Hayder H. Al-Azzawi

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.

Cholecystosteatosis: an Explanation for Increased Cholecystectomy Rates

IntroductionOver the past decade, obesity has become epidemic, and the number of cholecystectomies as well as the percentage with acalculous cholecystitis have increased. We have recently reported that congenitally obese mice and lean mice fed a high fat diet have increased gallbladder wall lipids and poor gallbladder emptying. Therefore, we tested the hypothesis that compared to patients with a normal gallbladder, patients with both acalculous and calculous cholecystitis would have increased gallbladder wall fat.MethodsSixteen patients who underwent cholecystectomy for acalculous cholecystitis were identified. Sixteen nondiseased controls who underwent incidental cholecystectomy during surgery for liver or pancreatic disease and 16 diseased controls whose gallbladder was removed for chronic calculous cholecystitis were chosen to match the acalculous patients for gender and Body Mass Index. Pathology specimens were reviewed in a blinded fashion for gallbladder wall fat, thickness, and inflammation.ResultsAcalculous cholecystitis patients were younger (p < 0.01) than nondiseased or diseased controls. Gallbladder wall fat was significantly increased (p < 0.02) in the acalculous and calculous cholecystitis patients compared to the nondiseased controls. Gallbladder wall thickness (p < 0.02) and inflammatory score (p < 0.01) were highest in the calculous cholecystitis patients.ConclusionsThese data suggest that compared to nondiseased controls, (1) patients with acalculous cholecystitis are younger and have increased gallbladder fat and (2) patients with calculous cholecystitis have increased gallbladder fat and inflammation. We conclude that increased gallbladder fat may lead to poor gallbladder emptying and biliary symptoms. Thus, cholecystosteatosis may explain, in part, the increased need for cholecystectomy and the higher percentage of these patients with acalculous cholecystitis.

Nonalcoholic fatty gallbladder disease : The influence of diet in lean and obese mice

The obesity epidemic has contributed to an increased prevalence of gallstones and a higher percentage of chronic acalculous cholecystitis. Obesity is associated with Type II diabetes and hyperlipidemia in murine models. In addition, we have previously demonstrated that serum glucose, insulin, cholesterol, and triglycerides correlated with gallbladder contractility in murine models. However, the relative role of in sulin resistance and gallbladder fat infiltration in this phenomenon remain unclear. Therefore, we tested the hypothesis that gallbladder wall lipids are related to obesity and diet and are inversely correlated with gallbladder contractility. One hundred lean control (C7BL/6J) and 36 obese leptin-deficient (Lepob) 8-week-old female mice were fed either a chow diet or a 1.0% cholesterol, 15% butterfat (high-lipid) diet for four weeks. Pooled gallbladders were then analyzed for free fatty acids (FFA), phospholipids (PL), total cholesterol (TC), and triglycerides (TG). Cholesterol/phospholipid ratios were then calculated. The Lepob mice fed a chow diet had significantly higher (P<0.01) gallbladder lipids than the three other groups. The lean mice that were fed a high-lipid diet had increased (P<0.05) gallbladder TC compared to the lean mice on a chow diet. In addition, the cholesterol/phospholipid ratio was significantly in creased (P<0.01) in the lean mice fed a high-lipid diet compared to the other three groups. Finally, the high-lipid diet decreased gallbladder FFA (P<0.01), PL (P=0.08), and TC (P<0.05) in Lepob mice. These data suggest that (1) obese mice have increased gallbladder lipids; (2) a high-cholesterol, high-fat diet increases gallbladder lipids and the cholesterol/phospholipid ratio in lean mice; but (3) de creases gallbladder fatty acids, phospholipids, and cholesterol in obese mice. Prior studies have docu mented similarly decreased gallbladder response to neurotransmitters in obese mice on a chow diet, as well as lean and obese mice on a high-lipid diet. Therefore, we conclude that leptin-deficient obesity and/or a high-fat diet causes nonalcoholic fatty gallbladder disease, which is manifested by diminished gallbladder contractility.

