University of Paris 7, Paris, France.
Clin Res Hepatol Gastroenterol. 2011 Feb;35(2):85-8. doi: 10.1016/j.clinre.2010.10.005.
The pathogenesis of chronic cholangiopathies, in particular primary biliary cirrhosis and primary sclerosing cholangitis, is still obscure. A stimulating hypothesis is proposed by Beuers et al. They reason that, since cholangiocytes are exposed to high concentrations of hydrophobic bile salts that are toxic at μM concentrations, these cells had to develop protective mechanisms. Apart from micelle formation, the authors argue that biliary HCO₃⁻ secretion serves to maintain an alkaline pH near the apical surface of cholangiocytes by forming a HCO₃⁻ "umbrella". In this alkaline environment, glycine conjugated bile salts (which are predominant in man), with a pKa of ~4, remain deprotonated and are unable to permeate the apical membrane and cause cell damage. Functional impairment of biliary HCO₃⁻ secretion leads to enhanced vulnerability of cholangiocytes toward the attack of hydrophobic bile salts, causing cell damage and cholangitis. Such an impairment could be due to genetic factors, like mutations of the anion exchanger 2 (a variant of the Cl⁻/HCO₃⁻ exchanger) in primary biliary cirrhosis or of TGR5 (a bile salt receptor implicated in the regulation of HCO₃⁻ secretion) in primary sclerosing cholangitis. This stimulating hypothesis is amenable to experimental testing and has potential pathophysiological and therapeutic implications.
慢性胆管疾病（尤其是原发性胆汁性肝硬化和原发性硬化性胆管炎）的发病机制仍不清楚。Beuers 等人提出了一个有启发性的假说。他们推断，由于胆管细胞暴露于高浓度的疏水性胆汁盐中，这些胆汁盐在微摩尔浓度下具有毒性，因此这些细胞必须发展出保护机制。除了形成胶束外，作者还认为胆汁碳酸氢盐分泌通过形成 HCO₃⁻“伞”来维持胆管细胞顶膜附近的碱性 pH 值。在这种碱性环境中，与 pKa 值约为 4 的甘氨酸共轭胆汁盐（在人类中占主导地位）保持去质子化状态，无法渗透顶膜并导致细胞损伤。胆汁碳酸氢盐分泌的功能障碍导致胆管细胞对疏水性胆汁盐的攻击更加脆弱，从而导致细胞损伤和胆管炎。这种功能障碍可能是由于遗传因素引起的，例如原发性胆汁性肝硬化中阴离子交换器 2（Cl⁻/HCO₃⁻交换器的一种变体）或原发性硬化性胆管炎中 TGR5（一种参与调节 HCO₃⁻分泌的胆汁盐受体）的突变。这个有启发性的假说可以进行实验测试，具有潜在的病理生理学和治疗意义。
