary tree stem cells, which sprouted towards the surface epithelium. In PSC, PBGs and myofibroblasts displayed enhanced expression of Hedgehog pathway components. PBGs in ducts with onion skin-like fibrosis expressed epithelial-to-mesenchymal transition traits associated with components of Hedgehog pathway, markers of senescence and autophagy. The biliary tree stem cell compartment is activated in PSC, its activation contributes to biliary fibrosis, and is sustained by the Hedgehog pathway. Our findings suggest a key role for peribiliary glands in the progression of bile duct lesions in PSC and could explain the associated high risk of cholangiocarcinoma. This work was supported by grants from MIUR FIRB 2010 and MIUR PRIN-2009.

Gut Inflammation in Primary Sclerosing Cholangitis and Autoimmune Sclerosing Cholangitis-Contrasting Pattern of Liver-gut Cross Talk

Gut Inflammation in Primary Sclerosing Cholangitis and Autoimmune Sclerosing Cholangitis-Contrasting Pattern of Liver-gut Cross Talk

PTH-099 Vap-1 is elevated in psc, correlates with clinical outcome and exhibits amine oxidase activity in a substrate-dependent manner

Introduction Vascular adhesion protein (VAP)-1 is an adhesion molecule and potent amine-oxidase. Activation on hepatic sinusoidal endothelial cells (HSEC) leads to H 2 O 2 release, NFκB activation and expression of gut-homing receptor MAdCAM-1, which promotes homing of gut-tropic lymphocytes to the liver. Given the proposed role of this pathway in hepatic disorders complicating inflammatory bowel disease (IBD); we quantified serum (sVAP-1) titre and intrahepatic/colonic enzyme activity in primary sclerosing cholangitis (PSC)/IBD, as well as investigated consequences of activation with variant amine substrates. Method sVAP-1 was quantified by ELISA in PSC (n = 105); PBC (90); AIH (99); IBD-alone (50) and healthy controls (21). Correlation with clinical outcome was assessed using Cox proportional hazards assumption/KM-estimates. VAP-1 activity was determined (Amplex red assay) in protein lysates extracted from (a) explanted liver (PSC=9; PBC=10, AIH=5, normal donor, n = 10) and (b) colonic resections (n = 7). Putative VAP-1 substrates were selected based on inclusion in the human metabolome database, and induced kinetic rates measured (Michaelis-Menton analysis). Induction of MAdCAM-1 on HSEC was evaluated quantitatively (cell-ELISA) and functionally (flow-adhesion assays). Results PSC patients had higher sVAP-1 concentration (median 517 ng/mL) than those with AIH (475), PBC (472), IBD-alone (413) and healthy controls (425) (p 530 ng/ml in PSC were associated with significantly worse transplant-free survival (unadj. HR:2.94, p = 0.008), and retained independent predictive value when controlling for other significant risk factors (cirrhosis, ascending cholangitis and liver biochemistry; adj. HR:3.85, p = 0.003). Intrahepatic VAP-1 enzyme activity was significantly greater in PSC (227 pmol H 2 O 2 /min/mg protein) compared with PBC (124), AIH (128) and donor liver (109) (p cat /K m :5.4 × 10 7 ); an amine secreted by Escherichia. which induces colitis in mice. Cysteamine+TNFa provision resulted in greater MAdCAM-1 expression by HSEC ELISA than that with other substrates or TNFa alone (p Conclusion Elevated levels of circulating sVAP-1 exist in PSC and predictive of poor outcome. Intrahepatic VAP-1 enzyme activity is also increased in PSC and akin to that seen in the colon. The ability of VAP-1 to catabolise amine substrates secreted by gut commensals/enteric pathogens, provides a theoretical link between altered colonic microbiota and mucosal immunity in the pathogenesis of PSC. Disclosure of interest None Declared.

Biomarkers for disease progression of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. There is no medical treatment of proven benefit on survival; once patients have progressed to end-stage liver disease, the only treatment option is liver transplantation. Over the last years, some progress has been made in identifying biomarkers of PSC disease progression. Categories that can be distinguished include clinical and biochemical biomarkers, histology, imaging, prognostic modelling and genetics. With this review, we summarize biomarkers for progression of PSC from these six categories, which have been studied to date. Biomarkers for the progression of PSC disease course can be used for several purposes. First of all, they can be implemented as surrogate endpoints for clinical trials. Second, biomarkers of disease progression form the basis of prognostic modelling, which is needed for proper patient counselling and management. Lastly, these biomarkers may yield a better understanding of PSC pathogenesis.

