Effects of artificial depletion of the bile acid pool in man.

In order to elucidate the relationship between bile acid pool size and cholesterol saturation index of fasting state gall bladder bile, we artificially depleted the bile acid pool in 12 healthy volunteers. Bile acid pool size decreased from 7.6 +/- 0.9 to 5.8 +/- 0.7 mmol (mean +/- SEM, p less than 0.01), and saturation index of fasting state gall bladder bile increased from 0.93 +/- 0.07 to 1.18 +/- 0.07 (p less than 0.001). There was no alteration in saturation index of basal or stimulated hepatic bile. There was no change in gall bladder storage of basal hepatic bile, nor in the proportion of the bile acid pool stored in the gall bladder. The bile acid mass in the gall bladder fell from 4.9 +/- 0.5 to 3.4 +/- 0.4 mmol (p less than 0.05) and phospholipid mass from 1.6 +/- 0.3 to 1.2 +/- 0.2 mmol (p less than 0.05), but there was no change in cholesterol mass. The gall bladder volume fell from 30 +/- 4 to 18 +/- 2 ml (p less than 0.01). These results suggest that artificial depletion of the bile acid pool increased saturation index of fasting state gall bladder bile without altering saturation index of basal or stimulated hepatic bile; it probably increased the ratio of basal: stimulated hepatic bile within the gall bladder by decreasing gall bladder storage of stimulated hepatic bile.     

Intestinal transit, deoxycholic acid and the cholesterol saturation of bile--three inter-related factors.

There is considerable evidence that the level of deoxycholic acid in the bile influences biliary cholesterol saturation. Deoxycholic acid is formed in the colon and absorbed slowly. Hence changes in colonic transit rate might influence biliary deoxycholic acid and the cholesterol saturation of bile. When 14 constipated subjects took standardised senna tablets for six weeks in a dose sufficient to lower mean whole gut transit time from 134 to 54 hours, deoxycholic acid as a proportion of biliary bile acids fell from 25.9 +/- 8.6 to 17.2 +/- 8.3% (p less than 0.0001) and deoxycholic acid pool measured by isotope dilution fell from 0.64 +/- 0.34 to 0.45 +/- 0.29 g (p less than 0.0001). In those subjects (n = 8) whose bile was initially supersaturated with cholesterol, the saturation index fell from 1.40 +/- 0.22 to 1.20 +/- 0.19 (p = 0.02). Conversely, when 12 normal volunteers took loperamide capsules sufficient to cause symptomatic constipation and to prolong mean transit-time from 48 to 103 hours, the deoxycholic acid pool increased from 0.40 +/- 0.24 to 0.57 +/- 0.17 g (p = 0.008). The percentage deoxycholic acid did not alter significantly, because the estimated total bile acid pool expanded (from 1.98 +/- 0.61 to 2.81 +/- 0.48 g; p less than 0.001), presumably because of loperamide slowing down small bowel transit. Despite this expansion of the bile acid pool, loperamide increased the cholesterol saturation index from 1.10 +/- 0.31 to 1.20 +/- 0.32 (p = 0.01). Changes in colonic transit rate alter the size of the deoxycholic acid pool and bile cholesterol saturation. These findings suggest that constipation or slow colonic transit might increase the chance of supersaturated bile and hence of gall stones.     

Diet and gall stones: effects of refined and unrefined carbohydrate diets on bile cholesterol saturation and bile acid metabolism.

It has been suggested that consumption of refined carbohydrate foods (notably sugar and white flour) increases bile cholesterol saturation and hence the risk of cholesterol gall stone formation. To test this hypothesis, 13 subjects with probable cholesterol gall stones ate refined and unrefined carbohydrate diets, each for six weeks in random order. On the refined carbohydrate diet, subjects ate more refined sugar (mean = SEM: 106 +/- 7 vs 6 +/- 1 g/day, p less than 0.001), less dietary fibre (13 +/- 1 vs 27 +/- 3 g/day, p less than 0.001), and had a higher energy intake (9.17 +/- 0.66 vs 7.16 +/- 0.64 MJ/day, p less than 0.001). After each diet, the lipid composition of duodenal bile and bile acid kinetics was determined. The cholesterol saturation index of bile was higher on the refined carbohydrate diet in all but one subject, with a mean value of 1.50 +/- 0.10 compared with 1.20 +/- 0.12 on the unrefined diet (p less than 0.005). On the refined carbohydrate diet, bile contained relatively less cholic acid and slightly more deoxycholic acid. There were, however, no significant differences in total or individual bile acid pool sizes. There were also no differences in the rates of primary bile acid synthesis or fractional turnover on the two diets. Consumption of carbohydrate in refined form increases bile cholesterol saturation. The risk of gall stones might be reduced by avoidance of refined carbohydrate foods.     

