New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease and one of the most important progressive cholangiopathies in adults. Damage to cholangiocytes triggers the development of intrahepatic cholestasis, which progresses to cirrhosis in the terminal stage of the disease. Accumulating data indicate that damage to biliary epithelial cells [(BECs), cholangiocytes] is most likely associated with the intracellular accumulation of bile acids, which have potent detergent properties and damaging effects on cell membranes. The mechanisms underlying uncontrolled bile acid intake into BECs in PBC are associated with pH change in the bile duct lumen, which is controlled by the bicarbonate (HCO₃^-) buffer system "biliary HCO₃^- umbrella". The impaired production and entry of HCO₃^- from BECs into the bile duct lumen is due to epigenetic changes in expression of the X-linked microRNA 506. Based on the growing body of knowledge on the molecular mechanisms of cholangiocyte damage in patients with PBC, we propose a hypothesis explaining the pathogenesis of the first morphologic (ductulopenia), immunologic (antimitochondrial autoantibodies) and clinical (weakness, malaise, rapid fatigue) signs of the disease in the asymptomatic stage. This review focuses on the consideration of these mechanisms.

Keywords: Antimitochondrial autoantibodies; Biliary bicarbonate umbrella; Chloride/bicarbonate anion exchanger 2; Dihydrolipoyl transacetylase (E2 subunit); Inositol-1,4,5-trisphosphate receptor type 3; MicroRNA 506; Primary biliary cholangitis; Pyruvate dehydrogenase complex.