Steatocholecystitis: the influence of obesity and dietary carbohydrates

INTRODUCTION: We have recently demonstrated that obese and lean mice fed a high fat diet have increased gallbladder wall fat and decreased gallbladder contractility, cholecystosteatosis. Animal and human data also suggest that diets high in refined carbohydrates lead to gallstone formation. However, no data are available on the role of dietary carbohydrates on gallbladder wall fat and inflammation. Therefore, we tested the hypothesis that both obesity and dietary carbohydrates would increase gallbladder fat and cytokines, steatocholecystitis. METHODS: At 8 wk of age, 47 lean and 22 obese female mice were fed a 45% carbohydrate (CHO) diet while an equal number of lean and obese mice were fed a 75% CHO diet for 4 wk. All mice underwent cholecystectomy, and the gallbladders were snap-frozen. Individual and total lipids were measured by gas chromatography. Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were measured by enzyme-linked immunosorbent assay. Data were analyzed by analysis of variance and Tukey test. RESULTS: Gallbladder total fat, triglycerides, and cholesterol were maximum (P < 0.001) in obese mice on the 75% CHO diet. Gallbladder TNF-alpha and IL-1beta as well as serum cholesterol levels showed a similar pattern (P < 0.001). Gallbladder saturated free fatty acids and IL-6 levels were highest (P < 0.001) in obese mice on the 45% CHO diet. CONCLUSIONS: These data suggest that (1) both obesity and dietary carbohydrates increase gallbladder total fat, triglycerides, cholesterol, TNF-alpha, and IL-1beta and (2) obesity also increases gallbladder free fatty acids and IL-6. Therefore, we conclude that obesity is associated with steatocholecystitis and that a high carbohydrate diet exacerbates this phenomenon.     

Effect of bile diversion and sphincterotomy on gallbladder muscle contractility and gallstone formation

Feeding prairie dogs a diet rich in cholesterol induces gallstone formation that is preceded by a sustained decrease in gallbladder smooth muscle contractility. Sphincterotomy is known to prevent gallstone formation in cholesterol-fed prairie dogs. Experiments were designed to determine whether the effect of sphincterotomy is a consequence of hepatic bile diversion, and whether bile diversion prevents the altered contractility. Following sham operation, surgical biliary enteric bypass, or sphincterotomy, prairie dogs were fed a high-cholesterol or a regular diet. Gallbladder muscle contractility and the presence of crystals and stones were determined. In sham-operated animals, the cholesterol diet induced a decrease in gallbladder muscle contractility and caused the formation of cholesterol gallstones. In animals with bile diversion and sphincterotomy, the effects of cholesterol feeding were reduced or prevented. Thus, these procedures may prevent stone formation by preventing a reduction in gallbladder contractility. Contractility was depressed in animals with bile diversion fed a regular diet, compared with animals with a sham operation fed a regular diet. The mechanism for this depression may differ from that induced by the cholesterol diet. Diversion, and perhaps sphincterotomy, impairs gallbladder filling. Thus, gallbladder muscle is not stretched and does not contract against a load. This could result in a "disuse atrophy." If the results from our study apply to humans, sphincterotomy may reduce stone formation by preventing the effects of lithogenic bile on gallbladder muscle contractility and by enhancing the ability of the muscle to empty the lithogenic bile.     

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.     