Leptin Regulates Gallbladder Genes Related to Gallstone Pathogenesis in Leptin-Deficient Mice

BACKGROUND Little is known about the genetic factors that cause alterations in gallbladder motility, cholesterol crystal nucleation, biliary lipids, and, ultimately, cholesterol gallstones. Obese, leptin-deficient (Lep(ob)) mice have large gallbladder volumes with decreased contraction in vitro and are predisposed to cholesterol crystal formation. Leptin administration to these mice causes weight loss and restores gallbladder function. We hypothesize that administration of leptin to Lep(ob) mice would cause weight loss, decrease gallbladder volume, and change gallbladder genes related to gallbladder motility, nucleating factors, and lipid metabolism. STUDY DESIGN Twenty-four 8-week-old Lep(ob) mice were fed a nonlithogenic diet for 4 weeks. Twelve mice received daily IP saline injections, and 12 received 5 mug/g recombinant leptin. Gallbladder mRNA was pooled and analyzed on murine genome microarray chips. Selected genes were confirmed by real-time polymerase chain reaction (PCR) in a second group of mice treated by the same protocol. RESULTS Leptin-deficient mice given leptin had significant weight loss and reductions in gallbladder volume. These mice had upregulation of the leptin receptor (p = 0.007; PCR = 1.1-fold increase) but downregulation of leptin (p = 0.003; PCR = 13.5-fold decrease). Leptin upregulated the cholecystokinin A receptor (p < 0.001; PCR = 3.1-fold increase), acetylcholine beta2 receptor (p = 0.005), and the Ca+-calmodulin-dependent protein kinase (p = 0.002) genes. Leptin also altered immunoglobulin heavy chain 4 (p = 0.005; PCR = 17.7-fold increase), mucin 3 (p = 0.006), and carboxylesterase (p = 0.016; PCR = 2.5-fold decrease) genes. Leptin downregulated 3-hydroxy 3-methylglutaryl coenzyme A reductase (p = 0.006; PCR = 2.5-fold decrease) and LDL receptor (p = 0.003). CONCLUSIONS Leptin modulates obesity and regulates gallbladder genes related to cholesterol gallstone pathogenesis.

The burden of incisional hernia in necrotizing pancreatitis: how can we improve?

BACKGROUND Necrotizing pancreatitis (NP) patients frequently require pancreatic debridement, and have risk factors for incisional hernia (IH). However, no published data exist regarding the incidence of IH in NP. The aim of the current study was to define the incidence of and identify risk factors for developing IH after pancreatic debridement. METHODS Hernia presence was determined by clinical examination and patient interview. Technical and clinical considerations were noted: type of incision, closure, suture material, age, body mass index (BMI), diabetes mellitus (DM), preoperative albumin, and number of operations. RESULTS Sixty-three (42%) of 149 debrided patients with NP developed IH. IH patients were older (P<.05). No differences in surgical technique or clinical risk factors were seen between groups. CONCLUSION The incidence of IH in NP patients requiring operative debridement is substantially higher than that in patients undergoing routine laparotomy. Innovative fascial closure techniques such as primary fascial buttress with nonsynthetic mesh should be considered.

166: Ezetimibe ameliorates cholecystosteatosis

Cholecystosteatosis is the accumulation of gallbladder wall fats leading to decreasedgallbladder emptying. Ezetimibe inhibits intestinal fat absorption and prevents murine gallstoneformation. However, the influence of ezetimibe on gallbladder emptying and cholecystosteatosis has notbeen studied. Therefore, we tested the hypothesis that ezetimibe would improve gallbladder motility bypreventing the buildup of fats in the gallbladder wall.

M1759 Does Adiponectin Upregulation Attenuate the Severity of Acute Pancreatitis in Obesity

Introduction Obesity is an independent risk factor for severe acute pancreatitis, though the mechanisms underlying this association are unknown. The powerful anti-inflammatory adipokine adiponectin is decreased in obesity. We recently showed that the severity of pancreatitis in obese mice is inversely related to circulating adiponectin levels, and therefore hypothesized that adiponectin upregulation would attenuate the severity of pancreatitis in obese mice.