An explanation for gallstones in normal-weight women: slow intestinal transit

Heaton, K W; Emmett, Pauline M; Symes, CL; Braddon, Fem

doi:10.1016/0140-6736(93)92479-d

Cited by 92 publications

(50 citation statements)

References 23 publications

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“…Although it has been suggested in the past (41)(42)(43)(44) that motility of the small bowel as well as the large bowel is sluggish in cholesterol gallstone patients, the pathogenetic mechanisms for the putative role of these conditions in cholelithogenesis are not known. In these earlier studies the authors focused on the role of the large intestine in cholelithogenesis, and so their hypothesis differs fundamentally from our observations in the CCK-1R -/-mouse model.…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Wang¹,

Schmitz²,

Kopin³

et al. 2004

J. Clin. Invest.

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Cholecystokinin (CCK) modulates contractility of the gallbladder, the sphincter of Oddi, and the stomach. These effects are mediated through activation of gastrointestinal smooth muscle as well as enteric neuron CCK-1 receptors (CCK-1Rs). To investigate the potential physiological and pathophysiological functions linked to CCK-1R-mediated signaling, we compared male WT and CCK-1R-deficient mice (129/SvEv). After 12 weeks on either a standard mouse chow or a lithogenic diet (containing 1% cholesterol, 0.5% cholic acid, and 15% dairy fat), small-intestinal transit time, intestinal cholesterol absorption, biliary cholesterol secretion, and cholesterol gallstone prevalence were compared in knockout versus WT animals. Analysis of mice on either the chow or the lithogenic diet revealed that CCK-1R -/-animals had larger gallbladder volumes (predisposing to bile stasis), significant retardation of small-intestinal transit times (resulting in increased cholesterol absorption), and increased biliary cholesterol secretion rates. The elevation in bile cholesterol, coupled with a tendency toward gallbladder stasis (due to the absence of CCK-induced contraction), facilitates nucleation, growth, and agglomeration of cholesterol monohydrate crystals; this sequence of events in turn results in a significantly higher prevalence of cholesterol gallstones in the CCK-1R-null mice.

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Section: Discussionmentioning

confidence: 99%

Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Wang¹,

Schmitz²,

Kopin³

et al. 2004

J. Clin. Invest.

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“…[8][9][10]16,17 This in turn changes biliary lipid secretion, as well as bile salt pool size and kinetics, including an increase in deoxycholic acid. 4,10,13,16,17 These interdependent events form a vicious circle and act in concert to promote the three pathogenetic stages of cholesterol gallstone formation: cholesterol supersaturation, crystal nucleation, and gallbladder stasis, leading to crystal aggregation and stone growth. 10,25,[31][32][33] During fasting, the gallbladder partially empties before phase III of the MMC, delivering bile into the duodenum.…”

Section: Discussionmentioning

confidence: 99%

“…3,10,18,28,29 An alternative explanation for the observed motility defects may relate to an increased deoxycholate content of the bile salt pool. 13,16,17 More hydrophobic bile salts such as deoxycholate (as low as 5 µmol/L) can directly suppress gallbladder and small intestinal contractions. 35,36 Such defective gallbladder and intestinal contractility would then impede the enterohepatic cycling of bile salts and lead to reduced hepatic secretion of bile salts.…”

Section: Discussionmentioning

confidence: 99%

“…3,4,[8][9][10][11][12] Among the growing list of pathogenic events implicated in cholesterol gallstone formation, prolonged intestinal transit and gallbladder stasis both impede enterohepatic cycling and are thus able to lower the bile salt secretion, predisposing to the formation of bile with an increased cholesterol saturation. 10,[13][14][15][16][17] Ground squirrels fed a 1% high-cholesterol diet exhibit abnormal biliary lipid secretion, increased mucin accumulation on the epithelial surface of the gallbladder, defective gallbladder motility, and delayed intestinal transit as the cholesterol saturation in bile increases. [17][18][19] These unique features characterize this well-established animal model and mimic the proposed sequential events in cholesterol gallstone formation in humans.…”