Ezetimibe抑制胆固醇结石形成的实验研究

目的 探讨ezetimibe（Eze）对胆囊胆固醇结石形成的抑制作用。方法 将30只雄性成年C57BL/6小鼠随机分为普通饲料喂养(chow)组、成石饲料喂养(LD)组和成石饲料加Eze组[Eze 5 mg/（kg·d）灌胃]。饲养8周后收集血清、肝脏、小肠和胆囊。观察胆囊内胆固醇结石形成情况。采用酶法测定血清、胆汁成分、肝组织胆固醇含量。采用实时定量PCR测定肝脏和小肠胆固醇代谢相关基因mRNA相对表达量。结果 chow组小鼠胆囊内未发现结石形成。LD组小鼠胆囊结石形成率为100%。Eze组完全无结石形成。Eze组小鼠小肠胆固醇吸收率(9.29%±4.32%),较LD组(58.62%±3.10%)和chow组(56.42%±2.67%)均显著降低（P<0.01）。LD组血清胆固醇[(4.99±0.50) mmol/L]和肝组织胆固醇含量[(22.92±2.39) mg/g]均较chow组[(2.87±0.06) mmol/L和(2.45±0.08) mg/g]显著增加（P<0.05）。Eze组血清胆固醇[(1.11±0.10） mmol/L]和肝组织胆固醇含量[(2.70±0.07) mg/g]均较LD组显著降低（P<0.05）。LD组小鼠胆汁胆固醇含量[LD组(10.87±1.46) mmol/L比chow组(3.67±0.58) mmol/L]和胆固醇饱和指数[LD组(1.42±0.19)比chow组(0.59±0.02)]显著增加。Eze组胆汁胆固醇含量[(2.72±0.29) mmol/L]和胆固醇饱和指数(0.57±0.07)均较LD组显著降低（P<0.01）。结论 Eze抑制小肠胆固醇肠道摄取,具有预防胆囊胆固醇结石形成的作用。     

Leptin-resistant obese mice have paradoxically low biliary cholesterol saturation

BACKGROUND: Human obesity is associated with leptin resistance, elevated serum glucose and lipids, hepatic steatosis, and cholesterol gallstone formation. These gallstones are thought to result from hypersecretion of biliary cholesterol as well as biliary stasis. Leptin-resistant Lep(db) obese mice, which are known to have elevated serum leptin, glucose, and lipids, as well as hepatic steatosis, should be an appropriate model for human gallstone formation. Therefore, we tested the hypothesis that leptin-resistant mice would have increased gallbladder volume, biliary cholesterol saturation, and cholesterol crystal formation. METHODS: Sixty lean control mice and 60 Lep(db) obese mice on a low cholesterol chow diet were studied. Gallbladder volumes were measured and bile was pooled to calculate cholesterol saturation index. Serum cholesterol, glucose, and leptin levels were determined from pooled serum. Hepatic fat vacuoles were counted. Bile from a second group of 90 lean control and 59 obese mice was observed microscopically for cholesterol crystal formation. RESULTS: Leptin-resistant obese mice have significantly higher serum cholesterol, glucose, and leptin levels, hepatic fat vacuoles, and gallbladder volume than lean control mice. However, biliary cholesterol saturation index and cholesterol crystal formation were significantly diminished in the obese mice. CONCLUSIONS: These data suggest that leptin-resistant Lep(db) obese mice have (1) increased gallbladder volume, (2) decreased biliary cholesterol saturation despite elevated serum cholesterol and hepatic steatosis, and (3) decreased in vitro cholesterol crystal formation. We conclude that the link between obesity and gallstone formation does not require hypersecretion of biliary cholesterol.     

Leptin-resistant obese mice do not form biliary crystals on a high cholesterol diet

