Review: pathogenesis of gallstones

The aim of this article is to review selected aspects of the pathogenesis o f cholesterol-rich, gall-bladder stones (GBS) - with emphasis on recent dev elopments in biliary cholesterol saturation, cholesterol microcrystal nucle ation, statis within the gall-bladder and, particularly, on the roles of in testinal transit and altered deoxycholic acid (DCA) metabolism, in GBS deve lopment. In biliary cholesterol secretion, transport and saturation, recent developm ents include evidence in humans and animals, that bile lipid secretion is u nder genetic control. Thus in mice the md-2 gene, and in humans the MDR-3 g ene, encodes for a canalicular protein that acts as a' flippase' transporti ng phospholipids from the inner to the outer hemi-leaflet of the canalicula r membrane. In the absence of this gene, there is virtually no phospholipid or cholesterol secretion into bile. Furthermore, when inbred strains of mi ce that have 'lith genes' are fed a lithogenic diet, they become susceptibl e to high rates of GBS formation. The precipitation/nucleation of cholesterol microcrystals from supersaturat ed bile remains a critical step in gallstone formation. methods of studying this phenomenon have now been refined from the original nucleation time' t o measurement of cholesterol appearance/detection times, and crystal growth assays. Furthermore, the results of recent studies indicate that, in addit ion 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 formation - including iatrogenic stone formatio n in acromegalic patients treated chronically with octreotide (OT). As well as GB stasis, however, OT-treated patients all have 'bad' bile which is su persaturated with cholesterol, has excess cholesterol in vesicles, rapid mi crocrystal mulceation times and a two-fold increase in the percentage DCA i n bile. This increase in the proportion of DCA seems to be due to OT-induce d prolongation of large bowel transit time (LBTT). Thus LBTT is linearly re lated to (i) the percentage of DCA in serum; (ii) the DCA pool size; and (I II) the DCA input or 'synthesis' rate. Furthermore, the intestinal prokinet ic, cisapride, counters the adverse effects of OT on intestinal transit, an d 'normalizes' the percentage of DCA in serum/bile. Patients with spontaneous gallstone disease also have prolonged LBTTs, more colonic Gram-positive anaerobes, increased bile acid metabolizing enzymes and higher intracolonic pH values, than stone-free controls. Together, thes e changes lead to increased DCA formation, solubilization and absorption. T hus, in addition to the 'lithogenic liver' and 'guilty gall-bladder' one mu st now add the 'indolent intestine' to the list of culprits in cholesterol gallstone formation.