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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.

Free radical-mediated damage of the gall bladder epithelium predisposes to the development of both gall bladder inflammation and gallstone formation, which often coexist. Melatonin, a pineal and gut secretory product, due to its antioxidant activity along with its effect on the aging gall bladder myocytes, inhibits gallstone formation. Melatonin reduces the biliary levels of cholesterol by inhibiting cholesterol absorption across the intestinal epithelium and by increasing the conversion of cholesterol to bile acids. The incidence of gallstones is increasing and is expected to rise dramatically with the increase in the longevity and the risk factors such as obesity. The change in the prevalence of cholelithiasis is associated with a proportionate rise in the incidence of cholangiocarcinoma. In an attempt to improve the quality of life of the rapidly increasing aging population, this article reviews up-to-date information on the pathophysiology of the gall bladder function and discusses the development of new therapies with potential good patient compliance and lower cost than the current treatments.

We aimed to determine if exogenous adenosine triphosphate or adenosine modulated sphincter of Oddi motility and involved neural mechanisms. Sphincter of Oddi motility was recorded in anesthetized possums by manometry. Adenosine triphosphate or adenosine (1 microM-10 mM) was applied topically to the sphincter before and after pretreatment with tetrodotoxin, hexamethonium, atropine, or Nomega-nitro-L-arginine methyl ester. Sphincter contraction amplitude and frequency were quantified. Adenosine triphosphate induced a concentration-dependent increase in proximal sphincter contraction amplitude and frequency (P < 0.05). This response was reduced by tetrodotoxin and atropine but enhanced by hexamethonium and Nomega-nitro-L-arginine methyl ester. Adenosine concentration dependently increased proximal sphincter contraction amplitude (P < 0.05) only. This response was reduced by tetrodotoxin, atropine, and Nomega-nitro-L-arginine methyl ester, whereas hexamethonium had no effect. We conclude that exogenous adenosine triphosphate and adenosine stimulate proximal sphincter of Oddi motility via neural mechanisms, involving cholinergic motor neurons. Adenosine triphosphate may further modulate sphincter motility via nicotinic and nitrergic pathways.

Acalculous biliary-type abdominal pain is a commonly encountered clinical problem whose pathophysiology is unclear and evaluation and management are controversial. Cholecystokinin cholescintigraphy to measure the gallbladder ejection fraction (GEF) has been advocated as a criterion for cholecystectomy. However, there is no consensus regarding the dose and rate of infusion of cholecystokinin, both of which can alter the GEF, and the definition of an abnormal ejection fraction varies among studies. Many but not all studies have concluded that a low GEF predicts good outcomes after cholecystectomy, but most studies suffer from poor methodology and there is only one prospective randomized controlled trial. Also, some patients with a normal GEF have responded to cholecystectomy. Another controversial area has been the role of sphincter of Oddi dysfunction (SOD) in patients with biliary-type pain and gallbladder in situ. Some reports suggest an overlap between SOD and low GEF, although a causal relationship has not been established. Yet another subject of interest is the role of visceral hyperalgesia in patients with acalculous biliary-type pain. We have reviewed the relevant literature relating to these issues and have highlighted the controversial aspects. In the absence of high-quality studies, an evidence-based treatment algorithm is difficult to design but will be proposed. More prospective controlled trials are warranted to better define the appropriate evaluation and management of patients with this syndrome.

The role of female sex hormones in the pathogenesis of gallstones is well established. Pregnancy, contraceptive use, estrogen replacement therapy in postmenopausal women, and estrogen therapy in men for the treatment of prostatic carcinoma have been found to be associated with increased risk of cholesterol gallstones. Alterations in gallbladder emptying and in bile lithogenicity in postmenopausal women receiving hormone replacement therapy (HRT) have not been studied to date. The present study was undertaken to study the effect of HRT on gallbladder emptying and bile lithogenicity. Sixteen postmenopausal women were included in the study. None of the patients had gallstone disease and none had received prokinetic drugs, such as, erythromycin, metoclopramide, domperidone or cisapride, aspirin, and nonsteroidal antiinflammatory drugs. Gallbladder emptying (n = 16), bile microscopy (n = 7), cholesterol saturation index (CSI) (n = 7), and nucleation time (n = 7) were studied before and 3 months after HRT (conjugated estrogen, 0.625 mg, + medroxyprogesterone acetate, 2.5 mg, everyday). Fasting and residual volumes increased (fasting volume, 18.2 +/- 2.2 mL pre-HRT vs 27.6 +/- 3.2 mL post-HRT, P = 0.0003; residual volume, 3.9 +/- 0.6 mL pre-HRT vs 10.3 +/- 2.0 mL post-HRT, P = 0.00009) and ejection fraction decreased (78.2 +/- 2.5% pre-HRT vs 62.2 +/- 3.8% post-HRT; P = 0.0017) after 3 months of HRT. There was no change in CSI (2.32 +/- 0.36 pre-HRT vs 2.60 +/- 0.51 post-HRT; P = NS) or in nucleation time (19.0 +/- 1.2 days pre-HRT vs 17.6 +/- 1.3 days post-HRT; P = NS). None of the bile samples either pre-HRT or post-HRT showed cholesterol monohydrate crystals. Though impairment of gallbladder emptying occurs in the short term with HRT in postmenopausal women, there is no change in CSI and nucleation time.

