Concanavalin A-binding cholesterol crystallization inhibiting and promoting activity in bile from patients with Crohn's disease compared to patients with ulcerative colitis.

BACKGROUND/AIMS: Crohn's disease is a risk factor for gallstone formation. In contrast, patients with ulcerative colitis have an incidence of gallstone formation comparable to the general population. The reason for this difference is not known. The aim of this study was to elucidate the factors controlling cholesterol crystallization in gallbladder bile of Crohn's disease and ulcerative colitis patients. METHODS: Gallbladder bile was obtained by aspiration during bowel resections (26 Crohn's disease patients, 20 ulcerative colitis patients). Biliary lipid composition, crystal detection time and the effect of extraction of the concanavalin A-binding fraction on crystal formation were determined. RESULTS: Cholesterol crystals were present in seven of the 26 bile samples of Crohn's disease-patients and one of the 20 ulcerative colitis patients. Four of the bile samples of Crohn's disease patients were fast nucleating. None of the 20 ulcerative colitis patients had fast nucleating bile. Lipid composition, total lipid concentration and CSI were not significantly different between the two groups. In Crohn's disease patients extraction of concanavalin A-binding fraction decreased crystallization in 10 bile samples but accelerated crystallization in one bile sample. In eight bile samples from ulcerative colitis patients crystallization increased after concanavalin A-binding fraction extraction. CONCLUSIONS: Compared to ulcerative colitis patients, gallbladder bile of Crohn's disease patients showed increased cholesterol crystallization despite comparable lipid composition and cholesterol saturation index. This difference is caused by increased cholesterol crystallization-promoting activity. Bile from ulcerative colitis patients contains a Con A-binding factor which inhibits cholesterol crystallization.     

Bile acids in serum and bile of patients with cholesterol gallstone

ＢｉｌｅａｃｉｄｓｉｎｓｅｒｕｍａｎｄｂｉｌｅｏｆｐａｔｉｅｎｔｓｗｉｔｈｃｈｏｌｅｓｔｅｒｏｌｇａｌｓｔｏｎｅＨＡＮＴｉａｎＱｕａｎ１,ＺＨＡＮＧＳｈｅｎｇＤａｏ１,ＴＡＮＧＷｅｎＨａｏ２ａｎｄＪＩＡＮＧＺｈａｏＹａｎ１Ｓｕｂｊｅｃｔｈｅ...     

胆汁刀豆球蛋白A（ConA）结合蛋白在胆固醇性结石早期形成阶段的作用：胆汁ConA结合蛋白量与质分析

为了解胆固醇结石患者胆汁ＣｏｎＡ结合蛋白（ＣＰｓ）量与质的异常，应用亲和层析等方法对胆固醇结石、色素性结石及胆囊胆固醇息肉等患者的胆汁Ｃｐｓ进行了定量，并对不同个体的Ｃｐｓ与模拟胆汁泡相结合量及成核影响进行了比较。结果：色素结石（ｎ＝７）及非胆石患者（ｎ＝１０）胆汁ＣＰｓ浓度分别为０．２６±０．１２ｇ／Ｌ和０．２７±０．０９ｇ／Ｌ明显低于胆固醇结石患者（ｎ＝３６）的０．３９±０．１１ｇ／Ｌ（Ｐ＜０．０１）和胆固醇息肉患者（ｎ＝９）的０．４０±０．０９ｇ／Ｌ（Ｐ＜０．０１）；色素结石（ｎ＝５）及非胆石患者（ｎ＝２５）的成核活性（成核时间比）分别为０．７１±０．１９和０．７３±０．１１，也明显弱于胆固醇结石患者（ｎ＝２５）的０．５７±０．２１（Ｐ＜０．０１）和胆囊胆固醇息肉患者（ｎ＝５）的０．４４±０．２３（Ｐ＜０．０１）；胆固醇结石患者（ｎ＝２６）的ＣＰｓ与泡相结合量显著高于色素性结石患者（ｎ＝６）（２．４±０．９％比０．９±０．５％，Ｐ＜０．０１）。总结认为：胆汁ＣＰｓ量的升高及促成核活性增强，尤其是亲泡相ＣＰｓ的增加是胆固醇结石形成的重要原因。     

Effect of apolipoprotein E polymorphism on bile lipid composition and the formation of cholesterol gallstone

