胆酸、小肠消化间期移行性复合波与胆固醇结石的关系

胆酸理化特性、代谢特性影响胆固醇结石形成。但同时在消化间期 ,胆酸肝肠循环作为结石形成的动力因素 ,可通过影响小肠消化间期移行性复合波 (MMC)和胆囊运动 ,以脱氧胆酸为中介 ,促进致石胆汁形成 ,提高结石发生率。胆固醇结石胆囊切除术改变胆酸池体积、胆酸肝肠循环和小肠MMC。     

胆酸、小肠消化间期移行性复合波与胆固醇结石的关系

胆酸理化特性、代谢特性影响胆固醇结石形成。但同时在消化间期，胆酸肝肠循环作为结石形成的动力因素，可通过影响小肠消化间期移行性复合波(MMC)和胆囊运动，以脱氧胆酸为中介，促进致石胆汁形成，提高结石发生率。胆固醇结石胆囊切除术改变胆酸池体积、胆酸肝肠循环和小肠MMC。     

胆固醇结石与小肠MMC相互关系的研究现状

胆固醇结石的形成中,机械性因素具有重要作用。健康人胆囊运动与小肠移行运动复合波(mi-grating motor complex,MMC)在消化间期存在对应关系,神经与激素调控必不可少,形成相对稳定的胆汁酸循环,引起胆囊周期排空与周期性小肠MMC。对胆固醇结石患者的观察显示,胆囊与小肠运动同时发生改变,在消化间期其胆囊排空较健康人明显减退,小肠MMC周期与幅度异于健康人。小肠运动功能的减退导致胆汁酸循环减退及胆汁酸池成分的改变,特别是其中脱氧胆酸含量的增加是结石形成中的重要环节     

胆固醇结石与小肠MMC相互关系的研究现状

胆固醇结石的形成中，机械性因素具有重要作用。健康人胆囊运动与小肠移行运动复合波(migrating motor complex，MMC)在消化间期存在对应关系，神经与激素调控必不可少，形成相对稳定的胆汁酸循环，引起胆囊周期排空与周期性小肠MMC。对胆固醇结石患的观察显示，胆囊与小肠运动同时发生改变，在消化间期其胆囊排空较健康人明显减退，小肠MMC周期与幅度异于健康人。小肠运动功能的减退导致胆汁酸循环减退及胆汁酸池成分的改变，特别是其中脱氧胆酸含量的增加是结石形成中的重要环节。     

脱氧胆酸与胆结石发病机制

屡有报道,认为脱氧胆酸(DCA)在胆固醇结石形成中可能起有作用。但关于胆结石发病机制的权威性评论并未提到这种可能性。每天到达结肠的循环胆盐不超过10%,未被末端回肠吸收的任何一种胆酸到结肠时,经过厌氧菌的7α-脱羟基作用后,很快转变为DCA,新形成的DCA1/3～1/2通过被动扩散被吸收,并进行再循环,DCA循环池约500mg。老年人、女性、高甘油三脂血症及食肉类者常伴有胆汁内DCA浓度增高,美国一项胆结石协作对包括280例男子在内的几个人群组的研究表明,十二指肠胆酸中的DCA比例与胆囊中胆汁(或肝内胆汁)的胆固醇克分子量%或胆固醇饱和指数(CSI)之间有     

高胆固醇饮食对胃肠移行性复合运动及胃肠激素影响的实验研究

胆固醇结石形成的因素包括：饮食因素、代谢障碍、运动障碍（胆囊平滑肌收缩能力减弱、胆汁淤积、肠道转运减慢）及反常的遗传背景。小肠运动障碍对胆固醇结石形成的影响作用日益受到重视。胃肠消化间期移行性复合运动（MMC）是胃肠道的重要运动形式。其发生及调控是神经、体液协同作用的结果。实验证明胃动素（motilin，MOT）、5-羟色胺（5-HT）和一氧化氮（NO）在MMC的调控机制上发挥重要作用。     

