PATHOGENESIS OF CALCIUM-CONTAINING GALLSTONES

这项资助的目的是确定 含钙的胆结石，以制定一个合理的， 预防和医疗。 由于钙盐是一种主要的 所有色素结石的成分，钙沉淀与各种 阴离子（碳酸盐，碳酸盐，磷酸盐，“棕榈酸盐”）是一个明确的 胆色素结石的发生和发展的必要事件。 在 此外，由于所有的胆固醇结石已被发现有色素 石中心，我们假设，作为第一个主要假设，钙 沉淀是引发胆固醇的关键事件 胆结石，因此后者应被视为一个2部分的问题：（1） 钙盐沉淀形成病灶，和（2） 胆固醇在这个病灶上的过饱和状态 根据该 钙在色素形成中起着至关重要的作用， 胆固醇结石，延缓或抑制胆固醇结石 通过鹅去氧胆酸或熊去氧胆酸溶解。 进一步阐明 因此，胆结石形成需要定义和量化 胆汁中的游离Ca++，与 “钙敏感”阴离子。 第二个主要假设是胆汁酸 阴离子是胆汁中Ca ~（++）的主要缓冲剂，游离[Ca ~（++）] 主要由钙与胆盐的络合作用决定。 第三个主要 假设是pH值在决定哪些 钙敏感阴离子将沉淀。 第四个假设是 胆汁钙主要来源于肝脏， 小管，并且其分泌与胆汁酸的分泌偶联。 的 第五，也是最重要的假设是胆结石可能是 可通过防止胆汁中的钙沉淀来预防。 任何措施 这将减少胆汁中的游离[Ca++]， 分泌，或通过增加Ca++络合，将减少钙 成石性 拟议的实验将测试这些和其他具体的 假设，并将提供第一个系统的研究：（1）免费 [Ca（2）Ca ~（++）-胆盐相互作用; (3)胆汁和胆汁盐溶液中的CO2系统;以及（4）钙 胆汁中碳酸盐和胆红素钙的溶解度。 结果 应该导致新的方法来医疗管理和预防 胆结石病

The purpose of this grant is to define the pathogenesis of calcium-containing gallstones in order to develop a rationale for their prevention and medical treatment. Since calcium salts are a major constituent of all pigment stones, precipitation of calcium with various anions (bilirubinate, carbonate, phosphate, 'palmitate') is a clear requisite event in the initiation and growth of pigment gallstones. In addition, since all cholesterol stones have been found to have pigment stone centers, we postulate, as a first major hypothesis, that calcium precipitation is a critical event in the initiation of cholesterol gallstones, so that the latter should be considered a 2-part problem: (1) Precipitation of calcium salts to form a nidus, and (2) precipitation of cholesterol from its supersaturated state on this nidus. According to this view, calcium plays a crucial role in the fomation of both pigment and cholesterol gallstones, and retards or inhibits cholesterol stone dissolution by cheno- or ursodeoxycholic acids. Further elucidation of gallstone formation therefore requires definition and quantification of free Ca++ in bile, the reactive species for precipitation with 'calcium-sensitive' anions. The second major hypothesis is that bile acid anions are the major buffers for Ca++ in bile, and that free [Ca++] is largely governed by calcium complexation with bile salts. The third major hypothesis is that pH plays a key role in determining which of the calcium-sensitive anions will precipitate. The fourth hypothesis to be tested is that the biliary calcium originates primarily at the hepatic canaliculus, and that its secretion is coupled to that of bile acids. The fifth, and most important hypothesis is that gallstones are potentially preventable by prevention of calcium precipitation in bile. Any measure which will reduce free [Ca++] in bile, either by reducing calcium secretion, or by increasing Ca++ complexation, will reduce calcium lithogenicity. The proposed experiments will test these and other specific hypotheses, and will provide the first systematic studies of: (1) Free [Ca++] in bile and bile salt solutions; (2) Ca++-bile salt interactions; (3) The CO2 system in bile and bile salt solutions; and (4) Calcium carbonate and calcium bilirubinate solubilities in bile. The results should lead to new approaches to the medical management and prevention of gallstone disease.