This study was performed to evaluate any predictable factors associated with recurrence of biliary pain in symptomatic gallstone patients who did not undergo cholecystectomy because of operative risk, advanced age, and/or their refusal. The relationships among age, gender, body mass index, frequency of biliary pain before diagnosis, period between the last symptom attack and the hospital visit, size and number of gallstones, gallbladder ejection fraction (GBEF), compliance of ursodeoxycholic acid therapy, and recurrence of biliary pain were examined. The recurrence of biliary pain developed in 15 of 31 patients during the median 29-month follow-up. The cumulative 1-, 2-, and 3-year recurrence rates of biliary pain were 22.8, 40.9, and 53.0% and significantly associated with abnormal GBEF (hazard ratio, 3.12; 95% CI, 1.10-8.87; P = 0.032). In symptomatic gallstone patients with abnormal GBEF, cholecystectomy is strongly advisable because of the high risk of repeated pain attacks.

In addition to cholecystokinin, other hormones have been suggested to be involved in regulation of postprandial gallbladder contraction. We aimed to evaluate effects of growth hormone (GH) on gallbladder contractility and cholecystokinin release. Gallbladder and gastric emptying (by ultrasound) and cholecystokinin release were determined before and after 6 months of recombinant human GH (rhGH) therapy in 12 patients with GH deficiency, after either a mixed (n = 5) or a liquid (n = 7) meal. Basal postprandial gallbladder contraction was severely impaired (19 +/- 2 and 26 +/- 3% of fasting volume after mixed and liquid meal, respectively). Histology and cholecystokinin sulfation patterns in duodenal biopsies from two patients were normal. After 6 months of rhGH therapy, fasting gallbladder volumes increased (from 20.8 +/- 0.9 to 25.9 +/- 1.1 mL, P < 0.05) and postprandial gallbladder emptying was restored (70 +/- 6 and 70 +/- 7% of fasting volume after mixed and liquid meal, respectively), without change of gastric emptying. Cholecystokinin secretion after a mixed meal and gallbladder sensitivity to cholecystokinin were significantly enhanced during rhGH replacement compared to the basal state. Postprandial cholecystokinin release, gallbladder responsiveness to cholecystokinin, and gallbladder emptying are severely impaired in the absence of GH. Reversibility during GH suppletion suggests its involvement in regulation of gallbladder contractility.

Patients with acalculous biliary-like pain present a difficult clinical challenge. Our aim was to evaluate the outcome of patients with recurrent biliary-like pain without gallstones who underwent testing of gallbladder ejection fraction (GBEF) by cholecystokinin-cholescintigraphy (CCK-CS) in order to determine clinical factors that may predict symptom resolution. We reviewed the records of patients with recurrent acalculous biliary-like pain who underwent CCK-CS from January 1995 to December 1999. For comparison, we also studied an age- and sex-matched group of patients who underwent cholecystectomy for symptomatic cholelithiasis. Outcome was obtained by telephone interview, using a scale from 0 to 3 where 0 = no improvement and 3 = clinical remission. Patient demographics, predominant symptom(s), method of management, gallbladder pathology, and response to treatment were recorded. One hundred twenty-nine patients underwent CCK-CS. Of 69 with an abnormal GBEF, 48 (70%) were available for interview. Forty patients underwent cholecystectomy. Twenty-seven patients reported symptom resolution after surgery while 4 nonsurgical patients reported the same (P = NS). Univariate analysis revealed no association between symptom outcome and presence of gastrointestinal symptom(s), severity and duration of abdominal pain, management, or gallbladder pathology. In addition, no GBEF cutoff level predicted symptom outcome. Of the remaining 60 patients with a normal GBEF, 30 (50%) were available for interview. Twenty-eight patients in this group were managed medically and 2 patients underwent cholecystectomy. Eighteen patients managed medically were asymptomatic, as were the 2 who underwent cholecystectomy. There was no difference in symptom outcome between patients who had GBEF >35% vs <35%. In conclusion, in a group of patients with recurrent acalculous biliary-like pain who underwent CCK-CS, we found a high rate of symptom resolution following cholecystectomy; however, this was not statistically different from a smaller cohort who did not undergo surgery. We were unable to determine any variable predictive of symptom resolution.

