Gallbladder Dysmotility Research Articles

Administration of ursodeoxycholate failed to prevent sludge and/or gallstone formation in cholecystokinin-1(A) receptor-deficient mice

Gallstone disease is one of the most prevalent digestive diseases. The frequency of gallstone disease is about 10% in middle-age persons and 20% in aged persons. Gallbladder dysmotility and stasis of bile flow promote sludge and/or gallstone formation. Gallbladder contraction depends on cholecystokinin (CCK) via CCK-1 receptors (R)s. Previously, we raised CCK-1R deficient (-/-) mice and observed sludge and/or gallstone formation in more than 30% at 12-24 months of age. As ursodeoxycholate (UDCA) is commonly used for patients with gallstone disease, we expected that continuous administration of UDCA could prevent sludge and/or gallstone formation in CCK- 1R(-/-) mice. A diet containing 0.1% UDCA was administered in age-matched CCK-1R(-/-) and wild-type male and female mice for 8 months. Administration of UDCA decreased the frequency of sludge and/or gallstone formation compared with the control (CRF-1) diet (39%→26% in male, 35%→25% in female mice); however, these effects did not attain a level of statistical significance. Although the body weight was significantly higher in UDCA-fed than CRF-1-fed male mice regardless of genotypes, the plasma lipid concentrations did not differ between the two diets. In conclusion, administration of UDCA was less effective than expected at preventing sludge and/or gallstone formation in CCK-1R(-/-) mice.

T1625 Is Pain Provocation With Cholecystokinin Administration on Cholescintigraphy Predictive of Relief of Symptoms for Biliary Dyskinesia Following Cholecystectomy?

Introduction Biliary dyskinesia, also referred to as chronic acalculous gallbladder disease (CAGD), falls within the spectrum of diseases associated with gallbladder dysmotility. Cholecystokinin cholescintigraphy (CCK-CS) has been used to evaluate for CAGD, with a gallbladder ejection fraction (GBEF) of <35% being indicative of gallbladder dysfunction. The reproduction of biliary colic upon administration of CCK has been cited as indicative of CAGD. Our purpose was to determine if reproduction of pain during CCK-CS is a predictor of surgical outcomes or as a correlate to pathology. Methods A retrospective review of patients was performed to evaluate adults with a diagnosis of CAGD who underwent CCK-CS prior to surgical intervention. CPT and ICD-9 coding queries were used to identify the patient population. Patients with cholelithiasis were excluded. This study was approved by the institutional Human Assurances Committee. Results 64 patients met inclusion criteria. Two patients were lost to follow up and were excluded. During CCK administration, 41 patients (66.13%) reported symptoms similar to their presenting complaint. 21 patients reported no symptoms with CCK administration. Pathology review demonstrated either normal histology (n=4), cholesterolosis (n=4), chronic cholecystitis (n=47), both cholesterolosis and chronic cholecystitis (n=6), or autolysis (n=1). There was no significant relationship between pathology and either GBEF or reproduction of symptoms with CCK administration. 81% of patients (n=50) had relief of symptoms following cholecystectomy (mean EF of 19.55% ± 12.16%). 33 of these patients (66.00%) had reproduction of symptoms with CCK-CS. Twelve patients had recurrence of symptoms (mean EF of 17.18% ± 7.59%) despite surgery. Eight of these patients (66.67%) had symptom reproduction with CCK administration. There was no significant correlation with either the EF or reproduction of symptoms following CCK administration as a predictor of postoperative outcome on assessment by unpaired Student's t-test. Conclusion Provocation of pain CCK-CS is an unreliable indicator of postoperative relief of symptoms than GBEF.

52 Timing of Appearance of Gallbladder and Gastric Dysmotility in Gallstone-Free Obese Subjects From Different Age Classes. A Clue for Gallstone Disease in Adults?

52 Timing of Appearance of Gallbladder and Gastric Dysmotility in Gallstone-Free Obese Subjects From Different Age Classes. A Clue for Gallstone Disease in Adults?

