cholecystokinin and Gallstones

Cholecystokinin (CCK) is an important neuro-intestinal peptide hormone produced by the enteroendocrine I-cells in the upper part of small intestine. Protein- and fat-enriched food plays an important role in triggering CCK secretion from the intestine. Carbohydrates stimulate only small amounts of CCK release. The CCK-1 receptor (CCK-1R) is largely localized in the gallbladder, sphincter of Oddi, pancreas, small intestine, gastric mucosa, and pyloric sphincter, where it is responsible for CCK to regulate multiple digestive processes including gallbladder contraction, pancreatic secretion, small intestinal transit, and gastric emptying. Accumulated evidence clearly demonstrates that CCK regulates gallbladder and small intestinal motility through CCK-1R signaling cascade and the effect of CCK-1R on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. Disruption of the Cck or the Cck-1r gene in mice significantly increases the formation of cholesterol gallstones by disrupting gallbladder emptying and biliary cholesterol metabolism, as well as promoting intestinal absorption of cholesterol. Abnormalities in gallbladder motility function in response to exogenously administered CCK are found primarily in patients with cholesterol gallstones. Patients with pigment gallstones display an intermediate degree of gallbladder motility defect without gallbladder inflammation and enlarged fasting gallbladder. Dysfunctional gallbladder contractility has been found under several conditions such as pregnancy, obesity, diabetes, celiac disease, and total parenteral nutrition although gallstones are not observed. The gallbladder-specific CCK-1R-selective agonist may lead to an efficacious novel way for preventing gallstone formation by promoting gallbladder emptying, particularly for pregnant women and subjects with dysfunctional gallbladder motility function such as celiac patients, as well as patients with total parenteral nutrition.

Topics: Animals; Cholecystokinin; Cholesterol; Gallbladder Emptying; Gallstones; Gastrointestinal Motility; Humans; Intestinal Absorption; Receptors, Cholecystokinin

Coeliac disease is a chronic, small intestinal, immune-mediated enteropathy caused by a permanent intolerance to dietary gluten in genetically predisposed individuals. Clinical studies have found that intestinal cholecystokinin secretion and gallbladder emptying in response to a fatty meal are impaired before coeliac patients start the gluten-free diet (GFD).. However, it was never really appreciated whether coeliac disease is associated with gallstones because there were very few studies investigating the mechanism underlying the impact of coeliac disease on the pathogenesis of gallstones.. We summarize recent progress on the relationship between coeliac disease and gallstones and propose that coeliac disease is an important risk factor for gallstone formation because defective intestinal cholecystokinin secretion markedly increases susceptibility to cholesterol gallstones via a mechanism involving dysmotility of both the gallbladder and the small intestine. Because GFD can significantly improve the coeliac enteropathy, early diagnosis and therapy in coeliac patients is crucial for preventing the long-term impact of cholecystokinin deficiency on the biliary and intestinal consequences. When gluten is reintroduced, clinical and histologic relapse often occurs in coeliac patients. Moreover, some of the coeliac patients do not respond well to GFD.. It is imperative to routinely examine by ultrasonography whether gallbladder motility function is preserved in coeliac patients and monitor whether biliary sludge (a precursor of gallstones) appears in the gallbladder, regardless of whether they are under the GFD programme. To prevent gallstones in coeliac patients, it is urgently needed to investigate the prevalence and pathogenesis of gallstones in these patients.

Topics: Animals; Celiac Disease; Cholecystokinin; Disease Models, Animal; Forecasting; Gallbladder Emptying; Gallstones; Humans; Intestine, Small; Mice, Knockout; Receptors, Cholecystokinin; Risk Factors

In patients with Crohn's disease, the prevalence of gallstones is increased, especially in patients with ileal disease or after ileal resection. Recent studies point to alterations in enterohepatic bilirubin cycling, resulting in increased biliary bilirubin levels leading to pigment rather than cholesterol gallstones. Gallbladder (hypo)motility is another important factor in the pathogenesis of gallstones leading to bile stasis, crystallisation and stone formation. Postprandial gallbladder emptying is not markedly reduced in patients with Crohn's disease but lower fasting gallbladder volumes have been observed in patients with colonic disease or after ileocaecal resection. Prolonged and repeated bowel rest before and after intestinal surgery has been recognised as a significant risk factor for gallstone formation in patients with Crohn's disease.