Effects of a new, concentrated wheat fibre preparation on intestinal transit, deoxycholic acid metabolism and the composition of bile.

When the cholesterol saturation index of bile is reduced by wheat bran there is generally a fall in the deoxycholic acid content of bile. As the same effects occur with senna, bran might act on bile simply via its accelerating effect on colonic transit. We have studied the effects of a new, concentrated, wheat fibre preparation (Testa Triticum Tricum, Trifyba, which is 80% dietary fibre) upon bile composition, deoxycholic acid metabolism and intestinal transit time, and have assessed whether these effects are related. Twenty constipated volunteers were prescribed Testa Triticum Tricum in doses (10-32 g/day) sufficient to relieve their symptoms for at least six weeks. Before and at the end of this period, duodenal bile was sampled to enable measurement of deoxycholic acid pool (by isotope dilution), total bile acid pool, bile acid composition and cholesterol saturation index. Whole gut transit time fell from 120 +/- SD35 to 68 +/- 35 hours. At the same time, biliary % deoxycholic acid fell from 26.6 +/- 12.0 to 23.0 +/- 11.8 (p = 0.002), the total bile acid pool expanded from 2.36 +/- 0.88 to 2.75 +/- 0.90 g (p = 0.008) and cholesterol saturation index fell from 1.13 +/- 0.32 to 1.07 +/- 0.29 (p = 0.04). In subjects with initial cholesterol saturation index over 1.0 (n = 12), it fell from 1.33 +/- 0.25 to 1.22 +/- 0.21 (p = 0.008). There was no significant correlation between change in saturation index and change in % deoxycholic acid or deoxycholic acid pool, nor between any of these parameters and change in transit time. Testa Triticum Tricum reduces the cholesterol saturation index of supersaturated bile but this action appears to be independent of its effect on colonic transit and of changes in deoxycholic acid metabolism.     

Factors affecting gall-stone dissolution rate during chenic acid therapy.

Gall-stone dissolution rate was measured in 52 patients with radiolucent gall stones in a functioning gall bladder receiving chenic acid 15 mg/kg/day. Percentage reduction in gall-stone area at six months was inversely related to initial gall-stone diameter (n = 52; r = -0.53; p less than 0.001), and to cholesterol saturation index of fasting gall-bladder bile during treatment (n = 28; r = -0.61; p less than 0.001). The duration of treatment required for complete dissolution was directly related to initial gall-stone diameter (r = 0.47; p less than 0.02). We conclude that the rate of gall-stone dissolution depends not only on gall-stone size but also on the degree of unsaturation of gall-bladder bile achieved during chenic acid treatment.     

Effects of cisapride on gall bladder emptying, intestinal transit, and serum deoxycholate: a prospective, randomised, double blind, placebo controlled trial

BACKGROUND: Octreotide inhibits gall bladder emptying and prolongs intestinal transit. This leads to increases in the proportion of deoxycholic acid in, and cholesterol saturation of, gall bladder bile, factors that contribute to the pathogenesis of octreotide induced gall stones. AIMS: To see if an intestinal prokinetic, cisapride, could overcome these adverse effects of octreotide and if so, be considered as a candidate prophylactic drug for preventing iatrogenic gall bladder stones. METHODS: A randomised, double blind, placebo controlled, crossover design was used to examine the effects of cisapride (10 mg four times daily) on gall bladder emptying, mouth to caecum and large bowel transit times, and the proportions of deoxycholic acid and other bile acids, in fasting serum from: (i) control subjects (n=6), (ii) acromegalic patients not treated with octreotide (n=6), (iii) acromegalics on long term octreotide (n=8), and (iv) patients with constipation (n=8). RESULTS: Cisapride had no prokinetic effect on the gall bladder. In fact, it significantly increased both fasting and postprandial gall bladder volumes. However, it shortened mouth to caecum (from 176 (13) to 113 (11) minutes; p<0.001) and large bowel (from 50 (3.0) to 31 (3.4) h; p<0.001) transit times. It also reduced the proportion of deoxycholic acid in serum from 26 (2.3) to 15 (1.8)% (p<0.001), with a reciprocal increase in the proportion of cholic acid from 40 (3.5) to 51 (3.8)% (p<0.01). There were significant linear relationships between large bowel transit time and the proportions of deoxycholic acid (r=0.81; p<0.001) and cholic acid (r=-0.53; p<0.001) in fasting serum. INTERPRETATION/SUMMARY: Cisapride failed to overcome the adverse effects of octreotide on gall bladder emptying but it countered octreotide induced prolongation of small and large bowel transit. Therefore, if changes in intestinal transit contribute to the development of octreotide induced gall bladder stones, enterokinetics such as cisapride may prevent their formation.     

