The Biliary HCO3 − Umbrella: A Unifying Hypothesis on Pathogenetic and Therapeutic Aspects of Fibrosing Cholangiopathies

Abstract

This review focuses on the hypothesis that biliary HCO 3− secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine‐conjugated bile acids. Functional impairment of this biliary HCO 3− umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y‐ and bile salt/TGR5‐mediated Cl−/ HCO 3− exchange and HCO 3− secretion, and alkaline phosphatase–mediated ATP breakdown may guarantee a stable biliary HCO 3− umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO 3− umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. (HEPATOLOGY 2010)

A Biliary HCO3 − Umbrella Constitutes A Protective Mechanism Against Bile Acid–Induced Injury in Human Cholangiocytes

“…We proposed that HCO À 3 -mediated alkalization of bile close to the apical membrane is a protective mechanism of human cholangiocytes against bile salt toxicity. 7 A candidate transporter for biliary apical HCO À 3 secretion in humans is AE2. 18,39 We knocked down AE2 expression in H69 cells and tested their sensitivity to bile salt toxicity in comparison to control-transduced cells.…”

“…7 Human biliary HCO À 3 secretion accounts for 25%-40% of total bile flow and, by far, exceeds that of rodents. 8 The physiologic role of the enormous difference in biliary HCO À 3 secretion between humans and rodents has remained obscure.…”

“…8 The physiologic role of the enormous difference in biliary HCO À 3 secretion between humans and rodents has remained obscure. We recently hypothesized 7 that biliary HCO À 3 secretion might constitute a biliary HCO À 3 umbrella on the apical cholangiocyte surface, a, so far, unrecognized protective mechanism of cholangiocytes against bile-salt-induced toxicity.…”

“…15,16 By altering sensitivity toward bile salt toxicity and increasing frequency of apoptotic events in cholangiocytes, genetic and acquired defects disrupting the biliary HCO À 3 umbrella may be a common pathogenetic factor in various cholangiopathies. Genetic variants of key modulators of the biliary HCO À 3 umbrella 7 have been associated with the manifestation or progression of chronic cholestasis, as demonstrated for anion exchanger 2 (AE2) in PBC, [17][18][19][20] TGR5 in primary sclerosing cholangitis (PSC), 21 or cystic fibrosis transmembrane conductance regulator (CFTR) 22,23 in cystic-fibrosis-associated liver disease.…”

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

“…Biliary secretion of bicarbonate by biliary epithelial cells is considered an important protective mechanism against the cytotoxic effects of hydrophobic bile salts, which is known as the "bicarbonate umbrella". 20,28 Early recovery of the biliary function after SCS is clinically relevant because hydrophobic bile salts have been shown to play a role in worsening biliary injury and subsequent formation of NAS after transplantation. 29,30 Taken together, these findings indicate that a short period of oxygenated MP after conventional SCS not only reduces the amount of biliary epithelial injury after reperfusion, but also contributes to an early recovery of biliary bicarbonate secretion, which helps cholangiocytes to protect themselves against the cytotoxic effects of hydrophobic bile salts.…”