Glucagon-Like Peptide 2 Inhibits Postprandial Gallbladder Emptying in Man: A Randomized, Double-Blinded, Crossover Study.

INTRODUCTION: A recent study in mice points to the gut-derived hormone glucagon-like peptide 2 (GLP-2) as an important regulator of gallbladder motility inducing gallbladder relaxation and refilling. In this study, we evaluated the effect of exogenous GLP-2 on postprandial gallbladder motility in healthy men. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effect of 4-hour intravenous infusions of high-dose GLP-2 (10 pmol × kg × min), low-dose GLP-2 (1 pmol × kg × min), and placebo (saline) on postprandial gallbladder motility. A 300-kcal liquid-mixed meal (added 1.5 g of acetaminophen for indirect measurement of gastric emptying) was served 30 minutes after start of intravenous infusions. Gallbladder volume was assessed by ultrasonography. RESULTS: Fifteen healthy men, age 24.3 (22.4-26.1) years (mean [95% confidence interval]) and body mass index 22.5 (21.7-23.4) kg × m, were included. Basal plasma GLP-2 concentration was 14 (11-17) pmol/L. During low-dose and high-dose GLP-2 infusions, steady-state postprandial plasma GLP-2 concentrations amounted to 201 (188-214) and 2,658 (2,443-2,873) pmol/L, respectively, compared with maximum postprandial plasma GLP-2 concentration of 34 (25-44) pmol/L during placebo. Gallbladder emptying (assessed as baseline-subtracted area under the curve for gallbladder volume) was reduced by low-dose GLP-2 (-0.8 [0.7-1.9] L × min, P < 0.0001) and nearly abolished by high-dose GLP-2 (1.3 [-1.7 to 0.01] L × min, P = 0.029) compared to placebo (-2.0 [-2.8 to -1.1] L × min). Compared to placebo, gastric emptying was reduced by high-dose GLP-2 (P = 0.0060 and 0.019), whereas low-dose GLP-2 did not affect gastric emptying (P = 0.13 and 0.85). DISCUSSION: Exogenous GLP-2 exerts a dose-dependent inhibitory effect on postprandial gallbladder emptying in healthy men.

Utilizing the Cholecystagogue, Ensure Plus, Results in Similar Hepatobiliary Scintigraphy Study Results and Patient Outcomes Status Post Cholecystectomy, in Comparison With Sincalide.

OBJECTIVE: To determine if use of the oral cholecystagogue, Ensure Plus (EP), in hepatobiliary scintigraphy (HBS) leads to a similar distribution of normal and abnormal gallbladder ejection fractions (GBEFs) versus other historical secondary findings of chronic biliary disease in a similar patient population compared with the conventional cholecystokinin analog, sincalide. The HBS findings analyzed included the GBEF, small bowel transit time, gallbladder fill time, and reversal of the normal gallbladder versus small bowel transit. The secondary objectives were to determine whether patient outcomes were significantly different for EP and sincalide HBS study patients following cholecystectomy, namely, the surgical pathology and patient-reported biliary-type pain. METHODS: We reviewed all HBS examinations over a retrospective 34-month period. Data from 446 patients who underwent sincalide or EP HBS with GBEF determination for evaluation of chronic symptoms concerning for biliary etiology met the inclusion criteria. The aforementioned HBS findings and postsurgical patient outcomes were obtained for each patient group. RESULTS: Comparing HBS examinations performed with sincalide or EP, no significant differences were noted in the major HBS findings of similar patient populations. Outcomes for the sincalide and EP groups status post cholecystectomy were assessed to determine their sensitivity, specificity, positive predictive value, and negative predictive value. The outcomes assessed were the histopathology and patient-reported amelioration of biliary-type pain. No significant differences were noted. CONCLUSIONS: The sincalide and EP cholecystagogues did not lead to significantly different HBS findings for similar patient populations or postcholecystectomy outcomes.

New Avenues in the Regulation of Gallbladder Motility-Implications for the Use of Glucagon-Like Peptide-Derived Drugs.

