The immunobiology of primary sclerosing cholangitis

An understanding of the immunobiology of primary sclerosing cholangitis (PSC) is essential to improving both diagnosis and treatment. There have been significant gains in the discovery of genetic polymorphisms that generate susceptibility to disease, but only limited data on etiologic events that may initiate the inflammatory response. Colonic inflammation produces memory T cells that have the ability to bind both biliary and colonic endothelial cells. One possible mechanism for the development of PSC is the homing of these memory T cells to the biliary tree. In addition, TNF(alpha) may contribute to the oxidative damage of the biliary system. Finally, although speculative, mononuclear cell responses against biliary epithelial cells may create a persistent inflammatory response, eventually leading to fibrosis.     

The immunology of primary sclerosing cholangitis

Conclusion A number of recent studies have been discussed which provide strong evidence that genetic and immunological factors are important in the pathogenesis of PSC. Current evidence suggests that PSC is, like primary biliary cirrhosis, an immunologically mediated disease [8]. It seems likely that the immunological destruction of the biliary system is triggered in genetically predisposed individuals by viruses or bacteria [8]. The association with ulcerative colitis may be explained by the passage of viral or bacterial organisms across the damaged colonic epithelial barrier into the systemic circulation. Further studies are needed to confirm this attractive hypothesis.     

Immunopathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology; however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease— especially ulcerative colitis—and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (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, therefore, evoking an abnormal immune response.     

Unusual variant of primary sclerosing cholangitis.

Two cases of primary sclerosing cholangitis are described, in which the characteristic bile duct lesions were unusual because there was an exuberant and exaggerated fibrous replacement of the ducts which produced dense fibrotic scars in portal tracts.     

Diagnosis and classification of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of the liver and that is characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts. It is progressive in most patients and leads to cirrhosis. It is a rare disease, mostly affecting people of northern European descent, males greater than females. The diagnosis is best established by contrast cholangiography, which reveals a characteristic picture of diffuse, multifocal strictures and focal dilation of the bile ducts, leading to a beaded appearance. Inflammatory bowel disease (IBD) is present in ~ 75% of the patients with PSC, mostly ulcerative colitis (~ 85% of the cases). In addition to biliary cirrhosis, complications of PSC include dominant strictures of the bile ducts, cholangitis, cholangiocarcinoma, colon dysplasia and cancer in patients with IBD, gallbladder polyps and cancer, and hepatic osteodystrophy. The etiology of PSC is not clear, but studies are ongoing. The median survival without liver transplantation is 12 to 15 years after diagnosis. Currently there are no effective treatments except liver transplantation. Immunosuppressive medications have not been shown to be effective but antibiotics and anti-fibrotic agents seem promising.     

Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas

Pancreatic involvement in primary sclerosing cholangitis (PSC) is an extremely rare condition, and its pathologic features are poorly documented. We report two cases of an unusual lymphoplasmacytic sclerosing inflammatory disease involving the total pancreas, common bile duct, gallbladder, and, in one patient, the lip. Two elderly men presented with waxing and waning obstructive jaundice, and exhibited radiologic and ultrasonographic findings highly suggestive of pancreatic carcinoma. Gross appearance of the pancreas showed firm and mass-like enlargement with regional lymph node swelling. Histologic findings were characterized by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Similar inflammatory processes involved the bile duct and the gallbladder. Lymphoplasmacytic sclerosing pancreatitis with cholangitis is thought to be a more appropriate term for this condition, of which a similar lesion has been previously noted in a single case of "PSC involving pancreas". Differences in age, radiologic appearance, and the negative history of ulcerative colitis exist, but the two cases in this study could be considered as a variant of PSC extensively involving pancreas, which can readily be mistaken for pancreatic carcinoma.     