Topics: Cholecystokinin; Fasting; Gallbladder; Gallstones; Humans; Inflammatory Bowel Diseases; Postprandial Period

Measurement of gallbladder motility is a powerful research tool, but its value in clinical practice is uncertain. Three main conditions have been investigated for potential clinical application of this measurement. The first potential application is for identification of patients at risk of recurrence following gallstone dissolution with medical therapy. Results in this clinical setting are disappointing due to the low positive predictive value for gallstone recurrence in sluggish gallbladder emptying. The second potential application is for identification of obese patients at risk of gallstone formation during rapid weight loss. In this condition, a high negative predictive value has been reported for a normal gallbladder emptying pattern. The third potential application is for patients with recurrent biliary colic and acalcolous gallbladder disease. The diagnostic value of a provocative test involving intravenous cholecystokinin injection as a method of identifying patients likely to benefit from cholecystectomy is uncertain, partly as a consequence of non-standardized methodology. The balance of evidence reported in this review suggests a low inherent value of measurement of gallbladder motility in clinical practice. Acalcolous gallbladder disease is the clinical setting deserving further investigation on the value of the cholecystokinin provocative test, but this test needs to be standardized.

Topics: Acalculous Cholecystitis; Cholecystography; Cholecystokinin; Gallbladder; Gallbladder Emptying; Gallstones; Humans; Postprandial Period; Ultrasonography; Weight Loss

Topics: Ampulla of Vater; Animals; Cholecystectomy; Cholecystokinin; Common Bile Duct Diseases; Constriction, Pathologic; Endoscopy; Gallstones; Hormones; Humans; Manometry; Sphincter of Oddi

To examine the mechanisms of action of ursodeoxycholic acid (UDCA) on gallbladder (GB) muscle cells in patients with symptomatic cholesterol gallstones (GSs) as it reduces the incidence of acute cholecystitis.. A double-blind study was performed on 15 patients, 7 randomised to UDCA and 8 to placebo, treated for 4 weeks before cholecystectomy. Muscle contraction induced by cholecystokinin (CCK)-8, acetylcholine (ACh) and potassium chloride (KCl) was determined in enzymatically isolated GB muscle cells, and cholesterol levels were determined in plasma membranes. H(2)O(2), lipid peroxidation, platelet-activating factor (PAF)-like lipids, prostaglandin E(2) (PGE(2)) and catalase activity were determined as biochemical markers of oxidative stress and inflammation in muscle cells.. UDCA significantly increased GB muscle cell contraction induced by all concentrations of CCK-8, ACh and KCl, and reduced the plasma membrane cholesterol (mean (SD) 0.32 (0.16) vs 0.72 (0.5) micromol/mg of protein) compared with placebo. In GB muscle cells, UDCA treatment significantly decreased the levels of H(2)O(2) (4.4 (1.9) vs 13.7 (5.3) micromol/mg of protein), lipid peroxidation (malondialdehyde levels 1.3 (0.4) vs 2.52 (0.7) nmol/100 mg of protein), PAF-like lipids (8.9 (4.9) vs 29.6 (7.1) pg/mg of protein) as well as the production of PGE(2) (142 (47) vs 365 (125) pg/mg of protein) and catalase activity (14.5 (9.4) vs 35.8 (12.7) units/mg of protein) when compared with placebo.. These studies suggest that UDCA treatment improves GB muscle contractility by decreasing the cholesterol content in the plasma membrane of muscle cells, and the biochemical parameters of oxidative stress, thus explaining its possible therapeutic mechanisms in patients with symptoms of cholesterol GSs.

Topics: Acetylcholine; Adult; Aged; Cell Membrane; Cells, Cultured; Cholecystitis, Acute; Cholecystokinin; Cholesterol; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gallstones; Humans; Lipid Peroxidation; Male; Middle Aged; Muscle Contraction; Peptide Fragments; Potassium Chloride; Ursodeoxycholic Acid