INTRODUCTION: Human obesity is associated with leptin resistance and cholesterol gallstone formation. Previously, we demonstrated that leptin-resistant (Lep(db)) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite elevated serum cholesterol. Obese humans, however, consume a high cholesterol diet. Therefore, we hypothesized that on a high cholesterol diet, leptin-resistant mice would have cholesterol saturated bile and would form biliary crystals. METHODS: Eight-week old female lean control (n = 70) and leptin-resistant (n = 72) mice were fed a 1% cholesterol diet for 4 weeks. All animals then had cholecystectomies. Bile was collected, grouped into pools to determine cholesterol saturation index (CSI), and examined for cholesterol crystals. Serum cholesterol and leptin were also measured. RESULTS: Gallbladder volumes for Lep(db) mice were enlarged compared with the lean mice (35.8 microl versus 19.1 microl, P < 0.001), but the CSI for the Lep(db) mice was lower than for the lean animals (0.91 versus 1.15, P < 0.03). The obese animals did not form cholesterol crystals, whereas the lean animals averaged 2.2 crystals per high-powered field (hpf) (P < 0.001). Serum cholesterol and leptin were also elevated (P < 0.001) in the obese animals. CONCLUSIONS: These data suggest that Lep(db) obese mice fed a high cholesterol diet have increased gallbladder volume and decreased biliary cholesterol saturation and crystal formation despite elevated serum cholesterol compared with lean control mice. We conclude that the link among obesity, diet, and gallstone formation may not require hypersecretion of biliary cholesterol and may be related to the effects of diabetes, hyperlipidemia, or both on gallbladder motility.     

The Use of Simvastatin for the Prevention of Gallstones in the Lithogenic Prairie Dog Model

Background: Surgery for morbid obesity is rapidly increasing. Patients undergoing bariatric surgery are prone to gallstone development during the rapid weight loss. These patients are often given medications such as ursodeoxycholic acid to prevent gallstone formation; however, these medications are often poorly tolerated by patients, who subsequently discontinue them. We performed a study in a lithogenic animal model to assess the effectiveness of a potential alternate medication for gallstone prevention. Methods: 20 male prairie dogs were randomly separated into 2 groups and fed a lithogenic diet for 28 days. The study group animals were given 2.5 mg of the HMG-CoA reductase inhibitor simvastatin. Total cholesterol and triglycerides were measured and an open cholecystectomy was performed on each animal at the conclusion of the study period. The gallbladder was visually inspected for gallstones and microscopic biliary cholesterol crystal formation. Results: There was a decrease of 36% in the total cholesterol of the study animals compared to controls. The animals treated with simvastatin showed gallstone formation in 5/10 (50%) of animals, compared with 6/10 (60%) of control animals. The study animals demonstrated microscopic cholesterol crystal formation in 80%, identical to the number found in the control animals. Conclusion: Despite a reduction in cholesterol, simvastatin prevented neither gallstone formation nor biliary cholesterol crystals in this animal model. Given the rapid increase in the number of bariatric surgical procedures coupled with the poor tolerance of ursodeoxycholic acid, viable alternatives should continue to be sought for these patients.     

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.     

Cholecystosteatosis: an Explanation for Increased Cholecystectomy Rates

Introduction Over 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. Methods Sixteen 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. Results Acalculous 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. Conclusions These 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. Presented at the 2006 SSAT (DDW) annual meeting, May 20–25, 2006, Los Angeles, CA     

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.     

High dietary carbohydrates decrease gallbladder volume and enhance cholesterol crystal formation

BACKGROUND: Animal and human data suggest that a diet high in refined carbohydrates leads to gallstone formation. However, no data are available on the role of dietary carbohydrates on gallbladder volume or on cholesterol crystal formation. Therefore, we tested the hypothesis that a high carbohydrate diet would alter gallbladder volume and enhance cholesterol crystal formation. METHODS: At 8 weeks of age, 60 lean and 36 obese leptin-deficient female mice were fed a 45% carbohydrate diet while an equal number of lean and obese mice were fed a 75% carbohydrate diet for 4 weeks. All animals then underwent cholecystectomy, and gallbladder bile volume was recorded. Bile was pooled, filtered, and maintained in a water bath at 37 degrees C for 14 days. Birefringent cholesterol crystals in bile were counted daily; crystal observation time and crystal mass were determined. RESULTS: The crystal observation time was significantly shortened in both lean and obese mice on the 75% diet compared with their counterparts on the 45% diet. The crystal mass was significantly increased in the lean mice on the 75% diet compared with the 45% diet. Gallbladder volumes were significantly reduced in both lean and obese mice on the 75% diet compared with their counterparts on the 45% diet. CONCLUSIONS: These data suggest that a high carbohydrate diet decreases gallbladder volume, shortens cholesterol crystal observation time, and increases crystal mass. We conclude that dietary carbohydrates may play a role in cholesterol gallstone formation by altering biliary motility and by enhancing crystal formation.     

