An experimental study on preventing gallstone formation by exogenous cholecystokinin

It is well known that stasis of lithogenic bile in the gallbladder is an important factor in cholesterol gallstone formation. In this study, hamsters fed with standard lithogenic diet were given physiologic dose of exogenous cholecystokinin-octapeptide daily to facilitate emptying of the gallbladder. It was found that there was significant reduction in the gallstone formation. This study suggests that gallbladder motility is closely correlated with cholesterol gallstone formation, and administration of exogenous cholecystokinin-octapeptide can effectively prevent gallbladder stasis and reduce the incidence of cholelithiasis. This method may be useful for gallstone prophylaxis in high-risk individuals.     

Cholecystokinin prophylaxis of parenteral nutrition-induced gallbladder disease.

Recent studies indicate that long-term total parenteral nutrition (TPN) induces gallstone formation and acalculous cholecystitis in humans. Cholecystectomy is hazardous for these patients because they frequently have multiple medical problems and have undergone numerous abdominal operations. The present study was designed to develop a method to prevent TPN-induced gallbladder disease. The authors tested the hypothesis that a single daily intravenous infusion of cholecystokinin-octapeptide (CCK-OP) will prevent TPN-induced gallbladder stasis. Eleven prairie dogs received TPN for 10 days. Six of these animals were given a daily infusion of CCK-OP. Control animals were fed ad lib. Each animal's bile salt pool was labeled with intravenous 3H-cholic acid 16 hours prior to acute terminal experiments. The ratio of gallbladder to hepatic bile 3H-cholic acid specific activity (Rsa) provides an index of gallbladder stasis. A Rsa of less than 1.0 indicates gallbladder stasis. TPN animals had a Rsa of 0.54 +/- 0.13 (p less than 0.01 vs. controls), indicating stasis of bile in the gallbladder. Daily CCK-OP infusions resulted in a Rsa of 0.92 +/- 0.10 (p less than 0.05 vs. TPN without CCK-OP), indicating that TPN-induced gallbladder stasis is prevented by daily CCK-OP. Control animals had a Rsa of 1.03 +/- 0.06. The cholesterol saturation indices of gallbladder and hepatic bile were not increased by TPN or CCK-OP. These data indicate that 1) TPN induces gallbladder stasis but does not increase bile lithogenic index; and 2) daily injections of CCK-OP prevent TPN-induced gallbladder stasis.     

The role of cystic duct resistance in the pathogenesis of cholesterol gallstones

Several recent clinical and laboratory observations suggest that impaired gallbladder emptying is important in the pathogenesis of cholesterol cholelithiasis. However, the exact mechanism by which gallbladder stasis occurs in the majority of patients who form gallstones has not been clear. We tested the hypothesis that impaired gallbladder emptying antedates cholelithiasis and results from increased resistance to bile flow. Using the prairie dog gallstone model, resistance to flow through the cystic duct (CD) and sphincter of Oddi (SO) was measured in control and cholesterol-fed animals. Prairie dogs were fed either a control (trace cholesterol) or a 0.4% cholesterol-enriched diet known to induce gallstones in 6 weeks. Resistance across the CD and SO was measured at 4 weeks (pregallstone) and 16 weeks (gallstone). Resistance was measured by infusing lactated Ringer's solution through the CD and SO at four separate flow rates while gallbladder and distal common bile duct pressures were recorded. Resistance to flow through the cystic duct increased prior to gallstone formation and continued to increase during the 16 weeks of cholesterol feeding. In comparison, sphincter of Oddi resistance remained normal despite chronic exposure to lithogenic bile and formation of stones within the gallbladder. The increased cystic duct resistance observed prior to gallstone formation provides a mechanism for diminished gallbladder emptying and suggests an etiological role for increased cystic duct resistance in the pathogenesis of cholesterol gallstones.     