The incidence of gallstones and gallbladder sludge is higher in patients after total gastrectomy than in general population. Formation of gallstones after gastrectomy is multifactorial. Here, we investigate the changes in gallbladder and biliary tract functions by cholescintygraphy and monitored changes in cholecystokinin (CCK) release in long-term survivors after total gastrectomy for gastric carcinoma.. Patients had undergone total gastrectomy for gastric carcinoma at least five years ago. The final study population consisted of 25 patients.. Eight patients had undergone cholecystectomy before or at the time of gastrectomy. Gallstone formation was observed in seven of the remaining 17 patients during follow-up (41%). Maximum uptake of radioactivity and gallbladder maximum uptake was significantly delayed in the gastrectomy group than in the control group. There was no significant difference in CCK levels after the overnight fasting and at 60 minutes after stimulation among patients with or without stones in situ compared with healthy volunteers, but 30 minutes after the energy-rich drink patients had higher CCK levels than the control group.. In gastrectomy patients, technetium isotope visualisation of the gallbladder and time for maximum activity was significantly delayed. This may indicate impaired gallbladder function. On the contrary, CCK release was not impaired.

Topics: Aged; Biliary Tract; Carcinoma; Case-Control Studies; Cholecystectomy; Cholecystokinin; Female; Follow-Up Studies; Gallbladder; Gallstones; Gastrectomy; Humans; Male; Middle Aged; Multivariate Analysis; Radionuclide Imaging; Stomach Neoplasms; Technetium Tc 99m Disofenin

Celiac disease is an autoimmune enteropathy caused by a permanent intolerance to dietary gluten in genetically predisposed individuals. Cholecystokinin (CCK) release from the proximal small intestine and gallbladder emptying in response to a fatty meal are greatly reduced in celiac patients before they start the gluten-free diet, showing a genetic predisposition to gallstones.. To elucidate the complex pathophysiological mechanisms determining the biliary characteristic of celiac disease, we investigated the effect of the absence of endogenous CCK on cholesterol crystallization and gallstone formation in mice fed a lithogenic diet for 28 days.. Fasting gallbladder volumes were increased and the response of gallbladder emptying to the high-fat diet was impaired in CCK knockout (KO) mice compared to wild-type mice. Because of the absence of CCK, small intestinal transit time was prolonged and intestinal cholesterol absorption was increased. During 28 days of feeding, elevated biliary cholesterol concentrations and gallbladder stasis promoted the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. Thus, cholesterol crystallization and gallstone formation were accelerated in CCK KO mice. In contrast, daily intraperitoneal administration of CCK-8 reduced gallstone formation in CCK KO mice even on the lithogenic diet.. The lack of endogenous CCK enhances susceptibility to gallstones by impairing gallbladder contractile function and small intestinal motility function. These findings show that celiac disease is an important risk factor for gallstone formation and the gallbladder motility function should be routinely examined by ultrasonography and gallbladder stasis should be prevented in celiac patients.

Topics: Animals; Bile; Celiac Disease; Cholecystokinin; Gallbladder Emptying; Gallstones; Gastrointestinal Transit; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction

"Black" pigment gallstones form in sterile gallbladder bile in the presence of excess bilirubin conjugates ("hyperbilirubinbilia") from ineffective erythropoiesis, hemolysis, or induced enterohepatic cycling (EHC) of unconjugated bilirubin. Impaired gallbladder motility is a less well-studied risk factor. We evaluated the spontaneous occurrence of gallstones in adult germfree (GF) and conventionally housed specific pathogen-free (SPF) Swiss Webster (SW) mice. GF SW mice were more likely to have gallstones than SPF SW mice, with 75% and 23% prevalence, respectively. In GF SW mice, gallstones were observed predominately in heavier, older females. Gallbladders of GF SW mice were markedly enlarged, contained sterile black gallstones composed of calcium bilirubinate and <1% cholesterol, and had low-grade inflammation, edema, and epithelial hyperplasia. Hemograms were normal, but serum cholesterol was elevated in GF compared with SPF SW mice, and serum glucose levels were positively related to increasing age. Aged GF and SPF SW mice had deficits in gallbladder smooth muscle activity. In response to cholecystokinin (CCK), gallbladders of fasted GF SW mice showed impaired emptying (females: 29%; males: 1% emptying), whereas SPF SW females and males emptied 89% and 53% of volume, respectively. Bilirubin secretion rates of GF SW mice were not greater than SPF SW mice, repudiating an induced EHC. Gallstones likely developed in GF SW mice because of gallbladder hypomotility, enabled by features of GF physiology, including decreased intestinal CCK concentration and delayed intestinal transit, as well as an apparent genetic predisposition of the SW stock. GF SW mice may provide a valuable model to study gallbladder stasis as a cause of black pigment gallstones.

