Advances in pharmacotherapy for primary biliary cirrhosis

Abstract

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.

Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.

Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.

Trial registration: ClinicalTrials.gov NCT00746486 NCT01389973 NCT01430429 NCT01473524.

Keywords: biologics; farnesoid X receptor agonists; primary biliary cirrhosis; ursodeoxycholic acid.

Figure 1. Bile acid based new therapeutics for PBC

(1) FXR-agonists exert their effect both on enterocytes and hepatocytes, inhibiting de novo synthesis of bile acids and promoting their excretion. (2) Recombinant FGF-19 interacts with the FGFR-4 receptor expressed on hepatocytes to inhibit bile acid synthesis. (3) ASBT blocker interferes with the reabsorption of bile acids from the intestinal lumen. Dashed green line: not all bile acids can activate the FXR receptor (see text). ASBT: Apical Sodium-dependent Bile acid Transporter. Ostα/β: Organic Solute Transporter α and β. NTCP: Na+ - Taurocholate Cotransporting Polypeptide. BSEP: Bile Salt Export Pump. FXR: Farnesoid X Receptor. FGF-19: Fibroblast Growth Factor-19. FGFR-4: Fibroblast Growth Factor Receptor-4.