Primary biliary cirrhosis and bile acids

The dihydroxylated bile acid ursodeoxycholic acid (UDCA) has now been regarded for 20 years as the standard treatment for primary biliary cirrhosis (PBC), a chronic cholestatic immune-mediated condition marked by progressive destruction of small intrahepatic bile ducts, impaired biliary secretion, hepatocellular retention of toxic endogenous bile acids and, ultimately, the development of fibrosis leading to cirrhosis that commonly requires liver transplantation. At first sight, it seems intriguing that a bile acid could be considered for use as a therapeutic agent in a bile-acid secretion disorder. Yet, in addition to its inherently greater hydrophilic nature and competitive effect on endogenous bile-acid recycling, UDCA has indeed been demonstrated to be a potent post-transcriptional secretagogue as well as a potential anti-inflammatory and anti-apoptotic agent. While the combined glucocorticoid receptor/pregnane X receptor (PXR) agonist budesonide, in combinaison with UDCA, has been shown to exert additional beneficial effects in PBC, significant progress in understanding the regulatory mechanisms involved in bile-acid homeostasis has led to the identification of nuclear [farnesoid X receptor (FXR), PXR, peroxisome proliferator-activated receptor alpha (PPAR alpha)] and membrane (the membrane G protein-coupled bile acid receptor TGR5) receptors as critical pharmacological targets for future therapeutic approaches. Encouraging data from recent experimental and phase-II studies tend to confirm that the FXR agonist obeticholic acid and the PPARa agonists bezafibrate and fenofibrate may be used as add-on therapies in PBC patients with inadequate responses to UDCA or even as alternative first-line agents. These results could mark the beginning of a new therapeutic era for PBC. (C) 2012 Elsevier Masson SAS. All rights reserved.