Gall stone disease without gall stones--bile acid and bile lipid metabolism after complete gall stone dissolution.

Although bile acid and bile lipid metabolism have been studied in established cholelithiasis, little is known about them in patients destined to develop gall stones, but in whom the stones have not yet appeared (prestone gall stone disease). After confirmed complete gall stone dissolution and withdrawal of treatment, gall stones recur frequently. Before the stones reappear, these patients have 'poststone gall stone disease'. In 13 such patients we confirmed complete gall stone dissolution with two normal cholecystograms and in 11 of the 13 by normal ultrasonography, measured bile acid and bile lipid composition in fasting duodenal bile, bile acid synthesis from marker corrected three day faecal bile acid excretion, bile acid pool size using an abbreviated isotope dilution technique, 'steady-state' bile lipid secretion using a duodenal amino acid perfusion system and then calculated the enterohepatic cycling frequency of the bile acid pool and the relationship between pool size and body weight. The results confirm that after withdrawal of treatment the biliary cholesterol saturation index reverts to levels (1.6 +/- SEM 0.4) comparable with those before dissolution therapy first began (1.6 +/- 0.2; NS). The mean bile acid pool size in the 13 patients of 4.4 +/- 0.5 mmol was comparable with that in untreated gall stone patients. Pool size was significantly smaller in the nine non-obese patients (3.5 +/- 0.3), than in the four obese (6.0 +/- 0.8; p less than 0.05). It also correlated significantly with body weight (r = 0.72) and with %IBW (r = 0.79). The coefficients of variation for biliary bile acid, phospholipid and cholesterol secretion were high, but the mean hourly secretion rates were of the same order as those seen in untreated gall stone patients studied with the amino acid duodenal perfusion stimulus. These results provide a baseline for assessing the response to postdissolution treatment and may indicate metabolic events leading to gall stone formation.     

Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones.

BACKGROUND--Octreotide treatment of acromegalic patients increases the % deoxycholic acid conjugates and the cholesterol saturation of gall bladder bile, and induces gall stone formation. AIMS--To study the roles of gall bladder emptying and intestinal transit in these phenomena. METHODS AND PATIENTS--Gall bladder emptying and mouth to caecum transit was measured in (a) control subjects and acromegalic patients given saline or 50 micrograms of octreotide, and (b) acromegalic patients taking long term octreotide. In the second group, large bowel transit was also measured. RESULTS--A single dose of octreotide inhibited meal stimulated gall bladder emptying, the ejection fraction falling from mean (SEM) 66.0 (2.3)% to 7.0 (5.3)% in controls (p < 0.001); from 72.5 (2.1) to 16.6 (5.1)% in untreated acromegalic patients (p < 0.001), and to 30.4 (9.5)% in acromegalic patients taking long term octreotide (p < 0.001 v untreated acromegalic group). Octreotide prolonged mouth to caecum transit time, from 112 (15) min to 237 (13) min in controls (p < 0.001), from 170 (13) min to 282 (11) min in untreated acromegalic patients (p < 0.001), and to 247 (10) min in acromegalic patients taking long term octreotide (p < 0.001 v untreated acromegalic patients). The mean large bowel transit in octreotide untreated compared with treated acromegalic patients remained unchanged (40 (6) h v 47 (6) h). CONCLUSIONS--Prolongation of intestinal transit and impaired gall bladder emptying may contribute to lithogenic changes in bile composition and gall stone formation in patients receiving long term octreotide.     

Effect of simvastatin, ursodeoxycholic acid and simvastatin plus ursodeoxycholic acid on biliary lipid secretion and cholic acid kinetics in nonfamilial hypercholesterolemia.