OBJECTIVE: It remains a matter of controversy whether possession of the apolipoprotein E4 (apoE4) allele is a genetic risk factor for the formation of cholesterol gallstones. The aim of the present study was to test this hypothesis by investigating the effect of apoE4 on bile lipid composition in normal subjects and in patients with cholesterol gallstones and to evaluate the distributions of apoE alleles in these two groups. METHODS: The study population consisted of 79 patients who underwent open or laparoscopic cholecystectomy for symptomatic cholesterol gallstone disease. The control group (n = 53) included 11 patients with benign gallbladder polyps and 42 normal subjects acting as donors in living donor liver transplantation. The apoE genotypes were assessed by dot blot hybridization with digoxigenin-labeled probes. Bile lipid composition was determined by enzymatic assays and high performance liquid chromatography. RESULTS: Bile lipid composition and cholesterol saturation index (CSI) were similar in the control subjects harboring the apoE4 allele and those without apoE4 (mean CSI, 85.9% and 72.2%, respectively, p = 0.69). Likewise, in the cholesterol gallstone patients, bile lipid composition and CSI were similar in the patients with and without apoE4 allele (mean CSI, 134.9% vs 152.2%, p = 0.6). Furthermore, the prevalence of the apoE4 allele was similar in the patients with cholesterol gallstones and in the control group (8.5% vs 7.6%, p = 0.46, OR = 0.88; 95% CI = 0.64-1.22). CONCLUSIONS: The apoE4 allele is not a contributory factor to cholesterol gallstone formation, at least in the Japanese population.     

Cisapride improves gallbladder emptying and bile lipid composition in patients with gallstones

BACKGROUND AND AIM: Biliary cholesterol supersaturation, gallbladder stasis and delayed intestinal transit are the key events in cholesterol gallstone formation. We studied the effect of cisapride, a prokinetic drug, on gallbladder emptying and bile composition in patients with gallstone disease undergoing cholecystectomy. METHODS: Gallbladder emptying, cholesterol saturation index (CSI) and nucleation time were studied in 21 patients with gallstone disease. Eleven patients (cisapride group, age 41.9 +/- 2.9 years) received tablet cisapride 10 mg t.i.d. for 2 weeks, while 10 patients (placebo group, age 42.1 +/- 1.9 years) received placebo for the same duration. Gallbladder emptying was repeated in all patients after a 2-week treatment with cisapride or placebo. Gallbladder bile was obtained at the time of surgery for the measurement of CSI and nucleation time. RESULTS: Residual volume of the gallbladder decreased (mean +/- SE, 18.6 +/- 2.5 mL vs 10.0 +/- 1.1 mL, P = 0.007), and the ejection fraction increased (43.5 +/- 5.3% vs 60.0 +/- 3.2%, P = 0.007) in patients in the cisapride group, while no change was observed in placebo group patients. Nucleation time was higher in the cisapride group than in the placebo group (14.9 +/- 1.3 days vs 8.0 +/- 0.9 days, P = 0.003). Patients in the cisapride group had a significantly lower cholesterol concentration (molar percentage, 5.1 +/- 0.3% vs 6.8 +/- 0.8%, P = 0.049) and CSI (1.0 +/- 0.1 vs 1.36 +/- 0.11, P = 0.034) than patients in the placebo group. CONCLUSION: Cisapride improves gallbladder emptying and bile lithogenicity in patients with gallstone disease.     

The effects of the 3-hydroxy, 3-methylglutaryl coenzyme A reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease

3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce biliary cholesterol saturation index (CSI) in duodenal bile in hypercholesterolemic patients and might be useful for gallstone dissolution. However, preliminary data suggest that these drugs are not effective in this respect. We therefore studied 33 patients with radiolucent gallstones in an opacifying gallbladder who were scheduled for elective cholecystectomy. Patients were treated with 40 mg pravastatin day⁻¹ or placebo during the 3 weeks before surgery. Six patients could not be evaluated. Baseline characteristics (age, sex, body mass index, serum cholesterol, and the solitary/multiple gallstone ratio) were similar in both groups. Serum cholesterol fell by 39% in the pravastatin group (P < .001) and remained unchanged in the placebo group. Biliary cholesterol (9.5 ± 1.3 vs. 14.3 ± 1.5 mmol/L, P = .026), and phospholipid concentrations (24.8 ± 3.9 vs. 36.7 ± 3.9 mmol/L, P = .043) were lower in the pravastatin group. Although bile salt concentrations were lower in the pravastatin group (114 ± 21 vs. 152 ± 15 mmol/L), this difference was not significant. CSI was not different between both groups (142 ± 27% [pravastatin]vs. 113 ± 6% [placebo], P = NS). Cholesterol crystals were present in fresh bile in 7 of 13 patients in the pravastatin group and in 11 of 14 controls (P = NS). Nucleation time was comparable between the 2 groups (13 ± 3 vs. 9 ± 3 days, P = NS). Bile salt species and molecular species of phospholipids determined with high-performance liquid chromatography did not differ either between both groups. Not only cholesterol but also phospholipid concentrations decrease in gallbladder bile during pravastatin treatment in cholesterol gallstone patients, with comparable CSI and nucleation time. This study does not support the use of HMG-CoA reductase inhibitors for dissolution of cholesterol gallstones.     

