Pathogenesis of calcium-containing gallstones. Canine ductular bile, but not gallbladder bile, is supersaturated with calcium carbonate

Abstract

Calcium precipitation in bile is a requisite event in the initiation and growth of all pigment gallstones. Calcium solubility in bile is thus of great importance. This is the first attempt to define the ion-product of CaCO3 in bile in any species. If the ion-product: [Ca++]·[CO3--] exceeds solubility product (K'(sp)), the sample is supersaturated and CaCO3 precipitation is thermodynamically possible. We have recently determined K'(sp) of calcite to be 3.76 x 10-8 mol/liter at 37°C and total ionic strength = 0.16 M. Gallbaldder (GB) bile was obtained from 15 anesthetized dogs after 12-24-h fasts. Duct bile was obtained from three dogs (n = 12) during variable taurocholate infusion. Samples were assayed for pH, partial pressure of carbon dioxide (PCO2), total bile salt concentration ([TBS]), total calcium concentration ([Ca]), and free calcium ion concentration ([Ca++]). With increasing [TBS] in both GB and duct bile, there was a linear decline in pH, a curvilinear decline in [HCO3-] and [CO3--], and linear increase in [Ca++] and [Ca]. All ductular samples were supersaturated with CaCO3, with saturation indices (SI) as high as 17.5 and a mean of 8.36 ± 1.43 (SE). In sharp contrast, none of the GB samples were supersaturated, due to the marked decline in [CO3--] upon concentration and acidification of bile. In GB bile the SI ranged from 0.006 to 0.126, with a mean of 0.039 ± 0.011. The gallbladder thus produced a change in the SI from a value as high as 17.5 to a value as low as 0.006 in concentrated GB bile, which is a nearly 3,000-fold change. The average change in the SI was ~215-fold. Since all duct samples were supersaturated, and since the dog does not normally form gallstones, the data support our previous hypotheses that :(a) in canine bile, as in canine pancreatic juice, a nucleating factor is necessary for CaCO3 precipitation; (b) bile salts are important buffers for Ca++ in bile; and (c) normal GB mucosal function (concentration and acidification of bile) plays an important role in reducing CaCO3 lithogenicity in GB bile.