Topics: Age Factors; Animals; Bile Pigments; Body Weight; Calcium; Cholecystokinin; Female; Gallbladder; Gallstones; Genetic Predisposition to Disease; Germ-Free Life; Hydrogen-Ion Concentration; Logistic Models; Male; Mice; Muscle Contraction; Muscle, Smooth; Risk Factors; Sex Factors; Species Specificity; Time Factors

Regular gall bladder contraction reduces bile stasis and prevents gallstone formation. Intraduodenal administration of exogenous pancreatic secretory trypsin inhibitor-I (PSTI-I, also known as monitor peptide) causes cholecystokinin (CCK) secretion.. We proposed that stimulation of CCK release by PSTI would produce gall bladder contraction and prevent gallstones in mice fed a lithogenic diet. Therefore, we tested the effect of overexpression of rat PSTI-I in pancreatic acinar cells on plasma CCK levels and gall bladder function in a transgenic mouse line (TgN[Psti1]; known hereafter as PSTI-I tg).. Importantly, PSTI tg mice had elevated fasting and fed plasma CCK levels compared to wild-type (WT) mice. Only mice fed the lithogenic diet developed gallstones. Both fasting and stimulated plasma CCK levels were substantially reduced in both WT and PSTI-I tg mice on the lithogenic diet. Moreover, despite higher CCK levels PSTI-I tg animals developed more gallstones than WT animals.. Together with the previously observed decrease in CCK-stimulated gall bladder emptying in mice fed a lithogenic diet, our findings suggest that a lithogenic diet causes gallstone formation by impaired CCK secretion in addition to reduced gall bladder sensitivity to CCK.

Topics: Acinar Cells; Animals; Cholecystitis; Cholecystokinin; Diet; Gallbladder; Gallbladder Emptying; Gallstones; Intercellular Signaling Peptides and Proteins; Lipid Metabolism; Male; Mice, Inbred C57BL; Organ Size; Pancreas; Rats; Trypsin Inhibitor, Kazal Pancreatic

Altered motility of the gallbladder is associated with an increased risk of gallstones and can result in biliary tract cancers. Cholecystokinin (CCK) is an important modulator of gallbladder motility which functions by activating CCK type-A receptor (CCKAR). The aim of this study was to determine whether genetic variants in CCK and CCKAR are associated with the risk of biliary tract cancers and stones.. We investigated the associations between nine single nucleotide polymorphisms in CCK and CCKAR in a population-based case-control study, including 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct, and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in Shanghai, China.. We found that women with the CCKAR rs1800855 AA genotype had an increased risk of gallbladder cancer (odds ratio = 2.37, 95% confidence interval (CI): 1.36-4.14) compared with subjects with the TT genotype, and remained significant after Bonferroni correction (P = 0.0056). Additionally, female carriers of the CCKAR haplotype C-T-C-T (rs2071011-rs915889-rs3822222-rs1800855) had a reduced risk of gallbladder cancer (odds ratio = 0.61, 95% confidence interval: 0.43-0.86) compared with those with the G-C-C-A haplotype; the association also remained significant after Bonferroni correction.. These findings suggest that variants in the CCKAR gene may influence the risk of gallbladder cancer in women. Additional studies are needed to confirm our findings.

Topics: Adult; Aged; Biliary Tract Neoplasms; Case-Control Studies; China; Cholecystokinin; Female; Gallstones; Genetic Predisposition to Disease; Genotyping Techniques; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Cholecystokinin A; Risk Assessment; Sex Factors

