Impaired Gallbladder Emptying Research Articles

An Update on the Lithogenic Mechanisms of Cholecystokinin a Receptor (CCKAR), an Important Gallstone Gene for Lith13.

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

1280 Biliary Sludge and Acute Pancreatitis Following Treatment of Sexually Transmitted Infection

INTRODUCTION: Ceftriaxone has been shown to cause transient biliary and cholecystic sludge evident on imaging in asymptomatic subjects. This sludge may result in obstruction, and hence, acute pancreatitis and cholecystitis. Here we report a case of acute pancreatitis presenting three days following treatment with ceftriaxone which may be attributed to this phenomenon. No other risk factors could be identified. CASE DESCRIPTION/METHODS: A 34-year-old male patient with no past medical history presented to the hospital with the complaint of stabbing epigastric abdominal pain radiating to the back with associated nausea and vomiting of one day duration. He was seen by his primary care doctor three days prior to presentation for urethral discharge and was given an intramuscular injection of 250 mg ceftriaxone in addition to 1 g oral azithromycin with complete resolution of symptoms. Physical examination was notable for epigastric tenderness without rebound tenderness or guarding and was otherwise normal. Laboratory work up was remarkable for WBC 15200 per microliter and lipase 1961 U/L. Liver function test, serum calcium, triglycerides, and IgG4 were all within normal limit. Computed tomography (CT) scan of the abdomen confirmed findings of acute pancreatitis with well-defined pancreatic borders. This was followed by a right upper quadrant ultrasound which showed biliary and cholecystic sludge. Upon further questioning the patient denied alcohol and tobacco use, recent travel, or any prior history of mumps and herpes simplex virus infections. Furthermore, no family history of acute pancreatitis was reported. The time frame of symptoms and the absence of other risk factors point towards a drug adverse reaction. The patient was managed conservatively and discharged the following day with significant clinical improvement. DISCUSSION: Younger patients, patients receiving a prolonged or larger dose and patients with impaired gallbladder emptying are at a greater risk for developing sludge secondary to ceftriaxone use. This is often asymptomatic with discontinuation of the drug usually resulting in resolution of this phenomenon. This case highlights the fact that ceftriaxone induced biliary sludge may rarely result in potentially serious adverse events including acute cholecystitis and pancreatitis.

Biliary Sludge and Acute Pancreatitis Following Treatment of Sexually Transmitted Infection

Ceftriaxone has been shown to cause transient biliary and cholecystic sludge evident on imaging in asymptomatic subjects. This sludge may result in obstruction, and hence, acute pancreatitis and cholecystitis. Here we report a case of acute pancreatitis presenting three days following treatment with ceftriaxone which may be attributed to this phenomenon. No other risk factors could be identified. A 34 year old male patient with no past medical history presented to the hospital with the complaint of stabbing epigastric abdominal pain radiating to the back with associated nausea and vomiting of one day duration. He was seen by his primary care doctor three days prior to presentation for urethral discharge and was given an intramuscular injection of 250 mg ceftriaxone in addition to 1 g oral azithromycin with complete resolution of symptoms. Physical examination was notable for epigastric tenderness without rebound tenderness or guarding and was otherwise normal. Laboratory work up was remarkable for WBC 15200 per microliter and lipase 1961 U/L. Liver function test, serum calcium, triglycerides, and IgG4 were all within normal limit. Computed tomography (CT) scan of the abdomen confirmed findings of acute pancreatitis with well-defined pancreatic borders. This was followed by a right upper quadrant ultrasound which showed biliary and cholecystic sludge. Upon further questioning the patient denied alcohol and tobacco use, recent travel, or any prior history of mumps and herpes simplex virus infections. Furthermore, no family history of acute pancreatitis was reported. The time frame of symptoms and the absence of other risk factors point towards a drug adverse reaction. The patient was managed conservatively and discharged the following day with significant clinical improvement. Younger patients, patients receiving a prolonged or larger dose, and patients with impaired gallbladder emptying are at a greater risk for developing sludge secondary to ceftriaxone use. This is often asymptomatic with discontinuation of the drug usually resulting in resolution of this phenomenon. This case highlights the fact that ceftriaxone induced biliary sludge may rarely result in potentially serious adverse events including acute cholecystitis and pancreatitis.

