Mark Stolk

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall‐bladder emptying.

Motilin induces gall bladder emptying and antral contractions in the fasted state in humans

Background—Animal studies have shown that motilin affects gall bladder motility. In humans, no effect has been shown, but erythromycin, a motilin receptor agonist, induces gall bladder emptying. Aims—To explore the effect of increasing doses of exogenous motilin on gall bladder volume and antral contractility in the fasted state in humans. Methods—After an overnight fast, eight healthy men received increasing intravenous doses of Leu13-motilin (KW-5139) or 0.9% NaCl in a double blind, randomised fashion. Gall bladder volume and antral contraction frequency were determined by ultrasonography. Results—Infusion of motilin increased plasma motilin levels. Motilin induced a reduction in gall bladder volume of 8.0 (5.0)%, 17.1 (5.0)%, 18.5 (4.7)%, and 16.1 (4.9)% of baseline volume at the end of infusion of 2, 4, ,8 and 16 pmol/kg/min respectively, compared with mean stable gall bladder volumes during placebo infusion (p<0.05). Antral contraction frequency increased during motilin infusion, but not during placebo infusion (p<0.05). Conclusions—Exogenous motilin reducted fasting gall bladder volume and increased antral contractions. After reaching maximal reduction, the gall bladder volume did not decrease further during continuous motilin infusion at higher doses and stayed at the same reduced volume. The degree of gall bladder volume reduction during motilin infusion mimicked gall bladder emptying preceding antral phase III activity of the migrating motor complex in humans. This study indicates that motilin may play a physiological role in the regulation of gall bladder emptying in the fasted state.

Cholesterol and pigment gallstone disease: comparison of the reliability of three bile tests for differentiation between the two stone types

Gallbladder biles and stones were obtained at 116 cholecystectomies for symptomatic gallstone disease. All 33 patients younger than 50 years had cholesterol stones, whereas 40% of the older patients had pigment stones. We compared the reliability of three different bile tests for the differentiation between cholesterol and pigment stone patients. Whereas both the presence of cholesterol monohydrate crystals in fresh gallbladder bile and a nucleation time less than or equal to 20 days in ultrafiltered gallbladder bile had a specificity of 100% for cholesterol gallstone disease, biliary supersaturation with cholesterol (cholesterol saturation index greater than 1.0) had a low specificity. The sensitivity of nucleation time less than or equal to 20 days for cholesterol gallstone disease was 78% in concentrated gallbladder biles (biliary total lipid concentration greater than or equal to 5 g/dl) but only 21% in dilute biles (biliary total lipid concentration less than 5 g/dl). In contrast, examination for the presence of cholesterol crystals in fresh bile was reasonably sensitive both in concentrated and dilute gallbladder biles (sensitivity, 84% and 72%, respectively). In addition, duodenal bile obtained from 16 patients (10 cholesterol, 6 pigment) before cholecystectomy showed cholesterol crystals in 7 of the cholesterol but in none of the pigment stone patients. We conclude that examination of fresh bile for cholesterol crystals is a specific and reasonably sensitive test for cholesterol gallstone disease.

Fasting gallbladder volume, postprandial emptying and cholecystokinin release in gallstone patients and normal subjects

Since abnormal gallbladder emptying may be a contributing factor in the development of gallstone disease, we determined fasting gallbladder volume and postprandial contraction in 20 gallstone patients and 20 normal subjects with the aid of ultrasonography. Moreover, basal plasma cholecystokinin levels and postprandial cholecystokinin (CCK) release were determined. Gallstone patients were divided into strong contractors (13 pts) and weak contractors (below 95% confidence interval for AUC contraction in % during 90 min: 7 pts). Strong contractor patients had significantly larger mean fasting volumes than normal subjects (mean +/- S.E.: 34.9 +/- 6.1 ml and 18.9 +/- 1.6 ml, respectively). This was not true for weak contractor patients (mean fasting volume 23.2 +/- 3.2 ml). Both strong contractor and weak contractor patients had significantly higher mean residual volumes than normal subjects (17.0 +/- 4.1 ml, 18.0 +/- 2.9 ml, and 8.8 +/- 1.1 ml, respectively). Absolute gallbladder emptying was significantly higher for strong contractor patients than for normal subjects, but relative emptying was the same. Opposite patterns of CCK release occurred in gallstone patients and normal subjects. In normal subjects, more CCK release was associated with stronger gallbladder emptying. In contrast, weak contractor gallstone patients had significantly higher CCK release than strong contractor patients. (AUC CCK: 304 +/- 89 pmol/l x 90 min and 106 +/- 29 pmol/l x 90 min, respectively). The present study indicates that strong contractor gallstone patients may have large residual gallbladder volumes due to large starting volumes, whereas weak contractor patients may have large residual volumes due to impaired contraction. Subjects with large fasting and residual volumes may be at increased risk for gallstone disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ursodeoxycholic acid on gallbladder contraction and cholecystokinin release in gallstone patients and normal subjects.