S1785 Gallbladder and Gastric Dysmotility in Obese Children: A Prologue to Cholesterol Gallstones in Adult Age?

S1785 Gallbladder and Gastric Dysmotility in Obese Children: A Prologue to Cholesterol Gallstones in Adult Age?

Macronutrients and Insulin Resistance in Cholesterol Gallstone Disease

Cholelithiasis is a major source of digestive morbidity worldwide. Cholesterol stones account for the majority of gallstones in the United States and other Western countries. The pathogenesis of cholesterol gallstone disease is multifactorial with key factors including cholesterol supersaturation of bile, altered biliary motility, and nucleation and growth of cholesterol crystals. Increasing evidence suggests that many, but not all, causative factors of cholesterol gallstones are related to insulin resistance which, in association with obesity, has reached an epidemic level worldwide. Experimental studies show that hyperinsulinemia, a key feature of insulin resistance, may cause increased hepatic cholesterol secretion and cholesterol supersaturation of bile and gallbladder dysmotility, and thereby may enhance gallstone formation. Insulin resistance syndrome can be modified by environmental factors, including dietary factors. The impact of diet on insulin sensitivity is mediated by both dietary composition and its energy content. The contribution of specific dietary elements to the prevalence and incidence of cholesterol gallstone disease has been explored in animal and human studies. There is considerable evidence to suggest that different types of fatty acids, independent of the total amount of fat consumption, affect insulin sensitivity and cholesterol gallstone disease differently. The effects of salt intake, consumption of protein and carbohydrates, and alcohol drinking on insulin resistance are controversial. Additional intervention trials and controlled experimental feeding studies are needed to further clarify these relationships and to provide useful prophylactic and therapeutic strategies.

Prevalence of Gall Bladder Dyskinesia in Gastroparesis

Purpose: The aim of this study is to assess the gall bladder ejection fraction (GBEF) by cholescintigraphy in a cohort of gastroparetic patients with prominent postprandial abdominal pain. Methods: 17 patients with gastroparesis (14 females) underwent the hydroxyl iminodiacetic acid (HIDA) scan to measure their GBEF over the last 2 years. A GBEF between 35%–50% on the HIDA scan was considered as a borderline positive test for gall bladder dysmotility and a GBEF < 35% was considered as definite evidence of gall bladder dyskinesia. Gastroparesis for this study was defined as retention of >10% of a standardized low fat isotope labeled egg beater meal at the end of 4 hours by scintigraphy. Demographic data, the etiology of gastroparesis, duration of gastroparetic symptoms, and bowel movement pattern were also recorded. Results: 11/17 (65%) of patients had a GBEF of < 50%, 8 of these patients had definite evidence of gall bladder dyskinesia, while the other 3 had a borderline positive test. 7/8 patients with a definitely positive test underwent cholecystectomy, of which 5 had chronic cholecystitis on pathology. 6/7 patients reported improvement in pain after the cholecystectomy. None of the patients with borderline evidence of gall bladder dysmotilily underwent cholecystectomy. Clinical characteristics of patients are summarized in table. There was no significant difference (p > 0.05) in age, or duration of gastroparetic symptoms in patients with normal and abnormal gall bladder ejection fraction. Gall bladder dysmotility was numerically more likely in females (OR 5; 95% CI: 0.35–72%), idiopathic gastroparesis (OR 5; 95% CI: 0.6–46), and in patients with constipation (OR 2; 95% CI: 0.2–13) Conclusion: 1) This pilot study shows that gall bladder dysmotility is present in a majority of patients with gastroparesis; particularly of idiopathic etiology 2) Underlying neuromuscular dysfunction in gastroparesis may also extend to the gall bladder, consistent with a neuropathic etiology to explain the gall bladder dyskinesia. 3) Appreciating the need to diagnose and treat biliary dyskinesia in gastroparesis could be an important strategy to address the pain component in this challenging clinical setting.Table: Clinical Characteristics of gastroparetic patients who underwent HIDA scan

