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Background and Objective: Studies in humans and mice have demonstrated that the gut hormone glucagon-like peptide 2 (GLP-2) promotes gallbladder relaxation and refilling. Here, we assessed the effect of exogenous GLP-2 on gallbladder motility in the fasted state of healthy men with and without infusion of the potent gallbladder-contracting hormone cholecystokinin (CCK)., Methods: In a randomized, double-blind, placebo-controlled, crossover study, 15 male participants (mean [SD]: age 24.7 [3.6] years; body mass index 22.9 [1.6] kg/m2) underwent 4 experimental days receiving 2 infusions on each day: either CCK (0.4 pmol × kg-1 × min-1, time 0-180 minutes) + GLP-2 (10 pmol × kg-1 × min-1, time 30-240 minutes), CCK + placebo, placebo + GLP-2, or placebo + placebo, respectively. Gallbladder volume was measured at baseline and throughout the 4-hour study day using ultrasonography., Results: Compared to placebo + placebo, GLP-2 + placebo did not affect gallbladder volume, but when infused in combination with CCK, GLP-2 completely abolished the strong gallbladder-contracting effect seen during CCK + placebo infusion, restoring baseline levels of gallbladder volume., Conclusion: Exogenous GLP-2 counteracts exogenous CCK-induced gallbladder emptying in healthy men, pointing to a possible therapeutic potential for GLP-2 as a relaxing modulator of gallbladder smooth muscle tone (eg, as a bridge to surgery in biliary colic). The effect may also explain the gallbladder-related adverse events reported for GLP-2 receptor agonists used in the treatment of short bowel syndrome., Clinical Trial Registration Number: NCT04651868., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background : Celiac Disease (CD) is an immune-mediated disorder which primarily affects the small intestine; however, extra-intestinal organs are often affected by the pathological process, too. As regards the digestive system, liver alterations in CD patients have been widely described, which can also extend to the biliary tract. Notably, gallbladder function can be altered in CD patients. In this review, we specifically analyze and summarize the main pathophysiological aspects and clinical evidence of gallbladder dysfunction in CD patients, in order to discuss the potential medical complications and clinical research gaps. In addition to some perturbations of bile composition, CD patients can develop gallbladder dysmotility, which mainly expresses with an impaired emptying during the digestive phase. The main pathophysiological determinant is a perturbation of cholecystokinin secretion by the specific duodenal enteroendocrine cells in response to the appropriate nutrient stimulation in CD patients. This situation appears to be reversible with a gluten-free diet in most cases. Despite this gallbladder impairment, CD patients do not seem to be more predisposed to gallbladder complications, such as calculous and acalculous cholecystitis. However, very few clinical studies have actively investigated these clinical aspects, which may not be completely evidenced so far; alternatively, the substantial improvements in the last two decades regarding CD diagnosis, which have reduced the diagnostic delay (and related dietary treatment), may have lessened the potential clinical consequences of CD-related gallbladder dysfunction. Specific clinical studies focused on these aspects are needed for a better understanding of the clinical implications of gallbladder alterations in CD patients.

The cholecystokinin A receptor (CCKAR) is expressed predominantly in the gallbladder and small intestine in the digestive system, where it is responsible for CCK's regulation of gallbladder and small intestinal motility. The effect of CCKAR on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. The Cckar gene has been identified to be an important gallstone gene, Lith13 , in inbred mice by a powerful quantitative trait locus analysis. Knockout of the Cckar gene in mice enhances cholesterol cholelithogenesis by impairing gallbladder contraction and emptying, promoting cholesterol crystallization and crystal growth, and increasing intestinal cholesterol absorption. Clinical and epidemiological studies have demonstrated that several variants in the CCKAR gene are associated with increased prevalence of cholesterol cholelithiasis in humans. Dysfunctional gallbladder emptying in response to exogenously administered CCK-8 is often found in patients with cholesterol gallstones, and patients with pigment gallstones display an intermediate degree of gallbladder motility defect. Gallbladder hypomotility is also revealed in some subjects without gallstones under several conditions: pregnancy, total parenteral nutrition, celiac disease, oral contraceptives and conjugated estrogens, obesity, diabetes, the metabolic syndrome, and administration of CCKAR antagonists. The physical-chemical, genetic, and molecular studies of Lith13 show that dysfunctional CCKAR enhances susceptibility to cholesterol gallstones through two primary mechanisms: impaired gallbladder emptying is a key risk factor for the development of gallbladder hypomotility, biliary sludge (the precursor of gallstones), and microlithiasis, as well as delayed small intestinal transit augments cholesterol absorption as a major source for the hepatic hypersecretion of biliary cholesterol and for the accumulation of excess cholesterol in the gallbladder wall that further worsens impaired gallbladder motor function. If these two defects in the gallbladder and small intestine could be prevented by the potent CCKAR agonists, the risk of developing cholesterol gallstones could be dramatically reduced.

Cholecystokinin cholescintigraphy is used clinically to quantify gallbladder ejection fraction as an indicator of functional gallbladder disorder. It can also provide the opportunity to quantify an individual's responsiveness to the physiologic stimulant of gallbladder contraction, cholecystokinin, which is a major regulator of appetite and postprandial satiety. Methods: In the current work, we use cholecystokinin cholescintigraphy to quantify the kinetics of gallbladder emptying, including average and peak rates, in response to a standard cholecystokinin infusion. Results: We demonstrated that patients with no gallstones or biliary obstruction who empty their gallbladders completely in response to cholecystokinin, having an ejection fraction greater than 80%, exhibit a broad range of sensitivity to this hormone. Three distinct kinetic profiles were observed, with those most sensitive to cholecystokinin achieving the earliest peak and the fastest rate of gallbladder emptying, whereas those least sensitive to cholecystokinin have the latest peak and the slowest rate of emptying. Conclusion: Patients can have abnormal cholecystokinin stimulus-activity coupling as an effect of endogenous negative allosteric modulation by membrane cholesterol. This was predicted in ex vivo studies but has not, to our knowledge, previously been demonstrated in vivo. This type of kinetic analysis provides a tool to quantify cholecystokinin responsiveness in patients and identify patients who might benefit from a drug that would positively modulate cholecystokinin action to improve their appetite regulation and to better control their weight., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

As a staple food, bread digestibility deserves a marked nutritional interest. Combining wide-spectrum characterization of breads, in vitro nutritional indices, and in vivo postprandial markers of gastrointestinal function, we aimed at comparing the digestibility of sourdough and baker's yeast breads. Microbiological and biochemical data showed the representativeness of the baker´s yeast bread (BYB) and the two sourdough breads (SB and t-SB, mainly differing for the time of fermentation) manufactured at semi-industrial level. All in vitro nutritional indices had the highest scores for sourdough breads. Thirty-six healthy volunteers underwent an in vivo challenge in response to bread ingestion, while monitoring gallbladder, stomach, and oro-cecal motility. SB, made with moderate sourdough acidification, stimulated more appetite and induced lower satiety. t-SB, having the most intense acidic taste, induced the highest fullness perception in the shortest time. Gallbladder response did not differ among breads, while gastric emptying was faster with sourdough breads. Oro-cecal transit was prolonged for BYB and faster for sourdough breads, especially when made with traditional and long-time fermentation (t-SB), whose transit lasted ca. 20 min less than BYB. Differences in carbohydrate digestibility and absorption determined different post-prandial glycaemia responses. Sourdough breads had the lowest values. After ingesting sourdough breads, which had a concentration of total free amino acids markedly higher than that of BYB, the levels in blood plasma were maintained at constantly high levels for extended time.

