The Medical Management of Primary Sclerosing Cholangitis

Cullen, Susan N.; Chapman, Roger W.

doi:10.1055/s-2006-933563

Cited by 57 publications

(45 citation statements)

References 91 publications

(93 reference statements)

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“…This evidence includes (1) association with other autoimmune diseases in the same individual [11] and first degree relatives [12] , (2) infiltration of T-lymphocytes in the portal tracts [13] with restriction in T cell receptor V gene usage [14] , (3) a statistical association with particular human leukocyte antigen (HLA) haplotypes [15] and (4) the presence of autoantibodies [16] . On the other side, there is no documented effect of immunosuppressants in PSC [2] , and in contrast to the female predominance of many diseases regarded as autoimmune, approximately 2/3 of PSC patients are male [17] . These notions suggest that additional pathogenetic factors may exist (e.g.…”

Section: Introductionmentioning

confidence: 98%

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Autoantibodies in primary sclerosing cholangitis

Hov¹,

Boberg²,

Karlsen³

2008

WJG

150

100

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The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients, but the specificity of these antibodies is generally low, and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecific dysregulation of the immune system, but the literature in PSC points to the possible presence of specific antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC, with a particular emphasis on the prevalence, clinical relevance and possible pathogenetic importance of each individual marker.

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Section: Introductionmentioning

confidence: 98%

“…No effective medical treatment is currently available [2] and PSC is a major indication for liver transplantation [3] . The PSC population is heterogeneous, comprising subgroups of regular "large-duct" PSC, patients with "small-duct" affection only [4] and an "overlap-syndrome" between PSC and autoimmune hepatitis (AIH) [5] .…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies in primary sclerosing cholangitis

Hov¹,

Boberg²,

Karlsen³

2008

WJG

150

100

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“…The corticosteroid dexamethasone is a potent PXR and glucocorticoid receptor (GR) agonist, but is no treatment option for patients with PSC: the high rate of systemic side effects including induction of osteoporosis during long-term treatment prohibits use of dexamethasone in PSC. In addition, GR agonists have not been shown to be effective in most patients with PSC 1,23 . Still, the effect of GR agonists may need to be better defined for subgroups particularly at young age and early stages of disease 77 .…”

Section: Pxr Agonistsmentioning

confidence: 99%

Medical Treatment of Primary Sclerosing Cholangitis: A Role for Novel Bile Acids and other (post-)Transcriptional Modulators?

Beuers

Kullak‐Ublick

Pusl³

et al. 2008

Clinic Rev Allerg Immunol

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Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC. Beuers et al.: Future treatment of PSC Clinical Reviews in Allergy and Immunology 2008In press Medical treatment of primary sclerosing cholangitis: AbstractPrimary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical, and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregna...

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“…Overall, PSC carries a poor prognosis (medium survival free of liver transplantation of 12 years; 10-year survival approx. 65%) [5,6,7,8,9,10,15,16] and - according to Michael Manns (Hannover Medical School) - represents one of the last remaining black boxes of hepatology [M. Manns, Vienna, January 31 2011, pers. commun.]…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies

Trauner¹,

Halilbasic²,

Kazemi-Shirazi³

et al. 2014

Dig Dis

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Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C₂₃ homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3-4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC.

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The Medical Management of Primary Sclerosing Cholangitis

Cited by 57 publications

References 91 publications

Autoantibodies in primary sclerosing cholangitis

Autoantibodies in primary sclerosing cholangitis

Medical Treatment of Primary Sclerosing Cholangitis: A Role for Novel Bile Acids and other (post-)Transcriptional Modulators?

Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies

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