Cholesterol gallstones are associated with slow intestinal transit in humans as well as in animal models, but the molecular mechanism is unknown. We investigated in C57L/J mice whether the components of a lithogenic diet (LD; 1.0% cholesterol, 0.5% cholic acid and 17% triglycerides), as well as distal intestinal infection with Helicobacter hepaticus, influence small intestinal transit time. By quantifying the distribution of 3H-sitostanol along the length of the small intestine following intraduodenal instillation,we observed that, in both sexes, the geometric centre (dimensionless) was retarded significantly (P <0.05) by LD but not slowed further by helicobacter infection (males, 9.4±0.5 (uninfected), 9.6±0.5 (infected) on LD compared with 12.5±0.4 and 11.4±0.5 on chow). The effect of the LD was reproduced only by the binary combination of cholesterol and cholic acid. We inferred that the LD-induced cholesterol enrichment of the sarcolemmae of intestinal smooth muscle cells produced hypomotility from signal-transduction decoupling of cholecystokinin (CCK), a physiological agonist for small intestinal propulsion in mice. Treatment with ezetimibe in an amount sufficient to block intestinal cholesterol absorption caused small intestinal transit time to return to normal. In most cholesterol gallstone-prone humans, lithogenic bile carries large quantities of hepatic cholesterol into the upper small intestine continuously, thereby reproducing this dietary effect in mice. Intestinal hypomotility promotes cholelithogenesis by augmenting formation of deoxycholate, a pro-lithogenic secondary bile salt, and increasing the fraction of intestinal cholesterol absorbed.

Topics: Animals; Azetidines; Bile; Bile Acids and Salts; Biological Transport; Cholecystokinin; Cholesterol; Cholic Acid; Diet, High-Fat; Ezetimibe; Female; Gallbladder; Gallstones; Gastrointestinal Transit; Helicobacter hepaticus; Helicobacter Infections; Intestinal Absorption; Intestine, Small; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Sarcolemma; Sterols

We investigated the effect of gallbladder hypomotility on cholesterol crystallization and growth during the early stage of gallstone formation in CCK knockout mice. Contrary to wild-type mice, fasting gallbladder volumes were enlarged and the response of gallbladder emptying to a high-fat meal was impaired in knockout mice on chow or the lithogenic diet. In the lithogenic state, large amounts of mucin gel and liquid crystals as well as arc-like and tubular crystals formed first, followed by rapid formation of classic parallelogram-shaped cholesterol monohydrate crystals in knockout mice. Furthermore, three patterns of crystal growth habits were observed: proportional enlargement, spiral dislocation growth, and twin crystal growth, all enlarging solid cholesterol crystals. At day 15 on the lithogenic diet, 75% of knockout mice formed gallstones. However, wild-type mice formed very little mucin gel, liquid, and solid crystals, and gallstones were not observed. We conclude that lack of CCK induces gallbladder hypomotility that prolongs the residence time of excess cholesterol in the gallbladder, leading to rapid crystallization and precipitation of solid cholesterol crystals. Moreover, during the early stage of gallstone formation, there are two pathways of liquid and polymorph anhydrous crystals evolving to monohydrate crystals and three modes for cholesterol crystal growth.

Topics: Animals; Bile Acids and Salts; Cell Movement; Cholecystokinin; Cholesterol; Crystallization; Diet; Female; Gallbladder; Gallstones; Male; Mice; Mice, Inbred C57BL; Mice, Knockout

A significant relationship exists among food intake and nutritional status and cholelithiasis, including gallstone and hepatolithiasis. Leptin is associated with obesity. This study was to investigate the differences in serum leptin levels in patients with gallstone and hepatolithiasis and to evaluate the relationships among leptin, cholecystokinin (CCK), lipid and lipoprotein concentrations.. Body mass index (BMI), serum leptin, CCK, insulin, lipid and lipoprotein concentrations, and liver function were measured in 382 patients with gallstone (GS group), 83 patients with hepatolithiasis (HS group) and 30 healthy controls (control group). The values of these indices were compared among the groups. In each group, Pearson's product-moment correlation coefficient among these indices were evaluated.. There were notable differences in serum leptin, CCK, total cholesterol, total triglycerides, apolipoprotein-a (APO-a), globulin, direct reacting bilirubin, and BMI between the GS and HS groups (P<0.05). Positive correlations between serum leptin and BMI, CCK, total cholesterol, gamma-glutamyl transpeptidase (GGT), aminotransferase, and insulin were found in the GS group (P<0.05). Positive correlations were observed between serum leptin and CCK, bilirubin, aminotransferase, GGT, in the HS group (P<0.05), but negative correlations between serum leptin and albumin or APO-a (P<0.05).. Leptin participates in modulating lipid metabolism. There are notable differences in leptin, serum lipid, and CCK between patients with gallstone and those with hepatolithiasis. The role of leptin in the pathophysiological course of cholelithiasis needs further investigation.