Objectives: To evaluate whether abdominal ultrasound (US) with a gallbladder (GB) contractility study or motor function test can be used as a diagnostic tool in patients with dengue and warning signs in acute and recovery phases., Methods: Fifty-one individuals in the acute phase of dengue presenting with warning signs (dengue group) and 49 healthy individuals without a history of dengue or hepatobiliary disease (control group) were studied with abdominal US and a GB contractility study., Results: Statistical differences in US measurements of the liver (right lobe, P = .012; left lobe, P = .001) and spleen (P = .008) dimensions, GB wall thickness (P < .001), and the GB emptying fraction (P < .001) were observed in dengue during the acute phase compared with the control group. After 60 days, abdominal US of the dengue group showed a statistical difference in liver (right lobe, P < .001; left lobe, P = .078) and spleen (P < .001) dimensions, GB wall thickness, and the GB emptying fraction (P < .001) compared with the results obtained during the acute phase. Furthermore, a statistical difference in the spleen volume and GB emptying fraction (P < .001) was observed when comparing dengue after clinical recovery and the control group. Abdominal pain in patients with dengue was positively associated with hepatomegaly (P = .031), splenomegaly (P = .008), increased GB wall thickness (P = .016), and a reduced GB emptying fraction (P = .038) during the acute phase and with splenomegaly (P = .001) and a reduced GB emptying fraction (P = .003) after clinical recovery., Conclusions: Abdominal US with a GB motor function test can be used as a diagnostic tool in patients with dengue during acute and recovery phases., (© 2018 by the American Institute of Ultrasound in Medicine.)

Context: Several cases of cholelithiasis and cholecystitis have been reported in patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and GLP-2 receptor agonists (GLP-2RAs), respectively. Thus, the effects of GLP-1 and GLP-2 on gallbladder motility have been investigated. We have provided an overview of the mechanisms regulating gallbladder motility and highlight novel findings on the effects of bile acids and glucagon-like peptides on gallbladder motility., Evidence Acquisition: The articles included in the present review were identified using electronic literature searches. The search results were narrowed to data reporting the effects of bile acids and GLPs on gallbladder motility., Evidence Synthesis: Bile acids negate the effect of postprandial cholecystokinin-mediated gallbladder contraction. Two bile acid receptors seem to be involved in this feedback mechanism, the transmembrane Takeda G protein-coupled receptor 5 (TGR5) and the nuclear farnesoid X receptor. Furthermore, activation of TGR5 in enteroendocrine L cells leads to release of GLP-1 and, possibly, GLP-2. Recent findings have pointed to the existence of a bile acid-TGR5-L cell-GLP-2 axis that serves to terminate meal-induced gallbladder contraction and thereby initiate gallbladder refilling. GLP-2 might play a dominant role in this axis by directly relaxing the gallbladder. Moreover, recent findings have suggested GLP-1RA treatment prolongs the refilling phase of the gallbladder., Conclusions: GLP-2 receptor activation in rodents acutely increases the volume of the gallbladder, which might explain the risk of gallbladder diseases associated with GLP-2RA treatment observed in humans. GLP-1RA-induced prolongation of human gallbladder refilling may explain the gallbladder events observed in GLP-1RA clinical trials., (Copyright © 2019 Endocrine Society.)

Background: Gallbladder dyskinesia (gallbladder spasm, biliary dyskinesia or chronic acalculous cholecystitis) is a poorly defined entity which presents as biliary-type pain without any identifiable organic pathology. Abnormal gallbladder ejection fraction (GBEF) is used by some to select those likely to benefit from cholecystectomy. The validity of this approach has been questioned., Aim: To systematically review the literature and summarise the evidence surrounding the practice of cholecystectomy based on GBEF for gallbladder dyskinesia., Methods: We conducted a systematic search of PubMed/MEDLINE and SCOPUS from 1980 to 2016 to identify the relevant literature., Results: Twenty-nine studies including 2891 patients were included in the final analysis. In comparing cholecystectomy with medical management, patients with a normal GBEF did not benefit from cholecystectomy; whereas those with low GBEF had a higher chance (RR, relative risk = 2.37) of symptomatic improvement following surgery. When those classified as "low" and "normal" GBEF were compared in terms of outcome following cholecystectomy, the rate of improvement following surgery was similar in the two groups (RR 1.09) which suggests a placebo effect of surgery., Conclusions: While a low GBEF may provide some guidance in identifying those with gallbladder dyskinesia who may benefit from cholecystectomy, the available data are inconsistent and based on studies of poor quality which are often subject to bias and the impact of confounding factors. For these reasons, we conclude that the role of scintigraphy and cholecystectomy in the definition and management of this disorder remain unclear pending definitive study., (© 2019 John Wiley & Sons Ltd.)

Background and Aim: Several gallstone patients complain of dyspeptic symptoms, irrespective of the presence of typical colicky pain. Symptoms often persist after a cholecystectomy. Systematic studies on dyspepsia and dynamic gastrointestinal motor function are missing in gallstone patients with preserved gallbladder or after a cholecystectomy., Materials and Methods: Forty-six gallstone patients (age 55 ± 2 years; 15M, 31F) and 24 cholecystectomized patients (age 57 ± 2 years; 6M, 18F) (no difference in type and volume of gallstones between the two groups) were compared against a group of 65 healthy controls (age 51 ± 2 years; 30M, 35F). Dyspepsia occurring in the prior months was assessed by a questionnaire, gastric and gallbladder emptying by functional ultrasonography and orocecal transit time by a hydrogen breath test using a lactulose-enriched standard liquid meal., Results: Gallstone patients had significantly greater dyspepsia, fasting and residual gallbladder volumes, and slower gallbladder emptying, gastric emptying and small intestinal transit time than controls. In cholecystectomized patients, gastric emptying further delayed, compared to gallstone patients and controls., Conclusion: Gallstone patients with the gallbladder "in situ" or after a cholecystectomy display dyspeptic symptoms. Symptoms are associated with multiple gastrointestinal motility defects involving the gallbladder, stomach and small intestine. After cholecystectomy, gastric emptying worsens., (© 2018 Stichting European Society for Clinical Investigation Journal Foundation.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: A reduced number of interstitial Cajal-like cells (ICLCs) in the gallbladder have been proposed to play a role in the pathogenesis of cholelithiasis. Therefore, this prospective study was conducted to investigate the relationship between gallbladder contractility and the number of gallbladder ICLCs in patients with cholelithiasis., Material and Methods: Patients admitted to the Department of Hepatobiliary Surgery for cholecystectomy were divided into the cholelithiasis (n = 18) and non-cholelithiasis (n = 8) groups based on their clinical data. Patients' clinical data were collected on admission, and B-mode ultrasonography was performed to assess their gallbladder contractility. The resected gallbladder specimens were fixed, paraffin sections mounted on slides, and the immunofluorescence staining with the anti-human CD-117 and anti-human tryptase antibodies was performed to identify ICLSs and mast cells, respectively. The number of ICLCs was counted in 10 high-power fields (HPFs) randomly., Results: Independent sample t-tests revealed differences between the cholelithiasis and non-cholelithiasis groups in the number of ICLCs (mean ± standard deviation: 88.61 ± 28.22 vs. 115.89 ± 27.87 per HPFs, P = 0.032) and gallbladder contractility (43.94% ± 18.50% vs. 61.00% ± 20.50%, P = 0.046). Pearson and Spearman cor-relation analyses revealed no significant correlation between the number of ICLCs and gallbladder contractility., Conclusion: The results suggest that the number of gallbladder ICLCs in the wall of the gallbladder of patients with or without cholelithiasis is not a decisive factor affecting gallbladder contractility.