Carcinoembryonic antigen-related cell adhesion molecule 1 is the 85-kilodalton pronase-resistant biliary glycoprotein in the cholesterol crystallization promoting low density protein-lipid complex.

A pronase resistant 85-kd glycoprotein in the Concanavalin A-binding fraction (CABF) of biliary glycoproteins has been reported to act as a promotor of cholesterol crystallization. De Bruijn et al. (Gastroenterology 1996;110:1936-1944) found this protein in a low-density protein-lipid complex (LDP) with potent cholesterol crystallization promoting activity. This study identifies and characterizes this protein. An LDP was prepared from CABF by discontinuous gradient ultracentrifugation. Proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), blotting and immunochemical staining with anti-carcinoembryonic antigen, CEA-related adhesion molecule 1 (CEACAM1) cross-reacting antibodies. Biliary concentrations of CEA cross-reacting proteins were determined in patients with and without gallstones. Two isoforms of CEACAM1 (85- and 115-kd bands), CEA and 2 CEA cross-reacting protein bands of 40 and 50 kd were found in human bile. All bands were also present in CABF, but only a subfraction of the 85-kd band found in the LDP was resistant to digestion with pronase. CEACAM1-85 exhibited potent cholesterol crystallization promoting activity in vitro and accounted for most of the activity in CABF. Total CEA cross-reacting protein concentrations were the same in gallbladder biles from patients with cholesterol and pigment gallstones but only half of those in biles from nongallstone subjects. In conclusion, we have identified the protein component of the cholesterol crystallization promoting LDP to be CEACAM1-85.     

Bile acid synthesis is increased in Chilean Hispanics with gallstones and in gallstone high-risk Mapuche Indians

BACKGROUND & AIMS: Gallstone disease is an important, costly health-care problem in Western societies. It is still unclear whether hepatic lipid regulatory enzymes play primary or secondary roles in gallstone formation. In this study, the aim was to investigate whether the synthesis of bile acids and cholesterol is increased in gallstone disease and to test whether such a metabolic change, if present, might occur before gallstone formation. METHODS: A total of 125 Chilean Hispanic women (80 without gallstones and 45 with gallstones) matched for age and body mass index were investigated, along with 40 Chilean Mapuche Indian women (20 without gallstones and 20 with gallstones), a population group in which the prevalence for gallstone disease is very high. Fasting blood plasma samples were assayed for 7 alpha-hydroxy-4-cholesten-3-one and lathosterol, 2 strong indicators for hepatic bile acid and body cholesterol synthesis, respectively. RESULTS: Plasma 7 alpha-hydroxy-4-cholesten-3-one levels, corrected for plasma cholesterol, were significantly increased by 50% in Hispanic women with gallstones as compared with gallstone-free Hispanics (P < 0.006). As compared with Hispanic women without gallstones, plasma 7 alpha-hydroxy-4-cholesten-3-one levels were increased by > or =100% (P < 0.002) in Mapuche Indian women, independently of whether gallstones were present. Plasma lathosterol, corrected for plasma cholesterol, was significantly increased by 22% in Hispanic women with gallstones and in Mapuche Indian women compared with Hispanic women. CONCLUSIONS: The results indicate that the synthesis of bile acids and cholesterol is induced in gallstone disease and precedes gallstone development. These inductions presumably occur as a response to an increased intestinal loss of bile acids.     

Secretion of biliary lipids in young Chilean women with cholesterol gallstones.

