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.     

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??Correlation between Oddi’s sphincter abnormality and cholelithiasis WU Shuo-dong. Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
Abstract The etiology of cholelith is complicated with involvement of sphincter of Oddi(SO). For primary bile duct pigment stones, both duodenoscopy and barium meal revealed high incidence of periampullary diverticulum. SO manometry through “T” tube sinus showed hypomotiligy of SO. Oral intake of 99Tcm-DTPA and measurement of amylopsin-1 and enterokinase confirmed the existence of duodeno-biliary and pancreaticobiliary refluxes. Measurement of fatty acids in gallstones also suggested phospholipase A1 played a role in the formation of bile duct pigment stones. For gallbladder cholesterol stones, hypermotiligy of SO existed. SO dysfunction and recurrent of bile duct stones after cholecystectomy revealed, at least in part, some gallbladder stones were primarily caused by SO abnormality.     

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.     

Effects of cholecystokinin on gallbladder stasis and cholesterol gallstone formation

Recent studies suggest an etiologic role for gallbladder stasis in the genesis of cholesterol gallstones. The effect of periodic gallbladder emptying on stone prevention is not clear. Using the prairie dog model, we tested the hypothesis that daily cholecystokinin-octapeptide (CCK-OP) prevents gallbladder stasis and cholesterol gallstone formation. Prairie dogs were fed either a control or a 0.4% cholesterol-enriched chow for 6 weeks. Cholesterol-fed animals received a daily intramuscular injection of either saline, CCK-OP, 0.2 μg/kg or CCK-OP, 1.0 μg/kg. Gallbladder bile lithogenic index (LI), bile salt pool size (BSPS), and the degree of radioisotope equilibration between gallbladder and hepatic bile (Rsa-an index of stasis) were determined. The more physiologic dose of CCK-OP (0.2) significantly reduced BSPS and bile lithogenicity, prevented stasis and reduced the incidence of gallstones. Our data suggest that (1) periodic gallbladder emptying decreases bile lithogenicity, prevents stasis, and reduces the incidence of cholelithiasis, (2) stasis is essential to gallstone formation and (3) daily physiologic doses of CCK-OP may be useful for gallstone prophylaxis in high-risk patients.     

Oddi括约肌异常与胆结石的关系

胆石成因复杂,Oddi括约肌（SO）异常与其形成关系密切。对于原发胆管色素结石,经十二指肠镜及钡餐检查均发现较高的乳头周围憩室发生率。经T管窦道测压提示SO功能下降,通过口服99mTC-DTPA的方法及检测胰淀粉酶-1和肠激酶含量证实了肠胆反流和胰胆反流的存在。胆石中脂肪酸的测定亦提示细菌产生的磷脂酶A1在胆管色素结石形成中起作用;对于胆囊胆固醇结石,亦存在SO收缩亢进或者张力过高之现象。胆囊切除术后综合征中的SO异常及胆囊切除术后再发胆管结石的现象从一个侧面揭示某些病人的胆囊结石原本是由于SO异常引起。     

自制动力散预防胆囊结石形成的实验研究

为探讨中药动力散预防胆囊结石的机理，选用家兔37只，随机分为3组。对照组（n=13）给予基础饲料；高胆固醇组（n=14）给予含1．2％胆固醇的高胆固醇饲料；高胆固醇十动力散组（n=10）给予高胆固醇饲料加能促进胆囊收缩的中药动力散，分笼饲养4周后，对胆囊成石情况和胆囊管阻力等进行观察与检测。结果发现，高胆固醇组12／14只形成结石，高胆固醇十动力散组2／10只形成结石，后者动物胆囊排空率较高胆固醇组显著增加，胆汁中粘蛋白浓度和胆囊管阻力则明显降低。表明动力散能通过促进胆囊收缩而降低胆汁中粘蛋白含量，降低胆囊管阻力，促进胆囊排空，有利于减少胆囊结石形成。     

