The pathophysiological characteristics of bile from patients with gallstones: the role of prostaglandins and mucin in gallstone formation

Bile was obtained from 82 patients with various biliary tract diseases and concentrations of prostagloandins, leukotriens, mucin, and a number of lithogenic components were measured in order to evaluate the role of these substances in the pathogenesis of gallstone formation. The characteristics of bile in cases of cholesterol gallstones included high concentrations of prostaglandins and hexosamine and a high cholesterol saturation index. Prostaglandin E2 and prostaglandin F2 alpha concentrations in bile were correlated with hexosamine concentration, and prostaglandins and hexosamine were found to be actively synthesized and secreted in the gallbladder. Prostaglandins E2 and F2 alpha may therefore stimulate mucin secretion in the gallbladder with supersaturated bile. The characteristics of bile in cases of calcium bilirubinate gallstones included a high detection rate for bacteria, high beta-glucuronidase activity, a high percentage of unconjugated bilirubin, a low cholesterol saturation index and high concentrations of prostaglandins and hexosamine. Moreover, the synthesis and secretion of prostaglandins in the biliary tract were accelerated in cases of infected bile. Thus, hypersecretion of mucin, stimulated by prostaglandins, my participate in the onset and development of biliary tract infection or in the formation of calcium bilirubinate gallstones. Regarding the role of prostaglandins and mucin, the hypotheses for gallstone formation previously reported by many authors are supported by the clinical data obtained in the current study.     

The pathophysiological characteristics of bile from patients with gallstones: The role of prostaglandins and mucin in gallstone formation

Bile was obtained from 82 patients with various biliary tract diseases and concentrations of prostagloandins, leukotriens, mucin, and a number of lithogenic components were measured in order to evaluate the role of these substances in the pathogenesis of gallstone formation. The characteristics of bile in cases of cholesterol gallstones included high concentrations of prostaglandins and hexosamine and a high cholesterol saturation index. Prostaglandin E₂ and prostaglandin F_2α concentrations in bile were correlated with hexosamine concentration, and prostaglandins and hexosamine were found to be actively synthesized and secreted in the gallbladder. Prostaglandins E₂ and F_2α may therefore stimulate mucin secretion in the gallbladder with supersaturated bile. The characteristics of bile in cases of calcium bilirubinate gallstones included a high detection rate for bacteria, high β-glucuronidase activity, a high percentage of unconjugated bilirubin, a low cholesterol saturation index and high concentrations of prostaglandins and hexosamine. Moreover, the synthesis and secretion of prostaglandins in the biliary tract were accelerated in cases of infected bile. Thus, hypersecretion of mucin, stimulated by prostaglandins, my participate in the onset and development of biliary tract infection or in the formation of calcium bilirubinate gallstones. Regarding the role of prostaglandins and mucin, the hypotheses for gallstone formation previously reported by many authors are supported by the clinical data obtained in the current study.     

Bacteria and gallstone nucleation

This preliminary study reports for the first time that there might be a possible association between bacteria and the aetiology of some cholesterol calculi. The gall-bladder biles from 225 cholecystectomy patients underwent bacteriological and microscopic study. Cholesterol calculi from 13 patients (10.2%) were observed to be associated with gall-bladder bile profusely infected with at least one bacterial species that was shown to possess beta-glucuronidase activity, an enzyme that is thought to promote calcium bilirubinate precipitation in bile. Concomitantly, the associated gall-bladder bile was 'high' in calcium bilirubinate precipitation and the precipitate was also detected in the centre of the gallstones. Moreover, in approximately half of these patients (six of 13), the cholesterol gallstones' nuclear areas also contained calcium palmitate, which is also thought to be due to bacterial activity. The results also support the hypothesis that bacteria with active beta-glucuronidase (for example, Escherichia coli) can significantly influence the aetiology of brown pigment gallstones. In contrast, bacteria were observed to have no role in black pigment gallstone formation, as their associated gall-bladder biles were always observed to be sterile.     

Ileal resection-induced gallstones: altered bilirubin or cholesterol metabolism?