The role of interdigestive gallbladder emptying in gallstone formation is unknown. In fasting healthy subjects, gallbladder emptying is associated with antral phase III of the migrating motor complex (MMC) and high plasma motilin. Therefore, gallbladder volumes and motilin levels were measured during 13 MMC cycles in 10 cholesterol gallstone patients and compared with 20 MMC cycles in 10 healthy subjects. MMC cycle length was longer in gallstone patients than in healthy subjects (158.2 +/- 17.0 vs 105.5 +/- 10.4 min, respectively; P < 0.05), due to longer phase I (39.8 +/- 5.7 vs 17.2 +/- 3.7 min, respectively; P < 0.05). In contrast to healthy subjects, gallstone patients had no significant fluctuations of gallbladder volume during the MMC cycle, and motilin concentrations were not different in MMC cycles with phase III originating in antrum or duodenum. During MMC cycles with phase III originating in the duodenum, motilin levels were twice as high in gallstone patients as in healthy subjects (P < 0.002). In conclusion, cholesterol gallstone patients have an abnormal MMC and motilin release pattern. Their interdigestive gallbladder emptying is reduced and dissociated from the MMC. These disturbances may contribute to gallstone formation.

Our purpose was to determine whether pylorus-preservation in the Imanaga (PpPDI) method minimizes postoperative impairment of gastrointestinal function. Nine patients who had undergone PpPDI (postoperative years: 5.7 +/- 2.6) and nine patients who had undergone conventional Imanaga pancreatoduodenectomy (PDI) (postoperative years: 6.8 +/- 2.0) were evaluated for symptoms, nutritional parameters, and physiologic function of the biliary tract and residual stomach using gastric emptying and hepatobiliary scintigraphy. The body weight recovered to 99.3% +/- 3.8% of pre-illness body weight in PpPDI, showing a significantly better recovery than in patients after the PDI procedure (91.0% +/- 6.4%, P < 0.05). The mean gastric emptying half-time (GET1/2) in the upright position after PDI was significantly shorter (42.3 min) than after PpPDI (80.8 min, P < 0.05). Mixture of food with bile was conserved better in the PpPDI group than in the PDI group. In the long term, the pylorus-preserving Imanaga-type procedure minimizes disruption of gastric function and asynchrony between ingested food and bile.

Bile analysis is performed on duodenal bile obtained after stimulation of the gallbladder (GB) with cholecystokinin or its analog. Rapid amino acids (AA) infusion contracts the GB. Our objective was to assess qualitatively the adequacy of duodenal bile obtained following AA infusion. We prospectively studied 15 patients each with non ulcer dyspepsia (NUD) and gallstones (GS), and 17 patients with acute idiopathic pancreatitis (AIP). Duodenal bile was obtained after duodenal intubation and stimulation of GB by rapid AA infusion. The GB contractile response to AA infusion was assessed by functional ultrasonography. Bile was analyzed for lipids, nucleation time, cholesterol saturation index (CSI), and biliary crystals. Adequate duodenal bile could be collected in all but one patient with AIP and one with GS. The mean +/- SD percent ejection fraction of GB following AA infusion in patients with NUD, GS and AIP was 53.41 +/- 16.23, 52.06 +/- 16.07, and 43.37 +/- 14.16, respectively. Biliary microscopy showed the presence of cholesterol monohydrate crystals (CMC) in 7 of 16 patients with AIP, 12 of 14 patients with GS, and 1 of 15 patients with NUD. Mean CSIs in patients with NUD, GS, CMC-positive AIP, and CMC-negative AIP were 0.78, 1.97, 1.85, and 1.00, respectively. Nucleation time in patients with NUD and gallstones was 21.1 and 8.42 days. respectively. In conclusion, qualitatively adequate bile can be obtained for chemical and microscopic examination following rapid intravenous infusion of AA to stimulate the GB.