免疫球蛋白在胆囊胆固醇结石形成中的作用研究

目的:探讨胆囊胆汁和胆囊组织中免疫球蛋白在胆囊胆固醇结石形成中的作用。方法:采用放射免疫分析(RIA)方法分别测定了56例胆囊胆固醇结石及24例非胆石对照患者胆囊组织和胆囊胆汁中sIgA、IgG、IgM、IgE的含量。结果:胆囊胆固醇结石组胆囊组织和胆囊胆汁中sIgA、IgG、IgM、IgE均与对照组有显著性差异(P<0.01或P<0.05),并且胆囊胆固醇结石组胆囊组织中sIgA、IgM、IgE与胆囊胆汁中的sIgA、IgM、IgE成显著正相关关系。多发结石组胆囊胆汁中IgG与单发结石组有显著性差异(P<0.05),而其sIgA、IgM、IgE及胆囊组织中sIgA、IgG、IgM、IgE与单发结石组虽无显著性差异,但均有升高。结论:本实验结果提示:胆囊组织及胆囊胆汁中免疫球蛋白sIgA、IgG、IgM、IgE与胆囊胆固醇结石的形成密切相关,并在胆囊胆固醇结石的形成过程中起着重要作用,为胆囊胆固醇结石形成过程中的重要促成核因子。     

基因多态性参与胆固醇结石发病机制的研究进展

胆汁胆固醇过饱和及胆汁淤积是胆固醇结石的重要诱因。基因多态性通过影响胆固醇的转运及代谢,导致胆汁胆固醇过饱和、降低胆囊动力加重胆汁淤积,使个体对胆固醇结石的易感性增加。此文就近几年来对基因多态性在影响胆固醇结石发生方面的研究进展进行综述,以期进一步了解基因多态性在胆固醇结石发生中的作用,增进对胆固醇结石发病机制的了解,并为胆固醇结石的诊治提供新的思路。     

肝硬化患者胆囊胆汁脂类、胆红素及金属元素代谢的研究

目的 观察肝硬化患者胆囊胆汁成份改变,分析与肝硬变胆石多发的关系。 方法 术中抽取24例肝硬化患者胆囊胆汁,测定脂类、胆红素及金属元素钾、钠、钙、镁、铜、铁、锌。 结果 肝硬化胆囊胆汁中未结合胆红素水平明显增高,总胆汁酸、胆固醇、磷脂浓度和胆汁粘度明显下降。金属元素中钾、镁、铜、锌水平下降,铁含量显著升高。 结论 肝硬化胆囊胆汁具有明显成色素性结石趋势。因此,肝硬化胆汁成分改变是易于形成结石的基础。     

胆囊内胆汁与其粘膜的相互作用及其与胆结石形成之关系

胆囊在胆结石形成中起重要作用,故有必要了解胆囊及其与胆汁的相互作用。虽然源生于肝脏的胆固醇饱和性胆汁(称成石性胆汁)是胆结石形成的先决条件,但成石性胆汁也常存在于正常人,因而在胆汁或胆囊粘膜中肯定存在另一些因素。其中之一就是胆囊内胆汁的钙浓度。许多研究表明,在胆固醇或色素性胆结石患者,其胆汁中的钙常常是超饱和的,所以钙易沉淀。极大多数结石含有由钙酸盐组成的核心。当结石增大时,围绕核心沉积多层胆红     

Biliary lipids, bile acid metabolism, gallbladder motor function and small intestinal transit during ingestion of a sub-fifty oral contraceptive

