The aim of this article is to review selected aspects of the pathogenesis of cholesterol-rich, gall-bladder stones (GBS) – with emphasis on recent developments in biliary cholesterol saturation, cholesterol microcrystal nucleation, statis within the gall-bladder and, particularly, on the roles of intestinal transit and altered deoxycholic acid (DCA) metabolism, in GBS development.
In biliary cholesterol secretion, transport and satura- tion, recent developments include evidence in humans and animals, that bile lipid secretion is under genetic control. Thus in mice the md-2 gene, and in humans the MDR-3 gene, encodes for a canalicular protein that acts as a ‘flippase' transporting phospholipids from the inner to the outer hemi-leaflet of the canalicular membrane. In the absence of this gene, there is virtually no phospho- lipid or cholesterol secretion into bile. Furthermore, when inbred strains of mice that have ‘lith genes' are fed a lithogenic diet, they become susceptible to high rates of GBS formation.
The precipitation/nucleation of cholesterol micro- crystals from supersaturated bile remains a critical step in gallstone formation. methods of studying this phenomenon have now been refined from the original ‘nucleation time' to measurement of cholesterol appearance/detection times, and crystal growth assays. Furthermore, the results of recent studies indicate that, in addition to classical Rhomboid-shape monohydrate crystals, cholesterol can also crystallize, transiently, as needle-, spiral- and tubule-shaped crystals of anhydrous cholesterol. A lengthy list of promoters, and a shorter list of inhibitors, has now been defined.
There are many situations where GB stasis in humans is associated with an increased risk of gallstone forma- tion – including iatrogenic stone formation in acro- megalic patients treated chronically with octreotide (OT). As well as GB stasis, however, OT-treated patients all have ‘bad' bile which is supersaturated with cholesterol, has excess cholesterol in vesicles, rapid microcrystal mulceation times and a two-fold increase in the percentage DCA in bile. This increase in the proportion of DCA seems to be due to OT-induced prolongation of large bowel transit time (LBTT). Thus LBTT is linearly related to (i) the percentage of DCA in serum; (ii) the DCA pool size; and (III) the DCA input or ‘synthesis' rate. Furthermore, the intestinal prokinetic, cisapride, counters the adverse effects of OT on intestinal transit, and ‘normalizes' the percentage of DCA in serum/bile.
Patients with spontaneous gallstone disease also have prolonged LBTTs, more colonic Gram-positive an- aerobes, increased bile acid metabolizing enzymes and higher intracolonic pH values, than stone-free controls. Together, these changes lead to increased DCA formation, solubilization and absorption. Thus, in addition to the ‘lithogenic liver' and ‘guilty gall-bladder' one must now add the ‘indolent intestine' to the list of culprits in cholesterol gallstone formation.