小鼠胆囊胆固醇结石模型的建立

目的建立简单、可靠、高效的小鼠胆囊胆固醇结石模型,为研究胆石成因及防治提供重要手段。方法C57BL／6小鼠随机分为对照组和模型组,对照组喂饲基础饲料,模型组喂饲致石饲料（基础饲料加10％猪油、1％胆固醇及0．5％胆酸）。两组小鼠分别于喂养4周和8周后,计算小鼠存活率,同时各取一半数量小鼠在乙醚吸入麻醉下手术取胆囊及血液标本,分别检测成石率、血脂浓度及胆汁胆固醇饱和度。结果对照组小鼠8周存活率100％,模型组小鼠死亡1只,存活率95％。对照组8周成石率为零,模型组4周成石率80％,8周成石率100％。血脂分析表明,与对照组比较,模型组4周和8周总胆固醇及低密度脂蛋白显著升高（P〈0．01）,甘油三酯浓度轻度升高（P〈0．05）,高密度脂蛋白显著降低（P〈0．01）。4周和8周时胆汁胆固醇饱和度测定,对照组分别为0．48±0．29和0．58±0．21,模型组分别为1．36±0．36和1．52±0．37,模型组胆固醇浓度处于过饱和状态。结论本模型方法简单、成石率高、动物死亡率低,可作为研究胆石成因及防治的备选模型。     

Effect of dietary ethanol on gallbladder absorption and cholesterol gallstone formation in the prairie dog

Dietary ethanol has been reported to protect against cholesterol gallstone formation. Because enhanced gallbladder absorption of water is important in cholesterol cholelithiasis, we examined the hypothesis that ethanol acts by inhibiting the absorptive function of the gallbladder. Eighteen adult male prairie dogs were fed a lithogenic liquid diet containing 0.4% cholesterol. Half of the animals received 30% of total calories as ethanol, whereas their pair-fed controls received equicaloric amounts of maltose-dextrin. After 3 months, the gallbladders were inspected for gallstones and crystals, and gallbladder and hepatic bile were analyzed. Cholesterol stones and crystals were present in all nine controls. None of the alcohol-fed animals had stones, but four had cholesterol crystals. Gallbladder cholesterol, phospholipids, and total calcium were significantly decreased in alcohol-fed animals. In both gallbladder and hepatic bile, the cholesterol saturation index was significantly lower in alcohol-fed animals, as was the ratio of trihydroxy to dihydroxy bile salts. The ethanol-supplemented diet produced a significant decrease in the absorption of water by the gallbladder as indicated by changes in the gallbladder bile to hepatic bile ratios of the total bile salt concentration (7.29 +/- 1.25 versus 3.84 +/- 0.56; p less than 0.05) and the total calcium (3.37 +/- 0.24 versus 2.43 +/- 0.29; p less than 0.05). These findings indicate that the protective effect of ethanol may be related to its ability both to inhibit gallbladder absorption of water and to alter the composition of biliary lipids.     

