Review: pathogenesis of gallstones

Abstract

Summary 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.

Subcellular localization of the ABCG2 transporter in normal and malignant human gallbladder epithelium

“…24 As neither a difference in the expression nor in the cellular localization of ABCG2 in normal, cholelithiasis, and well-differentiated adenocarcinomas was observed in our study, ABCG2 is unlikely to participate in the pathogenesis of cholelithiasis and gallbladder carcinoma with respect to common risk factors. 1,41 An important finding in our study was that in advanced gallbladder carcinoma tissue, and also in ABCG2 in the biliary tract S Aust et al poorly differentiated CCC, ABCG2 is located in the intracellular compartment in addition to the membrane. The decline of membrane localized ABCG2 in these poorly differentiated carcinomas might suggest that ABCG2 is no longer working as a plasma membrane efflux pump in these tumors.…”

CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: A population‐based study in Shanghai, China

“…48,49 It is known that high levels of insulin as well as estrogens increase cholesterol saturation in the bile and impair gallbladder motility, thereby enhancing the likelihood of gallstone formation. 27,36,50 Moreover, insulin increases transcription of CYP17, 51 and carriers of the CYP17 A1 allele are reported to have higher serum levels of insulin and C-peptide as well as insulin resistance. 29,51,52 It is thus possible that the effect of the CYP17 A1 polymorphism on biliary disease operates through a mechanism involving insulin as well as estrogen metabolism.…”

Apical sodium bile acid transporter and ileal lipid binding protein in gallstone carriers

“…In conclusion, in normal weight female gallstone carriers, the decreased expression of ileal bile acid transporters may form a molecular basis for gallstone formation.-Bergheim, I., S. Harsch, O. Mueller, S. Schimmel, P. Fritz, and E. F. Stange Despite decades of research, gallstone disease remains a significant health problem worldwide, particularly in the female adult population. In the United States and European countries, 10-20% of adults develop gallstones, mostly cholesterol-rich stones (1). Even though cholesterol supersaturation of gallbladder bile has been identified as the underlying pathophysiologic defect (2), the molecular pathogenesis of cholesterol gallstone formation remains poorly understood.…”