A morphometric study of the hepatic arterioles in end-stage primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is typified by a heterogeneous histology with periductal fibroinflammatory lesions. The hepatic arterioles in PSC have not been well characterized. Using image analysis, we sought to examine the dimensions of hepatic arterioles in PSC. We identified 30 livers from patients transplanted for PSC as well as 10 explants each from cirrhotic patients (serving as controls) having primary biliary cirrhosis, hepatitis C (HCV), and alcoholic liver disease. At least two representative hematoxylin and eosin-stained slides were selected, and ten cross-sectioned hepatic arterioles were photographed for image analysis. The vessels were measured at their longest span and width based on the outer portions of the tunica media. Wall thickness was measured at its thickest portion from the intima to the outer portion of the tunica media; the perimeter of the luminal area was outlined by the endothelial lining, generating the total luminal area. Mean arteriolar length, width, and wall thickness (p = 0.012, p = 0.004, p = 0.001, respectively) were greater in the PSC group; luminal area was similar between the groups. When compared to the individual sub-groups, wall thickness of arterioles in PSC remained significantly greater. End-stage PSC has even larger-sized arterioles and greater wall thickness as compared to that of other cirrhotic livers. This increased wall thickness found in PSC cannot be solely attributed to cirrhosis itself. These vessel changes may potentially be the result of, or contribute to, the pathogenesis of PSC.

Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholangiopathy. The role of cholangiocytes (biliary epithelial cells) in PSC pathogenesis is unknown and remains an active area of research. Here, through cellular, molecular and next-generation sequencing (NGS) methods, we characterize and identify phenotypic and signaling features of isolated PSC patient-derived cholangiocytes. We isolated cholangiocytes from stage 4 PSC patient liver explants by dissection, differential filtration and immune-magnetic bead separation. We maintained cholangiocytes in culture and assessed for: (i) cholangiocyte, cell adhesion and inflammatory markers; (ii) proliferation rate; (iii) transepithelial electrical resistance (TEER); (iv) cellular senescence; and (v) transcriptomic profiles by NGS. We used two well-established normal human cholangiocyte cell lines (H69 and NHC) as controls. Isolated PSC cells expressed cholangiocyte (eg, cytokeratin 7 and 19) and epithelial cell adhesion markers (EPCAM, ICAM) and were negative for hepatocyte and myofibroblast markers (albumin, α-actin). Proliferation rate was lower for PSC compared with normal cholangiocytes (4 vs 2 days, respectively, P<0.01). Maximum TEER was also lower in PSC compared with normal cholangiocytes (100 vs 145 Ωcm2, P<0.05). Interleukin-6 (IL-6) and IL-8 (protein and mRNA) were both increased compared with NHCs and H69s (all P<0.01). The proportion of cholangiocytes staining positive for senescence-associated β-galactosidase was higher in PSC cholangiocytes compared with NHCs (48% vs 5%, P<0.01). Finally, NGS confirmed cholangiocyte marker expression in isolated PSC cholangiocytes and extended our findings regarding pro-inflammatory and senescence-associated signaling. In conclusion, we have demonstrated that high-purity cholangiocytes can be isolated from human PSC liver and grown in primary culture. Isolated PSC cholangiocytes exhibit a phenotype that may reflect their in vivo contribution to disease and serve as a vital tool for in vitro investigation of biliary pathobiology and identification of new therapeutic targets in PSC.

TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis?

