Primary sclerosing cholangitis: Diagnosis and management

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by progressive inflammatory destruction of intrahepatic and extrahepatic bile ducts, and ultimately cirrhosis. PSC occurs primarily in patients with underlying ulcerative colitis and affects primarily young to middle-aged men. PSC is believed to be an autoimmune disease mediated by immune dysregulation in patients with genetic susceptibility. One possible mechanism for the development of PSC is the homing of memory lymphocytes to the biliary tract. Cholangiography is the gold standard for diagnosis of PSC. The typical radiologic findings include multifocal strictures and dilation involving the intrahepatic or extrahepatic biliary tract, or both. Although no medical therapy has proved beneficial, a variety of agents have been tested, some of which appear promising and deserve further study. Highdose ursodeoxycholic acid may have benefit in slowing disease progression; a multicenter placebo-controlled trial is ongoing. Liver transplantation is a good option for patients with advanced PSC, although the disease can recur after successful transplantation.     

A shared and unique epitope(s) on human colon, skin, and biliary epithelium detected by a monoclonal antibody.

An immune-complex-mediated inflammation has been suggested in the pathogenesis of skin and biliary complications in ulcerative colitis, although specific antigen-antibody complexes have not been found. We recently identified an Mr 40,000 colonic protein that reacts with tissue-bound immunoglobulin G eluted from colon specimens of patients with ulcerative colitis and not with immunoglobulin G eluted from colon specimens of patients with other diseases (J Clin Invest 1985;7:311). Murine monoclonal antibodies to the purified Mr 40,000 colonic protein are developed. The presence of the Mr 40,000 protein was examined with a monoclonal antibody (7E12H12, immunoglobulin M isotype) by an immunoperoxidase assay against various human epithelial tissues (74 specimens) including colon, ileum, jejunum, duodenum, stomach, esophagus, pancreaas, liver, respiratory, urinary, and genital tracts. In addition, gall bladder, bile duct, hepatic ducts, skin, synovial membrane, and eye tissue were also examined for any cross-reactivity with 7E12H12 and another anti-Mr 40,000 monoclonal antibody (7E6A5, immunoglobulin G1 isotype). 7E12H12 reacted only with colonic-epithelial cells mainly along the basolateral domains of plasma membrane and apical areas. The reactivity was present in both adult and fetal colon including the appendix. Among all the noncolonic tissue specimens, 7E12H12 reacted only with the gall bladder, the bile duct, the hepatic ducts, and the skin. All other epithelial tissues from 15 different organs, including the small intestine, synovium, and eye tissue, did not react. In the skin and biliary tract the immunoreactivity was exclusively present in the epidermal epithelial cells and mucosal epithelium respectively. 7E6A5 stained colonic mucosal cells but did not react with skin, biliary epithelium, synoyium and eye tissue. These results indicate the presence of a unique epitope or epitopes on Mr 40,000 colonic epithelial protein that is shared by the skin and biliary tract epithelial cells. Future studies of this shared epitope or epitopes and its immune recognition may provide further understanding in the pathogenesis of extraintestinal complications involving these organs in patients with ulcerative colitis.     

Animal models for primary sclerosing cholangitis

Since the aetiopathogenesis of primary sclerosing cholangitis (PSC) in humans remains undefined, investigators have studied a variety of animal models to gain insights into immunopathogenetic mechanisms associated with obliterative fibrous cholangitis of intra- and extra-hepatic bile ducts. To date, no animal model has been developed that exhibits all of the attributes of PSC. Rodent models instigated by bacterial cell components or colitis are promising because they may help to explain the strong association between PSC and inflammatory bowel disease (IBD). Other models of direct injury to biliary epithelia, peribiliary vascular endothelia or portal venous endothelia indicate that inflammation, chemokines and cytokines can produce diffuse sclerosis of bile ducts. Models of toxic, infectious or intra-luminal injury of the biliary tract also exhibit focal biliary sclerosis mediated by inflammation and cytokines. The histopathology of several models suggests a sequence of events beginning with secretion of proinflammatory cytokines by activated hepatic macrophages followed by peribiliary infiltration with CD4 and CD8 T cells with a T helper 1 phenotype. These results strongly suggest co-ordinated, pathogenetic roles for both the innate and adaptive immune responses. However, the stimuli that initiate and perpetuate peribiliary fibrosis remain unknown. Interestingly, several models are also associated with the development of anti-neutrophil cytoplasmic antibodies that react in a perinuclear and cytoplasmic pattern similar to that observed in patients with ulcerative colitis and/or PSC. Finally, models of extra-hepatic biliary obstruction continue to provide important information about the pathogenesis of portal fibrosis and secondary biliary cirrhosis that occurs in PSC and other diseases with obstruction of bile flow. Future studies in either existing or new animal models should advance our understanding of the pathogenesis of PSC, the major prerequisite for the development of effective therapies.     