It has been recently shown that the newest hypocholesterolemic agent, simvastatin, lowers the biliary cholesterol saturation index and that its association with ursodeoxycholic acid renders it more effective. To determine the mechanism by which simvastatin decreases the biliary cholesterol saturation index, we evaluated hepatic secretion rates of cholesterol, bile acids and phospholipids, and cholic acid pool size, turnover and synthesis in eight hyperlipidemic patients (five women and three men, age range = 38 to 65 yr). These assessments were conducted before treatment, after 4 wk of simvastatin (40 mg/day), after 4 wk of ursodeoxycholic acid (600 mg/day) and after a further 4 wk of a combination therapy of simvastatin (40 mg/day) plus ursodeoxycholic acid (600 mg/day). The cholesterol saturation index was significantly reduced with simvastatin (from 1.51 +/- 0.10 to 0.94 +/- 0.05, mean +/- S.E.; p less than 0.02), with ursodeoxycholic acid (from 1.51 +/- 0.10 to 0.86 +/- 0.03, mean +/- S.E.; p less than 0.02) and with the combination of simvastatin plus ursodeoxycholic acid (from 1.51 +/- 0.01 to 0.70 +/- 0.05, p less than 0.02). The cholesterol saturation index during combination therapy was significantly lower (p less than 0.02) than that reached during the use of simvastatin and ursodeoxycholic acid. Both simvastatin and ursodeoxycholic acid significantly reduced the hepatic secretion rate of cholesterol (from 130 +/- 14 mumols/hr to 81 +/- 12 mumols/hr, p less than 0.01, and 70 +/- 9 mumols/hr, p less than 0.01) without affecting bile acid and phospholipid outputs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of small doses of deoxycholic acid on bile cholesterol saturation in patients with liver cirrhosis.

To test the hypothesis that the detergent power of each individual bile acid--that is, its separate capacity to solubilize cholesterol and to induce biliary cholesterol secretion, present in the biliary bile acid mixture might be one of the determinant factors of biliary cholesterol saturation, we studied the effect of feeding small doses of deoxycholic acid on biliary cholesterol saturation in patients with liver cirrhosis and low deoxycholic acid pool. Eleven hospitalised patients with cirrhosis of various degree of severity were put on a standard solid diet. Fasting bile rich duodenal fluid was obtained at the beginning of the study, after a three to four weeks treatment with deoxycholic acid (3 mg/kg/day, in two doses) and one month after discontinuing bile acid ingestion. Before treatment the fraction of deoxycholic acid was 5.3 +/- 4.9% (mean +/- SD); after treatment the fraction rose to 43.9 +/- 12.0 of total bile acids, but returned to the basal values after stopping bile acids. Bile cholesterol saturation increased significantly from a mean of 0.92 +/- 0.26 (before treatment) to a mean of 1.34 +/- 0.34 after deoxycholic acid feeding (p less than 0.005). One month after treatment, bile saturation was not significantly different from the basal values (0.91 +/- 0.44). We conclude that feeding low doses of deoxycholic acid to patients with liver cirrhosis induces a significant increase of the fraction of this bile acid in the total pool and this is followed by a sharp increase of bile cholesterol saturation. These data are compatible with the hypothesis that the detergent capacity of individual bile acids is one of the main determinants of bile cholesterol saturation.     

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.     

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.     

Diurnal variation in cholesterol saturation of gall-bladder bile.

In order to determine whether a diurnal variation in cholesterol saturation index is present in gall-bladder bile, samples of bile were taken by nasoduodenal intubation and cholecystokinin infusion at 9 am after the conventional 12 hour fast, and also at 5 pm five hours after a meal containing no cholesterol or phospholipid. In healthy controls saturation index (mean +/- SEM) fell from 1.02 +/- 0.08 at 9 am to 0.86 +/- 0.08 at 5 pm (n = 8, p less than 0.05). In untreated cholesterol gall-stone patients saturation index fell from 1.30 +/- 0.07 to 1.04 +/- 0.07 (n = 8, p less than 0.05); on chenodeoxycholic acid 15 mg/kg/day it fell from 0.91 +/- 0.06 to 0.78 +/- 0.07 (n = 16, p less than 0.01). The degree of diurnal variation was similar in those taking chenodeoxycholic acid at bedtime and in those taking it at mealtimes. The 9 am sample was supersaturated in three non-responders (showing no evidence of gall stone dissolution on oral cholecystogram after at least six months treatment) and in four responders. The 5 pm sample was a better predictor of treatment failure, being supersaturated in all four non-responders but in only one out of the 12 responders (p less than 0.01).     

Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia.

Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p less than 0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p less than 0.01) from 1.06 to 0.75 during treatment with pravastatin. A reduction of 24% (p less than 0.01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gall stones.     

Effect of long term lactulose ingestion on secondary bile salt metabolism in man: potential protective effect of lactulose in colonic carcinogenesis.

This study investigated whether colonic absorption of secondary bile acids, especially deoxycholate in patients with adenomas could be decreased by oral lactulose. Bile acid metabolism was studied using bile sampling and 14C-deoxycholate kinetics in patients with colonic adenomatous polyps before and after four and 12 weeks of lactulose, 60 g/day. The results indicate that lactulose decreased the deoxycholate pool size from a mean of 22.0 (SD: +/- 13.8) to 14.3 (+/- 7.6) mumol/kg (p less than 0.025). Deoxycholate absorption fell from 3.8 (+/- 2.3) to 2.9 (+/- 1.4 mumol/kg/d (ns). The biliary bile acid composition decreased significantly in deoxycholate after four and 12 weeks with a rise in primary bile acids. There was a highly significant correlation between the %-change in DCA input and the %-change in DCA pool size (r = 0.89). Intestinal transit measured by the pellet method (4.1 +/- 1.9 to 2.4 +/- 0.6 day; p less than 0.01) and faecal pH decreased, while stool frequency and weight rose significantly. Significant correlations between the %-change in gut transit time and the %-change in DCA pool size or %-change in DCA input were absent. The results show that it is possible to lower colonic secondary bile acid absorption by long term lactulose feeding. This effect can be mediated by accelerated transit and the acidification of the colonic contents.     

Mucin in gall bladder bile of gall stone patients: influence of treatment with chenodeoxycholic acid and ursodeoxycholic acid.

The concentration of hexosamine, a marker for mucin, was determined and related to the degree of cholesterol saturation and to the occurrence of cholesterol crystals in gall bladder bile of gall stone patients (n = 40) and gall stone free subjects (n = 25). Ten of the gall stone patients had been treated with chenodeoxycholic acid (CDCA) and eight with ursodeoxycholic acid (UDCA) three to four weeks before cholecystectomy. The hexosamine content was significantly higher in gall stone patients (137 (19) ng/ml, mean (SE) than in gall stone free subjects (83 (9) ng/ml, p less than 0.02). Treatment with CDCA or UDCA decreased cholesterol saturation, but did not significantly affect the hexosamine concentration. There was no difference in hexosamine concentration between gall stone patients with and without cholesterol crystals. The results do not support the hypothesis that the degree of cholesterol saturation is important for the mucin content of gall bladder bile in man. Neither do the data indicate that the formation and occurrence of cholesterol crystals in gall bladder bile from gall stone patients is caused by an increased concentration of mucin. As the studies were conducted on patients who had already had gall stones for several years, however, an effect of mucin in the very early stage of gall stone formation cannot be completely excluded.     

Dietary N-3 polyunsaturated fatty acids decrease biliary cholesterol saturation in gallstone disease.

Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n-1 monounsaturated or n-6 polyunsaturated fatty acids with n-3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n-3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n-3 polyunsaturated fatty acids. Intake of n-3 polyunsaturated fatty acids increased (p less than 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p less than 0.001) and arachidonic acids (p less than 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p less than 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 +/- 0.44 to 1.24 +/- 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile.     

Comparison of the effects of medium and long chain triglyceride containing liquid meals on gall bladder and small intestinal function in normal man

We investigated the effects of medium (MCT) and long (LCT) chain triglyceride test meals on gall bladder contraction (using ultrasonography) and small intestinal bile acid concentrations and ileal flow rates (using intubation techniques) in normal individuals. Comparing the effects of ingesting medium chain triglyceride and long chain triglyceride meals, the gall bladder volume was reduced by 23.4 +/- 33.6% and 59.0 +/- 17.1% respectively (mean +/- SD, p less than 0.01, n = 13), the jejunal bile acid concentrations increased significantly only after the ingestion of long chain triglyceride (p less than 0.05, n = 5), while the volume of the postprandial jejunal contents was not significantly different (540 +/- 150, 522 +/- 169 ml, medium chain triglyceride vs long chain triglyceride, p = 0.2, n = 5). The postprandial colonic inflow was 48.5 +/- 12.5 and 123.4 +/- 35.2 ml/h (medium chain triglyceride vs long chain triglyceride, p less than 0.01, n = 5). Thus medium chain triglyceride, compared with long chain triglyceride, produces a smaller input of bile acids into the small intestine and a smaller volume of fluid delivered to the colon. These observations may be relevant to the beneficial effects of medium chain triglyceride substitution for long chain triglyceride in the treatment of diarrhoea in patients with small intestinal disease.     

