Medical Treatment of Primary Sclerosing Cholangitis

August 31, 2008

Clin Rev Allergy Immunol. 2008 Aug 28. [Epub ahead of print]

Medical Treatment of Primary Sclerosing Cholangitis: A Role for Novel

Bile Acids and other (post-)Transcriptional Modulators?

Beuers U, Kullak-Ublick GA, Pusl T, Rauws ER, Rust C

Department of Gastroenterology and Hepatology, G4-213, Academic

Medical Center, University of Amsterdam, P. O. Box 22700, 1100, DE,

Amsterdam, The Netherlands, u.h.beuers@....

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. PMID: 18751930

_________________________

Dave

(father of (23); PSC 07/03; UC 08/03)

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