Postprandial sphincter of Oddi myoelectric activity and gallbladder emptying

Feeding initiates gallbladder emptying and bile delivery into the duodenum. It is not yet defined how the sphincter of Oddi regulates flow of bile into the duodenum during gallbladder emptying. The aim of this study was to assess postprandial spike burst activity in the sphincter of Oddi, while quantitating gallbladder emptying with noninvasive radioisotope imaging. Six adult opossums were prepared with bipolar electrodes in the sphincter of Oddi. After 2 weeks of recovery the animals were fasted overnight and positioned under a gamma camera, and myoelectric recordings were begun. After two cycles of the migrating motor complex (MMC), 2 mCi 99Tc-HIDA was infused intravenously and permitted to concentrate in the gallbladder for a period of 30 min. Subsequently, a 30-ml liquid meal, containing 0.9 g protein, 3.5 g carbohydrate, and 3.3 g fat, was instilled into the stomach. Sphincter of Oddi myoelectric activity (spike bursts/min) and gallbladder emptying (expressed as percentage of original 99Tc counts in the gallbladder) were measured at intervals for 120 min following feeding. Feeding resulted in prompt gallbladder emptying. Sphincter of Oddi spike burst activity was not altered significantly in the first 30 min after feeding, suggesting that motor activity in the sphincter of Oddi does not initially influence bile flow. Subsequently, spike burst activity increased progressively, suggesting that sphincter of Oddi motor activity may accelerate bile delivery into the duodenum during later phases of gallbladder emptying.     

Altered sphincter of Oddi Phasic Activity following truncal vagotomy

Neural as well as hormonal influences regulate sphincter of Oddi function. Therefore, we tested the hypothesis that truncal vagotomy alters sphincter of Oddi phasic activity and response to hormonal stimulation. Adult, male prairie dogs underwent either sham laparotomy or truncal vagotomy and pyloroplasty. Postoperatively, all animals were fed a trace-cholesterol (nonlithogenic) diet for 3 months. In acute terminal experiments the distal common bile duct was perfused with lactated Ringer's solution at 0.1 ml/min. Sphincter of Oddi (SO) phasic contractions as well as baseline resistance were recorded before and during a 30-minute intravenous infusion of 10 ng/kg/min of cholecystokinin-octapeptide (CCK-OP). Before the CCK-OP infusion, both the frequency and amplitude of SO phasic contractions were significantly greater (P < 0.01) in vagotomized animals. During CCK-OP, the frequency of SO phasic contractions remained significantly greater (P < 0.01) in the vagotomy animals. The amplitude of SO phasic contractions, however, increased significantly (P < 0.03) in response to CCK-OP only in sham animals. Vagotomized animals failed to develop any further increase in the amplitude of SO phasic contractions during CCK-OP infusion. No differences in baseline resistance were noticed between sham and vagotomized animals before or during the infusion of CCK-OP. These findings suggest that (1) vagal tone inhibits sphincter of Oddi phasic contractions, (2) vagotomy increases sphincter of Oddi phasic activity, and (3) parasympathetic denervation alters the sphincter of Oddi's response to CCK-OP. Since the sphincter of Oddi plays an important role in normal gallbladder filling and emptying, altered sphincter of Oddi function may, in part, be responsible for the gallbladder stasis observed following vagotomy.     

Progesterone alters biliary flow dynamics

OBJECTIVE: To test the hypothesis that progesterone alters sphincter of Oddi and gallbladder function and, therefore, bile flow dynamics. SUMMARY BACKGROUND DATA: Although the effects of progesterone on the biliary tract have been implicated in the increased incidence of gallstones among women, the specific effects of prolonged elevation of progesterone levels, such as occurs with contraceptive progesterone implants and during pregnancy, on the sphincter of Oddi and biliary flow dynamics are still incompletely understood. METHODS: Adult female prairie dogs were randomly assigned to receive subcutaneous implants containing either progesterone or inactive pellet matrix only. Hepatic bile partitioning and gallbladder emptying were determined 14 days later using 99mTc-Mebrofenin cholescintigraphy. RESULTS: Significantly less hepatic bile partitioned into the gallbladder in progesterone-treated than in control animals. The gallbladder ejection fraction was significantly reduced from 73+/-6% in controls to 59+/-3% in the progesterone-treated animals. The rate of gallbladder emptying was significantly reduced from 3.6+/-0.3%/minute to 2.9+/-0.1%/minute. CONCLUSIONS: Progesterone administered as subcutaneous implants alters partitioning of hepatic bile between gallbladder and small intestine and, therefore, gallbladder filling. Progesterone also significantly impairs gallbladder emptying in response to cholecystokinin. The effects of progesterone on the sphincter of Oddi and the gallbladder may contribute to the greater prevalence of gallstones and biliary motility disorders among women.     