Surgical treatment of primary biliary cirrhosis and primary sclerosing cholangitis

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are progressive cholestatic liver diseases of supposed auto-immune etiology. The clinical course is unpredictable and, in many patients, leads to end-stage liver disease or a poor quality of life. Conservative therapy only has a limited effect on the natural history, but orthotopic liver transplantation (OLT) offers a definitive therapeutic option. Retrospective analysis was performed for 38 patients with PBC and 17 patients with PSC who underwent OLT between January 1986 and June 2003 at our institution. Median follow-up after OLT was 72 mo. Cumulative survival at 5 yr post-OLT was 84% in the PBC group and 73% in the PSC group. Compared with OLT for other benign diseases, actuarial survival rates at 5 and 10 yr post-OLT were significantly better for patients with PBC, whereas there was no difference in survival after OLT for patients with PSC. Survival rate at 5 yr post-OLT was significantly increased for patients with PBC who had a Child-Pugh B liver cirrhosis (93%) compared with those who had Child-Pugh C cirrhosis (60%). Retransplantation rate was 18.2% (resulting from biliary complications in three cases). Surgical techniques had no effect on outcome after OLT in both groups. We concluded that liver transplantation represents a safe and beneficial therapy for patients with end-stage PBC. Cirrhotic patients with PSC also benefit from OLT, with an outcome comparable to that of liver cirrhosis of other etiologies.     

Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis

Chronic cholestasis is the main feature of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the most common chronic cholestatic liver diseases in adults. Although the etiology of both diseases remains poorly understood, auto-immune processes appear to be important, particularly in PBC. PBC and PSC usually slowly progress to cirrhosis, liver failure, and death, unless liver transplantation is performed. Ursodeoxycholic acid (UDCA), a hydrophilic dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC and is also used in patients with PSC. In addition to UDCA, patients with PSC should be referred to endoscopic dilatation of major bile duct stenoses. Several potential mechanisms of action of UDCA have been proposed, including intracellular modulation of signaling events and secretion. Various immunosuppressive drugs have been evaluated alone or in combination with UDCA—especially for the treatment of PBC. Of these drugs, the topical corticosteroid budesonide, together with UDCA, appears promising in the treatment of early stage PBC, but data remain insufficient to warrant use of budesonide outside of controlled studies.     

A case of longstanding primary sclerosing cholangitis.

A 45-year-old man is described in whom there is currently ERCP and histological evidence of primary sclerosing cholangitis (PSC). A liver biopsy obtained 29 years ago shows similar histological features confirming that he had PSC at that time. This case indicates that PSC may follow a relatively benign course.     

The spectrum of bile duct lesions in end-stage primary sclerosing cholangitis

Tissue from 15 livers with primary sclerosing cholangitis, obtained at transplantation, was examined histologically with respect to: small and medium sized bile duct lesions; large bile duct lesions; fibrosis/cirrhosis; and parenchymal changes. Lesions affecting small and medium-sized bile ducts were quantified by determining the percentage of 20 portal tracts involved. The two characteristic bile duct lesions of primary sclerosing cholangitis, periductal fibrosis and fibro-obliterative scars, were largely confined to medium-sized portal areas. Although present in each case, the number of such lesions varied considerably. Loss of bile ducts was the most conspicuous feature in small portal tracts, where the diagnostic duct lesions of primary sclerosing cholangitis were rarely observed. Inflammation, ulceration and cholangiectases of large intrahepatic ducts were common, and appear to be useful additional diagnostic features.     

Association of primary sclerosing cholangitis with HLA-DRw52a

We sought to determine whether there are specific HLA haplotypes in patients with either primary sclerosing cholangitis or primary biliary cirrhosis. Surprisingly, 100 percent of the 29 patients with primary sclerosing cholangitis had the HLA-DRw52a antigen, which is normally present in 35 percent of the population (relative risk, 109.5; P less than 0.00001). Fifteen of these patients had a single common haplotype: A1,B8,Cw7,DRw17,DQw2,DRw52a. In the remaining 17 patients there was a loss of at least one of these antigens. Of the 15 patients with the common haplotype, 12 also had ulcerative colitis, thereby linking the occurrence of ulcerative colitis in patients with primary sclerosing cholangitis to the presence of this haplotype. Although there was no association in 35 patients between primary biliary cirrhosis and specific HLA haplotypes, there was a significant association of the disease with DRw8 (relative risk, 3.1; P = 0.02). We conclude that the development of primary sclerosing cholangitis involves a strong genetic predisposition. Since the association of primary sclerosing cholangitis with HLA-DRw52a appears to be total, HLA typing should be helpful in differentiating this disease from primary biliary cirrhosis.     