Gallbladder motility is impaired in chronic cholelithiasis but has not been studied in acute acalculous cholecystitis. The aim of this study was to determine the effects of acute acalculous inflammation on gallbladder contractility using the common bile duct ligation (CBDL) model in guinea pigs. Three groups of guinea pigs were studied: CBDL, normal, and sham surgical controls. Gallbladder dimensions were measured, and muscle strips were used for histology and in vitro contractility studies. CBDL resulted in progressive gallbladder distension, increased serum bilirubin, and gallbladder inflammation. There was a progressive decline in muscle contractility in the CBDL group as evidenced by a decrease in the contractile response to potassium and bethanechol with the duration of CBDL. In conclusion, CBDL in the guinea pig produces acute gallbladder inflammation and decreased gallbladder muscle contractility. Direct inhibition of muscle function is indicated by impaired contractile responses to potassium depolarization and bethanechol stimulation. Although the mechanism of the decrease in contractility with CBDL is unknown, we speculate that impaired muscle contractility is secondary to inflammation and may play a role in the clinicopathology of acute acalculous cholecystitis.

Diets containing essentially no fat, 1-2 g fat per day, have resulted in cholesterol gallstones. Greater fat may result in less gallbladder stasis. Do gallstones form with greater fat content? We studied 272 moderately obese subjects who had normal gallbladder ultrasonograms. The 900 kcal/day liquid diets contained either 16 g fat (N = 94) or 30 g fat (N = 178) each day for 13 weeks. A second gallbladder ultrasound was performed. Sixteen of 94 (17.0%) of the 16-g fat group developed stones with a weight loss of 18 (+/- 7) kg and a body mass index (BMI) decrease of 6 (+/- 2) kg/m2. Twenty of 178 (11.2%) of the 30-g fat group developed stones (P = 0.18, no difference in stone formation) with similar weight loss of 20 (+/- 7) kg (P = 0.08) and BMI decrease of 7 (+/- 2) kg/m2 (P = 0.04). Substantial fat for rapid weight-reducing diets resulted in gallstone formation. Since experiments have shown that our higher fat diet, containing 10 g fat per meal, results in maximal gallbladder emptying, cholelithiasis from rapid weight loss may not be solely attributable to gallbladder stasis.

Gallbladder motility is modulated by intrinsic cholinergic neurons. The aims of this study were to determine: (1) the effect of electric field stimulation (EFS) on guinea pig gallbladder smooth muscle, and (2) the role of calcium channels in mediating neurotransmitter release. Gallbladder muscle strips were studied isometrically in vitro. EFS (1-16 Hz, 100 V, 0.5-msec pulse width, 30-sec train duration) was used to activate the intrinsic nerves. Exogenous acetylcholine was also used to directly stimulate the smooth muscle. EFS produced a frequency-dependent contractile response that was completely abolished by tetrodotoxin. EFS-induced contractions at 16 Hz were suppressed by 84 +/- 4% with atropine, whereas hexamethonium had no effect. The L-type calcium channel blocker, nifedipine, reduced EFS contractions by 51 +/- 4%, whereas it reduced contractions to acetylcholine by only 11 +/- 5%. The N-type calcium channel blocker, omega-conotoxin GVIA, reduced EFS-induced contractions by 22 +/- 9%, but did not affect acetylcholine-induced contractions. EFS-induced contractions of the guinea pig gallbladder are primarily mediated by activation of postganglionic cholinergic neurons. The acetylcholine release from these cholinergic neurons is regulated by L- and N-type calcium channels. The inhibitory effect of calcium channel blockers on the gallbladder seen in vivo may be in part related to inhibition of acetylcholine release from the intrinsic cholinergic nerves of the gallbladder.

In experimental animals, sphincterotomy facilitates passage of solids from the gallbladder and inhibits gallstone formation apparently by improvement in gallbladder emptying. In humans, however, gallbladder emptying has not been studied following endoscopic sphincterotomy (ES) in patients with gallstones. We therefore prospectively studied resting and cerulin-stimulated gallbladder volumes by real time ultrasonography in 15 patients of choledocholithiasis with gallbladder in situ (eight with and seven without gallbladder calculi) before and after (after bile duct clearance) ES. ES significantly lowered resting gallbladder volume (21.2 +/- 10.6 vs 11.1 +/- 5.0; P < 0.0001) and cerulin-stimulated residual gallbladder volume (10.8 +/- 5.6 vs 4.4 +/- 2.1; P < 0.0001). ES also significantly increased the gallbladder ejection fraction (47.3 +/- 12.1% vs 58.8 +/- 11.1%; P < 0.0001). The rate constant for gallbladder emptying after cerulin infusion also increased significantly after ES (-0.022/min vs -0.031/ min; P < 0.0001). Significant improvement in gallbladder motility was observed in both groups of patients with and without gallbladder calculi. ES significantly improves gallbladder motility in humans.