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.

Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs.

OBJECTIVE: Recent randomized and controlled trials of drugs derived from the gut hormone glucagon-like peptide-1 (GLP-1) show that the most frequent adverse symptoms are gastrointestinal, including gallbladder-related side effects such as cholithiasis and cholecystitis. Since the gut hormone cholecystokinin (CCK) stimulates bile secretion and regulates gallbladder motility and emptying, we examined the effect of GLP-1 on the secretion of CCK in normal subjects and patients with type 1 diabetes mellitus. MATERIALS AND METHODS: Plasma was sampled from 10 healthy subjects and 10 patients with diabetes. With plasma glucose concentrations clamped between 6 and 9 nmol/l, GLP-1 or saline was infused for 240 min during and after a meal. The plasma concentrations of CCK were measured with a highly specific radioimmunoassay. RESULTS: Basal plasma concentrations of CCK were similar in the normal subjects and in the diabetes patients. During the meal, the CCK concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of CCK significantly in both normal subjects and in the diabetes patients. CONCLUSIONS: The results show that GLP-1 suppresses the secretion of CCK after a meal in normal and diabetic subjects. The suppression attenuates the gallbladder contractility. Our data, therefore, offer an explanation for the increased risk of adverse gallbladder events during treatment with GLP-1-derived drugs.

Effect of prednisolone administration on gallbladder emptying rate and gallbladder bile composition in dogs.

OBJECTIVE To investigate effects of prednisolone administration on gallbladder emptying rate and gallbladder bile composition in dogs. ANIMALS 6 healthy Beagles. PROCEDURES Prednisolone was administered (2 mg/kg, SC, once daily for 2 weeks) to each dog and tapered over 2 weeks. Gallbladder emptying rate and bile composition were evaluated before and after administration of prednisolone for 2 weeks as well as 1 week after cessation of prednisolone administration. RESULTS Gallbladder emptying rate decreased significantly after prednisolone administration (median, 27%; range, 0% to 38%), compared with rate before administration (median, 59%; range, 29% to 68%), but then increased 1 week after cessation of administration (median, 45%; range, 23% to 48%). Gallbladder bile mucin concentration decreased significantly after prednisolone administration (median, 8.8 mg/dL; range, 6.2 to 11.3 mg/dL), compared with concentration before administration (median, 13.1 mg/dL; range, 10.7 to 21.7 mg/dL), but then increased 1 week after cessation of administration (median, 14.3 mg/dL; range, 9.6 to 26.7 mg/dL). Gallbladder taurochenodeoxycholic acid concentration decreased significantly after prednisolone administration (8.1 mmol/L; range, 6.8 to 15.2 mmol/L), compared with concentration before administration (median, 27.2 mmol/L; range, 22.0 to 31.9 mmol/L), but then increased 1 week after cessation of administration (median, 26.4 mmol/L; range, 15.1 to 31.5 mmol/L). CONCLUSIONS AND CLINICAL RELEVANCE A lower gallbladder emptying rate caused by prednisolone administration may be involved in the pathogenesis of gallbladder disease in dogs. Further studies are required to determine the clinical importance of lower gallbladder bile mucin concentrations caused by glucocorticoid administration in the pathogenesis of gallbladder disease in dogs.

Effects of a Gluten-Containing Meal on Gastric Emptying and Gallbladder Contraction.

The ingestion of gluten has been associated with gastrointestinal symptoms even in the absence of detectable immune responses. Little is known about the pathophysiological effects of gluten on the upper gastrointestinal tract. We aimed to assess whether the ingestion of gluten leads to an impairment of the physiological mechanisms of gastric emptying, gallbladder contraction and relaxation. A total of 17 healthy subjects underwent ultrasound evaluation of gastric emptying dynamics and gallbladder contractions at baseline and every 30 min after a standard gluten-containing and gluten-free meal (250 kcal, 70% carbohydrates). The pattern of gastric emptying was similar after a standard meal with or without gluten, but differed in terms of the peak of the antral filling curve, which was wider (mean area 5.69, median 4.70, range 3.71‒9.27 cm² vs. mean 4.89, median 4.57, 2.27‒10.22 cm², p = 0.023) after the gluten-containing meal. The pattern of gallbladder contractions was different after the gluten-free meal (p < 0.05), with higher gallbladder volumes in the late refilling phases. The results of this study show that gluten ingestion exerts objective effects on gastric and gallbladder motility. Although the underlying pathophysiological mechanism remains unknown, these results could account for some of the gluten-related symptoms reported by patients with celiac disease and non-celiac gluten sensitivity.

