Primary sclerosing cholangitis

Conclusion In this article, evidence has been presented that immune mechanisms play a major role in the pathogenesis of PSC. Although considerable progress has been made in our understanding of the pathogenesis and treatment of this disease, many questions remain unanswered. The factors that trigger the disease in a susceptible host are unknown and it is unclear whether an exogenous agent such as retroviral infection is involved or if there is an intrinsic abnormality in the immune system. It is unknown if the pathogenetic mechanisms are the same for patients with PSC alone or patients with PSC and IBD or whether these represent separate clinical entities. Moreover it is unclear if immunosuppressants as high-dose single agents or in combination may halt or slow disease progression. To answer some of these questions, the disease must be identified in patients early in its pathogenesis, perhaps even before the characteristic cholangiographic changes have occurred. Although new noninvasive techniques, such as magnetic resonance cholangiography, may allow screening of patients with UC, early diagnosis is likely to remain difficult. Animal models provide a way of exploring the relationship of PSC and IBD and the early events in pathogenesis. Previous animal models (144, 145) have provided limited insight into PSC because the hepatobiliary damage was more representative of acute rather than the chronic insidious damage of PSC. However studies of colitis in the “knockout” mouse offer the opportunity to explore the relationship between host genetic susceptibility, colitis, and hepatobiliary damage.     

Primary biliary cirrhosis and sclerosing cholangitis

Primary biliary disorders are often overlooked during routine assessment of liver biopsy specimens. Histological changes of large duct obstruction are now rarely observed as acute obstructive cholangiopathies are generally spotted on radiological imaging. Histopathologists are more likely to be confronted with chronic biliary disorders, in particular primary biliary cirrhosis (PBC) and ‘primary’ sclerosing cholangitis (PSC), where small and/or large segments of the bile ducts are injured and progressively destroyed. In this situation, the changes at the liver periphery may be misleading. Cholestasis is essentially absent in the early stages; the characteristic bile-duct lesions may not be sampled by biopsy needles, due to their uneven distribution and/or deep location within the liver; and portal and periportal biliary features may overlap with those of chronic hepatitis. The recognition of early biliary interface activity with subtle ductular reaction, cholate-stasis and copper-associated, orcein-positive granules, is critical to diagnose a cholangiopathy. This might confirm the clinical impression or provide valuable information to select additional investigations, such as autoantibody testing or performance of an ERCP. This article reviews the characteristic clinical, laboratory and radiological features, together with the morphological changes, which assist biopsy interpretation in both PBC and PSC. The main liver conditions in which bile ducts are prime targets of the injury, in particular those associated with a progressive loss of the intrahepatic bile ducts or ductopenia, are considered as they enter the differential diagnosis. The article ends with a brief note on idiopathic adulthood ductopenia, which remains a diagnosis of exclusion.     

Primary intrahepatic sclerosing cholangitis with inflammatory bowel disease

A case of primary intrahepatic sclerosing cholangitis associated with inflammatory bowel disease, which is rare in Japan, is reported. A 16-year-old Japanese boy was admitted to our hospital because of abdominal pain and fever. He was diagnosed as having primary intrahepatic sclerosing cholangitis by endoscopic retrograde cholangiography and liver biopsy. Inflammatory bowel disease was diagnosed by colonoscopy and biopsy of the colonic mucosa. Human lymphocyte antigen typing showed HLA-A2, A-9, -B52 and -DR2.     

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.     

Primary sclerosing cholangitis is associated with extended HLA-DR3 and HLA-DR6 haplotypes

Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.     

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.     

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

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.     

Reversible sclerosing cholangitis with ulcerative colitis

Sclerosing cholangitis (SC) with granulocytic epithelial lesion (GEL) responds well to immunosuppression therapy. We treated a 42‐year‐old Japanese female with ulcerative colitis, who was admitted for further evaluation of both an elevated alkaline phosphatase level and dilated intrahepatic bile ducts. A liver biopsy on the fourth hospital day revealed the infiltration of neutrophils into the bile duct epithelium, which was diagnosed as GEL. Because her ulcerative colitis was in an active stage, prednisolone (PSL) therapy was started. After the administration of PSL, laboratory data dramatically decreased. A liver biopsy was performed on the 66th hospital day to confirm the lesion around bile ducts in the portal tract. The infiltration of neutrophils into the bile duct epithelium disappeared after PSL administration, and IgG4‐positive plasma cells were not found in the liver. Herein, we report a rare case of GEL‐positive SC. The present case provides early evidence of treatment‐induced histological changes as well as serial changes in biochemical data during the course of immunosuppression therapy.     

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.     

Primary sclerosing cholangitis. Light and electron microscopy of hepatic tissue in two cases

In an 18 year-old woman presenting with an intra- and extrahepatic form of sclerosing cholangitis needle biopsy of the liver revealed, in addition to a conspicuous proliferation of biliary ductules and mild inflammatory infiltrations of the portal tract, piece-meal necroses and focal intralobular inflammatory changes. In the second case - a 49-year-old man - presenting with an extrahepatic location of stenoses there were infrequent proliferating biliary ductules in the enlarged fibrotic portal tracts. Ultrastructural investigations revealed in both patients adverse regressive changes in the epithelium of proliferating biliary ductules, seen as microvillous damage on the luminal surface, dilation of the endoplasmic reticulum and mitochondrial swelling; in the second patient there was, moreover, electrondense material in epithelial cytoplasm, probably corresponding to bile components. In the first patient predominated among ultrastructural changes increase of cytoskeletal filaments in some epithelia and pronounced reduplication of the basement membranes of small biliary ducts. These "cholestatic" modifications, expressed in different form in the two patients, were accompanied by dilatation and damage, sometimes total disappearance of microvilli of biliary canaliculi.     

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.     

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.