Fasting gastrointestinal motility and gallbladder motility during the interdigestive state and in the postprandial period was studied in eight patients who were operated for ulcer disease with an antrectomy and selective gastric vagotomy. Nocturnal motility recording revealed all three phases of the migrating motor complex (MMC) in all but one patient, where no phase III activity was recorded. In the rest of the patients 3-10 events with phase III activity were recorded. At scintigraphy ([75Se]HCAT) a cyclic gallbladder filling and emptying in relation to the MMC cycle was found. Episodes with emptying were confined to phase II and a total of 13 episodes with a median duration of 25 min (range 10-70 min) were observed. A median of 10.7% (6.1-17.7%) of the gallbladder contents was emptied. In a control group of eight healthy young men the values were 13.5 min (9-36 min) and 6.9% (3.7-31.1%), respectively. These differences were not significant. During the postprandial period, a lag period in gallbladder emptying of median 15 min (5-20 min) was observed when food ingestion took place during phase I of the MMC. Thereafter a gradual emptying occurred with a rate of 0.95% min (0.71-1.15%/min). In a control group of healthy young males, the lag period was 13.5 min (9-22.5 min) and the emptying rate 0.61%/min (0.08-0.77%/min). When food ingestion occurred during phase II of the MMC, the lag period of gallbladder emptying in the patient group was median 0 min (0-5 min) and the emptying rate was 0.77%/min (0.33-0.86%/min). The values in the control group were 0 min (-9 to 13.5 min) and 0.76%/min (0.54-2.25%/min), respectively. These differences between the patients and controls were not significant. In conclusion, antrectomy and selective gastric vagotomy do not influence fasting gastrointestinal motility or gallbladder motility during the interdigestive state or in the postprandial period.

Previous studies have provided conflicting results of cisapride on gallbladder emptying in response to a meal. We studied six volunteers and six patients after a truncal vagotomy in a double-blind, placebo-controlled, prospectively randomized study using 10 mg cisapride four times a day for three days. Gallbladder volume was quantitated using ultrasonography, and plasma CCK levels were measured with a sensitive and specific radioimmunoassay using the DINO antibody before and for 90 min after a fatty, mixed meal. Plasma effect was observed on the gallbladder either in normal subjects or vagotomized patients. Paradoxically, residual volume (RV) was increased in the vagotomized patients after treatment with cisapride: RV cisapride 7.1 (4.1-15.9) ml, RV placebo 5.1 (3.8-14) ml, P < 0.05. Further work is required to clarify the mechanisms of action of cisapride on the gallbladder and the sphincter of Oddi. The use of cisapride during litholytic therapy may impair gallbladder emptying and delay stone clearance.

There is recent evidence that nitric oxide, a soluble gas produced from L-arginine, is released by the smooth muscle cells and neurons of the gastrointestinal tract where it exerts a myorelaxive action. However, little is known about the effects nitric oxide has on gastric and gallbladder motility during the inter- and postprandial phases in man. We therefore investigated the effects 200 mg/kg/hr L-arginine exerts on the gastric and gallbladder motility induced by 2 mg/kg erythromycin or a liquid meal in 21 subjects in a double-blind, placebo-controlled study. Gastric and gallbladder emptying were evaluated by sonography. Fasting antral motility was expressed as antral motility index (MI). In fasting subjects, L-arginine administration determined a threefold increase in plasma nitrite concentrations. Administration of erythromycin caused a significant rise in the antral MI, which was inhibited by L-arginine (P < 0.05). Ingestion of a liquid meal also significantly increased antral MI, but it returned to basal values 90 min after the end of the meal. Although L-arginine administration caused a significant reduction in the antral MI (P < 0.05), it did not inhibit gastric emptying. L-Arginine provoked an approximately 40% increase in basal gallbladder volume, completely blocked erythromycin-induced emptying, and partially, but significantly, prevented the emptying induced by a liquid meal (P < 0.01). Our study suggests that nitric oxide may be implicated in the physiological modulation of gastric and gallbladder motility during the inter- and postprandial phases in man.