The effects of ethinylestradiol,a glucose diet and streptozotocin induced diabetes mellitus on gallstone formation and biliary lipid composition in the hamster

Possible risk factors for gallstone formation were examined and the concentrations of biliary lipids and each bile acid in the hepatic and gallbladder bile of hamsters were quantified. Forty female golden Syrian hamsters were divided into 4 groups according to diet; Group I, given control chow, Group II, given an ethinylestradiol and cholesterol supplemented diet, Group III, given a glucose rich diet without induced diabetes mellitus, and Group IV, given a glucose rich diet with diabetes mellitus induced by streptozotocin injection. The formation of cholesterol crystals but not gallstones was induced in Group II associated with a significantly decreased total bile acid concentration in the gallbladder bile but not in the hepatic bile. The formation of cholesterol gallstones and crystals with significantly higher concentrations of cholesterol and phospholipid was observed in Group III, while neither the formation of gallstones nor lithogenicity was enhanced by diabetes mellitus. However, a quite different lithogenicity was evident between the hepatic and gallbladder bile of the Group IV animals. These results suggest that neither the consumption of oral contraceptives nor diabetes mellitus induces gallstone formation, but that these factors can be responsible for dysfunction of the gallbladder.     

The effects of ethinylestradiol, a glucose diet and streptozotocin induced diabetes mellitus on gallstone formation and biliary lipid composition in the hamster

Possible risk factors for gallstone formation were examined and the concentrations of biliary lipids and each bile acid in the hepatic and gallbladder bile of hamsters were quantified. Forty female golden Syrian hamsters were divided into 4 groups according to diet; Group I, given control chow, Group II, given an ethinylestradiol and cholesterol supplemented diet, Group III, given a glucose rich diet without induced diabetes mellitus, and Group IV, given a glucose rich diet with diabetes mellitus induced by streptozotocin injection. The formation of cholesterol crystals but not gallstones was induced in Group II associated with a significantly decreased total bile acid concentration in the gallbladder bile but not in the hepatic bile. The formation of cholesterol gallstones and crystals with significantly higher concentrations of cholesterol and phospholipid was observed in Group III, while neither the formation of gallstones nor lithogenicity was enhanced by diabetes mellitus. However, a quite different lithogenicity was evident between the hepatic and gallbladder bile of the Group IV animals. These results suggest that neither the consumption of oral contraceptives nor diabetes mellitus induces gallstone formation, but that these factors can be responsible for dysfunction of the gallbladder.     

Stasis before gallstone formation: Altered gallbladder compliance or cystic duct resistance?

Gallbladder stasis occurs before gallstone formation and provides the link between the hepatic secretion of supersaturated bile and cholesterol cholelithiasis. We recently observed that cystic duct resistance increases while sphincter of Oddi resistance is unchanged in the presence of lithogenic bile without gallstones. Whether alterations in gallbladder function also lead to gallbladder stasis has been unclear. Therefore, we tested the hypothesis that before gallstone formation, stasis results from increased cystic duct resistance and altered gallbladder compliance. Adult, male prairie dogs were fed either a trace cholesterol (control) or a 0.4 percent cholesterol-enriched diet. Cystic duct resistance increased but gallbladder compliance was unchanged before gallstone formation. A significant correlation (p < 0.001) was found between the lithogenic index and cystic duct resistance in pregallstone animals. We conclude that increased resistance to flow across the cystic duct, and not altered gallbladder compliance, is etiologically related to bile stasis, an important event in gallstone formation.     

Role of gallbladder mucus in the pathogenesis of cholesterol gallstones

Recent observations indicate that the hepatic secretion of lithogenic bile, gallbladder mucus hypersection, and gallbladder stasis are all critical factors in the pathogenesis of cholesterol gallstones. Using the prairie dog gallstone model, we investigated the interaction of these factors and the sequence in which they develop. The results of this study indicated that (1) gallbladder bile mucus concentration is elevated before cholesterol precipitation and increases progressively with the formation of cholesterol crystals, (2) cystic duct resistance increases in the presence of cholesterol crystals, but not fine, sonicated crystals increase cystic duct resistance. We conclude that these alterations trigger a self-perpetuating cycle of mucus hypersecretion, cholesterol crystallization, and gallbladder stasis which culminates in the formation of cholesterol gallstones.     

