Nor-ursodeoxycholic acid in hepatobiliary diseases: A narrative review

Nor-ursodeoxycholic acid (nor-UDCA) is a side-chain shortened analogue of ursodeoxycholic acid (UDCA). Because of its biochemical modification, it is resistant to amidation. Nor-UDCA undergoes cholehepatic shunt, leading to increased bicarbonate secretion. In addition, it has shown potential antifibrotic activity in the animal model of cholestasis and fibrosis. Nor-UDCA has several advantages over UDCA in its pharmacokinetic and pharmacodynamic properties. However, its safety and efficacy data on cholestatic diseases are largely extrapolated from pre-clinical animal studies. Vitamin E, resmetirom, peroxisome proliferator-activated receptor agonists, and incretin-based therapies dominate the pharmacotherapeutic armamentarium for metabolic dysfunction-associated steatotic liver disease or steatohepatitis. Recently, nor-UDCA has been evaluated in patients with metabolic dysfunction-associated steatotic liver disease with conflicting therapeutic benefits and a controversial trial endpoint. This comprehensive narrative review focuses on its novel mechanism of action, comparison with UDCA, and underscores the limited evidence of its safety and efficacy in various hepatobiliary diseases. This review also discusses future research prospects of nor-UDCA in hepato-biliary diseases, which addresses the research gap in existing literature.