The Role of Calcium in the Pathogenesis of Gallstones: Ca++ Electrode Studies of Model Bile Salt Solutions and Other Biologic Systems†

Calcium is present in all pigment gallstones as a salt of one or more of the anions in bile which are most readily precipitable by calcium: (i) carbonate; (ii) bilirubinate; (iii) phosphate, and (iv) “palmitate”. We term these “calcium-sensitive” anions. In addition, since cholesterol stones have been found to contain pigment stone centers, we postulate that calcium precipitation in bile is a critical event in the initiation of cholesterol gallstones, so that the latter should be considered a two-stage process: (i) precipitation of calcium salts to form a nidus, and (ii) precipitation of cholesterol from its supersaturated state on this nidus. Any measure which will reduce free [Ca ++ ] in bile will reduce calcium lithogenicity; possible ways to reduce [Ca ++ ] in bile are presented. One way is to increase Ca ++ binding by normal biliary constituents; we have recently pointed out that bile salts are important buffers for Ca ++ in bile by virtue of binding to both free and micellar bile salts. Here, we consider some of our Ca ++ electrode studies of taurocholate, glycocholate, serum albumin, and simple molecules having terminal carboxyl (COO − ) or sulfonic (SO − 3) ions. A brief history of the development of the Ca ++ electrode is given, along with theoretical considerations of ionic activities and techniques of electrode measurements. From the various studies, a unifying hypothesis is proposed for the structural requirements of Ca ++ −binding to proteins (albumin) and free monomeric bile salts. For proteins, unconjugated bile salts and glycine-conjugated bile salts, it is proposed that Ca ++ binding involves a reversible ion-exchange “site” in which a Ca ++ ion is interposed between carboxyl (CO0 − ) and hydroxyl (OH) groups. For taurine-conjugated bile salts, this “site” is proposed to involve the interposition of a Ca ++ ion between the side-chain SO − 3 and cholanic ring OH groups. These studies are a first step toward modulation of Ca ++ activity in bile.