Postprandial gallbladder contraction is mainly regulated by cholecystokinin (CCK), but little is known about the dose-response relationship between CCK release and gallbladder contraction, in particular after meals with differing fat content. Decreased postprandial gallbladder emptying has been suggested to play a major role in the development of gallstones in man, and dietary factors may therefore be important in the pathogenesis of gallbladder stasis. We studied, in a randomized order, the effect of three isocaloric meals (250 ml) with identical osmolality on CCK release and gallbladder contraction in six healthy volunteers: (1) a pure fat meal (25 g triglycerides); (2) a mixed meal containing fat (8 g, 29% of caloric content), protein (10 g, 17%), and dextrose (32 g, 54%); and (3) a fat-free meal containing albumin (25 g, 46%) and dextrose (32 g, 54%). Gallbladder volumes and antral cross-sectional areas were determined by ultrasonography and plasma CCK and PP levels by RIA. The pure fat meal caused the highest CCK release (187 +/- 27; mean +/- SEM) and maximal (> 85% of fasting volume) gallbladder contraction (3172 +/- 361; AUC) as compared to the other two meals (P < 0.05). The mixed and the fat-free meal caused similarly low (< 50% of fasting volume) gallbladder contraction (6052 +/- 342 and 6134 +/- 500, respectively), although they induced markedly different CCK levels (157 +/- 12 and 87 +/- 13, respectively; P < 0.05). Gastric emptying rates were similar for all meals (18,500 +/- 3300, 18,600 +/- 2700 and 19,800 +/- 3100, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The postprandial release of cholecystokinin (CCK) regulates gallbladder (GB) contraction but little is known about the role, if any, of the still-elevated CCK blood levels on subsequent GB refilling. To assess the role of CCK in GB refilling, a CCK-receptor antagonist, loxiglumide, or saline were infused intravenously in a random double-blind fashion after the ingestion of a liquid test meal in 16 healthy subjects. An identical study protocol was performed in 10 GB "contractor" patient with radiolucent stones to ascertain whether the reported reduced CCK effect on GB emptying also affects GB refilling. GB volumes were assessed ultrasonographically in the fasting state and for 150 min at 15-min intervals after meal ingestion. GB volumes during postprandial refilling were significantly greater during loxiglumide than placebo infusion (P < 0.01), but they did not differ between gallstone and control subjects. In conclusion, postprandial endogenous CCK has a relevant role in delaying GB refilling, and this effect is not altered in patients with radiolucent gallstones.

Patterns of gallbladder contraction induced by a meal or cerulein were examined by means of real-time ultrasonography in conscious dogs. The postprandial gallbladder emptying was characterized by two parameters of the power-exponential function: the gallbladder half emptying time T1/2 = 47.3 +/- 4.7 min and the curve shape parameter S = 0.866 +/- 0.036. Cerulein infused at stepwise increasing rates of 0.7, 2.2, 7.4, 22.2, and 66.5 pmol/kg/hr, administered each for 10 min, evoked a gallbladder contraction to 87.4 +/- 3.8%, 66.7 +/- 2.4%, 44.5 +/- 1.5%, 25.9 +/- 2.1%, and 11.9 +/- 2.0% of the basal volume, respectively. The dependence of the gallbladder emptying on the dose of cerulein was described by the equation of linear regression y - 21.33 [ln(dose + 1)] + 95.81 (r = -0.963, P < 0.001). Accordingly, the cerulein dose required to evoke a 50% reduction of the gallbladder volume amounted to 7.6 pmol/kg/hr (95% confidence interval: 6.8-8.6 pmol/kg/hr). A plateau at the level of about 44% of the basal gallbladder volume characterized the time-course of the gallbladder emptying between 20 and 60 min of the infusion at a constant rate of 7.4 pmol/kg/hr. On the other hand, the 1-hr infusion of 22.2 pmol/kg/hr evoked a continuous decrease in the gallbladder volume with a nadir of 10.2 +/- 0.7% achieved at 60 min. Refilling of the gallbladder, contracted after a 1-hr infusion of cerulein, was complete within 30 and 60 min after the end of infusion for rates of 7.4 pmol/kg/hr and 22.2 pmol/kg/hr, respectively. The time course of the gallbladder filling after cessation of 1-hr infusion of cerulein at 7.4 pmol/kg/hr was described by the equation of linear regression of relative gallbladder volumes vs time: y = 1.732x + 48.61 (r = 0.739, P < 0.001). Refilling of the gallbladder was faster during the first 30 min (y = 2.191x + 7.13, r = 0.885, P < 0.001) and slower between 30 and 60 min (y = 1.218x + 74.97, r = 0.533, P < 0.001) after the end of a 1-hr infusion of cerulein at a rate of 22.2 pmol/kg/hr.