Ileal resection has been shown to increase the risk of cholelithiasis. Earlier studies in humans suggested that ileal resection increases the cholesterol saturation index. Recent data from patients on long-term parenteral nutrition and from animals, however, have suggested that ileal resection predisposes to pigment gallstone formation. We therefore tested the hypothesis that ileal resection alters bile calcium and bilirubin metabolism without affecting the cholesterol saturation index. Adult male prairie dogs underwent either sham laparotomy (eight prairie dogs) or ileal resection (16 prairie dogs). All animals were fed a trace cholesterol (nonlithogenic) diet before and for 4 weeks after operation. Pigment gallstones were present in 44% of the ileal-resected animals and in none of the sham animals (p less than 0.05). Calcium bilirubinate crystals were present in 94% of the ileal-resected animals and in none of the sham animals (p less than 0.01). Gallbladder bile calcium (25.6 +/- 2.4 versus 17.2 +/- 1.1 mg/dl; p less than 0.05) and total bilirubin (29.3 +/- 4.0 versus 9.4 +/- 1.8 mg/dl; p less than 0.01) concentrations were significantly greater in ileal-resected animals. The cholesterol saturation index of gallbladder bile, however, was no different in ileal-resected (0.53 +/- 0.04) and in sham-operated animals (0.50 +/- 0.04). Although initial studies suggested that the cholesterol saturation index of hepatic bile was increased after ileal resection, a second set of experiments demonstrated that this phenomenon resulted from washout of bile salts that were already in extremely low concentrations in hepatic bile. We conclude that alterations in bilirubin, but not cholesterol, metabolism result in pigment gallstone formation after ileal resection.     

Changes in bile components during the formation and prevention of black pigment gallstone in a guinea pig model

Black pigment gallstones were found in 22 out of 23 guinea pigs one week after the common bile ducts were partially ligated (S group). The incidence decreased to 11/20 (P less than 0.01) if the animals were fed with a chow containing bile salt mixture, glucurolactone, ane aspirin (S+M group). Three weeks after the ligation the incidence of gallstone in S group and S+M group was 17/18, and 9/10, respectively (P greater than 0.05). Glucuronidase (beta-G) activity in the bile of S group was not higher than that of control group (C group, P greater than 0.05), and all the bile samples were sterile. The biliary concentrations of ionized calcium (ICa), unconjugated bilirubin (UCB), total calcium (TCa), total bilirubin (TBr), glycoprotein (GIy. P), and PH significantly fluctuated among guinea pig groups and were parallel to gallstone incidence. The results of this study could hardly be explained by Maki beta-G theory, but were consistent with the assumption that the precipitation-dissolution equilibrium of calcium bilirubinate is the key of pigment gallstone formation, thus the increases of the above mentioned bile components, including beta-G activity, would bias this equilibrium towards calcium bilirubinate precipitation and therefore promote gallstone formation. On the contrary, stone formation would be prevented.     

The effect of parenteral nutrition on biliary calcium and bilirubin

Recent studies have suggested that patients maintained on prolonged total parenteral nutrition (TPN) are at increased risk for gallstone formation. Animal and human data suggest that TPN causes calcium bilirubinate sludge and pigment gallstones. However, the effect of TPN on bile bilirubin and calcium concentrations has not previously been investigated. We, therefore, tested the hypothesis that TPN alters biliary bilirubin and calcium. Eight adult male prairie dogs received TPN (dextrose 15%, FreAmine III 4.25%, Intralipid 10%, insulin 25 U, electrolytes, and vitamins) at a rate of 80 cc/kg/day for 10 days. Eight additional animals maintained on a trace cholesterol diet served as controls. Gallbladder and hepatic bile samples were assayed for bilirubin and calcium. Cholesterol saturation index (CSI) and Rsa, a measure of gallbladder stasis, were also calculated. Calcium bilirubinate crystals were seen in gallbladder bile or wall scrapings of 7 of 8 TPN animals but in none of the controls (P less than 0.001). Animals that received TPN had bilirubin levels that were significantly higher in gallbladder bile (24.8 +/- 7.0 vs 5.1 +/- 0.9, P less than 0.05). Similarly, TPN animals had calcium levels that were significantly higher in gallbladder (30.0 +/- 3.6 vs 13.9 +/- 2.1, P less than 0.005) as well as hepatic (10.5 +/- 0.6 vs 7.4 +/- 0.6, P less than 0.005) bile. The Rsa values were also significantly lower (P less than 0.01) in TPN animals (0.57 +/- 0.07 vs 1.06 +/- 0.14). CSI, serum bilirubin, serum calcium, hematocrit, and reticulocyte counts did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Infected bile and intrahepatic gallstones