The prevention of experimental cholesterol gallstones by ileectomy in mice

After a lithogenic diet containing 0.5 per cent cholesterol and 0.25 per cent sodium cholate was fed to a group of normal Crj-ICR male mice for 10 days, cholesterol gallstones developed. No formation of gallstones occurred, however, in a group of mice from which 20 cms of terminal ileum had been removed prior to the feeding of the lithogenic diet. The biliary concentrations of cholesterol, phospholipids and bile acids were markedly lower in the ileectomized mice, with the decrease in cholesterol concentration being most significant. On the other hand, fecal excretion of sterols and bile acids increased in the ileectomized mice. The pool size of bile acids increased after the feeding of the lithogenic diet, but ileectomy decreased the pool size in mice fed the ordinary or lithogenic diets. The biliary concentration of cholic acid increased after the feeding of the lithogenic diet, but decreased with ileectomy. The biliary concentration and fecal excretion of deoxycholic acid markedly increased, while those of beta-muricholic acid and its secondary bile acids, omega-muricholic acid and hyodeoxycholic acid, decreased. The increase in plasma and liver cholesterol levels after the feeding of the lithogenic diet was prevented by ileectomy. These data suggest that ileectomy prevents the formation of cholesterol gallstones after the feeding of a lithogenic diet due to a decrease in cholic acid absorption.     

Relationship between gallbladder contraction and progesterone receptors in patients with gallstones

Stasis of bile within the gallbladder has long been suspected of having an important role in the pathogenesis of gallstone disease. We postulated that the female preponderance of gallstone disease might partly be related to the effects of progesterone, a known smooth muscle relaxant, on specific receptors in the gallbladder wall, leading to stasis of bile. A total of 42 patients with gallstone disease and 28 control subjects underwent radionuclide scan imaging and their gallbladder ejection fractions were calculated in response to intravenous infusion of cholecystokinin octapeptide. Patients then underwent cholecystectomy and a piece of gallbladder fundus was assayed for the presence of progesterone receptors. Receptors were present in 60 percent of patients. As a group, gallstone patients had a decreased ejection fraction compared with control subjects. The presence of progesterone receptors in the gallbladder wall was associated with a decreased percentage of ejection compared with both healthy control subjects and patients whose gallbladders were receptor-negative. We conclude that progesterone receptors are present in the gallbladder wall of gallstone patients and that their presence correlates with impaired gallbladder emptying.     

Increased biliary cholesterol secretion in alloxan diabetic mice

Plasma and liver cholesterol levels and biliary cholesterol, phospholipid and bile acid concentrations were examined in normal and alloxan diabetic mice fed ordinary and 0.5 per cent cholesterol diets. The plasma and liver cholesterol levels markedly increased in the diabetic mice, and the cholesterol diet further increased the liver cholesterol level but not that in the plasma. The gallbladder bile weight increased in the diabetic mice, but not after the cholesterol diet. The biliary lipid concentrations markedly increased in the diabetic mice, and the increases of the cholesterol and phospholipids exceeded that of the bile acids, resulting in increases of the cholesterol molar concentration ratio (mole percent) and the lithogenic index. The cholesterol diet increased the biliary cholesterol concentration and slightly the phospholipid, but not the bile acids. Therefore, the cholesterol mole percent and the lithogenic index increased. Among the biliary bile acid composition, cholic and deoxycholic acids increased and beta-muricholic acid decreased in the diabetic mice, whereas the cholesterol diet feeding decreased cholic acid and increased chenodeoxycholic and alpha-muricholic acids. These data suggest that the mechanism of the increase of biliary cholesterol secretion in diabetic mice is different from that after cholesterol diet.     

The prevention of experimental cholesterol gallstones by ileectomy in mice

After a lithogenic diet containing 0.5 per cent cholesterol and 0.25 per cent sodium cholate was fed to a group of normal Crj-ICR male mice for 10 days, cholesterol gallstones developed. No formation of gallstones occurred, however, in a group of mice from which 20 cms of terminal ileum had been removed prior to the feeding of the lithogenic diet. The biliary concentrations of cholesterol, phospholipids and bile acids were markedly lower in the ileectomized mice, with the decrease in cholesterol concentration being most significant. On the other hand, fecal excretion of sterols and bile acids increased in the ileectomized mice. The pool size of bile acids increased after the feeding of the lithogenic diet, but ileectomy decreased the pool size in mice fed the ordinary or lithogenic diets. The biliary concentration of cholic acid increased after the feeding of the lithogenic diet, but decreased with ileectomy. The biliary concentration and fecal excretion of deoxycholic acid markedly increased, while those of β-muricholic acid and its secondary bile acids, ω-muricholic acid and hyodeoxycholic acid, decreased. The increase in plasma and liver cholesterol levels after the feeding of the lithogenic diet was prevented by ileectomy. These data suggest that ileectomy prevents the formation of cholesterol gallstones after the feeding of a lithogenic diet due to a decrease in cholic acid absorption.     