The risk of developing gallstone disease while using low dose oral contraceptives (OC) has been incompletely explored in man. In this study, biliary lipid composition, bile acid conjugation, primary bile acid kinetics, gallbladder storage and emptying by quantitative cholescintigraphy, and small intestinal transit by breath hydrogen analysis are reported in a group of non-obese healthy young women, both after 3-5 months OC, using 30 micrograms ethinyl oestradiol daily, and during an adjacent control period. OC use was associated with a significant rise of biliary cholesterol saturation in gallbladder bile. Total bile acid pool size did not change; however, mean cholic acid pool size was 36% greater than in the control period (P less than 0.001), due to its enhanced synthesis rate, at the expense of chenodeoxycholic acid and deoxycholic acid pool sizes (P less than 0.05). A rise in taurine conjugation of biliary bile acids was apparent in all subjects (P less than 0.0001). Gallbladder motor function was not influenced by ingestion of OC, whereas only a minor retardation of small intestinal transit was found. The findings show an effect of this sub-50 OC on biliary lipid composition and cholesterol saturation that is comparable with that of conventional OC. The predominance of more hydrophilic bile acid conjugates during oral contraception is in keeping with a hepatic effect of this preparation on bile acid metabolism.     

Sluggish small bowel motility is involved in determining increased biliary deoxycholic acid in cholesterol gallstone patients

OBJECTIVE: Our aim was to establish whether small intestine transit time is defective in subjects with cholesterol gallstones. METHODS: We enrolled 10 patients (eight women, two men; mean age, 48.7 yr; mean body mass index [BMI], 22.4 Kg/m2) with recently diagnosed cholelithiasis, with no liver pathology, who were not taking any drugs, and 11 comparable healthy volunteers (eight women, three men; mean age, 46.2 yr; mean BMI, 22.7 Kg/m2), who served as controls. All subjects underwent orocecal (by starch breath test technique and serum assays of salazopyrin), oroileal (by serum assays of tauroursodeoxycholic acid), and duodenoileal (by serum assays of taurocholic acid) transit times; cholesterol saturation index; and bile acid composition and gallbladder motility studies (by ultrasound). For serum assays, blood samples were collected over a period of 7 h. Gallbladder motility and orocecal transit time were evaluated simultaneously. RESULTS: All four means of assessing transit time gave longer times in cholesterol gallstone patients than in controls: orocecal transit time (salazopyrin) = 366 +/- 13 vs 258 +/- 16 min, p < 0.0005; orocecal transit time (starch breath test) = 415 +/- 139 vs 290 +/- 15 min, p < 0.01; duodenoileal transit time: 272 +/- 23 vs 205 +/- 23 min, p < 0.03; and oroileal transit time: 308 +/- 18 vs 230 +/- 19 min, p < 0.009. Cholesterol gallstone patients showed an increase in percent molar biliary deoxycholic acid (30% +/- 4.5% vs 16% +/- 1.3%, p < 0.02) and a decrease in percent molar cholic acid 32% +/- 2.2% vs 40% +/- 1.3%, p < 0.03) and chenodeoxycholic acid (34% +/- 3% vs 41% +/- 1.8%, p < 0.03), compared with controls; patients also had greater percent molar biliary cholesterol. A linear relationship (r2 = 0.6324, p = 0.0012) between biliary deoxycholic acid and small bowel transit time was found. Residual gallbladder volumes were larger in cholesterol gallstone patients (11.38 +/- 1.27 vs 7.55 +/- 0.39 ml, p < 0.04), whereas basal gallbladder volumes, although higher, did not reach statistical significance (24.25 +/- 2.41 vs 19.98 +/- 1.63 ml; p = ns). CONCLUSIONS: This study confirms that patients with cholesterol gallstones have delayed small bowel transit, defective gallbladder motor function, and increased biliary deoxycholic acid. Delayed small bowel transit may contribute to supersaturation of bile with cholesterol by increasing deoxycholic acid production.     

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.     

