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

Abstract

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...

Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health

“…Membrane transporters work together with drug-metabolizing enzymes in elimination of xenobiotics. Induction of intestinal detoxification may, therefore, represent a so far underestimated function of bile acids in the small intestine [18]. In cholestasis, impaired expression of the PXR-, VDR-, and FXR-triggered intestinal detoxification machinery may lead to increased exposure of the large intestine to toxins and procarcinogens [18].…”

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

“…Bile acids act as enterohepatic hormones that signal through acids signal through the nuclear hormone receptor FXR and the membrane associated G-protein coupled receptor TGR5, which may both serve as additional therapeutic targets in PSC [73,103] . Importantly, bile acid-induced intestinal hormone such as fibroblast growth factor 19 (FGF19) and glucagone-like peptide 1 mediate part of their metabolic and homeostatic bile acid effects.…”

Primary Sclerosing Cholangitis

“…Major steps in our understanding of the pathogenesis of cholestasis and elucidation of the role of nuclear orphan receptors such as PXR, FXR, VDR, CAR or PPAR may have an important therapeutic consequences in future, however at this point the data is limited to experimental works on laboratory animals (Beuers et al 2009). …”