It has been previously suggested that treatment with ursodeoxycholic acid leads to decreased gallbladder emptying. The proposed mechanism is decreased release of cholecystokinin through negative feedback control by an increased amount of intraduodenal bile acids. In the present study we examined cholecystokinin release and gallbladder contraction after oral administration of a commercial fatty meal (Sorbitract; Dagra, Diemen, The Netherlands) using ultrasonography in eight normal subjects and eight gallstone patients before and after 1 and 4 weeks of treatment with ursodeoxycholic acid (10 mg kg-1.day-1). Fasting gallbladder volume increased in 15 of 16 subjects during treatment (P less than 0.01). Minimal volume did not change. Therefore, both absolute and relative gallbladder emptying increased during therapy. Maximal decrement of gallbladder volume in milliliters and percentage as well as integrated gallbladder contraction during 90 minutes in milliliters and percentage were significantly increased after 1 and 4 weeks of treatment with ursodeoxycholic acid when compared with data before therapy. Gallstone patients tended to have larger fasting and residual gallbladder volumes than normal subjects, whereas parameters for the amount of bile expelled (maximal decrement of gallbladder volume and integrated gallbladder contraction in milliliters and percentage) did not differ. Release of cholecystokinin did not change during treatment and did not differ significantly between patients and normal subjects. Mean relative percentage of ursodeoxycholic acid in bile during treatment in 13 subjects consenting to have duodenal intubation was 47% (range 31%-60%). Changes of fasting gallbladder volume after institution of bile acid treatment correlated significantly (r = 0.74, P less than 0.01) with changes of cholesterol saturation index but not with relative percentage of ursodeoxycholic acid in bile. This study indicates that gallbladder emptying does not decrease during treatment with ursodeoxycholic acid. Moreover, there is no evidence of decreased cholecystokinin release.

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.

Gallbladder emptying in vivo, bile composition, and nucleation of cholesterol crystals in patients with cholesterol gallstones

BACKGROUND/AIMS Impaired postprandial gallbladder emptying may provide time for progressive bile concentration with formation of instable cholesterol-rich vesicles and fast nucleation of cholesterol crystals. The aim of this study was to assess postprandial gallbladder emptying, bile composition, and nucleation of cholesterol crystals in the same patient. METHODS In 30 patients with cholesterol gallstones, postprandial gallbladder emptying was measured ultrasonographically. In each patient, gallbladder bile composition (obtained at cholecystectomy) and nucleation of cholesterol crystals was determined. Patients were divided in 22 strong contractors (> 50% postprandial gallbladder emptying) and 8 weak contractors. RESULTS In weak contractors, bile salt and phospholipid concentrations were much higher than in strong contractors (234.6 +/- 24.7 vs. 130.3 +/- 10.8 mmol/L [P < 0.001] and 44.5 +/- 3.5 vs. 30.2 +/- 3.1 mmol/L [P < 0.05], respectively). Cholesterol concentrations were comparable in strong and weak contractors. Consequently, total lipid concentration was significantly higher (15.5 +/- 1.4 and 9.2 +/- 0.7 g/dL; P < 0.001) and cholesterol saturation index significantly lower (0.90 +/- 0.08 and 1.61 +/- 0.17; P < 0.001) in weak contractors. Nucleation time, percentage of cholesterol in vesicles, bile salt species, and molecular species of phosphatidylcholine were not significantly different. CONCLUSION Differences in bile composition can be linked to different patterns of postprandial gallbladder emptying and may point to two different pathways of gallstone formation.