Cholescintigraphy has traditionally been used as a tool to select patients with biliary pain for elective cholecystectomy. However, atypical biliary pain presents a clinical challenge and there is no literature evaluating the factors of the gallbladder (GB) wall related to abnormal ejection fraction of cholescintigraphy in such patients. Therefore, we aimed to evaluate characteristics of the GB wall in patients with abnormal gallbladder ejection fraction (GBEF) on cholescintigraphy and atypical biliary pain. Patients who underwent cholescintigraphy for atypical biliary pain and subsequent cholecystectomy were initially recruited for this study. Medical records and pathologic findings of these patients were retrospectively reviewed. Parameters that were significant on univariate analysis, including factors of GB wall and cholescintigraphy, were subsequently tested by multivariate analysis to identify independent predictors for abnormal GBEF. Abnormal or low GBEF was defined as GBEF <35%. A total of 41 adult patients were divided into a low GBEF (n = 15) and a high GBEF group (n = 26) based on the cutoff value of 35%. In univariate analysis mean muscle thickness, muscle to total layer ratio, and muscle to fibrosis layer ratio were significantly higher in the low GBEF group than in the high GBEF group. In multivariate analysis, the muscle to fibrosis layer ratio was found to be an independent risk factor for abnormal GBEF (odds ratio = 3.514, 95% confidence interval = 1.058-11.673, P = .04). The fibrosis to total layer ratio was negatively correlated with GBEF in the low GBEF group (r = -0.657, P < .01). Muscle to fibrosis layer ratio was significantly associated with decreased GBEF. The fibrosis thickness ratio also seems to play an important role in patients with decreased GBEF., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Context: Despite a position as the first-line pharmacotherapy in type 2 diabetes, the glucose-lowering mechanisms of metformin remain to be fully clarified. Gut-derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon-like peptide-1 (GLP-1) secretion, have been proposed., Objective: The aim of this study was to assess the GLP-1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes., Design: Randomized, placebo-controlled, and double-blinded crossover study., Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark., Patients: Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study., Interventions: Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline., Main Outcome Measure: Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve., Results: Single-dose metformin further enhanced bile acid-mediated induction of GLP-1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP-1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin-induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP-1-mediated induction of insulin secretion or suppression of glucagon was observed., Conclusions: Metformin elicited an enhancement of the GLP-1 response to cholecystokinin-induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting., (Copyright © 2017 Endocrine Society)

Background: 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)., Design: 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., Results: 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., Conclusions: 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., (© 2017 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: To quantify gallbladder dysfunction during critical illness., Design: Prospective observational comparison study of nutrient-stimulated gallbladder emptying in health and critical illness., Setting: Single-centre mixed medical/surgical ICU., Patients: Twenty-four mechanically ventilated critically ill patients suitable to receive enteral nutrition were compared with 12 healthy subjects., Interventions: Participants were studied after an 8-hour fast. Between 0 and 120 minutes, high-fat nutrient (20% intralipid) was infused via a postpyloric catheter into the duodenum at 2 kcal/min., Measurements and Main Results: Three-dimensional images of the gallbladder were acquired at 30-minute intervals from -30 to 180 minutes. Ejection fraction (%) was calculated as changes between 0 and 120 minutes. Blood samples were obtained at 30-minute intervals for plasma cholecystokinin. Data are mean (SD) or median [interquartile range]. In the critically ill, fasting gallbladder volumes (critically ill, 61 mL [36-100 mL] vs healthy, 22 mL [15-25] mL; p < 0.001] and wall thickness (0.45 mm [0.15 mm] vs 0.26 mm [0.08 mm]; p < 0.001] were substantially greater, and sludge was evident in the majority of patients (71% vs 0%). Nutrient-stimulated emptying was incomplete in the critically ill after 120 minutes but was essentially complete in the healthy individuals (22 mL [9-66 mL] vs 4 mL [3-5 mL]; p < 0.01]. In five critically ill patients (21%), there was no change in gallbladder volume in response to nutrient, and overall ejection fraction was reduced in the critically ill (50% [8-83%] vs 77 [72-84%]; p = 0.01]. There were no differences in fasting or incremental cholecystokinin concentrations., Conclusions: Fasted critically ill patients have larger, thicker-walled gallbladders than healthy subjects and nutrient-stimulated gallbladder emptying is impaired with "gallbladder paresis" occurring in approximately 20%.

The gallbladder stores and concentrates bile between meals. Gallbladder motor function is regulated by bile acids via the membrane bile acid receptor, TGR5, and by neurohormonal signals linked to digestion, for example, cholecystokinin and FGF15/19 intestinal hormones, which trigger gallbladder emptying and refilling, respectively. The cycle of gallbladder filling and emptying controls the flow of bile into the intestine and thereby the enterohepatic circulation of bile acids. The gallbladder also largely contributes to the regulation of bile composition by unique absorptive and secretory capacities. The gallbladder epithelium secretes bicarbonate and mucins, which both provide cytoprotection against bile acids. The reversal of fluid transport from absorption to secretion occurs together with bicarbonate secretion after feeding, predominantly in response to an adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pathway triggered by neurohormonal factors, such as vasoactive intestinal peptide. Mucin secretion in the gallbladder is stimulated predominantly by calcium-dependent pathways that are activated by ATP present in bile, and bile acids. The gallbladder epithelium has the capacity to absorb cholesterol and provides a cholecystohepatic shunt pathway for bile acids. Changes in gallbladder motor function not only can contribute to gallstone disease, but also subserve protective functions in multiple pathological settings through the sequestration of bile acids and changes in the bile acid composition. Cholecystectomy increases the enterohepatic recirculation rates of bile acids leading to metabolic effects and an increased risk of nonalcoholic fatty liver disease, cirrhosis, and small-intestine carcinoid, independently of cholelithiasis. Among subjects with gallstones, cholecystectomy remains a priority in those at risk of gallbladder cancer, while others could benefit from gallbladder-preserving strategies. © 2016 American Physiological Society. Compr Physiol 6:1549-1577, 2016., (Copyright © 2016 John Wiley & Sons, Inc.)