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??Study on the relationship between gallbladder cholesterol polyps and the pathogenesis of gallstones JIAO Da-hai*, HAN Tian-quan, JIANG Zhao-yan, et al. *Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Minimally Invasive Surgery Center, Shanghai 200025, China Corresponding author: WANG Ming-liang, Email: mingliangwang@hotmail.com Abstract Objective To study on the relationship between gallbladder cholesterol polyps and the pathogenesis of gallstone. Methods gallbladder stone, bile and part of gallbladder full-thickness tissue were collected from 62 patients who underwent laparoscopic cholecystectomy from April 2008 to september 2008 in our center, including 31 patients with gallbladder cholesterol polyps, 18 patients with cholesterol gallstones and 13 patients in control??6 patients with gallbladder adenoma and 7 patients with non-cholesterol gallstone ). sonography was applied to measure the gallbladder three diameter before and 1 hour after breakfast to evaluate the contracted function of gallbladder. The contents of cholesterol in gallstone and cholesterol, bile acid and phospholipid in bile were measured, and the full-thickness tissue of the gallbladder wall was done the pathological examination. Results Emptying Rate of Gallbladder in the patients with cholesterol polyps was(47.3±18.6) %, it was significantly decreased comparing with those that in the healthy people(71.7±8.1)%, P??0.01, but there ware no differences between the patients in group of cholesterol polyps and in group of gallstones??47.6±23.7??%. Cholesterol saturation index was higher in the patients with cholesterol polyps comparing with those that in control group(1.0±0.2 vs 0.6±0.3, P??0.01), but there ware no differences between the patients in group of cholesterol polyps and in group of gallstones (1.0±0.2 vs1.0±0.2, P??0.05). Gallstones and cholesterol polyps coexistence in 13 patients among 31 patients who with the gallbladder cholesterol polyps, and the incidence of gallstone is 41.9%. Conclusion the existence of gallbladder cholesterol polyps may lead to the formation of gallbladder stone.     

Risk of developing cholelithiasis after vagotomy

Summary As the vagotomy coupled with pyloroplasty is becoming increasingly popular in recent years as operation of choice for gastric and duodenal ulcer, it becomes important to determine whether or not gallstone incidence increases after vagotomy. Dog gallbladder bile can hold additional cholesterol than is normally present. It is this additional cholesterol holding capacity of bile which is responsible for the dissolution of human gallstones inserted in dog gallbladder. Therefore dissolution of human gallstones in dog gallbladder can in turn be used to indicate the extent of cholesterol unsaturation in dog gallbladder bile. In the present communication human gallstone inserted in dog gallbladder is found to become less soluble after vagotomy and change of bile composition after vagotomy seems to indicate that higher incidence of gallstone can be expected. Possible factors responsible for the change of bile composition after vagotomy is discussed.     

Why does somatostatin cause gallstones?

Long-term administration of the somatostatin analogue, octreotide, is complicated by gallstone formation. Somatostatin is known to inhibit hepatic bile secretion and gallbladder emptying. However, the effect of octreotide on gallbladder bile composition remains unknown. Therefore, we tested the hypothesis that octretide would alter hepatic bile composition and cause gallbladder stasis, thereby increasing gallbladder bile solute concentrations. Fourteen control prairie dogs received daily saline injections, whereas 10 animals received 1 micrograms of octreotide subcutaneously three times per day for 5 days. Cholecystectomy and common bile duct cannulation were then performed. Octreotide increased hepatic bile concentrations of bilirubin monoglucuronide (p less than 0.05), total bilirubin (p less than 0.05), and total protein (p less than 0.01). Rsa, an index of gallbladder stasis, was decreased (p less than 0.01) in the octreotide group. Gallbladder bile total calcium (p less than 0.05), bilirubin monoglucuronide (p less than 0.05), total bilirubin (p less than 0.01), total protein (p less than 0.05), and total lipids (p less than 0.05) were increased in the octreotide group. Animals receiving octreotide also had decreased hepatic (p less than 0.05) and gallbladder (p less than 0.001) bile pH. No differences in cholesterol saturation index were observed. These data suggest that in the prairie dog, octreotide (1) alters hepatic bile composition, (2) causes gallbladder stasis, and (3) increases gallbladder bile calcium, bilirubin, protein, lipid, and hydrogen ion concentrations. We conclude that octreotide causes alterations in gallbladder bile composition that increase the likelihood of cholesterol and calcium bilirubinate precipitation.     

The effects of amiloride on biliary calcium and cholesterol gallstone formation.