Gallbladder disease in Shetland Sheepdogs: 38 cases (1995–2005)

To determine risk, clinical features, and treatment responses for gallbladder disorders in Shetland Sheepdogs. Retrospective case-control study. 38 Shetland Sheepdogs with gallbladder disease. Medical records were reviewed for signalment, history, physical findings, laboratory results, imaging features, coexistent illnesses, histologic findings, treatments, and survival rates. Mature dogs with gastrointestinal signs were predisposed (odds ratio, 7.2) to gallbladder disorders. Gallbladder mucocele was confirmed in 25 dogs. Concurrent problems included pancreatitis, hyperlipidemia, corticosteroid excess, hypothyroidism, protein-losing nephropathy, diabetes mellitus, cholelithiasis, and gallbladder dysmotility. Mortality rate was 68% with and 32% without bile peritonitis. Nonsurvivors had high WBC and neutrophil count and low potassium concentration. Although preprandial hypercholesterolemia, hypertriglyceridemia, and high serum liver enzyme activities were common, gallbladder disease was serendipitously discovered in 11 of 38 dogs. Histologic examination (n=20 dogs) revealed gallbladder cystic mucosal hyperplasia in 20 dogs, cholecystitis in 16, periportal hepatitis in 9, and vacuolar hepatopathy in 7. Surgery included cholecystectomy (n=17) and cholecystoenterostomy (4). In 1 hyperlipidemic dog without clinical signs, gallbladder mucocele resolved 6 months after beginning use of a fat-restricted diet and ursodeoxycholic acid. Shetland Sheepdogs are predisposed to gallbladder disorders, with mucoceles and concurrent dyslipidemia or dysmotility in many affected dogs. Most dogs were without clinical signs during mucocele development. Low survival rate after cholecystectomy in clinically affected dogs suggested that preemptive surgical interventions may be a more appropriate treatment strategy.

Age-associated gallstone formation in male and female CCK-1(A) receptor-deficient mice

Gallbladder dysmotility accelerates cholelithiasis. In turn, gallbladder dysmotility can occur secondary to inflammation and excess cholesterol accumulation in gallbladder smooth muscle. The present study was designed to determine how much gallbladder dysmotility contributes to gallstone formation as a primary cause and whether a sex difference exists in gallstone formation by comparing cholecystokinin-1 receptor gene-deficient [CCK-1R(-/-)] male and female mice. No sludge or gallstone formation was observed in mice at 6 months of age. The frequency of sludge and gallstone formation in mice at 12 and 24 months of age was slightly higher in female CCK-1R(-/-) mice than in males, but the difference was not significant. Gallbladder dysmotility may have accelerated sludge and gallstone formation, but its contribution was limited. A 12-month period was required to produce gallstones, and after the mice reached 12 months of age, further ageing did not increase the frequency of gallstones. The effect of sex did not reach a significant level.

Resistin-Like Molecule Alpha Reduces Gallbladder Optimal Tension

IntroductionInsulin resistance is associated with increased gallbladder volume and impaired gallbladder emptying. Resistin and resistin-like molecule alpha (RELM-α) are adipose-derived hormones that are believed to mediate insulin resistance. Therefore, we tested the hypothesis that administration of resistin or RELM-α would cause insulin resistance and diminish gallbladder contractility. MethodsIn two sequential studies 40 eight-week-old nondiabetic lean mice were fed a chow diet for 4 weeks. In Study A, 10 mice received 20 μg of resistin IP, while in Study B 10 mice received 20 μg of RELM-α IP for seven days. In each study, 10 control mice received an equal volume of saline IP for seven days. At 12 weeks animals were fasted and underwent cholecystectomy, and in vitro gallbladder response to neurotransmitters was determined. Serum resistin, RELM-α, glucose, and insulin levels were measured. HOMA index, a measure of insulin resistance, was calculated. ResultsRELM-α significantly increased HOMA index. RELM-α decreased gallbladder optimal tension, but did not alter responses to neurotransmitters. Resistin had no effect on HOMA index or on gallbladder optimal tension or response. ConclusionThese data suggest that in nondiabetic lean mice: 1) resistin does not alter insulin resistance or gallbladder optimal tension, but 2) RELM-α increases insulin resistance and reduces gallbladder optimal tension. Therefore, we concluded that RELM-α may play a role in insulin-resistance mediated gallbladder dysmotility.