The early appearance of cholesterol gallstones is very common in Chile. To elucidate the mechanisms involved in this phenomenon, the size of the bile acid pool and the secretion of biliary lipids were studied in two groups of young women with normal weights and radiologically functioning gallbladders: nine with cholesterol gallstones and 14 healthy volunteers. The bile acid pool was similar in control and gallstone patients. The secretory rates of bile acids and phospholipids were comparable and significantly correlated in both groups. On the other hand, cholesterol output was higher in gallstone patients. In controls there was a significant correlation between the output of bile acids and cholesterol, but no correlation was found in the gallstone group. This study suggests that cholesterol hypersecretion into the bile is a major factor in the pathogenesis of cholesterol gallstone disease in young Chilean women with normal weights.     

Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile

BACKGROUND & AIMS: The role of the gallbladder in gallstone pathogenesis is still unclear. We examined the effects of gallbladder mucosal lipid absorption on lipid composition and cholesterol crystallization in bile. METHODS: The in vitro-isolated, intra-arterially perfused gallbladder model was used (1) to compare the absorption rates of lipids from standard bile by gallbladders obtained from 7 patients with cholesterol gallstones and 6 controls; and (2) to measure the microscopic cholesterol crystal detection time in cholesterol-enriched pig bile before and after lipid absorption by the pig gallbladder. RESULTS: Control gallbladders, but not cholesterol gallstone gallbladders, significantly reduced cholesterol (P < 0.02) and phospholipid (P < 0.01) and increased bile salt (P < 0.01) molar percentages in bile over a 5-hour period by efficient and selective cholesterol and phospholipid absorption. A histomorphometric study of the epithelial cells showed significantly higher values for nuclear density (P < 0.01) and nuclear (P < 0.05) and cytoplasmic (P < 0.05) areas in the cholesterol gallstone than the control group. Sequential microscopy of cholesterol-enriched pig bile showed significantly shorter cholesterol filament (P < 0.01) and typical cholesterol plate (P < 0. 02) detection times before than after exposure of bile to the gallbladder lipid absorption. CONCLUSIONS: In cholesterol gallstone disease, the human gallbladder epithelium loses its capacity to selectively and efficiently absorb cholesterol and phospholipids from bile, even if it is hyperplastic and hypertrophic. This epithelial dysfunction eliminates the positive effect that the normal gallbladder exerts on cholesterol solubility in bile and might be a pathogenetic cofactor for cholesterol gallstone formation.     

Biliary sludge is formed by modification of hepatic bile by the gallbladder mucosa.

BACKGROUND & AIMS: We studied 22 patients with symptomatic microlithiasis to determine whether a contributory role of the gallbladder in the early stage of cholesterol gallstone formation exists. We compared the merits of different methods (ultrasonography and microscopy) and sources (hepatic or gallbladder) of bile samples for diagnosing microlithiasis. METHODS: Paired hepatic and gallbladder bile samples were studied with polarizing microscopy. Nucleation time, bile salts, phospholipid, cholesterol, cholesterol saturation index (CSI), bilirubin, total protein, albumin and mucin concentration were measured. All patients had abdominal ultrasound examination. RESULTS: With polarizing microscopy as the standard, ultrasonography was positive in 13 patients (59%) and negative in 9 (41%). All gallbladder bile samples were positive for microlithiasis by microscopy. Only one hepatic bile sample was positive (P < .0001). There was a disproportional enrichment of total protein, albumin, and mucin (P < .05) in the gallbladder bile and a conversion of bilirubin diglucuronide to monoglucuronide (P < .01). Gallbladder samples had lower CSI but a faster nucleation time (P < .001), which correlates inversely with CSI, total protein, and mucin concentration. CONCLUSION: Biochemical composition and physical chemical behavior of hepatic bile are modified during residence in the gallbladder, contributing to sludge formation. Gallbladder bile has a lower calculated CSI, higher deconjugation of bilirubin, protein and mucin concentration and crystals were present. Hepatic bile samples are inappropriate for microscopic detection of microlithiasis.     

Nucleation time and lithogenic index in obese patients and in patients with cholecystolithiasis

The gallbladder bile of obese patients without gallstones is supersaturated with cholesterol. The cholesterol saturation index (CSI, LI) of 27 obese patients was 1.32 +/- 0.2. The CSI of 24 normal weight gallstone patients was determined with 1.16 +/- 0.37 and is therefore not significantly different from CSI of obese stone free individuals. The supersaturated bile from obese patients does not accelerated the nucleation of cholesterol crystals. The nucleation time of obese persons was statistically significant longer (16.0 +/- 3.0 days) than in gallstones patients (6.0 +/- 0.78 days) (p less than 0.001). In 50% of the patients with gallstones cholesterol monohydratcrystals were present in the native gallbladder bilde, whereas such crystals are found in only 3.7% of the obese group. Liquid crystals occurred more frequently and in larger number in the bile of the obese patients. The stone forming potency of gallbladder bile can be estimated better by the determination of nucleation time and cholesterol crystals occurrence than by the calculation of the saturation index (CSI).     