Recent studies indicate that gallbladder absorption increases during the early stages of experimentally-induced cholesterol gallstone formation. The purpose of the present study was to ascertain whether pharmacologic inhibition of gallbladder ion transport and absorption reduces the incidence of experimentally-induced cholesterol gallstones. Prairie dogs were fed either a control chow or a 1.2% cholesterol-enriched chow for 15 days. One group of cholesterol-fed animals received saline via an orogastric tube; another group received amiloride, a drug known to inhibit in vitro ion transport in the prairie dog gallbladder. The incidence of gallstones in cholesterol-fed animals was reduced from 83% to 13% (p less than 0.025) when the animals were treated with amiloride; this occurred despite a cholesterol-saturation index comparable to that observed in gallstone animals. Additionally, although biliary calcium decreased in the gallbladder, hepatic bile did not in the amiloride-treated animals. These data provide further evidence that altered gallbladder absorption and increased biliary calcium are important factors in the pathogenesis of cholesterol gallstones.     

单个与多发胆固醇结石患者胆道细菌感染状况及与免疫球蛋白相关性的对照研究

目的 多发胆固醇结石患者胆囊炎症程度较高,可能与结石形成有关.对多发和单个胆固醇结石患者胆道细菌感染状况及与免疫球蛋白含量的相关性进行对照研究.方法 :用半定量PCR法测定分析38例胆囊结石患者胆石、胆汁和粘膜的细菌DNA阳性率和菌落数,并测定相应胆汁和粘膜IgA、IgG、IgM含量.结果 :单个和多发胆石组的胆汁细菌DNA阳性率分别为75.0%和73.7%,胆囊粘膜细菌DNA阳性率分别为66.7%和64.0%,结石核心的细菌DNA阳性率分别为57.1%和85.7%,结石外周细菌阳性率分别为71.4%和85.7%,两组间差异均无显著性.两组间胆汁和粘膜IgA、IgG、IgM含量差异无显著性,菌落数与免疫球蛋白含量不相关.多发胆石组粘膜细菌DNA阳性者的胆囊粘膜IgA、IgG含量高于阴性者(P<0.05).单个和多发胆石组胆汁胆固醇饱和指数(CSI)差异无显著性,各组内胆汁细菌阳性与阴性者的CSI差异也无显著性.结论 :多发和单个胆固醇结石患者胆囊细菌感染率相似,细菌感染不是多发胆固醇结石患者胆囊炎症严重的原因.多发胆固醇结石患者胆囊粘膜细菌与IgA、IgG含量增高有关,可能间接参与胆固醇结石的形成过程.     

The relationship of cholecystectomy and taurocholic acid feeding to bile composition and hepatocyte function in prairie dogs

The prairie dog was used as a model for human gallstone formation. Stones formed in the gallbladder of all animals on a lithogenic diet. Hepatic bile was nonlithogenic, whereas gallbladder bile promoted cholesterol precipitation. Addition of taurocholate to the diet reduced the number of stones and lithogenicity. Cholecystectomy resulted in an increased bile flow and reduced secretion of cholesterol in the animals on a high cholesterol diet. Reduction of cholesterol and bile acid synthesis by negative feedback was demonstrated in isolated hepatocyte culture. The shift of bile salt production to chenodeoxycholates on a high cholesterol intake was demonstrated both in vivo and in vitro. A theory of gallstone formation is presented which hypothesizes a defect in hepatocyte storage of cholesterol rather than bile acid synthesis as the primary effect, relegating the problems to one of a disease of lipid metabolism.     

Triglyceride and cholesterol content in bile, blood, and gallbladder wall

Cholesterol gallstone disease is frequent in Chile compared with other countries, as is cholesterolosis of the gallbladder. The purpose of this study was to determine any differences in bile composition and cholesterol content in the gallbladder wall and serum of patients compared with findings in patients with gallstones and control subjects. In control subjects, cholesterol content of the gallbladder wall was determined in autopsy material. Patients with cholesterolosis had bile composition similar to that of patients with gallstones, with supersaturation of cholesterol in the bile. Also, these patients had increased levels of cholesterol in the gallbladder wall but normal serum cholesterol levels. These findings suggest that altered bile composition occurs in patients with cholesterolosis and gallstones.     

Altered bile composition during cholesterol gallstone formation: cause or effect?