Currently, the incidence of the upper stenotic type and intrahepatic stenotic type have been increasing in number. These changes may be attributed to the improvements of the diagnostic tools for hepatobiliary diseases, especially in the progress of imaging methods. In view of the type of gallstone, most intrahepatic gallstones are the calcium bilirubinate stones generated on the basis of bile stasis and bacterial infection. For the formation of calcium bilirubinate stones the mutual relationship of bacterial beta-glucuronidase and glucaro-1, 4-lactone in the bile is thought to important. Free bile acids and fatty acids are detected in fairly large amount in calcium bilirubinate stones. This suggests that precipitation of calcium bilirubinate in the bile may coincidently occur with the deconjugation of the conjugated bile acids and decomposition of lecithin. In the formation of calcium bilirubinate stones, it is believed that diet and bacterial infection accompanying biliary stasis are important inducements. Since these stones are formed mainly in bile ducts and recurrence rates are likely to high, it is important to remove these inducements from therapeutic viewpoint.     

细菌在含有游离胆红素的模拟胆汁体系中对胆固醇晶体形成的影响

目的探讨在含有游离胆红素(UCB)的模拟胆汁体系中细菌对胆固醇晶体形成的作用。方法大肠杆菌、铜绿假单胞菌和粪肠球菌分别加入含有不同浓度游离胆红素的模拟胆汁中,观察胆汁中胆固醇晶体形成时间(NT)的变化。结果游离胆红素缩短模拟胆汁中胆固醇晶体形成时间。铜绿假单胞菌和粪肠球菌缩短胆固醇晶体形成时间,但是同时加入游离胆红素后,NT未见进一步缩短。在CSI 0.6时单加铜绿假单胞菌的胆汁比单加UCB时的晶体形成时间更短。结论模拟胆汁体系中,细菌和游离胆红素对胆固醇晶体形成无协同作用。     

Carbohydrate diet-induced calcium bilirubinate sludge and pigment gallstones in the prairie dog

Epidemiologic studies suggest that consumption of diets rich in carbohydrates may, in part, be responsible for the increasing incidence of pigment gallstone disease. The mechanism by which these dietary components lead to pigment stone formation remains obscure. Furthermore, investigative efforts in this area have been hampered by the lack of a suitable animal model. The present study was undertaken to study the role of complex carbohydrates in pigment gallstone formation in the prairie dog. Two groups of eight animals each were maintained on either a control, nonlithogenic chow, or a high carbohydrate (35% sucrose, 32% rich starch) diet for 2 months. Neither crystals nor gallstones were observed in any of the control animals. All of the carbohydrate fed animals (P less than 0.005 vs control) had calcium bilirubinate crystals and sludge, while microscopic, black stones were present in six of these eight animals (P less than 0.05 vs control). Although hepatic bile bilirubin was unchanged in the carbohydrate-fed group, these animals had a significant increase in hepatic bile calcium (P less than 0.005) and phospholipids (P less than 0.005) when compared to controls. Carbohydrate-fed animals also had a significant increase in gallbladder bile concentrations of phospholipids (P less than 0.001), calcium (P less than 0.001), unconjugated (P less than 0.005), conjugated (P less than 0.005), and total bilirubin (P less than 0.001) as compared to controls. These data indicate that in the prairie dog, carbohydrate feeding results in increased biliary concentrations of phospholipids, calcium and bilirubin, and formation of calcium bilirubinate crystals, sludge and microscopic gallstones.(ABSTRACT TRUNCATED AT 250 WORDS)     

Supersaturation of canine gallbladder bile with calcium bilirubinate during formation of pigment gallstones

