Role of Bile Acids and the Biliary HCO3 − Umbrella in the Pathogenesis of Primary Biliary Cholangitis

The biliary HCO3 − umbrella hypothesis states that human cholangiocytes and hepatocytes create a protective apical alkaline barrier against millimolar concentrations of potentially toxic glycine-conjugated bile salts in bile by secreting HCO3 − into the bile duct lumen. This alkaline barrier may retain biliary bile salts in their polar, deprotonated, and membrane-impermeant state to avoid uncontrolled invasion of apolar toxic bile acids, which initiate apoptosis, autophagy and senescence. In primary biliary cholangitis, defects of the biliary HCO3 − umbrella, leading to impaired biliary HCO3 − secretion have been identified. Current medical therapies stabilize the putatively defective biliary HCO3 − umbrella and improve long-term prognosis.