Lack of a liver‐specific apolipoprotein (apo)A‐V in bile promotes cholesterol gallstone formation by disrupting biliary cholesterol homeostasis in mice

BackgroundApoA‐V is synthesized exclusively by the liver and secreted into the circulation, involving in plasma lipoprotein and lipid metabolism. Although its concentration in human plasma is extremely low (114–258 ng/mL), 1,000 to 10,000‐fold lower than that of apoB‐100 and apoA‐I, respectively, human and mice lacking functional apoA‐V suffer from hypertriglyceridemia. Because our new results found that apoA‐V is also secreted into bile, we hypothesize that it plays an important role in regulating biliary cholesterol metabolism, and its deficiency reduces cholesterol solubility in bile, promoting cholesterol crystallization and gallstone formation.MethodsTo explore the lithogenic mechanisms of biliary apoA‐V deficiency, male apoA‐V knockout (KO) and wild‐type (WT) mice (n=10 per group) were fed a lithogenic diet for 4 wk. Gallstones and cholesterol crystallization in bile were examined by physical‐chemical methods. Hepatic lipid output was determined by biliary secretion studies. Gene expression and protein content were analyzed by qRT‐PCR, Western blots, and ELISA.ResultsCompared to the chow diet, feeding the lithogenic diet significantly (P<0.01) reduced hepatic apoA‐V mRNA and protein levels by 55% and its bile concentrations from 45.7±12.4 ng/mL to 16.7±6.0 ng/mL in WT mice. ApoA‐V was associated only with vesicles, but not micelles, in bile of WT mice. Biliary cholesterol, but not phospholipid or bile salt, output was higher (P<0.05) in KO mice (29.0±8.5 μmol/h/kg) than in WT mice (20.4±5.5 μmol/h/kg), leading to cholesterol‐supersaturated bile. The deficiency of apoA‐V in bile reduced biliary cholesterol solubility and promoted cholesterol crystallization through the liquid crystalline pathway by enhancing biliary unilamellar vesicle aggregation and fusion to form unstable multilamellar vesicles in KO mice. After 50 ng/mL of apoA‐V protein isolated from WT mice was added to supersaturated model bile, cholesterol crystallization was significantly delayed than that added the protein at 0 ng/mL. This implies that apoA‐V plays a key role in regulating cholesterol solubility in bile by modulating the physical state of cholesterol carriers. In addition, the lack of apoA‐V impaired gallbladder emptying and refilling function, thus promoting the accumulation of excess mucin gel and the formation of biliary sludge, a precursor of gallstones. These abnormalities enhanced the growth and agglomeration of solid cholesterol crystal into microlithiasis. After 4 wk of feeding, gallstone prevalence was higher (P<0.05) in KO mice (60%) than in WT mice (25%).ConclusionsThese findings clearly demonstrate that the liver‐specific protein apoA‐V plays a critical role in the regulation of biliary cholesterol metabolism and transport, and its lack in bile dramatically enhances cholelithogenesis by disrupting biliary cholesterol homeostasis. Increasing biliary apoA‐V may be a novel and efficient approach for the prevention of cholesterol gallstones.Support or Funding InformationThis work was supported in part by research grants DK101793, DK106249 and AA03557, all from the National Institutes of Health (US Public Health Service).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Gallbladder Disease in Type-2 Diabetes Mellitus Patients