Gallbladder stasis, increased gallbladder absorption, and elevated biliary levels of calcium, hydrogen ion, and bilirubin have been implicated as factors potentially critical to cholesterol crystal precipitation. Previous studies, however, have analyzed bile only when crystals or gallstones have already formed. Therefore, we tested the hypothesis that changes in bile composition are a late effect, occurring only after crystal formation. Adult male prairie dogs were fed a standard nonlithogenic control diet (n = 7) or a lithogenic 1.2% cholesterol diet for 5, 9, or 14 days to cause cholesterol saturation (n = 7), cholesterol monohydrate crystals (n = 7), or gallstones (n = 7). Gallbladder bile was examined microscopically for crystals, and analyzed for ionized calcium, bilirubin, pH, total protein, and biliary lipids. The ratio of gallbladder to hepatic bile radiolabeled cholic acid specific activity (Rsa) was calculated as an index of gallbladder stasis. Cholesterol saturation index was calculated. The results demonstrate that increased gallbladder bile cholesterol saturation and total protein concentration precede cholesterol monohydrate crystal precipitation. However, changes in gallbladder ionized calcium, unconjugated bilirubin, pH, stasis, and absorption were noted only after crystals and gallstones had already formed. These data indicate that alterations in gallbladder bile calcium, bilirubin, pH, stasis, and absorption are not early changes, but occur simultaneously with or after crystal formation. Increased biliary protein, however, which was elevated prior to nucleation, may be an important mediator of cholesterol precipitation in cholesterol-saturated bile.     

Crystal morphology of cholesterol monohydrate in cholesterol gallstones and gallbladder bile

To understand the pathogenesis of cholesterol gallstones from a crystallographic point of view, we investigated gallstones and precipitates in gallbladder bile by the optical method used in crystallography. First, ground thin sections of cholesterol gallstones in 28 cases were examined by a polarizing microscope. The crystalline fragments which were peeled off from gallstones by sonication were also examined in the same manner. Secondly, the cholesterol monohydrate crystals in gallbladder bile were examined by a polarizing and phase contrast microscope. The bile samples were obtained from 15 patients with cholesterol gallstones by the needle puncture of gallbladder during surgery. The results of observation were as follows. 1) The cholesterol gallstones were composed of many small plated cholesterol monohydrate crystals aggregated radially. 2) Each small plated crystal was grown by the lateral growth mechanism in bile. Spiral growth patterns were often observed on the (001) faces. 3) The cholesterol gallstones were formed by two successive mechanisms: The aggregation of cholesterol monohydrate crystals and the lateral growth of each single crystal.     

瘦素在胆囊胆固醇结石形成中的作用

目的 通过临床病例研究,探讨血清及胆汁中的瘦素在胆囊胆固醇结石形成中的作用与影响.方法 选取2016年3月1日-11月30日在内蒙古自治区人民医院肝胆胰脾外科住院行腹腔镜下或开腹胆囊切除术患者共91例,分为胆囊胆固醇结石组(A组)58例和非胆囊胆固醇结石组(B组)33例,以体重指数=24 kg/m2为标准,又将A组分成A1组30例(体重指数≥24 kg/m2)和A2组28例(体重指数＜24 kg/m2);B组分成B1组18例(体重指数≥24 kg/m2)和B2组15例(体重指数＜24 kg/m2).对A、B两组病例一般情况、体重指数、血清瘦素含量、胆汁瘦素含量、高密度脂蛋白、低密度脂蛋白、脂蛋白(a)、载脂蛋白AI、载脂蛋白B、载脂蛋白AI/载脂蛋白B比值、血清总胆固醇、血清总胆汁酸、三酰甘油等指标进行检测.计量资料用均数±标准差(-x±s)表示,组间比较使用t检验或t’检验.计数资料用频数和百分数表示,组间比较使用x2检验.体重指数和血清瘦素的相关性采用Pearson相关系数描写.结果 胆囊胆固醇结石组患者血清瘦素含量与非胆囊胆固醇结石组血清瘦素含量分别为(7.92 +7.34) ng/ml和(4.81±1.79) ng/ml,差异有统计学意义(P＜0.05),同时该组血清瘦素水平与体重指数呈正相关(r=0.65,P=0.01),当体重指数≥24 kg/m2时相关性明显(r =0.73,P ＜0.01).胆囊胆固醇结石组血清总胆固醇、低密度脂蛋白、载脂蛋白B、三酰甘油水平分别为(4.85±0.74) mmol/L、(2.53±0.69) mmol/L、(0.97±0.3) g/L、(1.92±0.61) mmol/L,非胆囊胆固醇结石组分别为(4.47±0.8) mmol/L、(2.22±0.50) mmol/L、(0.8 ±0.2) g/L、(1.49 ±0.69) mmol/L,与后者相比前者含量显著性增高(P＜0.05).胆囊胆固醇结石组高密度脂蛋白和载脂蛋白AI含量分别为(0.93±0.28) mmol/L、(1.38±0.27) g/L,与非胆囊胆固醇结石组(1.24 ±0.26) mmol/L、(1.53±0.21) g/L相比显著性降低(P＜0.05);两组胆汁瘦素含量、总胆汁酸、脂蛋白(a)差异无统计学意义(P＞0.05).结论 血清瘦素含量的改变,可能通过影响血液脂质、脂蛋白水平,以及胆汁中瘦素的含量,最终影响胆固醇结石的形成过程.     