Increased biliary protein precedes gallstone formation

Although nucleation is critical to the pathogenesis of cholesterol gallstones, the factors responsible for this process are poorly defined. Numerous potential nucleating agents have been identified in the bile of humans and animals with cholelithiasis, including mucus, calcium, and bilirubin. Recent studies have shown that patients with cholesterol crystals and gallstones have increased biliary total protein, suggesting that protein may be a previously unrecognized nucleating factor. We tested the hypothesis that biliary total protein is increased prior to cholesterol gallstone formation. Prairie dogs were maintained on either control (N=22) or 0.4% cholesterol-enriched chow (N=18) for up to 18 weeks. Cholesterol-fed animals were classified as pregallstone (N=12) or gallstone (N=6) based on gross examination of the gallbladder bile. Both hepatic and gallbladder biles were then analyzed for lipid, bile acid, calcium, and protein content. Cholesterol feeding was associated with increased gallbladder concentrations of cholesterol, phospholipids, and calcium in the pregallstone and gallstone groups. Biliary total protein was significantly elevated in the pregallstone (5.8±0.4 mg/ml,P<0.001) and gallstone animals (6.0±0.6 mg/ml,P<0.001) as compared to controls (3.8±0.3 mg/ml). Regression analysis showed positive correlations between gallbladder bile total protein and the gallbladder bile cholesterol saturation index (CSI) (P<0.001), as well as between gallbladder total protein and calcium (P<0.001). Although the hepatic bile CSI was elevated in cholesterol-fed animals, total protein remained unchanged, suggesting that the alteration in biliary protein is a gallbladder phenomenon. The finding that gallbladder bile total protein increases during crystal agglomeration indicates that high concentrations of biliary total protein in combination with elevated levels of calcium may promote cholesterol crystal nucleation and gallstone formation.     

The role of Concanavalin A-binding fraction in cholesterol crystallization in native human bile

Background/Aims: Many Concanavalin A-binding glycoproteins have been proposed to influence cholesterol crystallization in human bile. This has been studied mainly by addition of the Concanavalin A-binding fraction to model bile. The physiological relevance of the proteins in native bile is not yet known. The aim of this study was to establish the role of the Concanavalin A-binding fraction in cholesterol crystallization in native human gallbladder bile.Methods: To determine the effects of the removal of Concanavalin A-binding fraction, fresh human gallbladder bile was incubated with either Concanavalin A-Sepharose or Sepharose alone. Beads were sedimented and crystallization was studied in the supernatant.Results: Extraction of Concanavalin A-binding fraction decreased crystallization in fast-nucleating biles (Crystal Detection Time <-4 days). Slow-nucleating biles were not affected. The effect could not be related to the content of known pronucleating proteins (IgA, IgM, haptoglobin, aminopeptidase N and α1-acid-glycoprotein), since the slow-nucleating biles contained similar amounts of these proteins.Conclusions: Although Concanavalin A-binding fraction always accelerated crystallization when added to model bile, removal of the same fraction from native bile often had no effect. We conclude that slow-nucleating biles in particular contain undertermined factors which regulate the activity of pronucleators.     

Correlation between biliaryα 1-acid glycoprotein concentration and cholesterol crystal nucleation time in gallstone disease

A biliary form of theα ₁-acid glycoprotein (AAG) promotes cholesterol crystallization in the lower-molecular-weight, concanavalin A-bound fraction of gallbladder bile. In addition, bile AAG concentration is higher in cholesterol gallstone patients with multiple stones than in control patients without gallstone disease. In this study we sought to determine whether the increased biliary concentration of AAG in cholesterol gallstone patients is accompanied by a more rapid nucleation time in patients with multiple stones. AAG concentration in native biles was measured by ELISA. Nucleation time was measured using a standard microscopy method. The concentration of biliary AAG was then related to nucleation time in biles from the same patients. Nucleation times were significantly shorter (≤5 days) in cholesterol gallstone patients with raised AAG concentrations (P<0.03). There was a significant (P=0.004) negative correlation (r=?0.53) between nucleation time and the AAG concentration in cholesterol gallstone patients with multiple stones. The concentration of biliary AAG appears to exert an important influence on the speed of cholesterol nucleation in bile in many patients with cholesterol gallstone disease.     