Topics: Adult; Aged; Apolipoproteins A; Bile Ducts, Intrahepatic; Bilirubin; Cholecystokinin; Cholelithiasis; Cholesterol; Female; Gallstones; Globulins; Humans; Leptin; Lipid Metabolism; Lipoproteins; Male; Middle Aged; Triglycerides

To explore the effects of Yanggan Lidan Granule (YGLDG), a compound traditional Chinese herbal medicine for nourishing liver and improving choleresis, on the rate of gallstone formation and content of plasma cholecystokinin in guinea pigs with induced cholesterol gallstones.. Eighty guinea pigs were randomly divided into 4 groups, which were normal control group, untreated group, YGLDG-treated group and ursodeoxycholic acid (UDCA)-treated group (n=20). Except the normal control group, gallstones were induced by high-cholesterol diet in the guinea pigs. YGLDG (1.81 g/kg daily) and UDCA (30.12 mg/kg daily) were given orally to guinea pigs in the corresponding group respectively for seven weeks; however, the guinea pigs of normal control group and untreated group were administered with normal saline. The physical signs of the guinea pigs and the rates of gallstone formation were examined, and the content of cholecystokinin (CCK) in the plasma was detected by radio-immunoassay.. YGLDG could obviously improve the ethological signs of the guinea pigs. Gallstone formation rate of the untreated group (82.35%) was significantly increased as compared with that of the normal control group (5.26%) (P<0.01), while the gallstone formation rates of the YGLDG-treated group (27.28%) and UDCA-treated group (38.89%) were lower than that of the untreated group (P<0.05). The content of CCK in plasma of the untreated group was significantly lower than that of the normal control group (P<0.01), while CCK content of the YGLDG-treated group and UDCA-treated group was lower than that of the normal control group, but both of them were significantly higher than that of the untreated group (P<0.01). The difference of CCK levels between YGLDG-treated group and UDCA-treated group had no statistical significance (P>0.05).. YGLDG can significantly decrease the rate of gallstone formation in guinea pigs. It may be related to elevating the content of CCK in the plasma.

Topics: Animals; Cholecystokinin; Cholesterol; Drugs, Chinese Herbal; Female; Gallstones; Guinea Pigs; Male; Phytotherapy; Random Allocation

Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione that has been shown to improve insulin resistance. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice fed a 25% carbohydrate diet.. Twenty eight-week-old insulin-resistant obese (Lep(ob)) mice fed a 25% carbohydrate diet for 4 weeks. Half of the animals had 0.3 g/kg pioglitazone added to their diet. At 12 weeks all animals were fasted and underwent cholecystectomy. Gallbladder volume and weight were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine (ACh 10(-5)M), neuropeptide Y (NPY 10(-8,-7,-6)M) and cholecystokinin (CCK 10(-10,-9,-8,-7)M). Serum glucose and insulin were measured, and HOMA Index, a measure of insulin resistance, was calculated.. Fasting serum insulin and HOMA Index were significantly decreased (P < 0.03), but gallbladder volume was significantly increased (P < 0.03) in the pioglitazone treated group. Pioglitazone did not alter gallbladder weight or response to ACh, NPY, or CCK.. These data suggest that in insulin-resistant obese mice pioglitazone 1) lowers insulin-resistance, 2) increases resting gallbladder volume, and 3) does not alter gallbladder response to neurotransmitters. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.

Topics: Acetylcholine; Age Factors; Animals; Blood Glucose; Cholecystokinin; Cholinergic Agents; Dietary Carbohydrates; Female; Gallbladder; Gallstones; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Peptide Fragments; Pioglitazone; Thiazolidinediones

