New therapies target the toxic consequences of cholestatic liver disease.

In most cholestatic liver diseases the primary cholestasis-causing lesions are located in the biliary tree and may be of (auto)immune origin. Bile salts are responsible for the secondary toxic consequences. Bile salt and nuclear hormone directed therapies primarily aim at improving this secondary toxic injury. In primary biliary cholangitis, trials show statistically significant responses on biochemical endpoints. Preclinical studies suggest that FXR- and PPAR-agonists, inhibitors of the apical sodium-dependent bile salt transporter (ASBT-inhibitors) and the C23 UDCA derivative nor-UDCA are promising agents for the treatment of primary sclerosing cholangitis (PSC). Area covered: Pharmaceuticals that interfere with bile salt signaling in humans for the treatment of chronic cholestatic liver disease are reviewed. Expert commentary: Nuclear hormone receptors, bile salt transport proteins and receptors provide targets for novel therapies of cholestatic liver disease. These drugs show positive results on biochemical endpoints. For histological endpoints, survival and transplant-free survival, long-term trials are needed. For relief of symptoms, such as fatigue and pruritus, these drugs have yet to prove their value.