Effects of liraglutide on gallbladder emptying: A randomized, placebo-controlled trial in adults with overweight or obesity.

AIMS: Treatment with liraglutide 3.0 mg has been associated with gallbladder-related adverse events. To conduct a single-centre, double-blind, 12-week trial comparing the effect of 0.6 mg liraglutide and steady-state liraglutide 3.0 mg with placebo on gallbladder emptying in adults with body mass index (BMI) ≥27 kg/m2 and without diabetes. METHODS: Participants were randomized 1:1 to once-daily subcutaneous liraglutide (n = 26) or placebo (n = 26), starting at 0.6 mg with 0.6-mg weekly increments to 3.0 mg, with nutritional and physical activity counselling. A 600-kcal (23.7 g fat) liquid meal test was performed at baseline, after the first dose and after 12 weeks. The primary endpoint was the 12-week maximum postprandial gallbladder ejection fraction (GBEFmax ), measured over 240 minutes after starting the meal. RESULTS: Baseline characteristics were similar between groups (mean ± SD overall age 47.6 ± 10.0 years, BMI 32.6 ±3.4 kg/m2 , 50% women). Mean 12-week GBEFmax (treatment difference -3.7%, 95% confidence interval [CI] -13.1, 5.7) and area under the GBEF curve in the first 60 minutes (-390% × min, 95% CI -919, 140) did not differ for liraglutide 3.0 mg (n = 23) vs placebo (n = 24). The median (range) time to GBEFmax was 151 (11-240) minutes with liraglutide 3.0 mg and 77 (22-212) minutes with placebo. Similar findings were noted after the first 0.6-mg liraglutide dose. Gastrointestinal disorders, notably nausea and constipation, were the most frequently reported adverse events. CONCLUSIONS: Treatment with liraglutide did not affect the GBEFmax but appeared to prolong the time to GBEFmax .

Ursodeoxycholic acid protects interstitial Cajal-like cells in the gallbladder from undergoing apoptosis by inhibiting TNF-α expression.

Hypomotility is a common symptom of gallstone disease, which is accompanied by a loss of interstitial Cajal-like cells (ICLCs) in the gallbladder. Ursodeoxycholic acid (UDCA) is widely used in treating gallstone disease, and has shown anti-apoptotic and anti-inflammatory effects apart from its ability to dissolve gallstones. In this study, we investigated the anti-apoptotic and anti-inflammatory effects of UDCA on ICLCs in guinea pigs with gallstones. Guinea pigs were fed a high-cholesterol diet for 8 weeks to induce the formation of gallstones. A group of animals was administered UDCA (50 mg·kg-1·d-1, ig) simultaneously. At the end of 8 weeks, the animals were euthanized with anesthesia, cholecystectomy was performed immediately and gallbladder was collected for further analysis. We showed that in the model group the contractility of gallbladder muscle strips in response to both acetylcholine (ACh) and CCK-8 was severely impaired, which was significantly improved by UDCA administration. Furthermore, UDCA administration significantly reduced the apoptotic ratio of ICLCs, based on the observation of co-localization imaging of apoptotic cells and c-kit-positive cells. Western blotting analysis and real-time PCR results revealed that the TNF-α/Caspase8/Caspase3 pathway was suppressed in the UDCA-treated animals, confirming the anti-apoptotic effect of UDCA in the gallbladder. The H&E staining showed that UDCA administration significantly attenuated inflammatory cell infiltration in the gallbladder wall. In conclusion, UDCA can protect ICLCs in the gallbladder from undergoing apoptosis by inhibiting the TNF-α/Caspase8/caspase3 pathway.