Reversal of pigment gallstone disease in a canine model

Unlike dietary-induced cholesterol gallstones, which may disappear spontaneously when the lithogenic diet is withdrawn, little is known about the natural history of pigment gallstones. We examined whether pigment gallstone disease, which can be uniformly induced in the dog by six weeks of a methionine-deficient diet, can be reversed by return to normal diet. As previously reported, all dogs develop pigment gallstones as well as significant increases in biliary total calcium, free ionized calcium, and cholesterol concentrations after six weeks of a lithogenic diet. These changes are accompanied by a significant increase in the concentration of unconjugated bile salts in bile. In addition, histologic changes in the gallbladder wall occur that are consistent with a moderate degree of chronic cholecystitis. This study clearly demonstrates that return to a normal diet for six weeks allows bile composition to normalize, gallstones to disappear in 50% of dogs, and gallbladder histologic changes to return toward normal. Thus, it would appear that pigment gallstone disease in this model may be reversible, at least early during its course. Although the relevance of these findings to pigment gallstones in humans must be established, the potential for nonoperative treatment of pigment gallstones should not be discounted.     

Increased biliary cholesterol secretion in alloxan diabetic mice

Plasma and liver cholesterol levels and biliary cholesterol, phospholipid and bile acid concentrations were examined in normal and alloxan diabetic mice fed ordinary and 0.5 per cent cholesterol diets. The plasma and liver cholesterol levels markedly increased in the diabetic mice, and the cholesterol diet further increased the liver cholesterol level but not that in the plasma. The gallbladder bile weight increased in the diabetic mice, but not after the cholesterol diet. The biliary lipid concentrations markedly increased in the diabetic mice, and the increases of the cholesterol and phospholipids exceeded that of the bile acids, resulting in increases of the cholesterol molar concentration ratio (mole percent) and the lithogenic index. The cholesterol diet increased the biliary cholesterol concentration and slightly the phospholipid, but not the bile acids. Therefore, the cholesterol mole percent and the lithogenic index increased. Among the biliary bile acid composition, cholic and deoxycholic acids increased and β-muricholic acid decreased in the diabetic mice, whereas the cholesterol diet feeding decreased cholic acid and increased chenodeoxycholic and α-muricholic acids. These data suggest that the mechanism of the increase of biliary cholesterol secretion in diabetic mice is different from that after cholesterol diet.     

Interaction of chenodeoxycholic acid and dietary cholesterol in the treatment of cholesterol gallstones

Standard doses of chenodeoxycholic acid (15 mg/kg/day) fail to dissolve gallstones in 30 to 50 percent of patients with radiolucent gallstones in a functioning gallbladder. In humans, increasing dietary cholesterol produces increased biliary secretion of cholesterol. Restriction of dietary cholesterol reduces the minimum effective dose of chenodeoxycholic acid and speeds gallstone dissolution. In this study we investigated the interaction of dietary cholesterol and chenodeoxycholic acid in the prevention of gallstones in the prairie dog gallstone model. In animals fed a moderately lithogenic diet, standard doses of chenodeoxycholic acid failed to prevent gallstones. Reduction of the cholesterol stimulus or doubling the dose of chenodeoxycholic acid prevented the formation of gallstones. These findings support the hypothesis that the formation and dissolution of cholesterol gallstones are an expression of the relative strengths of saturating and desaturating stimuli. Therefore, rational therapy for cholesterol gallstone dissolution and prevention requires both reduction of lithogenic stimuli and optimal titration of chenodeoxycholic acid.