Novel and Emerging Therapies for Cholestatic Liver Diseases

Jordan Goldstein; Cynthia Levy


Liver International. 2018;38(9):1520-1535. 

In This Article

Abstract and Introduction


While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.


Cholestasis is defined as a condition where bile flow is decreased, either due to impaired secretion by hepatocytes or by obstruction to the bile flow. Primary cholestatic liver diseases affecting adults are mainly primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). PBC is a rare disease in which a chronic, immune-mediated injury to the small intrahepatic bile ducts leads to an imbalance between cholangiocyte proliferation and apoptosis, with resulting ductopaenia, fibrosis and eventually biliary cirrhosis.[1] The diagnosis is made by a combination of unexplained biochemical cholestasis and a positive antimitochondrial antibody (AMA) titre, which is found in greater than 90% of patients.[2] When AMAs are not detected, a PBC diagnosis can be confirmed by the presence of PBC-specific antinuclear antibodies or typical findings on histology. Only 2 drugs have received FDA approval for the treatment of PBC: ursodeoxycholic acid (UDCA), as the first-line therapy, and obeticholic acid (OCA), for UDCA non-responders or intolerance to UDCA. Approximately 40% of patients with PBC fail to respond to UDCA, and only half of those respond to OCA.[3] Non-responders to treatment with UDCA and/or OCA are at risk for progression to biliary cirrhosis, end-stage liver disease and death or liver transplantation.[4]

Primary sclerosing cholangitis affects predominantly medium- to large-sized bile ducts, with progressive inflammation and fibrosis leading to multifocal biliary strictures. Effective medical therapy is not available for PSC; therefore, the disease invariably progresses towards biliary cirrhosis at variable rates. Moreover, patients with PSC may develop dominant strictures and bacterial cholangitis in addition to having an increased risk for malignancies. Liver transplantation is the only definitive treatment and its rates have remained stable since the 1990s.[5] Identifying an effective medical therapy for PSC is one of the greatest unmet needs in hepatology. A comparison of the clinical features of PBC and PSC is highlighted in Table 1.