High level of deoxycholic acid in human bile does not promote cholesterol gallstone formation

AIM: To study whether patients with excess deoxycholic acid (DCA) differ from those with normal percentage of DCA with respect to biliary lipid composition and cholesterol saturation of gallbladder bile. METHODS: Bile was collected during operation through puncturing into the gallbladder from 122 cholesterol gallstone patients and 46 gallstone-free subjects undergoing cholecystectomy. Clinical data, biliary lipids, bile acid composition, presence of crystals and nucleation time were analyzed. RESULTS: A subgroup of gallstone patients displayed a higher proportion of DCA in bile than gallstone free subjects. By choosing a cut-off level of the 90th percentile, a group of 13 gallstone patients with high DCA levels (mean 50 percent of total bile acids) and a large group of 109 patients with normal DCA levels (mean 21 percent of total bile acids) were obtained. The mean age of the patients with high DCA levels was higher than that of the group with normal levels (mean age: 62 years vs 45 years) and so was the mean BMI (28.3 vs. 24.7). Plasma levels of cholesterol and triglycerides were slightly higher in the DCA excess groups compared with those in the normal DCA group. There was no difference in biliary lipid composition, cholesterol saturation, nucleation time or occurrence of cholesterol crystals in bile between patients with high and normal levels of DCA. CONCLUSION: Gallstone patients with excess DCA were of older age and had higher BMI than patients with normal DCA. The two groups of patients did not differ with respect to biliary lipid composition, cholesterol saturation, nucleation time or occurrence of cholesterol crystals. It is concluded that DCA in bile does not seem to contribute to gallstone formation in cholesterol gallstone patients.     

Insulin injections enhance cholesterol gallstone incidence by changing the biliary cholesterol saturation index and apo A-I concentration in hamsters fed a lithogenic diet.

BACKGROUND/AIMS: A link between insulin and cholesterol gallstone disease has often been suspected but never demonstrated. The aim was to evaluate the direct implication of insulin in the gallbladder cholesterol gallstone formation process. METHODS: Hamsters fed with a soft-inducing lithogenic diet, enriched with sucrose, were injected daily, for 1 week, either with long-acting insulin or saline (controls). RESULTS: Insulin injections doubled the cholesterol gallstone incidence. The cholesterol saturation index (CSI) of bile significantly increased (+19%) and biliary apolipoprotein A-I (apo A-I) decreased, both in concentration (-71%) and the proportion relative to the total biliary proteins (-25%). No modifications in the biliary bile acid composition were noticed. Hepatic HMGCoA reductase activity was higher (+341%), CYP7A1 activity was lower (-52%), whereas CYP27A1 and CYP7B1 were not affected. The hepatic low-density liprotein (LDL)-receptor and SR-BI masses did not vary. The hepatic total cholesterol content increased (+42%). Fasting plasma phospholipid and triglyceride concentrations significantly decreased (-15 and -60%, respectively), but the cholesterol concentration remained constant. CONCLUSIONS: These results suggest that insulin injections enhance cholesterol gallstone incidence by increasing the CSI of bile and decreasing the concentration and proportion of a biliary anti-nucleating protein, apo A-I. Insulin modulates the major enzymes of cholesterol and bile acid metabolisms in vivo.     

环氧合酶2抑制剂在胆固醇结石形成中的作用

目的　探讨选择性环氧合酶 2 (COX 2 )抑制剂塞莱昔布 (celexibo)在家兔实验性胆固醇结石形成中的作用。方法　普通家兔 30只平均分为 3组 :成石组饲以高胆固醇饲料 ,实验组在高胆固醇饲料基础上按每天 10mg/kg体重加饲塞莱昔布 ,空白组饲以普通饲料。 7周后 ,观察各组胆囊胆汁结晶情况、胆囊上皮黏膜炎症情况及COX 2含量。结果　实验组比成石组形成胆固醇结晶机会明显减少 (9/ 10、2 / 10 ,χ2 =9 988,P <0 0 5 ) ;成石组比空白组胆囊黏膜炎症程度明显升高 (U =2 3,W =6 8,P <0 0 5 ) ,实验组与成石组相比 ,炎症程度显著降低 (U =18,W =6 3,P <0 0 1)。成石组胆囊黏膜COX 2表达量明显高于空白组 (0 0 5 5± 0 0 0 6、0 0 17± 0 0 0 3,P <0 0 0 1) ,实验组比成石组COX 2表达量明显降低 (0 16 9± 0 0 0 1、0 0 5 5± 0 0 0 6 ,P <0 0 0 1)。结论　胆固醇结石形成可能包含炎症机制 ,COX 2参与胆固醇结石的形成过程 ,且COX 2抑制剂可以抑制胆固醇结石的形成。     