Background: 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., Methods: 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., Key Results: 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., Conclusions & Inferences: 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., (© 2015 John Wiley & Sons Ltd.)

Aim: The study of mechanisms of regulation of biliary tract motility by divisions of autonomic nervous system (ANS)., Material and Methods: Experiments were carried out on rabbits, chinchillas weighing 3.5-4 kg using gentle methods of treatment of experimental animals. Electromotor activity of electromotor (EMA) of the gallbladder and sphincter of Oddi was recorded. Irritation of the nerve produces an electrical pulse duration of 2 ms, the amplitude of 1.5-15 V, frequency of 10 Hz., Results: The mechanism of vagal inhibition of sphincter of Oddi motility and unidirectional stimulatory influence of ANS divisions on the motility of the gallbladder and sphincter of Oddi was studied. It was established that in the mechanism of vagal inhibition of sphincter of Oddi motility involved intramural adrenergic neurons synaptically connected with preganglionic parasympathetic fibers. At the stimulatory effect of vagus on biliary tract motility serotonergic intramural neurons are involved transmitting excitation to serotonin receptors of effector tissue.

Background: To assess hepatobiliary (HB) scans for predicting recurrent symptoms in nonoperated patients with mild or vague symptomatic gallstones., Methods: Data of 170 patients with symptomatic gallstone and who had not undergone cholecystectomy were retrospectively enrolled. These patients were divided into two groups according to whether or not operations were performed due to recurrent symptoms during the follow-up period. The demographic factors and gallbladder ejection fraction (GBEF) of HB scans were compared between the groups. Additionally, symptom-free rate was obtained beginning from the date of the HB scan to the date of surgery, and analyzed based on the level of GBEF., Results: Among the 170 enrolled patients, two patients who underwent cholecystectomy for other disease were excluded. Thirty-four patients underwent cholecystectomy due to recurrent symptoms (OP group), and the remaining 136 patients did not experience recurrent symptoms and therefore did not undergo cholecystectomy (non-OP group). In the OP group, the mean GBEF was significantly lower than that of the non-OP group (28.8 ± 29.9 vs. 66.3 ± 20.0; P < 0.001). The rate of lower GBEF (<30 %, including non-visualization of the gallbladder) was significantly higher in the OP group than the non-OP group (54.9 vs. 5.1 %; P < 0.001). In patients with non-visualization of the gallbladder or GBEF <30 %, the 10-year symptom-free rate was significantly lower than those with a GBEF ≥ 30 % (19.8 % vs. 81.9 %; P < 0.001)., Conclusion: HB scanning is a useful objective modality to differentiate gallstone-related symptoms from other etiologies and predict recurrent symptoms.

Background: The relationship between gluten ingestion and gastrointestinal tract function is a matter of debate., Aim: We analysed the effect of gluten on gastric and gallbladder emptying and intestinal fermentation in healthy volunteers., Methods: Ultrasound measurement of gastric and gallbladder emptying after both gluten-containing and gluten-free meals was performed in 18 volunteers (8 women, age 25.0±2.5 years; BMI 22±1.9). Breath hydrogen excretion after a gluten-containing meal, a gluten-free meal and a gluten-free meal with added gluten powder was measured in 16 volunteers (10 women, age 25.2±2.7 years; BMI 22±1.8). The severity of symptoms was monitored., Results: Gluten presence in the meals was not recognised. Gastric emptying time was 81.6±13.8min after gluten-containing and 73.9±21.6min after gluten-free meals (p=0.11). Percentage ejection fraction after gluten-containing meals was 60±9% and 60.6±6% after gluten-free meals (p=0.68). Peak and cumulative hydrogen excretion were significantly higher after gluten-containing than after gluten-free meals (peak: 12.5±7.3 vs 6.5±5.1 parts-per-million, p<0.01; and cumulative: 2319±1720 vs 989±680 parts-per-million/minute, respectively; p<0.01). Adding gluten powder to the gluten-free meal did not modify fermentation. Symptoms were mild and not different after the meals., Conclusions: In healthy volunteers, gluten may induce gastrointestinal alterations. Further studies are needed to clarify which patients could benefit from dietary modification., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Goals and Background: Long-term outcomes of symptomatic gallbladder (GB) sludge are not fully established. This study aimed to determine whether patients with symptomatic GB sludge could experience subsequent biliary events., Study: This study investigated consecutive patients who presented with typical biliary pain and underwent abdominal ultrasonography from March 2003 to December 2012. A prospectively maintained database of these patients, excluding those with gallstones, was reviewed retrospectively. We compared the development of biliary events such as acute cholecystitis, acute cholangitis, and acute pancreatitis between both GB sludge and non-GB sludge cohorts., Results: In all, 58 and 70 patients were diagnosed with and without GB sludge, respectively. The 5-year cumulative biliary event rate was significantly higher in the GB sludge (33.9% vs. 15.8%, P=0.021) and the hazard ratio of subsequent biliary events was 2.573 (95% confidence interval, 1.124-5.889; P=0.025) in patients with GB sludge. The 5-year cumulative rate of each biliary event was higher in the GB sludge cohort (15.6% vs. 5.3% in acute cholecystitis, 15.5% vs. 5.3% in acute cholangitis, 18.4% vs. 11.1% in acute pancreatitis, respectively), although it was not statistically significant. Among the GB sludge cohort, subsequent biliary events were less frequent in patients who underwent cholecystectomy compared with those who did not (2/16, 12.5% vs. 17/42, 40.4%; P=0.067)., Conclusions: GB sludge accompanying typical biliary pain can cause subsequent biliary events and cholecystectomy may prevent subsequent biliary events. Therefore, GB sludge would be considered as a culprit of biliary events.

Background/aims: Studies in adults suggest that constipation may not be a purely colonic pathology and may be a component of a generalized gastrointestinal (GI) motor disorder in which proximal GI motility can be impaired. Pediatric data are scarce, and the natural history of the disorder remains undefined. We aimed to evaluate gallbladder motility in a subset of Asian children with chronic functional constipation., Methods: Abdominal ultrasound was performed on 105 children, including 55 patients (aged 3 to 13 years) with chronic functional constipation who met the inclusion criteria and 50 age- and gender-matched controls. The gallbladder contractility index was calculated based on the preprandial and postprandial gallbladder areas. Preprandial and postprandial values for gallbladder volume and wall thickness were evaluated., Results: The mean value of the contractility index for the patients (15.77±24.68) was significantly lower than the mean value for the controls (43.66±11.58) (p=0.001). The mean postprandial gallbladder volumes and areas were larger in children with gallbladder hypomotility (p<0.05). The mean duration of constipation (4.8 months) was significantly higher (p=0.004) in the children with gallbladder hypomotility., Conclusions: Gallbladder motility is significantly impaired in children with chronic functional constipation. This study contributes to the understanding of the underlying pathophysiology, which will enable advancement in and improved management of children with chronic constipation and associated gallbladder hypomotility.