We present a method for estimating volumes of abdominal organs using 3-D ultrasonography. In vitro validation experiments demonstrated excellent agreement between estimated and true volumes. In vivo estimations after ingestion of 500 ml meat soup showed greater antral filling and poorer emptying of the gallbladder in patients with functional dyspepsia (FD) than in healthy controls. Abnormal antral filling was associated with dyspeptic symptoms. The relationship between motility and transpyloric movements of luminal contents after ingestion of 500 ml meat soup was studied in healthy subjects by duplex technique. Accurate timing of antegrade and retrograde flow were recorded using bidirectional velocity curves. Mid-cycle and end-cycle reflux were often observed; end-cycle reflux was more frequent in conjunction with coordinated than with uncoordinated antroduodenal contractions. The peristaltic closure of the pylorus was normally preceded by a short gush of duodenogastric reflux.

Strips from human gallbladder removed at surgery were exposed to cholecystokinin octopeptide CCK-OP 15 nM and were subjected to electrical field stimulation (EFS) in vitro using parameters for selective stimulation of nerves (5- to 10-sec trains of 0.3-msec pulses at 10 Hz). An adjacent strip from the same specimen was processed for histological examination. These preparations were given a numerical score for inflammatory change. The strength of contraction in response to CCK-OP was inversely related to the severity of inflammation. Gallbladders with no response to EFS had a higher inflammation score (median 11, range 5-16) than those with a response (median 7, range 3-12). We conclude that inflammatory changes in human gallbladder impair responses to neural and hormonal stimulation, but we are unable to determine unequivocally in this study whether this is a result of damage to nerves or muscle cells. However, the observation that some strips were able to contract in response to CCK-OP but not to neural stimulation suggests the possibility of neural damage in gallbladder inflammation.

Theoretically, relative distal common bile duct obstruction due to sphincter of Oddi dysfunction may be a cause of poor gallbladder evacuation observed on quantitative cholescintigraphy. In this study, the relationship of sphincter of Oddi dysfunction to the gallbladder ejection fraction by quantitative cholescintigraphy was explored. Eighty-one patients with biliary-type pain and otherwise normal evaluations underwent quantitative cholescintigraphy, sphincter of Oddi manometry, and ERCP. Abnormalities of stimulated quantitative cholescintigraphy and/or sphincter of Oddi manometry were present in 70% of this study group. Manometric evidence of sphincter dysfunction was present in patients with similar frequency irrespective of the degree of gallbladder evacuation. In conclusion, abnormalities of quantitative cholescintigraphy and sphincter manometry appear to be independent factors, although frequent findings in this patient population.