Insulin Resistance Causes Human Gallbladder Dysmotility

Obesity, diabetes, and hyperlipidemia are known risk factors for the development of gallstones. A growing body of animal and human data has correlated insulin resistance with organ dysfunction. The relationship among obesity, diabetes, hyperlipidemia, and abnormal gallbladder motility remains unclear. Therefore, we designed a study to investigate the association among obesity, insulin resistance, hyperlipidemia, and gallbladder dysmotility. One hundred ninety-two healthy adult nondiabetic volunteers were studied. Gallbladder ultrasounds were performed before and after a standardized fatty meal. A gallbladder ejection fraction (EF) was calculated, and an EF of < 25% was considered abnormal. Serum was analyzed for cholesterol, triglycerides, cholecystokinin, leptin, glucose, and insulin. The homeostasis assessment model (HOMA) was used to determine insulin resistance. The volunteers had a mean age of 38 years (range, 18-77), and 55% were female. Thirty subjects (15%) had gallstones and were excluded from the study. Thirty subjects (19%) had abnormal gallbladder motility (EF < 25%). In lean subjects (n = 96) fasting glucose was significantly increased in the 16 subjects with gallbladder EF < 25% versus the 80 subjects with gallbladder EF > 25% (109 +/- 20 mg/dl versus 78 +/- 2 mg/dl, P < 0.05). Similarly, the HOMA index was significantly greater in subjects with gallbladder EF < 25% versus gallbladder EF >25% (3.3 +/- 1.2 versus 2.0 +/- 0.2, P < 0.05). In obese subjects (n = 66), fasting glucose, insulin, and insulin resistance were not associated with a gallbladder EF < 25%. These data suggest that in lean, nondiabetic volunteers without gallstones, gallbladder dysmotility is associated with an elevated fasting glucose as well as a high index of insulin resistance. We conclude that insulin resistance alone may be responsible for gallbladder dysmotility that may result in acalculous cholecystitis or gallstone formation.

Chemical mediators of gallbladder dysmotility.

In order to accomplish its contribution to the digestive process, the gallbladder must contract appropriately during its emptying phases and it must be able to relax adequately for filling to occur. A variety of neuro-hormonal inputs to gallbladder smooth muscle coordinate the gallbladder emptying process with other events occurring in the bowel. Gallbladder dysmotility can disrupt the normal flow of bile to the small bowel, resulting in digestive dysfunction. In addition to this, alterations in gallbladder motility may play a role in pathological conditions, such as cholesterol gallstone formation and cholecystitis. It is still not entirely clear whether impaired gallbladder emptying is a cause or consequence of cholesterol gallstones, but recent experimental evidences demonstrate that cholesterol can directly affect the plasma membrane of gallbladder smooth muscle cells to cause impaired contraction. In addition, gallbladder emptying is impaired in acute gallbladder inflammation, probably as the result of the deleterious neural and muscular actions of inflammatory mediators such as reactive oxygen species, prostaglandins and histamine. It should also be noted that opiate treatments in critically ill patients can reduce gallbladder motility by inhibiting neurotransmitter release, and may contribute to the onset of acalculous cholecystitis, which is associated with significant morbidity in these patients.

Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in beta-thalassemia major adults.