Background/aims: Impaired gallbladder motility has been suggested as a contributor to increased incidence of gallstones in patients with liver cirrhosis. The purpose of this study was to determine gallbladder function and its relation with autonomic neuropathy in liver cirrhosis., Materials and Methods: Gallbladder function was measured using ultrasonography in 48 patients with liver cirrhosis and in 31 controls. Autonomic neuropathy tests were applied in patients with liver cirrhosis. Patients with liver cirrhosis were analyzed in subgroups according to the severity of disease using the Child-Pugh classification., Results: Fasting gallbladder volume was 16.2 mL (range: 2.1 mL-71.9 mL) in patients and 17.6 mL (range: 4.9 mL-76.6 mL) in controls. There were no differences in fasting gallbladder volume among the study groups (p>0.05). Gallbladder ejection fraction was significantly higher in patients compared with controls (84% vs. 65%) (p<0.001). No correlation was found between gallbladder ejection fraction and autonomic neuropathy (p>0.05)., Conclusion: Our results indicate that liver cirrhosis does not impair gallbladder emptying, and that there is no association between gallbladder motility and autonomic neuropathy. Further investigations are required to explain increased gallbladder motility in liver cirrhosis.

Objective: The effects of hyperglycemia and normoglycemia on gallbladder emptying have not been studied in detail. This prospective case-control study was designed to investigate the gallbladder ejection fraction in patients with newly detected diabetes and to assess the impact of restoring normoglycemia on gallbladder ejection fraction in such patients., Methods: (99m)Tc-mebrofenin scintigraphy was performed in 22 patients with newly detected type 2 diabetes for measurement of gallbladder ejection fraction. The scintigraphy was performed at the time of first presentation and again 6 months after control of diabetes (glycated hemoglobin [A1C] <7%). Also, gallbladder ejection fraction was measured in 20 age- and sex-matched controls without diabetes., Results: Gallbladder ejection fraction was lower in patients with newly detected diabetes compared with controls (31.4%±5.9% vs. 70.7%±4.3%, p<0.001). Gallbladder ejection fraction did not improve after the treatment of diabetes mellitus (21.3%±5.7%, p=0.395)., Conclusions: Gallbladder ejection fraction was markedly reduced in patients with newly detected diabetes compared to controls without diabetes. Control of diabetes and normalization of A1C did not reverse the motility defect., (Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: To discuss the hazards of cholecystolithiasis recrudesce after cholecystolithotomy with gallbladder reservation; To provide a theoretical basis for reducing the recurrence rate of gallstone., Patients and Methods: The patients who were followed up for at least one year after minimally-invasive operation with gallbladder reservation because of cholecystolithiasis were selected. In this population, the patients with recurrence after surgery were as the case group, those patients with no recurrence after surgery were as the control group. Through collection of general data of selected cases, relevant information of Ultrasound Examinations of gallbladder and history data of the patients questionnaires were completed. Relevant factors of gallstone recurrence of patients, were observed through statistic analysis. Main factors go as follows: gender, age, nation, career, BMI, whether or not the patient had the history of chronic superficial gastritis, and regulation of gallbladder emptying function, family history, etc. The information of selected cases is complete., Results and Conclusions: The main hazards of cholecystolithiasis recurrence were BMI, family history of gallstone disease, and emptying function of gallbladder.

Background: 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., Design: 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)., Results: 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., Conclusions: 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., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Gallstone disease (GSD) is one of the most common biliary tract diseases worldwide in which both genetic and environmental factors have roles in its pathogenesis. Biliary cholesterol supersaturation from metabolic defects in the liver is traditionally seen as the main pathogenic factor. Recently, there have been renewed investigative interests in the downstream events that occur in gallbladder lithogenesis. This article focuses on the role of the gallbladder in the pathogenesis of cholesterol GSD (CGD). Various conditions affecting the crystallization process are discussed, such as gallbladder motility, concentrating function, lipid transport, and an imbalance between pro-nucleating and nucleation inhibiting proteins.

Results: Basal and stimulated serum CCK concentrations were not statistically significant differences (p > 0.05) with the control group in patients studied in the whole and in patients subgroups, formed by the diagnosis of biliary pathology and the character of gallbladder emptying. Increased stimulated CCK concentration was found in patients with symptomatic variants. Reduce of serum-cholecystokinin concentration growth (ACCK) after intake of Sorbitol was revealed in subgroup of patients with low-symptom variant. Reduced sensitivity of the gallbladder to CCK was observed in subgroups of patients with gallbladder hypokinetic dyskinesia and one with symptomatic variant of biliary pathology., Conclusion: The sensitivity of the gallbladder neuromuscular apparatus to CCK is associated with clinical and functional variability of the biliary pathology.

Introduction: Pre-operative ultrasound is the gold standard pre-operative investigation for patients undergoing a cholecystectomy. Ultrasound provides a sensitive approach for analysing characteristics of the gallbladder. Thus, we aimed to examine the importance of ultrasonic gallbladder characteristics on laparoscopic cholecystectomy conversion rates and then sought to devise a pre-operative predictive score for conversion based on our findings., Methods: A retrospective analysis of patients undergoing a laparoscopic cholecystectomy was performed between January 2000 and December 2006. Patient demographic data and pre-operative imaging results from abdominal ultrasounds were analysed. We then devised a pre-operative predictive score for conversion based on independent variables derived from multivariate analysis., Results: A total of 1061 patients underwent a laparoscopic cholecystectomy. Conversion to an open procedure was required in 58 cases. The overall conversion rate was 5.4%. Univariate analysis revealed male gender (p < 0.0001), gallbladder wall thickness >4 mm (p = 0.0024), a contracted gallbladder (p = 0.005) and a dilated CBD (p = 0.0416) as being significantly associated with conversion. These variables were then evaluated using multivariate analysis and three variables, namely, male gender, a contracted gallbladder and a thickened gallbladder wall were identified as independent predictors. A pre-operative predictive score for conversion was devised from a training cohort (n = 761) and tested on a sub-cohort (n = 300). Patients with a score of 2 or more had a 19.2% risk of conversion (p < 0.001)., Conclusion: Conversion to an open cholecystectomy shows a strong associated with gallbladder ultrasonic characteristics which are available pre-operatively. The likelihood of conversion can be accurately predicted using a pre-operative scoring system., (Copyright © 2012 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Inverse estimation of biomechanical parameters of soft tissues from non-invasive measurements has clinical significance in patient-specific modelling and disease diagnosis. In this paper, we propose a fully nonlinear approach to estimate the mechanical properties of the human gallbladder wall muscles from in vivo ultrasound images. The iteration method consists of a forward approach, in which the constitutive equation is based on a modified Hozapfel-Gasser-Ogden law initially developed for arteries. Five constitutive parameters describing the two orthogonal families of fibres and the matrix material are determined by comparing the computed displacements with medical images. The optimisation process is carried out using the MATLAB toolbox, a Python code, and the ABAQUS solver. The proposed method is validated with published artery data and subsequently applied to ten human gallbladder samples. Results show that the human gallbladder wall is anisotropic during the passive refilling phase, and that the peak stress is 1.6 times greater than that calculated using linear mechanics. This discrepancy arises because the wall thickness reduces by 1.6 times during the deformation, which is not predicted by conventional linear elasticity. If the change of wall thickness is accounted for, then the linear model can used to predict the gallbladder stress and its correlation with pain. This work provides further understanding of the nonlinear characteristics of human gallbladder., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background and Purpose: A large number of human and animal studies have challenged the hypothesis that cystic duct obstruction by gallstones causes cholecystitis. These studies suggest that lithogenic bile that can deliver high cholesterol concentrations to the gallbladder wall causes hypomotility and creates a permissive environment that allows normal concentrations of hydrophobic bile salts to inflame the mucosa and impair muscle function inhibiting gallbladder emptying. High concentrations of cholesterol increase its diffusion rates through the gallbladder wall where they are incorporated into the sarcolemmae of muscle cells by caveolin proteins. High caveolar cholesterol levels inhibit tyrosine-induced phosphorylation of caveolin proteins required to transfer receptor-G protein complexes into recycling endosomes. The sequestration of these receptor-G protein complexes in the caveolae results in fewer receptors recycling to the sarcolemmae to be available for agonist binding. Lower internalization and recycling of CCK-1 and other receptors involved in muscle contraction explain gallbladder hypomotility. PGE2 receptors involved in cytoprotection are similarly affected. Cells with a defective cytoprotection failed to inactivate free radicals induced by normal concentrations of hydrophobic bile salts resulting in chronic inflammation that may lead to acute inflammation. Ursodeoxycholic acid salts (URSO) block these bile salts effects thereby preventing the generation of free radicals in muscle cells in vitro and development of cholecystitis in the ligated common bile duct in guinea pigs in vivo. Treatment with URSO improves muscle contraction and reduces the oxidative stress in patients with symptomatic cholesterol gallstones by lowering cholesterol concentrations and blocking the effects of hydrophobic bile salts on gallbladder tissues., (© 2013 Blackwell Publishing Ltd.)