<p><strong>Background:</strong> Diabetes mellitus is a modern epidemic which leads to various complications over a period of time. Autonomic neuropathy is one such complication which may lead on to gallbladder dysmotility and gallbladder stones.</p><p><strong>Objectives:</strong> To determine the incidence of gallbladder disorders in patients of type 2 diabetes mellitus and to find out the incidence of autonomic dysfunction in type 2 diabetes mellitus and correlate it with presence of gall bladder disorders.</p><p><strong>Material and Methods:</strong> The present study was conducted in 50 cases of type 2 diabetes mellitus and 25 healthy age and sex matched normal individuals were taken as controls. The cases as well as the controls underwent ultrasonographic examination for gall bladder volume, wall thickness, intraluminal mass and contraction in response to fatty meal. Data thus collected was compared and analysed statistically by using students ‘t’ test and chi- square test.</p><p><strong>Results:</strong> Mean postprandial gallbladder volume was 20.56±8.87 cm<sup>3</sup> in diabetics with ANP with gallstones, 26.16±1.24 cm<sup>3</sup> in diabetics with ANP with dysmotility 13.0±6.26 cm<sup>3</sup> in diabetics with gallstones without ANP, 12.14±4.88 cm<sup>3</sup> in normal diabetics and 13.60±5.95 cm<sup>3</sup> in controls. The percentage contraction post fatty meal was calculated from these values and found to be 24.73±14.64% in diabetics with ANP with dysmotility, 26.38±17 .04% in diabetics with ANP with dysmotility, 43.48±8.45% in diabetics with gallstones without ANP, 56.84±9.02% in normal diabetics and 57 .64±9.92% in controls.</p><p><strong>Conclusion:</strong> Incidence of gallbladder disease is much higher in type 2 diabetics (40%) as compared to normal healthy adults (4%). It was concluded that diabetics with ANP had significantly impaired gallbladder emptying. Poor control of diabetes, hypercholesterolemia and diabetic autonomic neuropathy are important risk factors for the development of gallbladder disease.</p>

Gallbladder Disease in Type-2 Diabetes Mellitus Patients

Background: Diabetes mellitus is a modern epidemic which leads to various complications over a period of time. Autonomic neuropathy is one such complication which may lead on to gallbladder dysmotility and gallbladder stones. Objectives: To determine the incidence of gallbladder disorders in patients of type 2 diabetes mellitus and to find out the incidence of autonomic dysfunction in type 2 diabetes mellitus and correlate it with presence of gall bladder disorders. Material and Methods: The present study was conducted in 50 cases of type 2 diabetes mellitus and 25 healthy age and sex matched normal individuals were taken as controls. The cases as well as the controls underwent ultrasonographic examination for gall bladder volume, wall thickness, intraluminal mass and contraction in response to fatty meal. Data thus collected was compared and analysed statistically by using students ‘t’ test and chi- square test. Results: Mean postprandial gallbladder volume was 20.56±8.87 cm 3 in diabetics with ANP with gallstones, 26.16±1.24 cm 3 in diabetics with ANP with dysmotility 13.0±6.26 cm 3 in diabetics with gallstones without ANP, 12.14±4.88 cm 3 in normal diabetics and 13.60±5.95 cm 3 in controls. The percentage contraction post fatty meal was calculated from these values and found to be 24.73±14.64% in diabetics with ANP with dysmotility, 26.38±17 .04% in diabetics with ANP with dysmotility, 43.48±8.45% in diabetics with gallstones without ANP, 56.84±9.02% in normal diabetics and 57 .64±9.92% in controls. Conclusion: Incidence of gallbladder disease is much higher in type 2 diabetics (40%) as compared to normal healthy adults (4%). It was concluded that diabetics with ANP had significantly impaired gallbladder emptying. Poor control of diabetes, hypercholesterolemia and diabetic autonomic neuropathy are important risk factors for the development of gallbladder disease.

Gallbladder Kinetics: Correlation between Gall Bladder Emptying in Patients With and Without Cholelithiasis by Ultrasonography

Background: Gallstone disease or cholelithiasis, is one of the most common surgical problems worldwide. The assessment of gallbladder kinetics in patients with cholelithiasis as well as in patients with high risk for cholelithiasis could play a significant role in better management and is recommended as a routine workup of biliary system in these patients.Objectives: This study was carried out to establish the relationship between impaired gall bladder emptying and gall bladder stones. It also aimed at finding out correlation between chosen risk factors. Materials and Methods: Eighty six subjects with cholelithiasis and 35 controls (without cholelithiasis) were studied. Pre-prandial gall bladder volume was measured after 6 hours of fasting, gallbladder emptying was stimulated by fatty meals of 610 and 740Kcal and post-prandial gallbladder volume was measured after a period of two hours with ultrasound. The difference of pre-prandial and postprandial gall bladder volume was calculated. Results: Gallbladder emptying was significantly more (p < 0.001) in the control group than in the group of subjects with cholelithiasis. In the case group the mean difference of volume was 9.2±7.1 cc. While in control group the mean difference of volume was 17.6±14.3. The prevalence of cholelithiasis was significantly high in females between 26- 35 years of age group and in patients with nonalcoholic fatty liver disease and in patients who had first degree relative with gall stone. Incidence of silent gall stone was also statistically significant. Conclusion: Impaired gallbladder emptying was found to be strongly associated with gall stones. NJR I VOL 2 I ISSUE 1 13-17 Jan-June, 2012 DOI: http://dx.doi.org/10.3126/njr.v2i1.6973