Gallbladder and gastrointestinal motility defects exist in gallstones patients and to a lesser extent in pigment gallstone patients. To investigated the role of gallbladder and gastrointestinal motility disorders in pigment gallstone formation in beta-thalassemia major. Twenty-three patients with beta-thalassemia major (16 females; age range 18-37 years) and 70 controls (47 females, age range 18-40 years) were studied for gallbladder and gastric emptying (functional ultrasonography), orocecal transit (OCTT, H(2)-breath test), autonomic dysfunction (sweat-spot, cardiorespiratory reflex tests), bowel habits, gastrointestinal symptoms and quality of life (all with questionnaires). Gallbladder content (ultrasonography) was examined before and during 8-12 mo follow-up. Gallstones and/or biliary sludge were found in 13 (56%) patients. beta-thalassemia major patients had increased fasting (38.0+/-4.8 mL vs 20.3+/-0.7 mL, P = 0.0001) and residual (7.9+/-1.3 mL vs 5.1+/-0.3 mL, P = 0.002) volume and slightly slower emptying (24.9+/-1.7 min vs 20.1+/-0.7 min, P = 0.04) of the gallbladder, together with longer OCTT (132.2+/-7.8 min vs 99.7+/-2.3 min, P = 0.00003) than controls. No differences in gastric emptying and bowel habits were found. Also, patients had higher dyspepsia (score: 6.7+/-1.2 vs 4.9+/-0.2, P = 0.027), greater appetite (P = 0.000004) and lower health perception (P = 0.00002) than controls. Autonomic dysfunction was diagnosed in 52% of patients (positive tests: 76.2% and 66.7% for parasympathetic and sympathetic involvement, respectively). Patients developing sludge during follow-up (38%, 2 with prior stones) had increased fasting and residual gallbladder volume. Adult beta-thalassemia major patients have gallbladder dysmotility associated with delayed small intestinal transit and autonomic dysfunction. These abnormalities apparently contribute together with haemolytic hyperbilirubinemia to the pathogenesis of pigment gallstones/sludge in beta-thalassemia major.

Gallistono formation in patients with hypertriglyceridemia: Altered bile composition, gallbladder dysmotility or both?

Gallistono formation in patients with hypertriglyceridemia: Altered bile composition, gallbladder dysmotility or both?

Gallistono formation in patients with hypertriglyceridemia: Altered bile composition, gallbladder dysmotility or both?

Gallistono formation in patients with hypertriglyceridemia: Altered bile composition, gallbladder dysmotility or both?

4685 Comparison of egd with biliary drainage and cholesterol crystal analysis to cck-hida scan in the diagnosis of acalculous biliary colic.

INTRODUCTION: Biliary colic with documented gallstones is a frequently encountered problem. Treatment with cholecystectomy has been shown to be safe and effective especially in this era of laparoscopy. However, a variant of this disease is acalculous biliary colic without acute cholecystitis. Many have hypothesized that this may be due to gallbladder dysmotility and resultant biliary sludge. Current data does not provide a definitive work-up or treatment plan for this disease.AIM:To determine if an EGD with biliary drainage and cholesterol crystal analysis (CCA) is as effective as a CCK-HIDA scan in determining the etiology of acalculous right upper quadrant abdominal pain. METHOD: Retrospective review of patients presenting with typical biliary colic (post-prandial abdominal pain +/- nausea and vomiting) from January 1 through September 30, 1999. All patients had a normal abdominal ultrasound and normal laboratory evaluation. All patients then underwent an EGD with CCA and a CCK-HIDA scan for gallbladder ejection fraction (GBEF). All patients had no significant gastroduodenal disease on endoscopy and symptoms were refractory to acid suppression with proton pump inhibitors. Patients with either a GB-EF

Slow-transit constipation: solitary symptom of a systemic gastrointestinal disease.