Background & Aims: Patients with cystic fibrosis (CF) have poorly defined defects in biliary function. We evaluated the effects of cystic fibrosis transmembrane conductance regulator (CFTR) deficiency on the enterohepatic disposition of bile acids (BAs)., Methods: Bile secretion and BA homeostasis were investigated in Cftr(tm1Unc) (Cftr-/-) and CftrΔF508 (ΔF508) mice., Results: Cftr-/- and ΔF508 mice did not grow to normal size, but did not have liver abnormalities. The gallbladders of Cftr-/- mice were enlarged and had defects in emptying, based on (99m)technetium-mebrofenin scintigraphy or post-prandial variations in gallbladder volume; gallbladder contraction in response to cholecystokinin-8 was normal. Cftr-/- mice had abnormal gallbladder bile and duodenal acidity, and overexpressed the vasoactive intestinal peptide-a myorelaxant factor for the gallbladder. The BA pool was larger in Cftr-/- than wild-type mice, although there were no differences in fecal loss of BAs. Amounts of secondary BAs in portal blood, liver, and bile of Cftr-/- mice were much lower than normal. Expression of genes that are induced by BAs, including fibroblast growth factor-15 and BA transporters, was lower in the ileum but higher in the gallbladders of Cftr-/- mice, compared with wild-type mice, whereas enzymes that synthesize BA were down-regulated in livers of Cftr-/- mice. This indicates that BAs underwent a cholecystohepatic shunt, which was confirmed using cholyl-(Ne-NBD)-lysine as a tracer. In Cftr-/- mice, cholecystectomy reversed most changes in gene expression and partially restored circulating levels of secondary BAs. The ΔF508 mice overexpressed vasoactive intestinal peptide and had defects in gallbladder emptying and in levels of secondary BAs, but these features were less severe than in Cftr-/- mice., Conclusions: Cftr-/- and CftrΔF508 mice have defects in gallbladder emptying that disrupt enterohepatic circulation of BAs. These defects create a shunt pathway that restricts the amount of toxic secondary BAs that enter the liver., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective:   Impaired gallbladder (GB) emptying is a well-documented contributor to gallstone formation. The aim of this study was to evaluate GB motility in patients with polycystic ovary syndrome (PCOS)., Methods:   The study population consisted of 36 PCOS patients and 20 healthy controls. GB volume was calculated using the ellipsoid formula (π/6 × L × D × W) after three-dimensional measurements were made by ultrasound [length (L), width (W) and depth (D)]. Following the determination of fasting GB volume (V0), patients were given a standard liquid meal. GB volume measurement was then repeated after 10, 20, 30, 40, 50, 60, 75 and 90 min. Gallbladder ejection fraction (GBEF) was calculated after each measurement. PCOS patients were re-evaluated after a 12-week course of metformin therapy at a dose of 1000 mg/day., Results:   Mean baseline GB volume (V0) was significantly higher in the patient group compared to the control group (27·2 ± 12·5 cm(3) vs 13·3 ± 7·0 cm(3) , P < 0·001). While baseline GBEF values were similar between groups, increases in GBEF were significantly lower in the PCOS group starting from 20 min after consumption of a standard test meal. A 12-week course of metformin therapy resulted in significant improvements in GB volume and GBEF values with a reversal of metabolic and hormonal abnormalities., Conclusion:   For the first time in the literature, we managed to demonstrate impaired GB motility in patients with PCOS. Metformin therapy not only improves the metabolic and hormonal imbalances associated with PCOS but also has a positive influence on GB motility., (© 2012 Blackwell Publishing Ltd.)

Background: Alterations of small intestinal transit and gallbladder (GB) motility have been reported in celiac disease (CD) in studies involving, in most cases, non-physiological experimental conditions and artificial stimuli to motility. Our aims were to quantitate non-invasively small intestinal transit time and GB emptying during administration of a physiological and palatable solid meal, and to assess the effect of gluten-free diet (GFD)., Methods: We simultaneously measured mouth-to-cecum transit time (MCTT) using a validated H(2) breath test, and GB motility using ultrasonography. We studied CD patients before (n = 19) and during (n = 14) GFD, and healthy volunteers (n = 24) following administration of a physiological solid meal (Kcal 539)., Key Results: Mouth-to-cecum transit time was more prolonged in CD (mean ± SEM: 235 ± 96 min) than in controls (169 ± 65 min, P = 0.0039). The GB fasting volume and postprandial residual volume were significantly higher in CD than in controls, and GB emptying constant was slower in CD than in controls. During GFD, GB emptying reverted to normal, but MCTT remained unchanged (229 ± 69 min) and more prolonged in CD than in controls (P = 0.0139). During GFD, duodenal infiltration with lymphocytes and mast cells persisted higher than that in controls, and the number of mast cells lying in proximity of nervous endings did not change., Conclusions & Inferences: Slow postprandial MCTT in response to a physiological meal does not revert to normal during GFD, an effect mirroring incomplete histopathologic recovery., (© 2011 Blackwell Publishing Ltd.)