Primär sklerosierende Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by fibrosing inflammation and obliteration of intra and/or extrahepatic bile ducts. The disease belongs to the most common cholestatic diseases in adults and at present is diagnosed with increasing frequency. It is very often associated with ulcerative colitis. Patients with PSC have an increased incidence of bile duct carcinomas and those with ulcerative colitis also have an increased incidence of colonic carcinomas. Immunosuppressive treatment is little effective. Ursodeoxycholic acid (UDCA) has been shown to improve liver histology in PSC. The aim is to treat patients as early as possible to prevent progression to the advanced stages of the disease. During treatment with UDCA stenoses of major ducts may develop and early endoscopic dilatation is highly effective. In patients with endstage disease, UDCA is not effective and liver transplantation is indicated.     

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibrosing inflammation and obliteration of intra- and/or extrahepatic bile ducts. The disease is one of the most common cholestatic diseases in adults and is diagnosed with increasing frequency. It is very often associated with ulcerative colitis. Patients with PSC have an increased incidence of bile duct carcinomas, and those with ulcerative colitis also have an increased incidence of colonic carcinomas. In end-stage disease, liver transplantation is the treatment of choice. Immunosuppressive treatment has little effect. Ursodeoxycholic acid (UDCA), which has been shown to improve liver histology and survival in patients with primary biliary cirrhosis, has a beneficial effect in PSC, provided that patients who develop major duct stenoses are treated endoscopically. The aim is to treat patients as early as possible to prevent progression to the advanced stages of the disease. During treatment with UDCA, stenoses of major ducts may develop, and early endoscopic dilation is highly effective. Because UDCA treatment improves but does not cure cholestatic liver diseases, permanent treatment seems to be necessary. Such prolonged treatment with UDCA may be recommended because, until now, no side effects have been reported. In patients with end-stage disease, UDCA is not effective and liver transplantation is indicated.     

Papillary bile duct dysplasia in primary sclerosing cholangitis.

A 62-year-old man with a 20-year history of chronic ulcerative colitis and a 9-year history of primary sclerosing cholangitis (PSC) underwent orthotopic liver transplantation because of symptoms related to PSC and cholangiographic features compatible with a biliary neoplasm. Study of the excised liver revealed papillary mucosal lesions in the common hepatic duct and the right and left hepatic ducts as well as cholangiectases and other features typically associated with PSC. The papillary lesions consisted of abundant fibrovascular stroma covered by biliary epithelium with low-grade and high-grade dysplasia. Some periductal glands were also dysplastic. These features distinguished papillary dysplasia from classic biliary papillomatosis. Only one focus of microinvasion was found; there were no metastases. Among 60 cases of PSC in whom the entire liver could be studied after orthotopic liver transplantation, this was the only instance of unequivocal dysplasia. However, in one specimen, papillary hyperplasia was found. Detailed macroscopic and microscopic rereview of 23 livers from our patients with the longest history of PSC (range, 5-24 years) failed to reveal any additional cases with dysplasia. It is concluded that (a) papillary mucosal lesions in PSC may represent papillary dysplasia without invasion; (b) these lesions may evolve from papillary hyperplasia; (c) the process may be largely, if not entirely, in situ; and (d) the prevalence of dysplasia and carcinoma of bile ducts may be less than the 7%-9% reported in the literature for malignancies associated with PSC.     

Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis

The expression of HLA class I (HLA-A, B, C) and class II (HLA-DR) antigens on the biliary epithelium of 10 patients (nine men) with primary sclerosing cholangitis (PSC) was investigated using an immunoperoxidase technique on cryostat sections. Five patients were staged as grade II and five grade III on hepatic histology. None were cirrhotic. as grade II and five grade III on hepatic histology. None were cirrhotic. Controls were nine patients with primary biliary cirrhosis (PBC), five with extra hepatic biliary obstruction, 15 with other forms of chronic liver disease and six with normal livers. Bile ducts from the normal subjects and patients with chronic liver disease did not express HLA-DR antigens. In contrast, all 10 of the PSC biopsies showed varying degrees of HLA-DR staining of the biliary epithelium. Expression of DR antigens was also found on the bile ducts of all five patients with extra hepatic biliary obstruction and in six of nine patients with PBC. Expression of HLA class I antigens was seen on the biliary epithelium of all the biopsies examined. Increased numbers of helper and suppressor T-cells were seen in the portal tracts of all the PSC patients. This study has confirmed that aberrant expression of HLA-DR may occur on the biliary epithelium of some, but not all, patients with PBC. In addition, the study has shown that aberrant expression of HLA-DR always occurs in PCS at an early stage of histological liver damage. While this may be important in the pathogenesis of PSC, the aberrant expression in extra hepatic biliary obstruction suggests that it may be a secondary phenomenon.     

Epithelial deposits of immunoglobulin G1 and activated complement colocalise with the M(r) 40 kD putative autoantigen in ulcerative colitis.

The intestinal expression pattern and general tissue distribution of the M(r) 40 kD putative epithelial autoantigen in ulcerative colitis were re-examined by in situ two and three colour immunofluorescence staining including the murine monoclonal antibody 7E12H12. The intestinal distribution was also compared with the epithelial codeposition of IgG1 and activated complement (C3b and terminal complement complex) seen selectively in ulcerative colitis. The M(r) 40 kD antigen was found for the first time in goblet cells of normal terminal ileum and proximal colon but not in rectal goblet cells. By contrast, colonic enterocytes expressed this antigen apically with increasing intensity in a distal direction, expanding to intense cytoplasmic expression in rectal enterocytes. The antigen was also expressed by the epithelium of the fallopian tubes, major bile ducts, gall bladder, and epidermis but not by proximal gastrointestinal tract epithelium or 13 other extra-gastrointestinal organs. Activated complement and IgG1 often colocalised with the M, 40 kD antigen apically on the surface epithelium in active ulcerative colitis but not in Crohn's disease. Our results support the idea that an autoimmune response to this antigen, leading to complement activation mediated by IgG1, is a possible pathogenetic mechanism for epithelial damage and persistent inflammation in ulcerative colitis.     

Lack of Concomitant Expression of ICAM-1 and HLA-DR on Bile Duct Cells from Patients with Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis

In both primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) prominent infiltrates of lymphocytes surround the bile ducts, on which an abberrant expression of major histocompatibility complex class II antigens has been found, suggesting that the immune system is involved in the biliary destruction. Since the lymphocytes presumably must adhere to the bile ducts to initiate a cell-to-cell-mediated destruction, we have studied the expression of the lymphocyte function-associated antigen-1 (LFA-1) together with its ligand, the intercellular adhesion molecule-1 (ICAM-1), and the expression of HLA-DR, using immunoperoxidase staining of cryostat sections from patients with PBC (n = 10), PSC (n = 13), and normal healthy controls (n = 6). Most lymphocytes expressed LFA-1. ICAM-1 expression was found on hepatocytes from 9 of 10 PBC and 10 of 13 PSC patients but was not seen on hepatocytes from the controls. Hepatocytes expressing HLA-DR were only found in one patient with PBC. None of the septal bile ducts expressed ICAM-1, and only one PSC patient and three PBC patients expressed ICAM-1 on their interlobular bile ducts. The bile ducts in 22 of 23 patients, however, expressed HLA-DR. Proliferating bile ductules from two PBC patients and three PSC patients showed a concomitant expression of ICAM-1 and HLA-DR. None of the bile ducts from the controls expressed ICAM-1 or HLA-DR. Thus, since most bile ducts involved in the disease process of both PBC and PSC lack expression of ICAM-1, other adhesion molecules must be involved if a cell-to-cell-mediated destruction accounts for the biliary destruction in these two disease states. Furthermore, the lack of concomitant expression of HLA-DR and ICAM-1 on the bile ducts in PBC and PSC indicates that other regulatory mechanisms exist in the biliary epithelium than in most other epithelial cells.     

Etiopathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis（PSC） is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease.Associations with inflammatory bowel disease（IBD） especially ulcerative colitis（UC）,and with particular autoimmune diseases,as well as the genetic associations further suggest PSC may be an immune-mediated disease.The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease.Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.     

Peptide antibiotic human beta-defensin-1 and -2 contribute to antimicrobial defense of the intrahepatic biliary tree

Human beta-defensins (hBDs) are important antimicrobial peptides that contribute to innate immunity at mucosal surfaces. This study was undertaken to investigate the expression of hBD-1 and hBD-2 in intrahepatic biliary epithelial cells in specimens of human liver, and 4 cultured cell lines (2 consisting of biliary epithelial cells and 2 cholangiocarcinoma cells). In addition, hBD-1 and hBD-2 were assayed in specimens of bile. hBD-1 was nonspecifically expressed immunohistochemically in intrahepatic biliary epithelium and hepatocytes in all patients studied, but expression of hBD-2 was restricted to large intrahepatic bile ducts in 8 of 10 patients with extrahepatic biliary obstruction (EBO), 7 of 11 with hepatolithiasis, 1 of 6 with primary biliary cirrhosis (PBC), 1 of 5 with primary sclerosing cholangitis (PSC), 0 of 6 with chronic hepatitis C (CH-C), and 0 of 11 with normal hepatic histology. hBD-2 expression was evident in bile ducts exhibiting active inflammation. Serum C reactive protein levels correlated with biliary epithelial expression of hBD-2. Real-time PCR revealed that in all of 28 specimens of fresh liver, including specimens from patients with hepatolithiasis, PBC, PSC, CH-C and normal hepatic histology, hBD-1 messenger RNA was consistently expressed, whereas hBD-2 messenger RNA was selectively expressed in biliary epithelium of patients with hepatolithiasis. Immunobloting analysis revealed hBD-2 protein in bile in 1 of 3 patients with PSC, 1 of 3 with PBC, and each of 6 with hepatolithiasis; in contrast, hBD-1 was detectable in all bile samples examined. Four cultured biliary epithelial cell lines consistently expressed hBD-1; in contrast these cell lines did not express hBD-2 spontaneously but were induced to express hBD-2 by treatment with Eschericia coli, lipopolysaccharide, interleukin-1beta or tumor necrosis factor-alpha. In conclusion, these findings suggest that in the intrahepatic biliary tree, hBD-2 is expressed in response to local infection and/or active inflammation, whereas hBD-1 may constitute a preexisting component of the biliary antimicrobial defense system.     

Pathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.     

Immunological Similarities Between Primary Sclerosing Cholangitis and Chronic Sclerosing Sialadenitis

Primary sclerosing cholangitis (PSC) is characterized by destructive inflammation and fibrosis affecting the bile ducts. The etiology of PSC is still unknown, although lymphocytic infiltration in the portal areas suggests an immune-mediated destruction of the bile ducts. Patients with one autoimmune disease often suffer from one or more other autoimmune diseases. It is well known that there is a close relationship between PSC and inflammatory bowel disease, particularly ulcerative colitis(UC). However, the pathological findings in UC and other overlap diseases do not resemble those of PSC. In the present study, we report a patient with chronic sclerosing sialadenitis (Kuttner's tumor) and PSC. It is compared the sclerosing changes in both salivary glands and bile ducts histologically. In addition, the expression pattern of mast cell tryptase, b-FGF, and HLA-DR were examined in both tissues immunohistochemically. Histological features of sclerosing change in both salivary and bile ducts were quite similar. Marked mast cell infiltration and b-FGF expression were seen in the sclerosing areas in both tissues. In active inflammatory areas of the salivary glands, HLA-DR expression was also seen. We hypothesized that similar immune reactions occur in both the salivary gland and bile ducts and are responsible for the fibrosis that follows.     