The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes.

AIMS: Discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes. MATERIALS AND METHODS: We performed a randomized, placebo-controlled, double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min) or saline was administered in randomized order. The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed. RESULTS: CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions. CONCLUSIONS: Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.

Single-Dose Metformin Enhances Bile Acid-Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes.

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.

Effect of Albiglutide on Cholecystokinin-Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 µg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide (P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

Evaluation of anti-diabetic effect and gall bladder function with 2-thio-5-thiomethyl substituted imidazoles as TGR5 receptor agonists.

A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.

Normal Gallbladder Ejection Fraction Occurring Unexpectedly Obviates Need for Sincalide Stimulation.

A 25-year-old man was referred for chronic right upper quadrant abdominal pain for hepatobiliary scintigraphy to evaluate the gallbladder (GB) function. An unexpected GB contraction with ejection fraction (EF) of 90% was observed during the first hour of baseline imaging. Subsequent stimulation with sincalide produced GB EF of 99%. A similar case previously reported also showed normal unexpected GB EF that predicted similar post-sincalide GB EF. These examples support what should be evident: A normal unexpected GB EF is a sufficient evidence for a normal GB function and should obviate need for sincalide stimulation.

Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.

CONTEXT: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. OBJECTIVE: We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. DESIGN: A double-blinded, randomized study. SETTING: The study was conducted at a specialized research unit. PARTICIPANTS: Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). INTERVENTION: On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. MAIN OUTCOME MEASURES: Plasma levels of GLP-1. RESULTS: CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. CONCLUSIONS: CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

The cholecystokinin-1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice.

BACKGROUND: A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin-1 receptor (CCK-1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation. DESIGN: To study whether the CCK-1R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days. RESULTS: During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high-fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide-treated mice, increasing the bioavailability of chylomicron-derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization. CONCLUSIONS: The potent CCK-1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.

Oral Cholecystagogue Cholescintigraphy: A Systematic Review of Fatty Meal Options.

OBJECTIVES: Intermittent unavailability of sincalide for determination of gallbladder ejection fraction (GBEF) prompted increased usage of fatty meal cholecystagogues (FMCs). The aim of this systematic review was to identify the state of current FMC options in cholescintigraphy, focusing on the quality of corresponding normal GBEF values. METHODS: We performed an extensive literature search of the MEDLINE, Cochrane, and CINAHL databases without date or language restrictions with a broad spectrum of search terms. Selection criteria required both that the study use a FMC as part of a stimulated GBEF examination to gather data on normal volunteers or patients without evidence of gastrointestinal disease and that the meal used be described sufficiently for emulation. A cumulative point system was used to grade the quality of normal GBEF values: 1 point for screening ultrasound, 1 point for detailed screening questionnaire, 1 point for 20 or greater number of participants in a study, 1 additional point for 60 or greater number of participants in a study, 0.5 points for cursory screening questions, and 0 points when no screening process was mentioned. The meal was expressed in grams of fat per volume, when available. RESULTS: Twelve studies met inclusion criteria out of 15 studies claiming to report normal values. Two studies (17%) achieved a score of 3, 5 studies (42%) at 2 to 2.5, 3 studies (25%) at 1 to 1.5, and the remaining 2 studies (17%) at 0 to 0.5. Total number of participants examined ranged from 6 to 100. Meal composition varied widely. In 1 study, sham feeding was used. Most meals had components that could present problems to patients with relatively common dietary restrictions (ie, lactose intolerance, egg protein allergy, etc). Results for proposed normal values varied widely (from 16.3% to 85.6%). The commercial fatty meal products of Humana Infant Formula 1 and Ensure Plus offered the highest-quality normal values. CONCLUSIONS: There is a need to establish high-quality normal GBEF range for a ubiquitous fatty meal (ie, a meal that would be widely available, easy to prepare, inexpensive, and free of sensitivity-provoking ingredients). A corn oil emulsion, has immense potential as an ideal FMC, limited currently only by its lack of established normal values. Currently, the highest-quality normal GBEF values available for FMC exist for 2 commercial products, Humana Infant Formula 1 and Ensure Plus. However, these products may not be readily available at some institutions, and neither one is free from dietary restrictions.