Interdigestive Gallbladder Emptying, Antroduodenal Motility, and Motilin Release Patterns Are Altered in Cholesterol Gallstone Patients

The role of interdigestive gallbladder emptying in gallstone formation is unknown. In fasting healthy subjects, gallbladder emptying is associated with antral phase III of the migrating motor complex (MMC) and high plasma motilin. Therefore, gallbladder volumes and motilin levels were measured during 13 MMC cycles in 10 cholesterol gallstone patients and compared with 20 MMC cycles in 10 healthy subjects. MMC cycle length was longer in gallstone patients than in healthy subjects (158.2 ± 17.0 vs 105.5 ± 10.4 min, respectively; P < 0.05), due to longer phase I (39.8 ± 5.7 vs 17.2 ± 3.7 min, respectively; P < 0.05). In contrast to healthy subjects, gallstone patients had no significant fluctuations of gallbladder volume during the MMC cycle, and motilin concentrations were not different in MMC cycles with phase III originating in antrum or duodenum. During MMC cycles with phase III originating in the duodenum, motilin levels were twice as high in gallstone patients as in healthy subjects (P < 0.002). In conclusion, cholesterol gallstone patients have an abnormal MMC and motilin release pattern. Their interdigestive gallbladder emptying is reduced and dissociated from the MMC. These disturbances may contribute to gallstone formation.     

The influence of induced hyperglycaemia on the characteristics of intestinal motility and bile kinetics in healthy men.

Simultaneous recording of duodenal motility and biliary scintigraphy by continuous infusion of 99mTc-dimethyl-iminodiacetic acid was performed in 16 healthy fasted men, of whom eight had an intravenous glucose bolus injection immediately after the passage of a duodenal phase III of the migrating motor complex (MMC). This was followed by a continuous intravenous infusion of glucose. Characteristics of the time-activity curves from the gallbladder area and intestinal area were related to phase activity of the duodenal MMC. The median duration of the entire MMC cycle was significantly shorter in the glucose group than in the group without glucose. The difference was caused by shortening of phase II. Spontaneous gallbladder emptying appeared in all eight subjects from the group without glucose but in only a single subject from the glucose group. The relative amount of liver bile diverted to the gallbladder in the entire cycle was significantly higher in the subjects who received glucose, and in four subjects all the hepatic bile was diverted to the gallbladder. The results demonstrate that induced hyperglycaemia exerts a pronounced effect on gastrointestinal motility and bile kinetics. Available evidence suggests that the effects are caused by a 'medical vagotomy'.     

The Influence of Induced Hyperglycaemia on the Characteristics of Intestinal Motility and Bile Kinetics in Healthy Men

Simultaneous recording of duodenal motility and biliary scintigraphy by continuous infusion of ^99mTc-dimethyl-iminodiacetic acid was performed in 16 healthy fasted men, of whom eight had an intravenous glucose bolus injection immediately after the passage of a duodenal phase III of the migrating motor complex (MMC). This was followed by a continuous intravenous infusion of glucose. Characteristics of the time-activity curves from the gallbladder area and intestinal area were related to phase activity of the duodenal MMC. The median duration of the entire MMC cycle was significantly shorter in the glucose group than in the group without glucose. The difference was caused by shortening of phase II. Spontaneous gallbladder emptying appeared in all eight subjects from the group without glucose but in only a single subject from the glucose group. The relative amount of liver bile diverted to the gallbladder in the entire cycle was significantly higher in the subjects who received glucose, and in four subjects all the hepatic bile was diverted to the gallbladder. The results demonstrate that induced hyperglycaemia exerts a pronounced effect on gastrointestinal motility and bile kinetics. Available evidence suggests that the effects are caused by a ‘medical vagotomy'.     

Altered migrating myoelectrical complex in an animal model of cholesterol gallstone disease: the effect of erythromycin