Analogous to cholesterol gallstones forming in bile supersaturated with cholesterol, pigment gallstones may form in bile supersaturated with calcium bilirubinate. We tested this hypothesis in a dietary model of pigment gallstones. The concentration of ionized calcium (Ca++) and unconjugated bilirubin (UCB) was measured in 15 normal dogs and in 15 dogs with pigment gallstones induced by 6 weeks of a methionine-deficient diet. Although there was minimal change in the gallbladder's ability to acidify or concentrate bile, both [Ca++] and [UCB] markedly increased. These values were compared with equilibrium concentrations in model bile solutions. In all normal bile, the [UCB] was equal to or lower than the mean [UCB] concentration of model bile solutions with comparable [Ca++]. However, in all but one bile sample from dogs with pigment gallstones, the [UCB] exceeded this concentration and was therefore supersaturated with calcium bilirubinate. This supports the hypothesis that calcium bilirubinate precipitation is important in the formation and growth of pigment gallstones.     

The bacteriology of cholelithiasis--China versus Japan.

Cholelithiasis differs considerably from area to area in the world. Calcium bilirubinate stones or brown pigment stones are said to predominate in the Orient, however, this situation may differ within the Orient. In order to compare cases in China and Japan, 102 consecutive cases of cholelithiasis operated on in Shenyang, China were analyzed for the composition of gallstones and bacterial species isolated from bile in relation to the location and composition of gallstones. In Shenyang, calcium bilirubinate stones predominated, occurring in 49.0 per cent of the cholelithiasis cases. This was much higher than in Japan, which had 17.5 per cent. The incidence of bacteria was also very high, ranging from 20 to 96 per cent, with an average of 66.7 per cent depending on the kind of gallstone present. Bacterial species possessing beta-glucuronidase activity were present in nearly all the cases of calcium bilirubinate stones (92.0 per cent). The incidence of bacteria with beta-glucuronidase activity especially of E. coli was much higher than in Japan (50.8 per cent versus 21.8 per cent) in concordance with the higher incidence of calcium bilirubinate stones in China (49.0 versus 17.5 per cent).     

Short-term fasting increases biliary calcium and bilirubin

Fasting has been associated clinically with the development of gallbladder sludge and pigment gallstones, both of which are composed primarily of calcium bilirubinate. Although fasting has been demonstrated to increase the cholesterol saturation of bile, its effect on biliary calcium and bilirubin has not been investigated. We, therefore, tested the hypothesis that short-term fasting would increase gallbladder bile calcium and bilirubin levels. Fifteen prairie dogs were studied. Seven animals were not fasted, whereas eight were fasted for 16 hr prior to acute experiments. Gallbladder and hepatic bile samples were obtained and analyzed for calcium, bilirubin, pH, and biliary lipids. Gallbladder bile ionized calcium levels were significantly increased in fasted animals (1.7 +/- 0.2 mM) compared to those in nonfasted animals (1.1 +/- 0.1 mM). Similarly, total calcium (4.3 +/- 0.5 mM vs 2.3 +/- 0.3 mM), total bilirubin (63 +/- 12 microM vs 29 +/- 8 microM), and bilirubin monoglucuronide (58 +/- 10 microM vs 22 +/- 8 microM) were significantly increased in the fasted group. Fasted animals were also noted to have an increased biliary cholesterol saturation index (0.57 +/- 0.04 vs 0.36 +/- 0.03) and decreased biliary pH (6.9 +/- 0.1 vs 7.6 +/- 0.1). These data indicate that in the prairie dog short-term fasting results in significant alterations in gallbladder bile composition. The increased concentrations of gallbladder calcium and bilirubin observed in these experiments may account, in part, for the formation of pigment gallstones and gallbladder sludge seen clinically with prolonged fasting.     