Liquid gastric emptying as an adjunct to hepatobiliary scintigraphy when oral corn oil is used as a cholecystagogue for determining gallbladder emptying.

UNLABELLED: During times of sincalide shortage, a fatty meal can be used to stimulate gallbladder contraction during hepatobiliary scintigraphy. However, if a patient has an abnormal gallbladder ejection fraction (GBEF), is the cause chronic cholecystitis or is it inadequate cholecystokinin stimulation due to poor gastric emptying? Hence, during the 2014 sincalide shortage, simultaneous liquid gastric emptying using (99m)Tc-sulfur colloid along with corn oil emulsion was initiated as routine practice in patients evaluated for GBEF. The objective of this study was to retrospectively assess the time course of gastric emptying in these patients, especially with regard to whether delayed gastric emptying may be a factor in some patients with a poor GBEF. METHODS: My institution's clinical imaging procedure during the 2014 sincalide shortage consisted of routine (99m)Tc-mebrofenin hepatobiliary scintigraphy followed by corn oil emulsion and (99m)Tc-sulfur colloid orally. Dynamic imaging with regions of interest encompassing the gallbladder and the stomach allowed determination of GBEF and gastric emptying. For this study, the imaging records for 53 consecutive patients undergoing this clinical procedure were reviewed. The time for half gastric emptying, along with percentage gastric emptying at the end of imaging, was evaluated in relationship to GBEF. RESULTS: Seventeen patients had a normal GBEF (74% ± 14%) and satisfactory gastric emptying (31 ± 21 min for half emptying, 75% ± 14% emptying at end of imaging); 17 patients had a normal GBEF (77% ± 17%) despite unsatisfactory gastric emptying (only 30% ± 14% emptying at end of imaging); 5 patients had an abnormal GBEF (19% ± 9%) and satisfactory gastric emptying (26 ± 19 min for half emptying, 82% ± 14% emptying at end of imaging), supporting a diagnosis of chronic cholecystitis; 11 patients had an abnormal GBEF (26% ± 9%) but also unsatisfactory gastric emptying (only 26% ± 13% emptying at end of imaging), which did offer additional support for a diagnosis of chronic cholecystitis; and 3 patients had a borderline GBEF (40% ± 2%) with satisfactory gastric emptying (59% ± 6% emptying at end of imaging). CONCLUSION: Simultaneous liquid gastric emptying can provide additional information in the interpretation of GBEF when a fatty meal is used as an oral cholecystagogue, especially to help differentiate chronic cholecystitis from inadequate cholecystokinin stimulation due to poor gastric emptying.

Castanea sativa Mill. extract contracts gallbladder and relaxes sphincter of Oddi in guinea pig: a natural approach to biliary tract motility disorders.

Impaired gallbladder motility is a contributing factor to gallstone formation. Since many drugs delaying intestinal motility inhibit gallbladder emptying, the aim of the present study was to evaluate the effect on gallbladder and sphincter of Oddi motility of a Natural Chestnut Wood Extract (NEC) that reduces intestinal motility. In order to evaluate the effect of the extract in normal- and high-risk gallstone conditions, the investigation was performed using tissues from animals fed normal and lithogenic diet. Fifty guinea pigs were administered either control or lithogenic diet. The spontaneous motility of the gallbladder and sphincter of Oddi were recorded on isolated gallbladder tissues; thereafter, the effect of NEC on motility was tested and compared with carbachol (CCh), potassium chloride (KCl), noradrenaline (NA), and A71623. Compared to controls, the lithogenic diet induced an irregular and disordered motor pattern in both the gallbladder and sphincter of Oddi. NEC increased gallbladder and decreased sphincter of Oddi spontaneous motility independently of cholinergic, adrenergic, and CCK-1 receptor-mediated pathways both in controls and in lithogenic diet-fed animals, although the effect was lower in the latter group. The effect was reversible and mediated by calcium channels. The natural extract of chestnut increasing gallbladder contraction and inducing the relaxation of the sphincter of Oddi can be of benefit in pathological conditions associated with increased transit time at risk of gallstones.