Background—The ground squirrel on a highcholesterol diet exhibits prolonged intestinal transit, a pathogeneticfactor in cholesterol gallstone formation.
Aims—To examine the effect of a high cholesteroldiet on the characteristics of the migrating myoelectrical complex(MMC) and the potential benefit of erythromycin.
Methods—Twenty four animals received either atrace (controls) or a 1% (high) cholesterol diet. After four weeks,five bipolar jejunal and terminal ileal electrodes were implanted.Seven days later, myoelectric activity was measured in conscious,fasted animals before and after treatment with erythromycin. Biliary lipid composition was assessed.
Results—Compared with controls, animals fed thehigh cholesterol diet exhibited a prolonged MMC cycle period (70 (6)versus 83 (3) minutes; p<0.05), whereas MMC migration velocity and the proportions of the MMC represented by phases I, II, and III were unchanged. Oral erythromycin significantly shortened the MMC cycle period in animals on the control and high cholesterol diet by 59% and54% respectively, and increased the proportion of the cycle periodoccupied by phase III of the MMC in both dietary groups. Gall bladderbile became saturated with cholesterol and crystals developed in nineof 12 animals on the high cholesterol diet; controls had none.
Conclusion—Animals fed a high cholesterol diethad a prolonged MMC cycle period. This, along with diminished gallbladder motility, impairs the enterohepatic cycling of bile salts and reduces their hepatic secretion, contributing to the formation ofabnormal bile. Erythromycin initiated more frequent cycling of the MMC.Its therapeutic value in cholesterol gallstone formation warrantsfurther evaluation.

Keywords:migrating myoelectrical complex; intestinal transit; cholesterol saturation index; gallstone disease; erythromycin

     

Slow intestinal transit: A motor disorder contributing to cholesterol gallstone formation in the ground squirrel

Impaired gallbladder motility is an established factor in cholesterol gallstone formation. We assessed whether altered small intestinal smooth muscle contractility with slow transit might potentiate gallstone formation by further impeding enterohepatic cycling of bile acids. Ground squirrels were fed a 1% or a trace (controls) cholesterol diet. Small intestinal transit was evaluated from ⁵¹Cr distribution in conscious, fasted animals 20 minutes after infusion into the proximal jejunum. Small intestinal and gallbladder smooth muscle contractility was determined in vitro. Biliary lipid secretion was measured from the cannulated common duct and the bile salt pool size calculated by isotope dilution. Gas-liquid chromatography (GLC) assessed bile salt profile. In animals on the 1% cholesterol diet, aboral transit was significantly delayed, the maximal contractile response to bethanechol was markedly increased (P <.05) with no change in median effective concentration in either circular or longitudinal muscle strips from both the jejunum and ileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. Cholesterol saturation index and the fraction of deoxycholic acid in the pool doubled, whereas the total bile salt pool size remained unchanged in cholesterol-fed animals. In this model, a high-cholesterol diet is associated with altered small intestinal smooth muscle contractility and prolonged small intestinal transit, in addition to diminished gallbladder contractility. The resulting sluggish enterohepatic cycling of bile salts, associated with expanded deoxycholate pool, contributes to cholesterol gallstone formation. (Hepatology 1996 Jun;23(6):1664-72)     

Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease

In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies.     

Deoxycholic acid in gall bladder bile does not account for the shortened nucleation time in patients with cholesterol gall stones.

The relations between the concentration of deoxycholic acid (DCA), the cholesterol saturation index, and the nucleation time in gall bladder bile were measured to determine the role of DCA in bile in the pathogenesis of cholesterol gall stone disease. Bile was obtained from patients with cholesterol gall stones (n = 30), subjects without gall stones (n = 35), and patients with pigment gall stones (n = 9). Three of 30 cholesterol gall stone patients and 10 of 35 gall stone free subjects were treated with antibiotics by mouth to decrease the concentration of bile DCA and determine the effect of DCA on biliary lithogenecity. Both the percentage and concentration of DCA in bile were similar in patients with and without cholesterol gall stones despite significant differences in their cholesterol saturation indices and nucleation times. Neither the percentage nor the concentration of DCA in bile correlated with either the cholesterol saturation index or the nucleation time. Analysis of subgroups with matching cholesterol saturation indices showed no correlation between the proportion of DCA in the bile and the cholesterol nucleation time. The proportion of DCA in bile was decreased by antibiotic treatment, but this had no effect on the cholesterol saturation index or nucleation time. These results suggest that DCA in bile is not responsible for biliary cholesterol saturation or cholesterol nucleation time.