Oral calcium promotes pigment gallstone formation

Dietary calcium supplementation has been recommended for prevention of osteoporosis and has become a standard component of most "health food" diets. Biliary calcium has been recognized to play a central role in the formation of pigment gallstones. We have recently demonstrated that 5 days of oral calcium supplementation significantly increases biliary calcium in the prairie dog (K. D. Lillemoe, T. H. Magnuson, G. E. Peoples, et al., Gastroenterology 94: A563, 1988). We hypothesized, therefore, that long-term oral calcium supplementation would promote pigment gallstone formation. Sixteen adult male prairie dogs were maintained on a standard nonlithogenic diet. Eight animals received calcium supplementation (2.5 x control levels) in their water, while the remaining eight animals served as controls. After 8 weeks, cholecystectomy was performed, and the common bile duct was cannulated. Bile was examined microscopically and analyzed for ionized calcium, bilirubin, glycoprotein, and biliary lipids. The cholesterol saturation index (CSI) was calculated. Pigment stones and calcium bilirubinate sludge were present in all animals receiving calcium supplementation. Only one control animal had evidence of pigment stones (P less than 0.001). Biochemical analysis of gallbladder bile demonstrated a significant increase in total bilirubin and bilirubin monoglucuronide (P less than 0.01) as well as bile glycoprotein content (P less than 0.05) after oral calcium supplementation. Gallbladder bile ionized calcium was also increased although not significantly. These data suggest that oral calcium supplementation promotes gallbladder sludge and pigment gallstone formation in the prairie dog. This observation raises concern that oral calcium supplementation, especially in the older female population, may enhance gallstone formation.     

胆系感染的菌群结构分析及临床意义

目的：了解胆系感染的茵群结构新变化，为胆石的成因和发病机制的研究提供依据；对电穿孔治疗(electropvration therapy，EPT)术后病人的胆汁细菌学的研究，为该技术的可行性、科学性提供临床根据。方法：对55例确诊为胆系感染，对每例的胆汁、胆石进行需氧、厌氧茵培养，胆石分类后分别行电镜观察。结果：胆汁和胆石培养出的细菌种类相似，以肠球菌属占首位，其次是大肠杆菌和克雷伯茵属，且多为两种或两种以上细菌的复合感染，其中胆汁复合感染率为54．3％，胆石复合感染率为66．7％。HP的阳性率：胆汁：10／55(占18．2％)；胆石：8／46(占17．4％)；厌氧茵培养的阳性率：胆汁：20／55(占36．4％)；胆石：18／46(占39．1％)；对胆色素结石进行电镜扫描观察：均观察到有细菌存在，胆固醇结晶中少有细菌，结石核心可发现细菌；EPT术后：2例阳性(大肠杆茵)，3例阴性。结论：胆系感染病人的胆汁和胆石培养出的细菌种类相似，以肠球菌属占首位，其次是大肠杆菌和克雷伯茵属，且首次发现有幽门螺杆菌(HP)的存在。电镜观察细菌存在于结石的核心和外周，说明细菌在胆结石的成因和发病机制中充当始动因子作用。EPT治疗后病人胆汁细菌培养结果初步说明胆道仍保持有其封闭性和屏蔽作用。     

The bacteriology of cholelithiasis

Cholelithiasis differs considerably from area to area in the world. Calcium bilirubinate stones or brown pigment stones are said to predominate in the Orient, however, this situation may differ within the Orient. In order to compare cases in China and Japan, 102 consecutive cases of cholelithiasis operated on in Shenyang, China were analyzed for the composition of gallstones and bacterial species isolated from bile in relation to the location and composition of gallstones. In Shenyang, calcium bilirubinate stones predominated, occurring in 49.0 per cent of the cholelithiasis cases. This was much higher than in Japan, which had 17.5 per cent. The, incidence of bacteria was also very high, ranging from 20 to 96 per cent, with an average of 66.7 per cent depending on the kind of gallstone present. Bacterial species possessing β-glucuronidase activity were present in nearly all the cases of calcium bilirubinate stones (92.0 per cent). The incidence of bacteria with β-glucuronidase activity especially ofE. coli was much higher than in Japan (50.8 per centversus 21.8 per cent) in concordance with the higher incidence of calcium bilirubinate stones in China (49.0versus 17.5 per cent).     

胆固醇结石患者胆囊细菌感染的研究

目的 比较胆固醇类结石患者和非胆石症患者胆道细菌感染情况.方法 用不依赖细菌培养的半定量PCR和16SrRNA序列对照法,检测76例胆固醇类结石患者胆囊黏膜、胆汁和胆石中细菌DNA,与34例非胆石患者对照.结果 胆石组和非胆石组胆汁细菌DNA阳性率分别为77%和67%,胆囊黏膜细菌DNA阳性率分别为64%和69%,两组间差异均无统计学意义(P＞0.05).胆石组细菌种类主要为大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌、不动杆菌、链球菌、鞘氨醇单胞菌、脆弱类杆菌和痤疮丙酸杆菌,胆石组菌种比非胆石组丰富,非胆石组菌种基本上均能在胆石组中找到.结论 胆固醇结石与非胆石症患者胆道细菌感染率相似,胆固醇结石中存在细菌不足以证明细菌参与胆固醇结石的形成.     