To study the interactive relationship of gallbladder motor function, plasma cholecystokinin (CCK) and cholecystokinin A receptor (CCK-R) of gallbladder in patients with cholesterol stone disease.. Gallbladder motility was studied by ultrasonography in 33 patients with gallbladder stone and 10 health subjects as controls. Plasma CCK concentration was measured by radioimmunoassay in fasting status (CCK-f) and in 30 min after lipid test meal (CCK-30). Radioligand method was employed to analyze the amount and activity of CCK-R from 33 gallstone patients having cholecystectomy and 8 persons without gallstone died of severe trauma as controls.. The percentage of cholesterol in the gallstone composition was more than 70%. The cholesterol stone type was indicated for the patients with gallbladder stone in this study. Based on the criterion of gallbladder residual fraction of the control group, 33 gallstone patients were divided into two subgroups, contractor group (14 cases) and non-contractor group (19 cases). The concentration of CCK-30 was significantly higher in non-contractor group than that in both contractor group and control group (55.86+/-3.86 pmol/L vs 37.85+/-0.88 pmol/L and 37.95+/-0.74 pmol/L, P<0.01), but there was no difference between contractor group and control group. Meanwhile no significant difference of the concentration of CCK-f could be observed among three groups. The amount of CCK-R was lower in non-contractor group than those in both control group and contractor group (10.27+/-0.94 fmol/mg vs 24.59+/-2.39 fmol/mg and 22.66+/-0.55 fmol/mg, P<0.01). The activity of CCK-R shown as KD in non-contractor group decreased compared to that in control group and contractor group. Only was the activity of CCK-R lower in contractor group than that in control group. The ejection fraction correlated closely with the amount of CCK-R (r = 0.9683, P<0.01), and the concentration of CCK-30 correlated negatively with the amount of CCK-R closely (r = -0.9627, P<0.01).. The distinctive interactive relationship of gallbladder emptying, plasma CCK and CCK-R in gallbladder from this study suggested that the defect of CCK-R may be a key point leading to the impairment of gallbladder motor function and the pathogenesis of cholesterol gallstone formation may differ in two subgroups of gallstone patient, gallbladder non-contractor group or contractor group.

Topics: Cholecystokinin; Cholesterol; Female; Gallbladder; Gallbladder Emptying; Gallstones; Humans; Male; Receptor, Cholecystokinin A

Acute pancreatitis is a severe complication of gallstones with considerable mortality. We sought to explore the potential risk factors for biliary pancreatitis. We compared postprandial gallbladder motility (via ultrasonography) and, after subsequent cholecystectomy, numbers, sizes, and types of gallstones; gallbladder bile composition; and cholesterol crystallization in 21 gallstone patients with previous pancreatitis and 30 patients with uncomplicated symptomatic gallstones. Gallbladder motility was stronger in pancreatitis patients than in patients with uncomplicated symptomatic gallstones (minimum postprandial gallbladder volumes: 5.8 +/- 1.0 vs. 8.1 +/- 0.7 mL; P = .005). Pancreatitis patients had more often sludge (41% vs. 13%; P = .03) and smaller and more gallstones than patients with symptomatic gallstones (smallest stone diameters: 2 +/- 1 vs. 8 +/- 2 mm; P = .001). Also, crystallization occurred much faster in the bile of pancreatitis patients (1.0 +/- 0.0 vs. 2.5 +/- 0.4 days; P < .001), possibly because of higher mucin concentrations (3.3 +/- 1.9 vs. 0.8 +/- 0.2 mg/mL; P = .04). No significant differences were found in types of gallstones, relative biliary lipid contents, cholesterol saturation indexes, bile salt species composition, phospholipid classes, total protein or immunoglobulin (G, M, and A), haptoglobin, and alpha-1 acid glycoprotein concentrations. In conclusion, patients with small gallbladder stones and/or preserved gallbladder motility are at increased risk of pancreatitis. The potential benefit of prophylactic cholecystectomy in this patient category has yet to be explored.

Topics: Bile; Cholecystectomy; Cholecystokinin; Cholesterol; Crystallization; Female; Gallbladder; Gallbladder Emptying; Gallstones; Humans; Lipids; Male; Middle Aged; Osmolar Concentration; Pancreatitis; Postprandial Period; Proteins; Risk; Time Factors; Ultrasonography

Topics: Bile; Bile Ducts; Cholecystokinin; Gallstones; Humans; Stimulation, Chemical