Impaired gallbladder motility and the effect of metformin therapy in patients with polycystic ovary syndrome

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

Somatostatin receptor subtypes 2 and 5 mediate inhibition of egg yolk-induced gall bladder emptying in mice

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

Role of Quantitative Cholescintigraphy for Planning Laparoscopic Cholecystectomy in Patients With Gallbladder Dyskinesia and Chronic Abdominal Pain

Our aim was to examine the diagnostic role and therapeutic guide of quantitative cholescintigraphy in 122 patients with a biliary-type chronic abdominal pain and normal abdominal ultrasound. The patients with severe symptoms and an impaired ejection fraction (EF<or=35%) of the gallbladder in cholescintigraphy were operated by laparoscopic cholecystectomy (LC, n=32). The nonsurgical groups consisted of the patients with mild clinical symptoms and pathologic (<or=35%, n=52) or normal (>35%, n=38) EF. An impaired gallbladder emptying was found in 84/122 of patients (69%) and LC was performed in 32/122 (26%) of the patients, that is, 2.2% of all cholecystectomies in our hospital. After the mean follow-up of 4 years, chronic abdominal pain was totally improved or diminished in 92% in the LC group, 45% in the nonoperative group with EF<or=35%, and in 66% in the nonoperative group with EF>35%, respectively (P=0.0003). Quantitative cholescintigraphy is a useful aid when considering the treatment options in patients with chronic biliary-type abdominal pain and a negative abdominal ultrasound.

Multiple system atrophy and impaired gallbladder emptying

Multiple system atrophy and impaired gallbladder emptying

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.

Orlistat reduces gallbladder emptying by inhibition of CCK release in response to a test meal

Background and aims Orlistat is a covalent inhibitor of digestive lipase derived from lipstatin, the natural product of Streptomyces toxytricini. By blocking the active site of intestinal lipase, orlistat inhibits hydrolysis of dietary triglycerides and thus reduces the intestinal lipid absorption. It is uncertain whether intestinal inhibition of lipase by orlistat also interferes with nutrient-induced CCK release from intestinal I-cells. The aim of the present study was therefore to assess whether oral administration of orlistat inhibits CCK release in response to a test meal and thus causes impaired gallbladder emptying. Methods 22 healthy volunteers were given a test meal consisting of 200 ml dairy cream and two teaspoons of chocolate powder (552 kcal = 2328 kJ; 56.0 g fat; 5.2 g proteins, 6.6 g carbohydrates), with and without oral application of 120 mg orlistat. Gallbladder volume was determined by ultrasound before and 5, 10, 20, 30 and 40 min after meal ingestion. In parallel, a venous blood sample was collected for the measurement of bioactive CCK. CCK activity was assessed using a bioassay with isolated rat pancreatic acini cells. Results Oral administration of orlistat significantly impairs gallbladder emptying. After ingestion of the test meal the gallbladder contracted by 78.5% in the control group, whereas the test group with orlistat only showed a contraction of 45.7% ( p < 0.01). Maximal contraction was reached after 35 to 40 min, the maximal gallbladder emptying was delayed up to 10 min by orlistat. Orlistat induced a significant reduction of bioactive CCK levels in response to a test meal (CCK max with orlistat = 4.1 pmol/l; CCK max without orlistat = 7.8 pmol/l). CCK levels were reduced by 47% and the onset of maximal CCK secretion was delayed up to 10 min. Conclusion The inhibition of intestinal lipolytic activity by orlistat results in reduced gallbladder emptying through inhibition of meal-mediated CCK release. We therefore hypothesize that impaired gallbladder motility may represent a risk factor in chronic treatment of severe obesity using orlistat.