Objective: The purpose of this study was to determine the efficacy of 3D and 4D ultrasound in correlation with hepatoiminodiacetic acid (HIDA) scanning for calculating gallbladder ejection fraction (EF)., Subjects and Methods: A prospective study was conducted with 40 adult patients with suspected gallbladder dyskinesia. Cholecystokinin-provoked (99m)Tc-HIDA scintigraphy was performed, and concurrent 3D and 4D ultrasound images of the gallbladder were obtained before cholecystokinin infusion and 20, 30, and 40 minutes after infusion. The EF values calculated from the ultrasound images and HIDA scan were compared., Results: The gallbladder EF values (mean ± standard error of the mean) calculated 20 minutes after cholecystokinin infusion from HIDA scans and 3D and 4D ultrasound images were 54.1% ± 5.0%, 58.9% ± 6.3%, and 62.8% ± 5.5%. Thirty minutes after infusion the EF values were 56.3% ± 4.7%, 56.9% ± 5.7%, and 59.1% ± 4.6%. The numbers of patients with an EF less than 50% were 14, 12, and 13, and the numbers with an EF less than 35% were 10, seven, and eight. For the patients with an EF less than 50%, the kappa agreement between HIDA scanning and 3D ultrasound was 0.89 (95% CI, 0.73-1.00), between HIDA scanning and 4D ultrasound was 0.83 (95% CI, 0.65-1.00), and between 3D and 4D ultrasound was 0.83 (95% CI, 0.64-1.00)., Conclusion: Both 3D and 4D ultrasound techniques correlate well with HIDA scanning for calculating gallbladder EF in patients with suspected biliary dyskinesia.

Introduction: The objective of this study was to assess the variabilities of gallbladder contraction indices (GBCI) and derive a predictive model for gallbladder and gastric motility., Methods: The gallbladder volume and gastric antral measurements were obtained from 24 healthy male volunteers in preprandial and post-milk ingestion states. After preprandial measurement of the gallbladder volume and gastric antral area, each subject ingested 157 ml of full cream milk and 30 cl of ion-free water. In supine position, the gallbladder volume and the gastric antral area were obtained every five minutes for 40 minutes. For the gallbladder while only the 5(th), 10(th) and 15(th) measurement of gastric antral area were obtained. Gallbladder contraction indices were calculated and gastric emptying ratio obtained at the fifteenth minute is the indication of gastric motility. Statistical analyses were conducted using SPSS version 16.0 with p < 0.05 as criterion of statistical significance., Results: The GBCIs followed Gaussian response at some stages and did not at some other stages. The least variability occurred at the 35th measurement of GBCI. A cut- off value for the 35th minute GBCI value was established with the mean ± 2 SD (80.79 ± 11.5%). Obvious gallbladder refilling was noted after 35 minutes. A positive relationship was noted between gallbladder and gastric motilities., Conclusion: With milk dilution, the variability of gall bladder motility is least at the 35th minute. A significant positive relationship between gastric emptying and gallbladder contraction index was also observed.

Cholesterol gallstone formation is a complex process and involves phase separation of cholesterol crystals from supersaturated bile. In most cases, cholesterol hypersecretion is considered the primary event in gallstone formation. The sterol is transported through the hepatocytic canalicular membrane by ABCG5-G8. Expression of this transport protein is regulated by transcription factor Liver X Receptor-alpha, which may be responsible for biliary hypersecretion. Hydrophobic bile salt pool, bile concentration, excess pronucleating mucin, and impaired gallbladder and intestinal motility are secondary phenomena in most cases but nevertheless may contribute to gallstone formation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Functional gallbladder disorder, commonly referred to as gallbladder dyskinesia, is characterized by the occurrence of abdominal pain resembling gallbladder pain but in the absence of gallstones. The diagnosis and management of this condition can be confusing even for the most astute clinician. The aim of this article is to clarify the identification and management of patients with suspected functional gallbladder disorder., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Somatostatin inhibits gall bladder contraction. Impaired gall bladder emptying is associated with gall bladder stone formation. The incidence of cholecystolithiasis is high in patients treated with a somatostatin agonist octreotide, which predominantly interacts with somatostatin receptor subtype 2 (SSTR2). Therefore, it is believed that SSTR2 regulates gall bladder contraction; however, evidence has not been provided. Here, we evaluate the effects of SSTR1-SSTR5-selective agonists on egg yolk-induced gall bladder contraction in mice., Methods: Homozygous deletion of SSTR2 and SSTR5 was generated by cross-mating of SSTR2(-/-) with SSTR5(-/-) mice. Mice of different genotypes were injected with SSTR1-5-selective agonists or octreotide 15 min before induction of gall bladder emptying by egg yolk. One hour later, gall bladders were removed and weighed., Key Results: Egg yolk-reduced gall bladder weights in all mice, irrespective of their genotype. Octreotide was the most potent inhibitor of gall bladder emptying in wild-type mice. In contrast, agonists with high selectivity for SSTR2 or SSTR5 inhibited gall bladder emptying by approximately 50-60%, whereas SSTR1-, SSTR3- and SSTR4-selective agonists failed to influence gall bladder contraction. In SSTR2(-/-) mice, octreotide and an SSTR5-selective agonist inhibited gall bladder emptying by approximately 50%, whereas SSTR2-selective agonists were inactive. Octreotide inhibited gall bladder emptying in SSTR5(-/-) mice by approximately 50%, without any effect in SSTR2(-/-)/SSTR5(-/-) mice., Conclusions & Inferences: Our study provides evidence for the role of SSTR2 and SSTR5 in regulating gall bladder emptying in mice.

Hypothyroidism and hyperthyroidism are known to affect cholesterol metabolism, bile acid synthesis and bile content. There are previous studies reporting increased prevalence of gallstone and common bile duct stone formation in hypothyroidism. The aim of this study was to compare gallbladder (GB) motor function between euthyroid, hypothyroid and hyperthyroid subjects by conventional ultrasonography. Eighteen euthyroid, 14 hypothyroid and 20 hyperthyroid, age, sex and body mass index matched subjects were included in the study. Etiology of hypothyroidism comprised of thyroidectomy, Hashimoto's thyroiditis and previous radioactive iodine therapy. Hyperthyroid group included patients with toxic nodular goitre and Graves' disease. Patients who have diseases or are under drug treatment known to affect biliary function were not included in the study. Fasting and post-stimulus GB volumes were measured by real-time conventional ultrasonography and computer unit (Aloka UST-979, 3.5 mHz electronic convex probe, Japan). No significant differences were noted for fasting, post-stimulus GB volumes and GB ejection fraction between euthyroid, hypothyroid and hyperthyroid subjects. Measuring GB motility accurately is not straightforward because besides being not static during fasting, after a meal, intermittent emptying and refilling of GB occurs. Ultrasonography is affected by GB filling and measures "net" GB emptying. Although cumbersome, additional evaluation with cholescintigraphy which detects "absolute" GB emptying and is not affected by GB filling may provide complete assessment of motor function and may be more informative in evaluating subjects with different thyroid hormone status., (J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart.New York.)