Sluggish gallbladder emptying and gastrointestinal transit after intake of common alcoholic beverages.

To study the movement along the gut and the effect upon the gallbladder volume of alcoholic beverages taken in the interdigestive state. The study comprised three research blocks attended by 12 healthy subjects each. Within a given research block volunteers underwent three examination sessions held on separate days, being offered an alcoholic beverage, or an aqueous ethanol solution of an identical proof, or a corresponding volume of isotonic glucose solution; the order of administration of the drinks was randomized. The beverages tested were: beer (4.7% vol, 400 ml), red wine (13.7% vol, 200 ml), whisky (43.5% vol, 100 ml) within the "Beer", "Wine", and "Whisky" research block, respectively. Gastric myoelectrical activity was examined electrogastrographically, gastric emptying with ¹³C-sodium acetate breath test, orocaecal transit with lactulose H2 breath test, gallbladder emptying with ultrasonography, breath ethanol with alcotest. The study showed that alcoholic beverages were emptied from the stomach significantly slower than isotonic glucose. Alcoholic beverages produced by fermentation only (beer, red wine) were emptied from the stomach more slowly than ethanol solutions of identical proof, while gastric evacuation of whisky (distillation product) and matching alcohol solution was similar. The slower gastric evacuation of alcoholic beverages and ethanol solutions could not be ascribed to a disorganization of the gastric myoelectrical activity. The orocaecal transit of beer and red wine did not differ from that of isotonic glucose, whereas the orocaecal transit of whisky and high proof ethanol was markedly prolonged. Red wine and whisky, and to a similar extent control ethanol solutions caused an inhibition and delay of gallbladder emptying. We concluded that alcoholic beverages taken on an empty stomach exert a suppressive effect upon the transport function of the digestive tract and gallbladder emptying. The extent of this action depends on the type of a beverage (whether it is obtained from fermentation only, or fermentation followed by distillation) and ethanol concentration therein.

Effects of various food ingredients on gall bladder emptying.

BACKGROUND/OBJECTIVES: The emptying of the gall bladder in response to feeding is pivotal for the digestion of fat, but the role of various food ingredients in contracting the gall bladder postprandially is not well understood. We hypothesized that different food ingredients, when consumed, will have a different effect on stimulating gall bladder emptying. To investigate this we designed two randomized, investigator-blind, cross-over studies in healthy subjects using magnetic resonance imaging (MRI) to measure gall bladder volumes serially and non-invasively. SUBJECTS/METHODS: Study 1: exploratory study evaluating the effects of 10 different food ingredients on gall bladder emptying in eight healthy subjects. The choice of ingredients varied from common items like coffee, tea and milk to actives like curcumin and potato protease inhibitor. Study 2: mechanistic study investigating the cholecystokinin (CCK) dose response to the best performer ingredient from Study 1 in 21 healthy subjects four ways. RESULTS: The largest gall bladder volume change in Study 1 was observed with fat, which therefore became the dose-response ingredient in Study 2, where the maximum % gall bladder volume change correlated well with CCK. CONCLUSIONS: These serial test-retest studies showed that the fasted gall bladder volume varied remarkably between individuals and that individual day-to-day variability had wide coefficients of variation. Improved knowledge of how to stimulate bile release using food ingredients will be useful to improve in vitro-in vivo correlation of bioavailability testing of hydrophobic drugs. It could improve performance of cholesterol-lowering plant stanol and sterol products and possibly aid understanding of some cholesterol gallstone disease.