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease affecting the intrahepatic and extrahepatic biliary tree leading to bile duct strictures, progressive cholestasis, and development of liver fibrosis and cirrhosis. The pathogenesis of PSC is still elusive; however, both an immune-mediated injury of the bile ducts as well as increased recruitment of intestinal-primed T lymphocytes to the biliary tracts seem to contribute to disease development and progression. TGR5 (Gpbar-1) is a G-protein-coupled receptor responsive to bile acids, which is expressed in cholangiocytes, intestinal epithelial cells, and macrophages of the liver and intestine as well as in CD14-positive monocytes of the peripheral blood. Activation of TGR5 in biliary epithelial cells promotes chloride and bicarbonate secretion, triggers cell proliferation, and prevents apoptotic cell death. In immune cells, stimulation of TGR5 inhibits cytokine expression and secretion, thus reducing systemic as well as hepatic and intestinal inflammation. The expression pattern of TGR5 in the liver and intestine as well as the potential protective functions of TGR5 suggest a role for this receptor in the pathogenesis of PSC. While mutations in the coding region of the TGR5 gene are too rare to contribute to overall disease susceptibility, the expression and localization of the receptor have not been studied in PSC livers. Pharmacological activation of TGR5 in mice promotes protective mechanisms in biliary epithelial cells and reduces hepatic and systemic inflammation; however, it also provokes pruritus. Further studies are needed to predict the potential benefits as well as side effects of TGR5 agonist treatment in PSC patients.

Hepatobiliary manifestations of ulcerative colitis: an example of gut-liver crosstalk.

The interaction between inflammatory bowel disease (IBD) and hepatobiliary manifestations represents a classic example of liver–gut crosstalk. The importance of liver–gut crosstalk in IBD is demonstrated in the pathogenesis and outcome of primary sclerosing cholangitis (PSC) in IBD patients. Immunoglobulin G4-associated cholangitis (IAC), which has recently been described in UC patients, may also illustrate the significance of gut–liver interaction in these patients. Presence of these hepatobiliary manifestations influences the outcome of associated IBD, in particular ulcerative colitis (UC), and vice versa. The pathogenesis of PSC is postulated to be related to gut inflammation in IBD that results in inflammation in the portal tracts (the ‘leaky gut’). Enterohepatic circulation of lymphocytes from the gut to the liver is also of potential relevance to PSC pathogenesis and outcomes. The presence of PSC and gut inflammation in IBD influences the course and outcomes of both diseases. Further research is required, to understand the mutual effect of liver–gut crosstalk in the outcomes of UC patients, and highlights the importance of an interdisciplinary approach—involving gastroenterologists, hepatologists, advanced endoscopists and liver transplant surgeons—in the management of these patients.

Advances and controversies in the pathogenesis and management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic immune-mediated liver disease that results in end-stage liver disease requiring liver transplantation. PSC is closely associated with inflammatory bowel disease (IBD) with 70% of patients with PSC also suffering from IBD. Data for this review were obtained from PubMed. Historical and genome-wide association studies have established a strong human leukocyte antigen (HLA) linkage to PSC and defined specific haplotypes associated with enhanced PSC risk. Fifteen non-HLA loci have been defined in PSC. The biological role of risk loci in PSC and their place in PSC pathogenesis remain speculative but suggest significant interactions with the host microbiome and therapeutic opportunities. Genetics provides a platform to systematically target emerging therapies in PSC. Linking PSC genotypes with biology and disease phenotypes paves the way for a personalized medicine approach to manage PSC.

Genetics in PSC: what do the "risk genes" teach us?

A role of genetics in primary sclerosing cholangitis (PSC) development is now firmly established. A total of 16 risk genes have been reported at highly robust ("genome-wide") significance levels, and ongoing efforts suggest that the list will ultimately be considerably longer. Importantly, this genetic risk pool so far accounts for less than 10 % of an estimated overall PSC susceptibility. The relative importance of genetic versus environmental factors (including gene-gene and gene-environment interactions) in remaining aspects of PSC pathogenesis is unknown, and other study designs than genome-wide association studies are needed to explore these aspects. For some of the loci, e.g. HLA and FUT2, distinct interacting environmental factors may exist, and working from the genetic associations may prove one valid path for determining the specific nature of environmental triggers. So far the biological implications for PSC risk genes are typically merely hypothesized based on previously published literature, and there is therefore a strong need for dedicated translational studies to determine their roles within the specific disease context of PSC. Apparently, most risk loci seem to involve in a subset of biological pathways for which genetic associations exist in a multitude of immune-mediated diseases, accounting for both inflammatory bowel disease as well as prototypical autoimmunity. In the present article, we will survey the current knowledge on PSC genetics with a particular emphasis on the pathophysiological insight potentially gained from genetic risk loci involving in this profound immunogenetic pleiotropy.