胆道口括约肌运动功能与豚鼠胆固醇结石形成关系的研究

目的研究胆道口(Oddi)括约肌运动功能在豚鼠胆囊胆固醇结石形成过程中的作用。 方法34只成年雄性Hartley豚鼠随机分为胆固醇结石组(24只)和对照组(10只),其中胆固醇结石组(按被处死的时间,分为4个亚组,各6只)给予致石饮食,3、6、9、12周后对两组行胆道口括约肌测压并检测肌电活动。 结果胆固醇结石组3、6、9、12周的发生率分别为0、16.7%、16.7%、83.3%。肌电活动的频率在3周组和6周组减小(均P < 0.05),肌电活动幅度在9周组和12周组明显降低[从(146.44 ± 81.09) μV分别降至(68.18 ± 49.58) μV和(40.60 ±45.03) μV, P <0.05]。胆道口括约肌收缩频率在6周组和9周组明显减小(P < 0.05)。胆道口括约肌基础压及胆总管压在12周组明显升高[从(25.19 ± 7.77) mmHg至(52.38 ± 12.84) mmHg,(22.35 ± 7.60) mmHg至(50.11 ± 12.59) mmHg,均P < 0.01]。 结论致胆固醇结石饮食能诱发胆道口括约肌功能紊乱,其张力增加、活动性下降。胆道口括约肌运动功能紊乱是胆色素结石形成的一个重要因素。     

Transport of fluid and biliary lipids in the canine gallbladder in experimental cholecystitis

In acute cholecystitis the cystic duct is usually obstructed by a gallstone and the gallbladder is often tensely distended with clear fluid. Because these findings suggest that fluid absorption in the gallbladder may be reversed in cholecystitis, we examined the effect of inflammation on the gallbladder mucosal function in dogs. In 20 dogs cholecystitis was induced by ligating the cystic duct and allowing inflammation to develop from bile stasis and the presence of a chronic indwelling cannula in the gallbladder. Every morning an aliquot of normal hepatic bile was infused into the gallbladder through a cannula in the gallbladder fundus. After either 4 or 24 hr the gallbladder contents were aspirated, the volume was measured, and the concentrations of bile acids, cholesterol, phospholipids, and protein were determined. Changes in volume were checked using [14C]PEG as a nonabsorbable tracer. A net absorption of fluid, bile acids, cholesterol, and phospholipids occurred during the first 24 to 48 hr after ligation of the cystic duct. Thereafter, fluid, cholesterol, and protein were secreted into the lumen, but absorption of bile acids continued. The lithogenic index of bile placed in the inflamed gallbladder was always greater when the bile was removed 24 hr later. The rate of fluid secretion into the lumen of the inflamed gallbladder increased after a meal and decreased after indomethacin. These findings demonstrate that inflammation can stimulate the gallbladder mucosa to secrete fluid, a process that may be important in the pathophysiology of acute cholecystitis in man. Since inflammation also resulted in an increased cholesterol saturation of gallbladder bile, cholecystitis per se may contribute to the formation of cholesterol gallstones.     

犬胆囊、Oddi括约肌电活动和胆囊胆总管压力的同步检测

目的探讨同步检测犬胆囊、Oddi括约肌肌电和胆囊、胆总管压力的实验方法。方法采用多通道生理仪同步记录麻醉后犬的胆囊和Oddi括约肌的肌电图以及胆囊、胆总管压力。剖腹显示肝、胆、胃及十二指肠,用7F静脉深穿管经肝穿刺进入胆囊腔内作为测压通道,再将一对铂金电极缝在胆囊底部浆膜上。把另一条7F静脉深穿管制作成带一对铂金电极的胆总管测压和Oddi括约肌肌电检测通道。结果Oddi括约肌峰电位为0．18～0．20mV,频率为2～5次／min;其慢波电位0．06～0．08mV,频率为8～10次／min,峰电位往往在某次慢波电位的基础上突然出现。胆囊肌电不明显。胆囊的压力为7～9cmH2O,胆总管压力为11～15cmH2O。结论同步检测Oddi括约肌肌电活动与胆囊、胆总管压力的实验方法是可行的,有利于研究Oddi括约肌肌电活动与胆囊及胆总管压力的关系,但是对于记录在体胆囊的肌电活动方法需要进一步改进。     