The management of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic hepatobiliary disease that usually progresses to biliary cirrhosis and liver failure; it also predisposes to cholangiocarcinoma. The cause of PSC is unknown, although evidence suggests that the tissue damage is mediated by the immune system. There is an unexplained close association between PSC and inflammatory bowel disease, particularly in ulcerative colitis, which coexists in the majority of patients with PSC. No medical therapy has been proven to halt or reverse disease progression; however, recent preliminary evidence suggests that ursodeoxycholic acid (UDCA) in a high dose of 20 to 25 mg/kg may slow the disease process. Evidence from a pilot study suggests that the combination of UDCA and immunosuppressive therapy, such as prednisolone or azathioprine, may also increase efficacy. For patients with end-stage PSC, liver transplantation remains the only effective therapy, although there is clear evidence that PSC may recur in the liver allograft.     

Will we ever model PSC? - "it's hard to be a PSC model!"

Cholangiopathies such as primary sclerosing cholangitis (PSC) represent an important group of liver diseases of the intra- and extrahepatic bile ducts frequently causing end-stage liver disease with significant morbidity and mortality due to limited treatment options. The relatively low incidence of PSC and the difficult accessibility of the human bile duct system for longitudinal studies may represent some of the critical reasons for the lack of profound knowledge in regard to PSC pathophysiology. Therefore, there is an urgent need for reliable, well-defined and easily reproducible animal models to learn more about the pathophysiology of PSC and to test novel treatment modalities. In an ideal world, immunogenetically predisposed animals would develop fibrous-obliterative cholangitis of the intra- and extrahepatic bile ducts in association with inflammation of the gut (especially colitis) in a highly reproducible manner allowing to test new drugs. To date, however, no such animal model is available. We aimed to provide a systematic overview of current available rodent models for sclerosing cholangitis and biliary fibrosis and therefore critically analyzed the characteristics of models for chemically-induced cholangitis, knock-out mouse models with cholangitis, cholangitis induced by infectious agents, models of experimental biliary obstruction, models involving enteric bacterial cell-wall components or colitis, and models of primary biliary epithelial and endothelial cell injury.     

Chronic postcolectomy pericholangitis and cholangiocarcinoma

Two patients with long-standing pericholangitis developed unresectable cholangiocarcinoma after colectomy for chronic ulcerative colitis. The natural history of their illnesses suggest that chronic inflammation of small bile ducts in ulcerative colitis may be a precursor of biliary cancer and may also account for the increased incidence of this tumor in the colitis population.     

Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis

Tight junctions (TJ) of biliary epithelial cells (BEC) and hepatocytes prevent bile regurgitation from the biliary tract. Alterations in these TJs may participate in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We examined the localization of 2 TJ proteins, ZO-1 and 7H6, in these diseases. Frozen sections from livers of PBC, PSC, extrahepatic cholestasis (Ex-C), and hepatitis C-associated cirrhosis (LC-C), as well as histologically normal livers, were processed for double-fluorescence immunohistochemistry. In controls and cirrhosis, 7H6 and ZO-1 colocalized surrounding the luminal space of the bile ducts and outlined the bile canalicular spaces between hepatocytes. In untreated PBC, immunostaining for ZO-1 in BEC of bile ducts 40 to 80 microm in diameter was preserved, but that for 7H6 was diminished to absent. In PBC treated with ursodeoxycholic acid (UDCA), immunostaining for 7H6 was well preserved. In PSC as well as in Ex-C, immunostaining for both 7H6 and ZO-1 was well preserved in bile ducts. In hepatocytes, ZO-1 showed preserved immunoreactivity, but immunostaining for 7H6 frequently disappeared. The percentage of bile ducts with immunostaining for 7H6 in all bile ducts with immunostaining for ZO-1 was significantly reduced in PBC compared with that in control, LC-C, Ex-C, and PSC (all P <.0001). Substantial alteration in the TJ protein occurs predominantly in bile ducts in PBC and in hepatocytes in PSC, suggesting increased paracellular permeability along different paracellular routes for bile regurgitation in these chronic cholestatic liver diseases.     