Successful dissolution of cholesterol gallstone during treatment with pravastatin

This case report describes a 51-year-old hypercholesterolemic male patient who had a large solitary cholesterol gallstone. The patient was treated with the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin, 40 mg/day. After 3 months of therapy, serum cholesterol level normalized (7.7 mmol/L before and 5.2 mmol/L during treatment), and biliary cholesterol saturation index decreased from 1.3 before to 0.8 during treatment. Repeatedly performed ultrasonography showed complete gallstone dissolution. Pravastatin may be valuable in the nonsurgical treatment of cholesterol gallstone disease particularly when there is an additional indication for HMG-CoA reductase inhibitors because of hypercholesterolemia.

Postprandial gall bladder motility and hormone release during intermittent and continuous subcutaneous octreotide treatment in acromegaly.

Repeated daily injections of the somatostatin analogue, octreotide (SMS201-995, Sandostatin) are an effective treatment for acromegaly, but lead to gall stone formation in about 50% of cases during longterm treatment. This is probably because of impaired gall bladder contraction. This study examined whether the timing of intermittent injections in relation to meals, or alternatively, continuous 24 hour subcutaneous octreotide infusion (CSOI) might avert adverse effects on gall bladder contraction. In six patients with active acromegaly, gall bladder volume, plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured in the fasting state and after consumption of a fatty meal. Measurements were made on five separate days: (a) without treatment, (b) 45 minutes after 100 micrograms octreotide given subcutaneously, (c) four hours after 100 micrograms octreotide given subcutaneously, (d) eight hours after 100 micrograms octreotide given subcutaneously, and (e) during CSOI of 300 micrograms/24 h for two weeks. Without treatment, postprandial gall bladder contraction was 86.2 (2.1%). Fasting gall bladder volume increased after octreotide injection and was almost doubled during CSOI. Octreotide injections impaired postprandial gall bladder contraction as well as CCK and PP release for at least four hours. Eight hours after injection and during CSOI, postprandial gall bladder contraction was partly restored (43.4% and 50.8% respectively). Postprandial CCK release was normal at eight hours after injection but very low during CSOI. PP release was suppressed by each mode of octreotide treatment. This study indicates that octreotide injections impair postprandial gall bladder contraction for at least four hours. Eight hours after injection and during CSOI, gall bladder contraction is partly restored.

Bile concentration promotes nucleation of cholesterol monohydrate crystals by increasing the cholesterol concentration in the vesicles

Abstract. Cholesterol in bile is solubilized in mixed micelles and cholesterol‐phospholipid vesicles. Biliary cholesterol supersaturation and increased concentration of bile in the gallbladder promotes nucleation of cholesterol monohydrate crystals and gallstone formation, possibly by creating unstable vesicles with a high cholesterol/phospholipid ratio. In the present study super‐saturated and unsaturated biles (cholesterol saturation index (CSI) 1.4 and 0.8 respectively) were prepared with concentrations typical of gallbladder and more dilute hepatic bile (total lipid concentration (TLCo) 10 and 2.5 g dl‐1 respectively). The distribution of cholesterol between vesicles and micelles, and vesicular cholesterol/phospholipid ratio were studied using ultracentrifugation and gel‐permeation chromatography. The nucleation time of cholesterol crystals was determined in whole model bile, and in the vesicular and micellar peak fractions. Increased CSI and bile dilution led to an increased proportion of cholesterol solubilized in vesicles. The concentration of bile did not influence vesicular cholesterol/phospholipid ratio. The vesicular cholesterol/ phospholipid ratio found in gel‐permeation chromatography experiments was similar at high and low CSI, whereas the ratio was significantly higher in supersaturated than in unsaturated biles in ultracentrifugation studies. Nucleation of cholesterol crystals from whole model bile was more rapid at the higher bile concentration and higher cholesterol saturation. Nucleation time in whole model bile correlated significantly with nucleation time in the corresponding vesicular peak fraction obtained by gel‐permeation chromatography (r = 0,58: P< 0.01) and with the cholesterol concentration in this vesicular peak (r= ‐0.77; P<0.002) but not with vesicular peak cholesterol/phospholipid ratio. Highest vesicular peak cholesterol concentrations and shortest nucleation times were found for concentrated supersaturated biles, whereas vesicular cholesterol/phospholipid ratio was not different from dilute or unsaturated biles. The present study indicates that increased concentration of bile promotes nucleation of cholesterol crystals by increasing the concentration of cholesterol in the vesicular peak rather than by changing its cholesterol/phospholipid ratio.