Autonomic neuropathy is thought to play a role in the pathogenesis of slow-transit constipation, but other gastrointestinal organs may also be involved, even if they are symptom-free. We investigated whether motility in gastrointestinal organs other than the colon was impaired in patients with slow-transit constipation and whether the autonomic nervous system was involved. Twenty-one consecutive patients (18 females; median age, 46 years) with severe chronic constipation (< or = 2 defecations/week and delayed colonic transit time) were studied. Autonomic neuropathy function was tested with esophageal manometry, gastric and gallbladder emptying (fasting and postprandial motility) by ultrasonography, orocecal transit time (H2-breath test), colonic transit time (radiopaque markers), and anorectal volumetric manometry. The integrity of the autonomic nervous system was assessed by a quantitative sweat-spot test for preganglionic and postganglionic fibers, tilt-table test, and Valsalva electrocardiogram R-R ratio. Esophageal manometry showed gastroesophageal reflux or absence of peristalsis in five of the seven patients examined. Gallbladder dysmotility (i.e., increased fasting, postprandial residual volume, or both) was observed in 6 of 14 (43 percent) patients. Gastric emptying was decreased in 13 of 17 (76 percent) patients. Orocecal transit time was delayed in 18 of 20 (90 percent) patients; median transit time was 160 (range, 90-200) minutes. Median colonic transit time was 97 (range, 64-140) hours. Anorectal function showed abnormal rectoanal inhibitory reflex and decreased rectal sensitivity in 11 of 19 (58 percent) patients. Signs of autonomic neuropathy of the sympathetic cholinergic system were found in 14 of 18 (78 percent) patients. Only one of nine patients had vagal abnormalities detected with the Valsalva test and four of five patients with a history of orthostatic hypotension had a positive tilt-table test. Slow-transit constipation may be associated with impaired function of other gastrointestinal organs. More than 70 percent of patients with slow-transit constipation present some degree of autonomic neuropathy. Severe constipation may be the main complaint in patients with a systemic disease involving several organs and possibly involving the autonomic nervous system. This should be considered in the management of such cases.

Do patients with systemic sclerosis have abnormal gallbladder function?

To determine gallbladder motility in patients with systemic sclerosis. Case control study. University hospital, out-patient department of rheumatology. Ten patients with systemic sclerosis according to the criteria of the American Rheumatism Association with documented involvement of the gastrointestinal tract and 10 healthy controls matched for age, sex and body mass index. Cephalic vagal cholinergic simulation by modified sham feeding and hormonal stimulation by infusion of cholecystokinin. Gallbladder volume obtained by ultrasonography and determination of plasma cholecystokinin concentrations. Fasting gallbladder volumes were not significantly different between patients with systemic sclerosis and controls (19.6 +/- 1.9 cm3 and 23.3 +/- 2.9 cm3, respectively, mean plus or minus standard error of the mean). Neither were there significant differences in reduction of gallbladder volume in response to modified sham feeding (35 +/- 4% and 33 +/- 4%, respectively) nor during cholecystokinin infusion (56 +/- 4% and 60 +/- 6%, respectively). The increase in plasma cholecystokinin levels during infusion was not different in the two groups. Gallbladder motility in patients with systemic sclerosis is preserved in response to both cholinergic and hormonal stimulation, even when other gastrointestinal motor disturbances are present. These results suggest that patients with systemic sclerosis are not at increased risk for cholelithiasis because of gallbladder dysmotility.

Managing gallbladder disease with prostaglandin inhibitors

Experimental studies have shown that prostaglandins increase hepatic bile flow and gallbladder mucin production, cause gallbladder dysmotility, and inhibit intraluminal fluid absorption, thus promoting gallstone formation. By virtue of their positive actions on gallbladder fluid secretion, muscle contraction, and inflammatory properties, prostaglandins may also have a role in the pain of acute cholecystitis. Although only a few clinical studies of the role of prostaglandin inhibitors in gallbladder disease have been done, results show that use of drugs such as aspirin or other nonsteroidal anti-inflammatory agents may prevent gallstone formation and promptly relieve acute pain.