Pioglitazone Increases Gallbladder Volume in Insulin-Resistant Obese Mice

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

Pioglitazone increases gallbladder volume in insulin- resistant obese mice

Introduction: Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione which has been shown to improve insulin resistance and has been employed to treat nonalcoholic fatty steatohepatitis. However, in a prior study with a high carbohydrate (75%) diet pioglitazone did not improve gallbladder motility in obese insulin-resistant mice. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice. Methods: Twenty eight-week old obese leptin-deficient (Lepob) female mice were fed a low carbohydrate (25%) diet for four weeks. Half of the animals had pioglitazone 0.03% added to their diet. At 12 weeks, all animals were fasted overnight and underwent cholecystectomy. Gallbladder volume(μl), weight and area were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine(ACh,10−6M), neuropeptide Y (NPY,10−8,−7,−6M) and cholecystokinin (CCK, 10−10,−9,−8,−7M). Serum glucose(mg/dl) and insulin (ηg/ml) were measured, and the HOMA Index, a measure of insulin resistance, was calculated. Results: Pioglitazone did not alter gallbladder weight, area or response to ACh, NPY or CCK. Results for glucose, insulin, HOMA Index and gallbladder (GB) volume were: Conclusion: These data suggest that in obese insulin-resistant mice, pioglitazone 1) lowers insulin and insulin-resistance, 2) does not alter gallbladder response to neurotransmitters, and 3) increases resting gallbladder volume. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.

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.

Predictors of successful outcome after cholecystectomy for biliary dyskinesia

Purpose Laparoscopic cholecystectomy is accepted therapy for children with ill-defined abdominal pain and impaired gallbladder emptying (biliary dyskinesia). Follow-up shows poor clinical response in many of these patients. The purpose of this report is to identify clinical and radiographic predictors of successful outcome after cholecystectomy for biliary dyskinesia. Methods The authors retrospectively reviewed records of 51 children after laparoscopic cholecystectomy for biliary dyskinesia (1990 to 2003). Clinical symptoms, radiographic findings, and pathology were evaluated. Subjective clinical improvement is stratified using an established patient satisfaction score. Logistic regression analysis determines statistically independent predictors of successful outcome. Results Thirty-eight of 51 (75%) patients were available for follow-up. Twenty-seven of 38 (71%) patients reported complete resolution of symptoms. Nausea was the only symptom predictive of successful outcome by univariate analysis (odds ratio, 5.00). A cholecystokinin-stimulated, gallbladder ejection fraction less than 15% also predicts successful outcome (odds ratio, 8.00). Children with an ejection fraction greater than 15% did not have predictable resolution of symptoms. When present with pain and nausea, gallbladder emptying less than 15% has a positive predictive value of 93% and a negative predictive value of 81%. Conclusions Together, nausea, pain, and decreased gallbladder emptying (<15%) most reliably predict which children will benefit from cholecystectomy for biliary dyskinesia.

Gallbladder dyskinesia: a cause of chronic abdominal pain in children.

Gallbladder dyskinesia (GD) is a well-established disorder in adults, but it is not clearly defined in the paediatric population. Therefore, the aim of this study was to review our experience in a group of children with chronic abdominal pain associated with impaired gallbladder emptying in the absence of cholelithiasis. The records of sixteen patients who underwent cholecystectomy with the diagnosis of GD were evaluated retrospectively. Clinical presentation, symptoms, diagnostic studies, and the effect of cholecystectomy in alleviating abdominal complaints were investigated. All patients had symptoms of upper abdominal pain in the absence of other attributable causes associated with low gallbladder ejection fractions (GEF) < 35 %, during cholecystokinin-stimulated hepatobiliary scan (CCK-HBS), and free of gallstones on ultrasound (USG). Abdominal pain and nausea were the most common presenting symptoms. Mean GEF was 15.3 %. All patients underwent cholecystectomy. The histopathological diagnoses of all operated patients were consistent with chronic cholecystitis. Symptoms were completely relieved in all except two patients. GD should be considered in the differential diagnosis of recurrent abdominal pain in children. Patients with this condition present with biliary-type pain and investigations show no evidence of gallstones in the gallbladder. Performing a CCK-HBS establishes the diagnosis. Patients with an abnormal GEF (< 35 %) should undergo cholecystectomy. This procedure has been shown to be effective in curing the symptoms in over 80 % of patients. To avoid late diagnosis, CCK-HBS should be employed early in the evaluation of biliary colic with negative sonographic findings.