To further elucidate the mechanism of impaired gallbladder emptying in diabetics with and without neuropathy, gallbladder function was assessed by ultrasonography following a medium-chain triglyceride (lipomul, 1.5 mg/kg) infusion into the duodenum and compared to that during intravenous infusion of cholecystokinin in diabetic women. Results were compared with five healthy control women. Mean (+/- SD) maximal percent gallbladder volume in diabetics following lipomul was reduced to 49 +/- 8% and after intravenous cholecystokinin to 47 +/- 9%, which was less than those in controls, 21 +/- 9% and 24 +/- 6%, respectively, but not significantly different. Further analysis of gallbladder emptying to lipomul differentiated two subgroups of diabetics: one subgroup (N = 5) had emptying comparable to controls (responders), while the other (N = 5) had very modest emptying (nonresponders). Two of the patients in the latter group had normal gallbladder emptying during exogenous cholecystokinin and their response would be compatible with visceral neuropathy. Blood levels of cholecystokinin, measured by bioassay, following lipomul and exogenous cholecystokinin were similar in controls and diabetics. Presence of diabetic neuropathy did not correlate with impaired gallbladder emptying. Follow up at 6 and 12 months of the three nonresponder diabetics revealed that no gallstones had developed and that two of them became responders to exogenous cholecystokinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Gallbladder dynamics, cholecystokinin (CCK), and pancreatic polypeptide (PP) release were studied in 14 patients with chronic pancreatitis (CP) (2 females, 12 males; age range 24-56 years) and 12 control subjects (4 females, 8 males, 21-50 years). On day 1, gallbladder contractility was investigated after ceruletide intravenous infusion (2.5 ng/kg/min for 10 min). On day 2, a mixed standard test meal (1450 kJ) was administered orally. Gallbladder volume was assessed at three time intervals before (-30, -15, 0 min) and at 5, 10, 20, 30, 40, 50, 60, 80, 100 and 120 min after stimulation by means of ultrasonography. CCK and PP plasma levels were determined at each time interval. Exocrine pancreatic function was assessed using the pancreolauryl serum test (PLT). Six patients with CP had severe exocrine pancreatic insufficiency (EPI) (PLT < 1.8 micrograms/ml) with steatorrhea, eight patients had mild-moderate EPI. Fasting gallbladder volume was increased in CP (32.3 +/- 3.1 cm3) as compared to controls (20.5 +/- 1.2 cm3) (P < 0.01). Peak gallbladder contraction (percent of initial volume) in CP ranged from 5 to 55% (controls: 8-46%) following ceruletide and from 17 to 86% (controls: 27-80%) following the test meal (NS). There was no correlation between the degree of EPI according to PLT and peak gallbladder contraction. Gallbladder emptying in CP patients was not different from controls, although the postprandial CCK response was significantly impaired (P < 0.01). Postprandial PP response in CP was correlated with the PLT result (r = 0.78; P < 0.01) but not with gallbladder emptying or refilling time.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired gallbladder contractility is a prerequisite for gallstone formation in animal models. Prostaglandins are important mediators of gallstone formation and may affect gallbladder contractility in animals. The aim of this study was to evaluate the effect of indomethacin, an inhibitor of prostaglandin synthesis, and misoprostol, a synthetic prostaglandin, on gallbladder contractility in man. Seven male volunteers (18-33 years old, mean age 23 years) were studied under blinded conditions after an overnight fast, during control periods and following ingestion of indomethacin 125 mg (75 mg at 10 PM, 50 mg at 6:30 AM) or misoprostol 800 micrograms (400 micrograms at 10 PM, 400 micrograms at 6:30 AM) orally. Gallbladder residual volume was determined by real-time ultrasonography before and 10, 20, 30, 40, and 50 min after ingestion of a standard liquid fatty meal stimulus. Fasting gallbladder volume (milliliters) was similar in all three periods [control 20.8 (1.6); indomethacin 20.8 (2.9); misoprostol 18.3 (1.6)]. The fatty meal stimulus caused prompt contraction, resulting in minimum residual volume of 7.5 (1.4) ml in the control period. Pretreatment with misoprostol or indomethacin did not affect the minimum volume obtained compared with control period [misoprostol: 5.8 (1.4) ml; indomethacin 5.9 (1.3) ml)]. Thus administration of indomethacin and misoprostol had no effect on fasting gallbladder volume or gallbladder contractility in humans as assessed by ultrasonography.

Gastric and gallbladder emptying after a standard liquid meal were studied in 65 patients with early satiety, bloating, pain at the right hypochondrium or the epigastrium, nausea, and occasionally vomiting. Fifty normal subjects were studied as a control group. Gastric and gallbladder emptying were evaluated by means of real-time ultrasonography (RUS). Serial RUS scans were made after a 12-hr fast and every 15 min after a standard meal for 2 hr. Patients were considered to have delayed gastric emptying or hypokinetic gallbladder when gastric diameters and gallbladder volume evaluated 45 min after meal were 2 SD above the corresponding mean values of the normal subject group. Fifteen patients (23%) were found with delayed gastric emptying and 20 (30.7%) a reduced gallbladder emptying. None of our patients showed delayed gastric emptying and hypokinetic gallbladder simultaneously. The 20 patients with reduced gallbladder emptying were included in a double-blind randomized, placebo controlled, change-over study with cisapride (10 mg three times a day) for 30 days. Cisapride treatment reversed the gallbladder hypomotility within the normal range while placebo did not change the response to meal. Symptom score improved significantly after cisapride and placebo. It is concluded that in dyspeptic patients with reduced gallbladder response to a meal cisapride may be of help in improving the kinetic abnormality. Dyspeptic symptoms, however, do not seem to be corrected with the described gallbladder motor abnormality.