Recent studies have shown that cholecystokinin (CCK) is involved in the induction and development of acute pancreatitis in experimental animals. In the present study we determined basal plasma CCK concentrations by a specific and sensitive radioimmunoassay using antiserum OAL656 in 17 patients with acute pancreatitis due to gallstone in the common bile duct (n = 7), alcoholic (n = 4), post endoscopic retrograde pancreatography (n = 1), and unknown causes (n = 4), and 37 patients with cholelithiasis (n = 18) and choledocholithiasis (n = 19). Plasma CCK concentrations in patients with gallstone pancreatitis on hospital day 1 (mean +/- SEM, 6.78 +/- 1.39 pM) were significantly higher than those in patients with other causes (1.33 +/- 0.16 pM) or in 20 healthy control subjects (1.55 +/- 0.11 pM). There was no relationship between plasma CCK and serum pancreatic enzyme levels, the severity of acute pancreatitis, or serum bilirubin concentrations. Plasma CCK levels in patients with acute symptomatic cholelithiasis (n = 7; 4.35 +/- 0.90 pM) and choledocholithiasis (n = 8; 4.52 +/- 1.17 pM) were significantly higher than those in patients without symptoms (cholelithiasis, n = 11, 1.40 +/- 0.17 pM; choledocholithiasis, n = 11, 1.88 +/- 0.49 pM) but tended to be lower than those in patients with gallstone pancreatitis. These present observations suggest that the increase in plasma CCK levels in gallstone pancreatitis appears not to be the cause but to be the result of gallstone pancreatitis probably due to a transient disturbance of bile flow into the duodenum by stones or edema of the bile duct. Our present results provide some evidence for the usefulness of CCK receptor antagonists for the treatment of biliary colics and acute pancreatitis.

Topics: Acute Disease; Adult; Aged; Bilirubin; Case-Control Studies; Cholecystokinin; Cholelithiasis; Female; Gallstones; Hormone Antagonists; Humans; Male; Middle Aged; Pancreatitis; Receptors, Cholecystokinin; Reference Values

The aim of the present work was to study the effect of substance P (SP) and somatostatin (SST) on hepatic bile flow. For this purpose a total of 54 anesthetized mongrel dogs were used. The gallbladder was excluded by ligation of the cystic duct and a common duct fistula was created by insertion of a catheter into the common duct. Both SP and SST were found to exert an anticholeretic effect in the dog. SST was also found to be anticholeretic in man. In the dog, SP was infused at dosages from 0.5-20 ng kg-1 min-1 and exerted a significant anticholeretic effect at a dosage of 2.5 ng or higher. At dosages of 2.5 and 20 ng kg-1 min-1, SP decreased the basal bile secretion by about 20 and 40% respectively. The decrease in bile flow was accompanied by decreased outputs of sodium, potassium, chloride, bicarbonate and amylase. With taurocholate-stabilized and taurocholate-stabilized and hormone-induced bile secretion, SP had the above mentioned effects and in addition the output of bile acids decreased. The effect of SP occurred within minutes and after withdrawal of SP there was a positive rebound effect, with a magnitude of about 30% following the 20 ng dosage. SST at dosages from 20-1000 ng kg-1 min-1 induced an anticholeretic effect with a magnitude of 10-25%. With both basal and taurocholate-stabilized bile secretion, the outputs of bile, bile acids and electrolytes decreased during the infusion period and remained diminished for 10-20 min after termination of the infusion. Unlike SP, SST had no anticholeretic effect in the presence of CCK or secretin. A simultaneous infusion of SP and SST decreased bile flow more than either agent alone. The anticholeretic effect of SST was verified in five patients. They had all been operated on for choledocholithiasis. In four patients a complete diversion of bile was obtained with a Foley catheter in the common duct and in the fifth patient from an impacted stone in the common duct. During infusion of SST, 250 ug h-1, the outputs of hepatic bile and bile acids decreased while the outputs of cholesterol and phospholipids were unchanged. The serum bile acid concentration was unaffected by SST and therefore SST is suggested to exert an inhibitory effect on bile acid synthesis. The changes in electrolyte outputs induced by SST in man corresponded to those in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Amylases; Animals; Bicarbonates; Bile; Bile Acids and Salts; Cholecystokinin; Cholesterol; Dogs; Dose-Response Relationship, Drug; Gallstones; Humans; Hydrogen-Ion Concentration; Phospholipids; Potassium; Secretin; Sodium; Somatostatin; Substance P; Taurocholic Acid; Vasoactive Intestinal Peptide

Topics: Carcinoma; Cholecystokinin; Cholestasis; Duodenum; Gallstones; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin

Topics: Ampulla of Vater; Anesthesia, Local; Cholangiography; Cholecystokinin; Common Bile Duct; Diagnosis, Differential; Gallstones; Humans; Lidocaine; Male; Middle Aged; Time Factors

Topics: Cholecystokinin; Ethyl Ethers; Gallstones; Humans; Oils; Postoperative Care