HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations

The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).     

Different HLA class II associations in ulcerative colitis patients with and without primary sclerosing cholangitis

Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have inflammatory bowel disease (IBD), the majority ulcerative colitis (UC). An inherent problem in interpreting positive findings in genetic association studies of PSC is thus to distinguish between factors associated with hepatobiliary versus intestinal pathology. We aimed to clarify to what extent human leukocyte antigen (HLA) class II associations in UC patients with and without PSC differ. High-resolution DRB1 and DQB1 typing was performed in 365 Scandinavian PSC patients, an independent cohort of 330 Norwegian UC patients and 368 healthy controls. HLA associations found in PSC were mostly distinct from those seen in UC, and no significant differences were noted between PSC patients with concurrent UC and PSC patients without IBD. This suggests different HLA associated genetic susceptibility to PSC and UC, and supports notions that UC in PSC may represent a distinct UC phenotype.     

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.     

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.     

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 immunobiology of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease histologically characterized by the presence of intrahepatic and/or extrahepatic biliary duct concentric, obliterative fibrosis, eventually leading to cirrhosis. Approximately 75% of patients with PSC have inflammatory bowel disease. The male predominance of PSC, the lack of a defined, pathogenic autoantigen, and the potential role of the innate immune system suggest that it may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC is associated with several classic autoimmune diseases, and the strongest genetic link to PSC identified to date is with the human leukocyte antigen DRB01*03 haplotype. The precise immunopathogenesis of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Currently, there is no effective therapy for PSC and developing a rational therapeutic strategy demands a better understanding of the disease.     

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.     

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.     

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.     

Endoscopic treatment of dominant stenoses in patients with primary sclerosing cholangitis

Primary sclerosing cholangitis is characterized by progressive fibrosing inflammation of the bile ducts, leading to their obliteration, which results in cholestasis and, finally, cirrhosis of the liver. Over time, the majority of patients with advanced disease develop dominant stenoses of major bile ducts. Ursodeoxycholic acid (UDCA) treatment does not prevent the development of such stenoses. Endoscopic measures allow the opening of short- and long-segment stenoses of the common bile duct and also of short segment stenoses of the hepatic ducts. Inpatients treated by early endoscopic dilatation of dominant stenoses, as well as with UDCA,survival may be significantly improved (compared with the predicted survival).     

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.     

Sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis.

AIMS--To study sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis (PSC). METHODS--One hundred and twelve biopsy specimens (that is, 56 pairs) from 44 patients with PSC, confirmed by cholangiography, were evaluated blindly. Six different features, qualitative grading of four other features and staging according to Ludwig were assessed. RESULTS--Quantitative sampling variability was confined mainly to just one grade or stage, although 11% (six of 56) of the biopsy specimen pairs differed by more than one stage (7% (one of 15) in pairs > 2 cm in length). Qualitative sampling variabilities were between 18 and 71%. Advanced disease (stages 3 or 4) was missed in 40% (two of five) of the biopsy specimens while cirrhosis was missed in 37%. CONCLUSION--Paired liver biopsy specimens should be taken in clinical studies of PSC using liver histology for evaluation or prognosis.     

Tissue distribution of autoantigen specific for primary sclerosing cholangitis.

AIM: To investigate the tissue distribution of the autoantigen specific for primary sclerosing cholangitis. METHODS: A range of normal frozen tissues including nervous system, muscle, uterus, ovary, prostate, pancreas, thyroid, salivary gland, adrenal gland, colon, gall bladder, stomach, jejunum, aorta, skin, kidney, liver, spleen and thymus was sectioned, fixed with acetone, and air-dried. Normal bone marrow and HL60, K562, and U937 cells were cytocentrifuged on to slides, air-dried, and alcohol fixed. Four sera from primary sclerosing cholangitis with high titre antibody (> 1/100) were used to screen the tissues using either two-step or APAAP immunohistochemistry. Normal sera were used as controls. RESULTS: Positive signal was detected in neutrophils in spleen with three out of four primary sclerosing cholangitis sera while one out of four primary sclerosing cholangitis sera stained spindle cells in the liver. All four sera stained mature neutrophils of the normal bone marrow. Some bone marrow neutrophil precursors (metamyelocytes and myelocytes) were also positive. All other tissues, including HL60, K562, and U937 cells, were negative. Normal sera were negative on all tissues. CONCLUSION: Antigen specific for primary sclerosing cholangitis seems to be unique to neutrophil polymorphs and is present only after myeloblast differentiation of the myeloid cell line. The antigen may be within the secondary granule of the neutrophil polymorph.     