Increases in gallbladder prostaglandin synthesis before the formation of cholesterol gallstones

Increased synthesis of prostaglandins in the wall of the gallbladder may play a role in the pathogenesis of cholesterol gallstones by mediating mucus hypersecretion and thereby accelerating nucleation and the precipitation of cholesterol-supersaturated bile. We induced gallstones in prairie dogs and guinea pigs by feeding a cholesterol-supplemented diet for periods as long as 6 weeks. Gallbladder prostaglandin synthesis was quantitated by specific radioimmunoassays that measured the amount of various prostanoids released from the gallbladder during in vitro incubation. The gallbladders of cholesterol-fed prairie dogs showed increased synthesis of prostaglandin E2, prostaglandin F2a, and thromboxane and increased concentrations of glycoprotein in gallbladder bile. These changes were evident as early as 2 weeks after institution of the cholesterol diet, although cholesterol gallstones did not form until 4 or more weeks. In contrast, cholesterol feeding of the guinea pig did not induce cholesterol supersaturation. In this species pigment gallstones formed, probably as a result of a cholesterol-induced hemolytic anemia, and gallbladder mucus hypersecretion did not occur. Pigment gallstone formation in the guinea pig was associated with an increase in prostacyclin synthesis, but the synthesis of prostaglandin F2a and thromboxane was decreased. Increased prostaglandin synthesis may contribute to the formation of cholesterol gallstones but does not appear to participate in pigment gallstone formation.     

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.     

The cholecysto-sphincter of Oddi reflex

Multiple factors including hormonal and neural influences as well as intravascular volume, body temperature, and pharmacologic agents have been shown to influence sphincter of Oddi function. Recent studies have also suggested that mechanical or electrical stimulation of the gallbladder and the degree of gallbladder filling may affect the frequency and amplitude of sphincter of Oddi phasic contractions. However, the effect of gallbladder filling on sphincter of Oddi phasic wave direction has not previously been studied. In acute terminal experiments, eight adult male prairie dogs underwent cannulation of the gallbladder with a pressure-monitored perfusion catheter. The common bile duct was cannulated proximally with a drainage catheter and distally with a triple-lumen, side-hole, closed-tipped catheter. The distal port of this catheter was positioned in the sphincter of Oddi (SO) while the proximal port was in the distal common bile duct (CBD). Distal CBD and SO phasic wave activity was recorded first with the gallbladder perfused with lactated Ringer's solution at 0.1 ml/min (mean intragallbladder pressure 8.1 ± 0.3 mm Hg) and then with the gallbladder (GB) empty. Sphincter of Oddi phasic wave frequency was 6.7 ± 0.9/min with the GB full and 5.4 ± 0.6/min with the GB empty (P < 0.02). Phasic wave amplitude was also greater with the GB full versus empty in both the distal CBD (6.4 ± 0.6 vs 4.3 ± 0.5 mm Hg, P < 0.05) and the SO (9.5 ± 1.5 vs 6.4 ± 0.8, P = 0.075). Baseline pressures and the direction of phasic waves were unaffected by the degree of gallbladder filling. It is concluded that the degree of gallbladder filling reflexly influences sphincter of Oddi phasic wave activity and should be considered in future studies of the choledochoduodenal junction.     

Bile acid pattern of gallbladder and hepatic bile in patients with and without cholesterol gallstones.

Bile acid composition of hepatic and gallbladder bile was examined in a group of 18 patients with uncomplicated cholelithiasis and a control group consisting of 13 patients with healed duodenal ulcers. Bile specimens were taken during laparotomy. Molar concentrations of the different bile acids in hepatic and gallbladder bile were determined. The ratios between the molar concentrations of the different bile acids were calculated. In order to compare these molar ratios in hepatic and gallbladder bile the quotients between identical molar ratios of hepatic and gallbladder bile were calculated in each subject. Bile acid concentration of the gallbladder bile was found to be lower in the gallstone patients. Trihydroxy or dihydroxy bile acid molar ratio was lower in the gallstone group. Hepatic to gallbladder relative trihydroxy to dihydroxy and cholate to deoxycholate bile acid ratios were elevated in the gallstone patients. This might indicate that an increased formation of deoxycholate is the main cause for the decreased trihydroxy to dihydroxy bile acid molar ratio observed in the gallbladder bile of patients with cholesterol gallstones.     

