Novel Aspects in the Management of Cholestatic Liver Diseases

2016 Digestive Diseases 34;4 (340-346)

BACKGROUND: There is a great need for risk stratification in patients with chronic cholestatic diseases in order to allow for more personalized care and adapted management as well as for well-designed therapeutic trials. Novel tools for monitoring primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) patients have been recently proposed. In addition, major insight has been gained into bile acid (BA) physiology during the last decade including the role of BAs as metabolic modulators and the gut-liver axis. As a consequence, alongside drugs targeting immune response or fibrotic processes, a number of novel anti-cholestatic agents have undergone pre-clinical and clinical evaluation and have shown promising results although none has been approved yet. KEY MESSAGES: Biochemical non-response to ursodeoxycholic acid (UDCA) (mainly defined by bilirubin and alkaline phosphatase levels at 1 year) is a strong prognostic factor in PBC whereas present biochemical surrogates are far from robust in PSC. By contrast, liver stiffness measurement by vibration-controlled transient elastography (VCTE) is a very promising tool in both PBC and PSC. Novel therapeutic approaches include (i) agonists of nuclear receptors, especially farnesoid X receptor (FXR), pregnane X receptor (PXR), glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor alpha (PPARalpha) that are transcriptional modifiers of bile formation; (ii) agonists of TGR5, a BA membrane receptor expressed in various tissues; (iii) inhibitors of the ileal apical sodium BA transporter; (iv) derivatives of the FXR-induced fibroblast growth factor 19 from the ileum that suppresses hepatic BA synthesis and (v) norUDCA, a side chain shortened UDCA derivative with specific physicochemical and therapeutic properties. The most advanced clinical evaluation (PBC patients) relates to agonists for PPARalpha, FXR and GR/PXR most often in combination with UDCA, namely fibrates, obeticholic acid (OCA) and budesonide, respectively. Existing results look promising even though some side effects are worrisome such as pruritus in OCA-treated patients. Results of large well-designed studies are eagerly awaited. CONCLUSIONS: Major advances in the management of cholestatic liver diseases are in progress and promising times for these patients seem likely in the near future.

Pubmed : 27170387