Bile acid therapy for primary biliary cholangitis: Pathogenetic validation

Abstract

Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its treatment. Because the cause of primary biliary cholangitis (PBC), a chronic, slowly progressive cholestatic liver disease, is still unknown, treatment remains symptomatic. Knowledge of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the disease. Advances in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this disease. For 35 years, ursodeoxycholic acid (UDCA) has been the unique drug of choice for the treatment of patients with PBC. In recent years, the list of hydrophilic bile acids used to treat cholestatic liver diseases, including PBC, has expanded. In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC.

Keywords: Primary biliary cholangitis; Treatment of primary biliary cholangitis with bile acids; Ursodeoxycholic acid; Obeticholic acid; Tauroursodeoxycholic acid; Norursodeoxycholic acid

Core Tip: The review is devoted to the issues of treatment of primary biliary cholangitis (PBC) with bile acid preparations. The mechanisms of beneficial action of ursodeoxycholic acid and its derivatives (tauroursodeoxycholic acid, obeticholic acid, norursodeoxycholic acid) are considered taking into account the pathogenetic mechanisms of PBC development known so far. The assumptions about the development of new therapeutic approaches in the treatment of PBC taking into account the discovery of the disruption of the mechanisms of bicarbonate formation by cholangiocytes in PBC were outlined. This may serve as a basis for the development of new targeting drugs aimed at local reduction of microRNA 506 activity or activation of anion exchanger 2 in cholangiocytes.