Primary sclerosing cholangitis in children

Primary sclerosing cholangitis (PSC), a chronic inflammatory process affecting the extrahepatic and/or medium to large bile ducts, is not rare in children. It has features suggesting an autoimmune pathogenesis, although the mechanism of tissue damage remains unknown. The clinical presentation of childhood primary sclerosing cholangitis is highly variable and frequently without obvious features of cholestasis. Clinical similarity to autoimmune hepatitis is common. Association with chronic colitis is less common than in adults. Cholangiography is essential for the diagnosis and examination of the medium to large intrahepatic ducts is mandatory, as 40% of children lack extrahepatic duct involvement. Histological findings may help to distinguish childhood PSC from autoimmune hepatitis. In children, sclerosing cholangitis may also develop secondary to other disease processes, notably Langerhans histiocytosis, congenital immunodeficiencies and cystic fibrosis. Neonatal sclerosing cholangitis is chronic inflammatory disease of bile ducts which presents initially with neonatal cholestasis; its pathogenesis remains uncertain and may not be the same as for primary sclerosing cholangitis. Effective treatment modalities for childhood PSC remain undetermined. Liver transplantation is required for children who progress to biliary cirrhosis and hepatic decompensation.     

Leukocyte migration inhibition in response to biliary antigens in primary biliary cirrhosis, sclerosing cholangitis, and other chronic liver diseases.

The leukocyte migration inhibition test has been used to investigate cellular immune responses to antigens in a protein fraction (BPF) of normal human gallbladder bile in patients with a variety of intra- and extrahepatic diseases. Inhibition of leukocyte migration in the presence of BPF was observed in 30 (81%) of 37 patients with PBC, in 8 (80%) of 10 patients with sclerosing cholangitis, and in 7 (26%) of 27 patients with chronic active hepatitis. Only 1 of 31 patients with other liver diseases or with uncomplicated ulcerative colitis showed a similar response to BPF. The BPF was found to contain three antigens which were distinct from plasma proteins. Immunofluorescence studies revealed that one of these antigens appears to be derived from that part of the hepatocellular membrane which forms the bile canaliculus and that a second appears to be associated with the epithelial cell membranes of interlobular and septal bile ducts. The site of origin of the third antigen could not be established. It is suggested that cellular immune responses to biliary antigens could be involved in the progressive bile duct destruction of chronic biliary disease.     

Diagnosis and endoscopic management of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a complex, chronic, and progressive fibroinflammatory destructive cholestatic biliary disease. The exact etiology and pathogenesis are unknown and possibly related to an enhanced immune-mediated response and reaction in the biliary system. PSC is closely associated with inflammatory bowel disease and specifically, ulcerative colitis. It can be characterized by both intrahepatic and extrahepatic bile duct stricturing and dilation. Clinical manifestations include abnormal liver tests, jaundice, pruritus, and fatigue. At more advanced stages, PSC can progress to cirrhosis and posttransplant disease recurrence is not uncommon. PSC is associated with an increased risk of cholangiocarcinoma and is an independent risk factor for colorectal cancer in patients with concomitant inflammatory bowel disease. Cholangiography is the mainstay of PSC diagnosis. Improved noninvasive biliary imaging has shifted the role of endoscopic retrograde cholangiopancreatography from disease diagnosis to management of complications, including dominant biliary strictures, bile duct stones, and assisting in the differentiation of benign vs malignant strictures. The role of additional endoscopic modalities, including endoscopic ultrasound, direct cholangioscopy, and probe-based confocal laser endomicroscopy is evolving. At the present time, medical treatment options are limited and the role of endoscopy is mainly supportive.