Aim: To assess gallbladder emptying and its association with cholecystitis and abdominal pain in patients with primary sclerosing cholangitis (PSC)., Methods: Twenty patients with PSC and ten healthy subjects were investigated. Gallbladder fasting volume, ejection fraction and residual volume after ingestion of a test meal were compared in patients with PSC and healthy controls using magnetic resonance imaging. Symptoms, thickness and contrast enhancement of the gallbladder wall and the presence of cystic duct strictures were also assessed., Results: Median fasting gallbladder volume in patients with PSC [67 (19-348) mL] was twice that in healthy controls [32 (16-55) mL] (P < 0.05). The median postprandial gallbladder volume in patients with PSC was significantly larger than that in healthy controls (P < 0.05). There was no difference in ejection fraction, gallbladder emptying volume or mean thickness of the gallbladder wall between PSC patients and controls. Contrast enhancement of the gallbladder wall in PSC patients was higher than that in controls; (69% +/- 32%) and (42% +/- 21%) (P < 0.05). No significant association was found between the gallbladder volumes and occurrence of abdominal pain in patients and controls., Conclusion: Patients with PSC have increased fasting gallbladder volume. Gallbladder Mucosal dysfunction secondary to chronic cholecystitis, may be a possible mechanism for increased gallbladder.

Aim: To investigate the effects of gallbladder stones on motor functions of the gallbladder and the dynamics of bile flow in asymptomatic gallstone disease., Methods: Quantitative hepatobiliary scintigraphy was performed to detect the parameters of gallbladder motor function [gallbladder ejection fraction (GBEF), gallbladder visualization time (GBVT), gallbladder time to peak activity (GBT(max)), gallbladder half emptying time (GBT(1/2)), and transit time of bile to duodenum (TTBD)] in 24 patients with asymptomatic cholelithiasis who were diagnosed incidentally during routine abdominal ultrasonographic examination and 20 healthy subjects with normal gallbladder., Results: Even though there was no significant difference in the clinical and laboratory parameters between the patient and control groups, all parameters of gallbladder function except TTBD were found to differ significantly between the two groups. GBEF in the patient group was decreased (P = 0.000) and GBVT, GBT(max), GBT(1/2) in the patient group were longer (P = 0.000, P = 0.015, P = 0.001, respectively)., Conclusion: Our results showed that even if there were not any clinical and laboratory findings, gallbladder filling and emptying could be impaired in patients with gallstone disease.

Since the early 1980s interventions have been used in conjunction with (99m)Tc-iminodiacetic acid (IDA) radiopharmaceuticals in many different clinical situations, eg, to prepare the patient for the study, to reduce the time of a study, to improve its diagnostic accuracy, and to make diagnoses not otherwise possible. Interventions all have underlying physiological rationales. Some of these interventions are as simple as having the patient fast before the study or eat a meal with high fat content. However, most are pharmacologic interventions, eg, morphine sulfate, cholecystokinin, and phenobarbital. Although these are probably the most common interventions used today, numerous other interventions have been used during the years and likely will be in the future. Interventions have aided in the diagnosis of acute cholecystitis, chronic cholecystitis, biliary obstruction, and sphincter of Oddi dysfunction. This review will discuss in detail the interventions commonly is use today and in somewhat less detail many that have been successfully used on an investigational basis and may have some larger role in the future.

We studied gall bladder contractility in 61 children with beta-thalassaemia who were asymptomatic for gall bladder disease and 51 sex- and age-matched controls in Cairo, Egypt, using, andreal-time ultrasonography. Multiple gall bladder stones were present in 18.0% of thalassaemia patients and sludge in 6.6%. There were statistically significant differences between thalassaemia patients controls in gall bladder fasting volume, residual volume, emptying time and contraction index. There was significant positive correlation between fasting and residual volumes and age, weight and height, and between fasting volume and body mass index and serum ferritin level. Contraction index was negatively correlated with serum total bilirubin. Impaired gall bladder motility was evident in patients with beta-thalassaemia and it may be related to disease duration, serum ferritin and total serum bilirubin level.

Background: Gallstones have been frequently diagnosed after Roux-en-Y gastric bypass (RYGBP). Gallbladder stasis associated with duodenal exclusion may play a role in their pathogenesis., Methods: Gallbladder emptying was studied before and on the 30th and 31st postoperative days (POD) after RYGBP in 20 morbidly obese patients. Gallbladder volume after fasting and every 15 min during a 2-h period following administration of a standard liquid meal was determined by sonography. On the 31st POD, the meal was administered through the gastrostomy in order to promote its transit through the duodenum. Fasting volume (FV), maximum ejection fraction (Max EF), and residual volume (RV) were determined. Biliary sludge and calculi were investigated after 1 and 6 months, respectively., Results: FV was 39.4 +/- 20.2 ml, 50.1 +/- 22.7 ml, and 47.9 +/- 23.4 ml, respectively, for the preoperative and two postoperative assessments (P = 0.09). RV was 7.6 +/- 8.7 ml, 25.1 +/- 20.0 ml, and 24.6 +/- 20.9 ml; and Max EF was 80.5 +/- 20.9%, 54.3 +/- 21.4%, and 50.5 +/- 29.0%, respectively, for the pre-, postoral, and postgastrostomy infusion measurements. There was only a significant difference between the preoperative value and the two postoperative values (P < 0.001). Biliary sludge was detected in 65% of the patients and 46% of them subsequently developed gallstones., Conclusions: Gallbladder emptying became significantly compromised after RYGBP. This impairment was unrelated to duodenal exclusion but it was associated with biliary sludge and stone formation.

Background/aims: Increased viscosity and supersaturation of cholesterol in gallbladder bile, as well as an impaired motility of the gallbladder, are considered to be important factors in the pathogenesis of cholesterol gallstones. However, the relation of these parameters has not yet been determined., Material and Methods: Bile viscosity (mPa s) was measured by rotation viscosimetry and the composition of gallbladder bile was determined using standard methodology. Gallbladder motility was calculated as ejection fraction in percent of total volume 45 min after a test meal using ultrasonography in patients with gallstones prior to elective cholecystectomy., Results: The study included 35 patients with cholesterol gallstones. Viscosity of gallbladder bile ranged between 0.9 and 12.5 mPa s (median 2.2 mPa s) and an ejection fraction of the gallbladder of 55.4 +/- 18.3% (mean +/- SD) was determined. No significant correlation (r = 0.19, p < 0.2) between the 2 parameters could be calculated. Analysis of the composition of gallbladder bile revealed a positive correlation of all components to biliary viscosity but not to the motility of the gallbladder, with the exceptions of a negative correlation (r = 0.39, p < 0.02) between mucin concentration and the ejection fraction at 45 min after the test meal., Conclusions: The motility of the gallbladder appears to be unrelated to the viscosity of gallbladder bile or gallbladder bile composition. The negative correlation between the ejection fraction of the gallbladder and mucin concentration of gallbladder bile suggests that chronic inflammation of the gallbladder wall is associated with both an impaired motility of the gallbladder and increased mucin release into gallbladder bile., (Copyright 2009 S. Karger AG, Basel.)