Comparison of gall bladder bile and endoscopically obtained duodenal bile.

In 10 patients with gall stone disease (eight women, two men; mean (SD) age 47.4 (13) years), bile was obtained by endoscopic aspiration after stimulation of the gall bladder with ceruletid and also by fine needle puncture of the gall bladder under local anaesthetic. The total lipid concentration of the puncture bile samples was mean (SD) 11.9 (4.7) g/dl, significantly higher than the endoscopic bile samples (3.9 (3.3) g/dl, p less than 0.001). Total bile acids, phospholipids, and biliary cholesterol (expressed in mol%) and cholesterol saturation index showed no significant differences between the two types of samples. The glycocholic acid concentration in the endoscopically obtained bile (27.7 (6.6) mol% v 23.3 (5.4) mol%; p less than 0.01) was significantly higher than the puncture bile samples. Puncture bile exhibited a significantly shorter nucleation time (3.5 (3.3) days v 19.6 (11.9) days; p less than 0.001). For determination of the nucleation time, endoscopic bile aspiration after gall bladder stimulation with ceruletid led to adequately concentrated samples in 50% of the study subjects. Cholesterol monohydrate crystal formation in native bile was observed in six samples of puncture bile and in three samples of the endoscopically obtained bile. The presence of cholesterol crystals and the determination of nucleation time in the puncture bile were the best discriminants between cholesterol and pigment gall stones and correlated well with computed tomogram analysis.     

Effects of simvastatin and cholestyramine on bile lipid composition and gall bladder motility in patients with hypercholesterolaemia.

Although the effects of 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and bile acid sequestrants on bile lipid composition have been studied separately, no data are available on combination therapy of these drugs. Moreover, the effects of prolonged (four weeks) administration of these drugs on gall bladder motility, an important determinant of cholesterol gall stone formation, have not been studied so far. A prospective study was therefore performed with eight patients who had hypercholesterolaemia (age 53 (5) (SEM), body mass index 27.4 (1.1) kg m-2, low density lipoprotein cholesterol 5.9 (0.3) mmol/l). They received treatment during three periods of four weeks with simvastatin 20 mg/day, cholestyramine 4 g twice daily, and a combination of both in random order, each treatment period separated by a two week wash out period. Before treatment and after each treatment period, postprandial gall bladder motility was studied with ultrasound, followed by duodenal bile sampling. Serum cholesterol decreased in all subjects in any treatment period illustrating good compliance. Molar percentages in duodenal bile of cholesterol, phospholipids, and bile salts were unchanged during simvastatin and cholestyramine treatment. During combined therapy percentage bile salts was lower (72.5 (2.9)% v 77.8 (1.7)% at baseline, p < 0.05) whereas phospholipids were higher (21.2 (2.4)% v 16.4 (1.3)% at baseline, p < 0.05). As a result cholesterol saturation index (CSI) did not change in any treatment period. No cholesterol crystals were detected in any bile sample, taken at baseline and after each treatment period. Bile salt hydrophobicity index during cholestyramine (0.19 (0.02)) and combined treatment (0.22 (0.01)) decreased strongly compared with baseline (0.34 (0.01), p < 0.001, p < 0.01, respectively), resulting from increased proportions of glycocholate (59.4 (3.9)% (cholestyramine), 55.6 (2.4)% (combination), and 28.2 (2.2) (baseline), p < 0.001)) and decreased proportions of deoxycholic acid and chenodeoxycholic acid. Fasting gall bladder volume was increased during simvastatin (28.7 (2.8) ml) v baseline (23.2 (2.3) ml, p < 0.01) whereas, residual volume did not differ (5.7 (0.9) ml (simvastatin) v 5.9 (0.7) (baseline). During cholestyramine and combined treatment, no significant differences in gall bladder motility were seen. In conclusion, this study suggests that HMG-CoA reductase inhibitors alone and combined with cholestyramine do not affect major determinants of cholesterol gall stone formation, for example, CSI and gall bladder emptying. In addition cholestyramine alone and combined with simvastatin leads to a strong decrease of bile salt hydrophobicity, which may be beneficial in the prevention of nucleation of cholesterol crystals.