Effect of sphincteroplasty on gallbladder function and bile composition.

The effect of sphincteroplasty on bile concentration and composition and on gallbladder function was investigated in the dog. Gallbladder and hepatic bile samples were analyzed for cholesterol, phospholipid (lecithin), bile salt concentration and individual bile salt content. Motor function was studied by cholecystokinin-cholecystography with changes in gallbladder volume computed from the radiographs. All bile samples were cultured and at the conclusion of the experiments, the gallbladders were histologically examined. Sphincteroplasty did not alter biliary cholesterol concentration but the concentration of lecithin and bile salts decreased in gallbladder bile and increased in hepatic bile (p less than .001). These changes depict a trend toward greater lithogenicity for gallbladder bile and lesser lithogenicity for hepatic bile. Postoperative analysis of individual bile salts in gallbladder bile showed an increase in monohydroxy and dihydroxy bile salts and a decrease in trihydroxy bile salts (p less than .001). This tendency has been shown to be conducive to gallstone formation. The concentrating ability of the gallbladder was partially eliminated by sphincteroplasty but gallbladder filling and motor response to stimulation by cholecystokinin was not affected. All gallbladders demonstrated histologic changes of chronic inflammation and all developed a significant bacterial flora following sphincteroplasty. It is concluded that cholecystectomy should always be performed following transduodenal sphincteroplasty not because of any resultant abnormality of motor function, as has previously been held, but because of the resultant abnormality of gallbladder pathophysiology.     

胆石病患者胆囊收缩素受体与胆囊动力关系的研究

研究胆囊平滑肌的胆囊收缩素-A受体(CCK-R)与胆囊动力的关系。方法:B超测定10例无胆石的正常者和33例胆囊结石患者的胆囊动力。采用放射配基法测定33例患者的胆囊和8例意外创伤死亡者正常胆囊中CCK-R含量和活性。根据无胆石正常者的胆囊残余指数,将胆石患者分为胆囊收缩“正常”组(14例)和收缩减弱组(19例),而将10例无胆石正常者和8例意外死亡者列为正常对照者。结果:收缩减弱组的CCK-R含量和活性都显著低于正常对照组(P<0.01),也显著低于收缩“正常”组。收缩“正常’组的CCK-R活性显著低于正常对照组(P<0.01),但含量与正常对照组无明显差异。CCK-R含量和活性分别与胆囊排空率相关(r=0.964,r=0.635,P<0.01)。结论:胆囊胆汁郁积在胆囊收缩“正常”组是由于胆囊空腹容积增加、胆囊CCK-R活性降低,在胆囊收缩减弱组是由于胆囊CCK-R含量和活性的降低。     

Effects of resection or bypass of the distal ileum on the lithogenicity of bile

Changes in the composition and lithogenicity of gallbladder bile after resection and bypass of the distal ileum were investigated in the prairie dog. In animals fed a trace cholesterol diet, both ileal resection and ileal bypass increased the cholesterol saturation of bile. In animals fed a cholesterol-enriched diet, the cholesterol saturation was increased by ileal resection but not by ileal bypass. In the animals fed the trace cholesterol diet, both ileal resection and ileal bypass induced the formation of bilirubinate gallstones.