Bilirubin monoglucuronide promotes cholesterol gallstone formation

Recent evidence suggests that cholesterol (Ch) solubility in bile is determined by a complex interaction of mixed micelles and lecithin-cholesterol vesicles. Bilirubin monoglucuronide (BMG), which binds to bile salts and incorporates into mixed micelles, may displace cholesterol from micelles into vesicles, thus favoring cholesterol monohydrate crystal precipitation. Therefore, we designed an experiment to test the hypothesis that BMG may enhance cholesterol gallstone formation without inducing cholesterol supersaturation. For 8 weeks, 28 adult male prairie dogs were fed either a control, nonlithogenic diet (0.03% Ch), a high carbohydrate diet (CHO) which has no cholesterol but increases hepatic bilirubin secretion, or the same CHO diet plus 0.03% Ch. Cholecystectomy was then performed, and bile was examined microscopically for stones or crystals and analyzed for BMG and biliary lipids. Cholesterol saturation index was calculated. Cholesterol gallstones were found in none of the control animals and in 13% of the CHO-fed animals. However, the addition of trace cholesterol to the CHO diet resulted in an 88% incidence of cholesterol gallstones (P less than 0.001 vs control, P less than 0.01 vs CHO, respectively). Gallbladder bile was unsaturated with cholesterol in all groups. (control = 0.65 +/- 0.05, CHO = 0.46 +/- 0.05, CHO + 0.03% Ch = 0.70 +/- 0.03). CHO feeding alone or with trace cholesterol significantly elevated gallbladder bilirubin monoglucuronide, phospholipid, and cholesterol concentrations when compared to controls. These data suggest that in the prairie dog a high carbohydrate diet with only trace amounts of cholesterol increases bilirubin monoglucuronide in gallbladder bile and causes cholesterol gallstone formation without inducing cholesterol supersaturation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary Bile Duct Stones and Bacterial Activity

The results of this study suggest that infection with beta-glucuronidase active bacteria is the initial event in the nucleation of primary bile duct stones (PBDS).PBDS from five patients were morphologically fragile and “earthy” with alternating light and dark brown pigment layers with no evidence of a distinct central nucleus that may have been reminiscent of a different structure. Chemically, calcium bilirubinate and calcium palmitate were prominent throughout their structure. All bile duct biles had a positive culture and were always associated with at least one bacterial species which was beta-glucuronidase active. Moreover, fragments of PBDS nuclear areas had positive cultures that were comparable with those present in their individual bile duct bile. Microscopic examination of bile showed abundant precipitation of calcium bilirubinate granules in all samples.Thus, bile duct bile infection with beta-glucuronidase active bacteria (e.g. E. coli, C. perfringens) appears to be a key factor in PBDS pathogenesis, having a precursor role, rather than being a consequence. Bile stasis is likely to be a co-factor which must have a supportive role in subsequent stone growth.     

胆固醇逆向转运紊乱在兔胆红素钙结石成石过程中的作用

对免胆道不全梗阻与感染致胆红素钙结石成石过程中脂蛋白，尤其是高密度脂蛋白（HDL）代谢全过程作了测定。结果：实验组与对照组相比，血清游离胆固醇及HDL3-胆固醇明显升高，而HDL2-胆固醇及HDL-胆固醇明显减少；血浆卵磷酯-胆固醇酸基转移酶（LCAT）活性及肝细胞膜HDL受体最大结合力明显下降；胆汁中甘氨胆酸、甘氨脱氧胆酸及总胆酸明显减少；而肝组织中总胆固醇、甘油三酯及磷脂则均无显著性差异。本实验结果提示：在胆道不全梗阻及感染致胆红素钙结石成石过程中，存在因LCAT活性不足所致的HDL合成减少及成熟障碍，并有肝细胞膜HDL受体结合力下降，由于胆固醇逆向转运过程紊乱，在其它致石因素共同作用下导致色素性胆石的发生。     

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.