Two distinct pathways of carcinogenesis in primary sclerosing cholangitis

Zen Y, Quaglia A, Heaton N, Rela M & Portmann B
(2011) Histopathology  59 , 1100–1110
Two distinct pathways of carcinogenesis in primary sclerosing cholangitis Aims: To identify clinicopathological characteristics of cholangiocarcinoma and premalignant lesions arising in patients with primary sclerosing cholangitis (PSC). Methods and results: This study consisted of 25 patients with PSC and bile duct neoplasia [16 with cholangiocarcinoma and nine with biliary intra‐epithelial neoplasia (BilIN) equivalent to biliary dysplasia]. Tumour cell morphology, growth patterns, history of inflammatory bowel disease and postoperative survival were recorded. Immunohistochemistry for CK7, CK20, MUC1, MUC2, MUC5AC, MUC6 and CDX2 was performed to characterize cell phenotypes. Cholangiocarcinoma and BilIN were classified into intestinal (n = 14) and non‐intestinal classical (n = 11) types. Intestinal‐type lesions showed histological features resembling intestinal dysplasia or adenocarcinoma. Intestinal‐type cholangiocarcinoma commonly showed intraductal papillary proliferation and mucinous nodule formation. Intestinal‐type lesions often had an intestinal immunophenotype that was not detected in classical‐type lesions: CK20, 50% versus 0% (P = 0.007); MUC2, 86% versus 0% (P < 0.001); CDX2, 54% versus 0% (P = 0.003). Less commonly, intestinal‐type cholangiocarcinoma showed perineural invasion (P = 0.003). Patients with intestinal‐type cholangiocarcinoma had a more favourable cancer‐specific prognosis than those with classical‐type cholangiocarcinoma (P = 0.043). Conclusions: Bile ducts in PSC show two distinct dysplasia–carcinoma sequences as evidenced by differences in cell morphology, growth patterns, immunophenotypes and grade of malignancy.     

Geoepidemiology of primary sclerosing cholangitis: A critical review

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin, characterized by progressive destruction of bile ducts caused by diffuse inflammation and fibrosis. Previous epidemiological studies in Northern Europe and North America demonstrated that incidence and prevalence rates are ranging from 0.5 to 1.3 and from 3.85 to 16.2 per 100,000 inhabitants per year, respectively. It is of note that the incidence of PSC appears to be gradually increasing. We have extensively reviewed the geoepidemiology of PSC and attempted to place it in context with the incidence in Japan. In 2012, the clinical diagnostic criteria of IgG4-SC were established and published by the Japan Biliary Association, rendering it possible for physicians to clinically differentiate PSC from IgG4-SC. We conducted a new nationwide survey for PSC as well as IgG4-SC, and have identified 197 patients with PSC and 43 patients with IgG4-SC without pancreatic involvement. In this survey we estimated prevalence rate of PSC in Japan as 0.95, lower than those in North America and European countries. Also we identified other unique features of Japanese PSC patients, including 2 peaks in age distribution at diagnosis and fewer presences of comorbid inflammatory bowel diseases, occurring in only 34% of PSC. This data is placed in the perspective of the international experience on PSC.     

No liver 99Tc-tin-colloid uptake in primary sclerosing cholangitis

A 99Tc-tin-colloid scintigraphy showed no uptake of the radiopharmaceutical in the liver of a patient with jaundice. The diagnosis was later established as primary sclerosing cholangitis.