Increased bile acid concentration in liver tissue with cholesterol gallstone disease

Patients with cholesterol gallstone disease have a reduced pool of bile acids. Overly sensitive feedback inhibition of bile acid synthesis has been postulated to explain this size reduction. To test this hypothesis, hepatic bile acid concentration and the activity of cholesterol 7-hydroxylase, the rate-limiting enzyme for bile acid biosynthesis, were determined in ten patients with cholesterol gallstones and ten patients without gallstones. The bile acids present in liver tissue are the sum of those returning to liver and those newly synthesized in liver. If an overly sensitive feedback inhibition truly existed in our gallstone patients, a decreased concentration of hepatic bile acids would have been expected. However, patients with cholesterol gallstones had significantly higher total (143.3 ±25.5 vs 64.5±10.8 nmol/g liver,P<0.01), chenodeoxycholic=" (64.1±9.9=" vs=">P<0.01), deoxycholic=" (22.8±10.9=" vs=">P<0.05), and=" ursodeoxycholic=" acid=" (6.2±1.4=" vs=">P<0.01) concentrations=" than=" patients=" without=" gallstones.=" the=" activity=" of=" cholesterol=">-hydroxylase did not differ significantly between the two groups. Impaired hepatic transport or secretion of bile acids is strongly suspected in cholesterol gallstone patients. The findings of the present study showed no evidence of overly sensitive feedback inhibition of bile acid synthesis in cholesterol gallstone patients. Bile acid pool size may be affected by the inappropriate increase of hepatic bile acids rather than by overly sensitive feedback inhibition.     

Alterations in Gallbladder Emptying and Bile Retention in the Absence of Changes in Bile Lithogenicity in Postmenopausal Women on Hormone Replacement Therapy

The role of female sex hormones in the pathogenesis of gallstones is well established. Pregnancy, contraceptive use, estrogen replacement therapy in postmenopausal women, and estrogen therapy in men for the treatment of prostatic carcinoma have been found to be associated with increased risk of cholesterol gallstones. Alterations in gallbladder emptying and in bile lithogenicity in postmenopausal women receiving hormone replacement therapy (HRT) have not been studied to date. The present study was undertaken to study the effect of HRT on gallbladder emptying and bile lithogenicity. Sixteen postmenopausal women were included in the study. None of the patients had gallstone disease and none had received prokinetic drugs, such as, erythromycin, metoclopramide, domperidone or cisapride, aspirin, and nonsteroidal antiinflammatory drugs. Gallbladder emptying (n = 16), bile microscopy (n = 7), cholesterol saturation index (CSI) (n = 7), and nucleation time (n = 7) were studied before and 3 months after HRT (conjugated estrogen, 0.625 mg, + medroxyprogesterone acetate, 2.5 mg, everyday). Fasting and residual volumes increased (fasting volume, 18.2 +/- 2.2 mL pre-HRT vs 27.6 +/- 3.2 mL post-HRT, P = 0.0003; residual volume, 3.9 +/- 0.6 mL pre-HRT vs 10.3 +/- 2.0 mL post-HRT, P = 0.00009) and ejection fraction decreased (78.2 +/- 2.5% pre-HRT vs 62.2 +/- 3.8% post-HRT; P = 0.0017) after 3 months of HRT. There was no change in CSI (2.32 +/- 0.36 pre-HRT vs 2.60 +/- 0.51 post-HRT; P = NS) or in nucleation time (19.0 +/- 1.2 days pre-HRT vs 17.6 +/- 1.3 days post-HRT; P = NS). None of the bile samples either pre-HRT or post-HRT showed cholesterol monohydrate crystals. Though impairment of gallbladder emptying occurs in the short term with HRT in postmenopausal women, there is no change in CSI and nucleation time.