Sonographic evaluation of gallbladder volume and ejection fraction in obese women without gallstones.

Obese people have an increased incidence of gallstones. Although the exact pathogenic mechanisms of gallstone development are unknown, impaired gallbladder emptying has been suggested as a possible underlying mechanism. Our aim was to investigate this possibility by evaluating gallbladder motility and related factors in obese and nonobese women without gallstones. This study included 79 obese women and 25 nonobese healthy women. Using real-time sonography, we evaluated fasting and postprandial (15th-, 30th-, 45th-, 60th-, 75th-, 90th-, 120th-, and 150th-minute) gallbladder volumes and ejection fractions. The smallest postprandial volume was considered the residual volume. Mean (+/- standard deviation) fasting and residual gallbladder volumes were 43.2 +/- 18.3 cm(3) and 21.4 +/- 11.2 cm(3), respectively, in the obese women and 28.1 +/- 12.3 cm(3) and 7.9 +/- 3.4 cm(3), respectively, in the nonobese women. Maximal ejection fraction was 49 +/- 19% in obese women and 63 +/- 29% in nonobese women (p = 0.001). The fasting and residual volumes and the postprandial volumes at all time points were higher in obese women than in nonobese women (p < 0.001). In addition, 15th-, 30th-, 45th-, 60th-, 75th-, and 90th-minute postprandial ejection fractions were lower in obese women than in nonobese women (p < 0.001). Positive correlations were found between fasting gallbladder volume and body mass index and body fat weight and between residual volume and body mass index, waist circumference, body fat percentage, and body fat weight (p < 0.05 for all comparisons). Our results show that fasting and postprandial gallbladder volumes are higher and that postprandial gallbladder motility is lower in obese than in nonobese women. There are positive correlations between fasting gallbladder volume and body weight, body mass index, and body fat weight.

Effect of short-time treatment with ursodeoxycholic acid on postprandial gallbladder bile flow in gallstone patients: a statistical-mathematical analysis of ultrasonographic data

Background: Gallstone disease is characterized by an impaired gallbladder (GB) emptying and a reduced GB turnover of bile, being the latter assessed by a mathematical analysis of UltraSonographic (US) data (1). In these patients administration of ursodeoxycholic (UDCA) acid seems to be associated to a reduced risk of bifiary pain and complications. The effect of UDCA on GB function is still matter of debate. Aim: To assess by means of statistical analysis of the US motility data, and GB bile flow with computer fluid dynamics the effect of UDCA therapy. Patients and Methods: in 3 GS patients, postprandial US assessment of GB volumes, for a study period of 90 minutes, with a time sampling of 1 minute, has been performed before and after 30 days of UDCA therapy (lOmg/Kg/die). The measured time series were successively analyzed with statistical tools and Fourier analysis. Results: The average volume of the gallbladder of patients is increased upon UDCA treatment (10.6%, 21.1%, 23.9%, respectively). The increase is statistically significant for the three patients. Indeed, a hypothesis test (a T-test) on the means of two distributions led to the conclusions that, with 95% significance, the null hypothesis of equal mean volumes pre and posttreatment must be rejected for the three patients. On the other hand, the organ motility is only slightly affected by UDCA administration, so that the characteristic GB-dimension oscillations remain essentially unaltered. In particular, the time series analysis shows that the volume oscillations have the same amplitude before and after UDCA treatment, and a Fourier analysis shows that also the characteristic frequencies (pre and post treatment) are basically unchanged. A simple geometrical reasoning proves that UDCA treatment improves the intra-GB bile turnover. Conclusions: Short-time treatment with UDCA induces an improvement of postprandial GB bile exchanges in GS patients. Application of standard statistical tests and time series analysis in the frequency domain to US GB motility data could provide additional insights into the assessment of intra-GB bile stasis, a key-event in the pathogenes is of GS disease. 1) M.Cicala et al. U l t rasound Med Blot 2001 Nov;27(11):1445-50.