Roles of lithogenic bile and cystic duct occlusion in the pathogenesis of acute cholecystitis

The hypothesis that the elements essential for the induction of acute cholecystitis are the presence of lithogenic bile and cystic duct occlusion was tested in the prairie dog gallstone model. Neither the presence of gallstones alone nor acute cystic duct occlusion alone resulted in acute inflammation of the gallbladder. Acute cholecystitis developed in prairie dog gallbladders containing cholesterol-saturated bile, with or without gallstones, shortly after cystic duct occlusion. These data suggest that the factors essential for the induction of acute cholecystitis are the presence of lithogenic bile and cystic duct occlusion and that gallstones, although frequently present, are not an essential prerequisite to acute inflammation.     

Changes in gallbladder volume do not affect cystic duct resistance

To our knowledge, the relationship between gallbladder volume and cystic duct function has not been studied. We hypothesized that changes in gallbladder volume would influence cystic duct resistance. The effect of gallbladder volume changes on cystic duct resistance to both prograde (emptying) and retrograde (filling) steady-state flow was tested in 12 dogs under basal cholecystokinin-stimulated conditions utilizing a multiport catheter with a highly compliant balloon placed within the gallbladder fundus. Gallbladder volume was regulated by varying balloon volume from empty to just beyond physiologic distention. Cystic duct resistance was not affected by balloon volume under basal or stimulated conditions or by the direction of perfusate flow. This study demonstrated no relationship between gallbladder volume and cystic duct resistance and did not demonstrate a cystic duct sphincter mechanism at physiologic gallbladder volumes.     

The classification of biliary calculi and the clinico-therapeutic implications

A new classification of gallstones is reported, which has interesting implications for diagnostic and therapeutic purposes. Gallstones have been divided according to "type" into the following categories: cholesterol (single, multiple), mixed, black pigment, brown pigment, combination and composite. In addition, gallstones primarily formed within the gallbladder have been distinguished from those initially formed in the common duct (before and after surgery) and within the intrahepatic ducts. Stone type and composition have been related to symptoms, on the basis of a new view, according to which gallstones are not a unique entity, but a heterogeneous disease including different entities, each of which has its own pathogenesis, clinical manifestations, biological behaviour and also deserves a different treatment. The proper treatment should be appropriate to the individual and his stones. Therapeutic guide-lines are suggested for each type of stones, in particular for stones complicated by cholangitis, pancreatitis, or for common duct stones concomitantly found with gallbladder stones. For the last group, techniques and therapeutic options preserving the function of the sphincter of Oddi are recommended. Suggestions are also reported concerning the treatment of various types of hepatolithiasis: primary, i.e. associated with cystic intrahepatic bile duct dilatation; post-surgical, i.e. occurring cranially to a biliary enteric anastomosis: secondary, i.e. associated with concomitant gallbladder and common duct stones.     

Sex differences in gallstone pancreatitis.

From a computerized database comprising 28 pertinent items in each of a consecutive series of 664 patients with cholelithiasis, differences were studied between men and women. In 52 patients there was a documented attack of acute pancreatitis (7.8%). Twenty-five of 174 men had pancreatitis, compared with 27 of 490 women (p less than 0.0001). Men developed gallstones later in life than women, but suffered gallstone pancreatitis earlier in life and in the course of their gallstone-related disease. A history of flatulent dyspepsia, chronic cholecystitis, and biliary colic was less common in men than in women with pancreatitis (p less than 0.0001). Men with pancreatitis had fewer stones in their gallbladders than did women (p = 0.0002). The cystic duct and the common bile duct in the pancreatitic patient were more likely to be dilated (p less than 0.0001). In the nonpancreatic group, these ducts were larger in men. Pancreatic duct reflux on operative cholangiography was more common both in patients with pancreatitis 62% cf 14% (p less than 0.0001), and in men (p less than 0.001). Predisposition to pancreatitis relates to duct size rather than stone size per se. Men are more susceptible to gallstone migration at an early stage of their disease. In addition they have a larger diameter duct system and possibly a different anatomic disposition of the sphincter of Oddi, which predisposes them to a higher incidence of pancreatitis than women. The data suggest that it is cystic duct size that is critical in the pathogenesis of gallstone pancreatitis.