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confidence: 99%

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Effect of the prokinetic agent, erythromycin, in the richardson ground squirrel model of cholesterol gallstone disease

Scott

Tan

et al. 1998

Hepatology

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“…They were then frozen in liquid in humans is a multifactorial phenomenon. [1][2][3][4] Calcium salts, nitrogen, stored at 080ЊC, and cut at 8 mm (Cryo-Cut Microtome; the major components of pigment gallstones, 5 are also found American Optical Corporation, Buffalo, NY). For immunoperoxidase in the central nidus region of all cholesterol stones.…”

Section: )mentioning

confidence: 99%

Membrane-bound carbonic anhydrase IV is expressed in the luminal plasma membrane of the human gallbladder epithelium

Parkkila¹

1996

Hepatology

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(CO 2 / H 2 O B H / / HCO 0 3 ). At present, seven isoenzymes Alkaline hepatic bile is acidified in the gallbladder to differing in their tissue distribution and enzymatic activity prevent calcium precipitation and gallstone formation.have been identified from mammals. These include cytoBecause membrane-bound carbonic anhydrase (CA) isoplasmic CAs I, II, and III 11 ; membrane-associated CA IV 12-14 ; enzyme IV participates with cytoplasmic CA II in the mitochondrial CA V 15,16 ; and a secretory isoenzyme CA VI. 17,18 acidification of urine in the kidney, we studied its ex-The most recently identified isoenzyme CA IX, originally despression in different regions of the human biliary tract ignated MN protein, has been detected in the human gastric using immunohistochemical techniques. The enzyme mucosa. 19 was expressed in the apical plasma membrane of the Cytoplasmic, high-activity CA II is present in the gallbladgallbladder epithelial cells and in the endothelium of der epithelium, where it has been linked to the concentration the subepithelial capillaries. In the liver, some epithelial and acidification of alkaline hepatic bile. 20,21 The membranecells of the large bile ducts showed positive staining. Its associated CA IV might also be involved in these processes presence in the gallbladder epithelium could be conbecause it participates in urinary acidification in the kidney firmed by Western blotting, which showed a single 35-kd and epididymal fluid acidification in the epididymal ducts. 22-24 polypeptide band, corresponding in molecular weight to Earlier histochemical studies also suggested that a memthe intact enzyme. The majority of the enzyme was brane-associated CA is expressed in the gallbladder epithephased to Triton X-114 detergent phase. A small amount lium. 25 To achieve a more comprehensive view of the bile of 35-kd polypeptide was also seen in the water phase.acidification process, we studied the expression of CA IV in Smaller proteolytic fragments of the enzyme were not the human bile tract epithelium by immunohistochemistry. 1108.)staining, the liver specimens and the gallbladder specimens from different regions were immersion-fixed in 4% neutral-buffered formaldehyde for 18 hours and washed in 20% sucrose in phosphate-A number of studies have shown that gallstone formation buffered saline (PBS) for 24 hours. They were then frozen in liquid in humans is a multifactorial phenomenon. 1-4 Calcium salts, nitrogen, stored at 080ЊC, and cut at 8 mm (Cryo-Cut Microtome; the major components of pigment gallstones, 5 are also found American Optical Corporation, Buffalo, NY). For immunoperoxidase in the central nidus region of all cholesterol stones. 5,6 The staining, the formaldehyde-fixed specimens were dehydrated, emmost abundant biliary calcium salt is calcium carbonate, 7,8 bedded in paraffin in a vacuum oven at 58ЊC, and sectioned at 5 mm. which is precipitated when the bicarbonate concentration inAntisera and Immunohistochemical Methods. Polyclonal rabbit antiserum to human recombinant CA IV was u...

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An explanation for gallstones in normal-weight women: slow intestinal transit

Cited by 92 publications

References 23 publications

Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Effect of the prokinetic agent, erythromycin, in the richardson ground squirrel model of cholesterol gallstone disease

Membrane-bound carbonic anhydrase IV is expressed in the luminal plasma membrane of the human gallbladder epithelium

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