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.     

HLA class II analysis in Jewish Israeli narcoleptic patients

HLA class II was investigated in eight Jewish narcoleptic patients, representing the total of such patients known in Israel at present, and in three patients suffering from sleep disturbances other than narcolepsy. All (11 out of 11) patients carried the serologic specificities DR2, DQ6 (DQ1). At the DNA level, all narcoleptics were found to be DRB 1^*1501, DQA1^*0102, DQB 1^*0602 which indicates that the susceptibility gene may be located within the HLA class II region, DR, and/or DQ. As for the nonnarcoleptic patients with idiopathic hypersomnia, they carried different alleles of DR2 and DQ6, namely DRB 1^*1502, DQA1^*0103, DQB1^*0601. This study confirms that the incidence of narcolepsy in Israel is extremely low and that HLA class II genes or a gene(s) tightly linked to them are involved in the disease.     

Serologic and molecular analysis of the HLA system in Israeli Jewish patients with oral erosive lichen planus

Abstract: Oral erosive lichen planus is a distinct subtype of the common dermatosis lichen planus. Although the etiology of lichen planus is still obscure, it is known that cell-mediated immune mechanisms and genetic factors underlie its pathogenesis. Previous studies have found an association between lichen planus and HLA-DR3 or DR9 in different population groups. The present work was designed to elucidate, at the serologic and molecular levels, whether and which HLA genes are associated with oral erosive lichen planus in Israeli Jewish patients. A significant association with HLA-DR2 (RR = 4.7; p_c < 0.0013) and a decrease in DR4 (RR = 0.3; p < 0.03) among the patients were noted. Oligotyping of DR2 alleles showed the presence of all three common variants (DRB1*1501, DRB1*1502 and DRB1*1601) in the patients, although none of the variants was overrepresented significantly. Three possible explanations for the role of HLA genes in the predisposition to oral erosive lichen planus are discussed. The most attractive theory for the pathogenesis of the disease seems to include the involvement of non-classical HLA genes.     

Expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis.

The aim of this study was to identify the pattern and significance of expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. Histological sections from 18 patients with cholangiocarcinoma (3 of the cases were associated with primary sclerosing cholangitis), 10 patients with primary sclerosing cholangitis without cholangiocarcinoma, and 7 patients with cirrhosis without cholangiocarcinoma or primary sclerosing cholangitis were stained immunohistochemically for p53 and PCNA. Samples from 17 patients with cholangiocarcinoma (94%) stained positively for p53. Among these 17 cases, nontumorous bile duct epithelium was positive in 7 (including 3 cases with primary sclerosing cholangitis and 2 with carcinoma in situ), and were positive proliferating bile ductules in 4 cases. The single p53-negative cholangiocarcinoma did not show p53 positivity in either the bile duct epithelium or the proliferating bile ductules. Bile ductal and ductular cells in all 10 patients with primary sclerosing cholangitis without cholangiocarcinoma and in the 7 controls were not reactive for p53. All 18 samples from patients with cholangiocarcinoma (100%) were positive for PCNA protein. Bile duct epithelium was positive for PCNA in nine cases (90%) of primary sclerosing cholangitis without cholangiocarcinoma and in six (85%) controls. Our study showed a high rate of p53 expression (94%) in cholangiocarcinoma. The adjacent uninvolved bile duct epithelium was also immunoreactive for p53 in 7 of 17 patients (41%). These findings suggest an early p53 mutation in bile ductal cells in cholangiocarcinogenesis. Expression of p53 may potentially be used to identify or screen, by bile duct brushings, cases of primary sclerosing cholangitis suspected of harboring cholangiocarcinoma. Expression of PCNA was a universal feature in cholangiocarcinoma.