LAUSR

Primary biliary cholangitis (PBC) is an immunemediated cholestatic liver disease characterized by destruction of the small intrahepatic bile ducts; if left untreated, persistent inflammation and cholestasis lead to biliary cirrhosis and end-stage liver disease. Although treatment with ursodeoxycholic acid (UDCA) definitely alters the course of PBC and improves transplant-free survival, a considerable subset of patients continues to progress toward liver failure despite treatment. More recently, a better understanding of the role of bile acids (BAs) as enterohepatic hormones has led to development of new therapeutic options for patients with PBC. Through activation of nuclear receptors and G-protein-coupled receptor-1 (TGR5), BAs regulate a number of physiological functions, including nutrient absorption, glucose and BA homeostasis, lipid metabolism, and inflammation pathways. Whereas BAs are the most efficacious ligands for farnesoid X receptor (FXR), BAs can also directly activate two other nuclear receptors, pregnane X receptor (PXR) and the vitamin D receptor, and impact several metabolic processes through a complex network of cell-signaling pathways. FXR activation modulates BA homeostasis through a variety of mechanisms (Fig. 1), with a net effect of decreased synthesis of BAs, increased sinusoidal secretion, decreased hepatic uptake, and increased biliary secretion of BAs. The downregulation of inflammatory pathways and inhibition of atherosclerosis result predominantly from activation of TGR5 in brown adipocytes, hepatic Kupffer cells, gallbladder epithelium, and intestine. FXR agonists are currently under investigation for several liver diseases, including PBC, primary sclerosing cholangitis, nonalcoholic fatty liver disease, alcoholic hepatitis, and portal hypertension. Obeticholic acid (OCA) is a synthetic BA with very strong FXR agonist activity. Following completion of a large international phase 3 study (The PBC OCA International Study of Efficacy; POISE), the U.S. Food and Drug Administration (FDA) granted conditional approval for OCA as second-line therapy in PBC, indicated in combination to UDCA for patients who had inadequate response after at least 1 year of treatment with UDCA or as monotherapy for those who were intolerant to UDCA. In the POISE trial, only 7% of enrolled patients were not taking UDCA and questions remain about the use of OCA as monotherapy. In this issue of HEPATOLOGY, Kowdley et al. report results of a randomized, double-blind, placebo-controlled trial investigating the use of OCA as monotherapy for PBC. The study aimed to enroll 40 patients in each of the three arms (placebo, OCA 10 mg/day, and OCA 50 mg/day), but enrollment was slow and the final sample size was of approximately 20 patients each. This was not surprising given the rarity of PBC and the widespread use of UDCA. Despite the reduced power, significant changes were noted in serum alkaline phosphatase (ALP), with a 53.9% Abbreviations: ALP, alkaline phosphatase; BAs, bile acids; FDA, U.S. Food and Drug Administration; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; HDLs, high-density lipoproteins; LDLs, low-density lipoproteins; OCA, obeticholic acid; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor; TGR5, G-protein-coupled receptor-1; UDCA, ursodeoxycholic acid.