deoxycholic-acid and Acromegaly

The aim of this article is to review selected aspects of the pathogenesis of cholesterol-rich, gall-bladder stones (GBS)--with emphasis on recent developments in biliary cholesterol saturation, cholesterol microcrystal nucleation, statis within the gall-bladder and, particularly, on the roles of intestinal transit and altered deoxycholic acid (DCA) metabolism, in GBS development. In biliary cholesterol secretion, transport and saturation, recent developments include evidence in humans and animals, that bile lipid secretion is under genetic control. Thus in mice the md-2 gene, and in humans the MDR-3 gene, encodes for a canalicular protein that acts as a 'flippase' transporting phospholipids from the inner to the outer hemi-leaflet of the canalicular membrane. In the absence of this gene, there is virtually no phospholipid or cholesterol secretion into bile. Furthermore, when inbred strains of mice that have 'lith genes' are fed a lithogenic diet, they become susceptible to high rates of GBS formation. The precipitation/nucleation of cholesterol microcrystals from supersaturated bile remains a critical step in gallstone formation. methods of studying this phenomenon have now been refined from the original 'nucleation time' to measurement of cholesterol appearance/detection times, and crystal growth assays. Furthermore, the results of recent studies indicate that, in addition to classical Rhomboid-shape monohydrate crystals, cholesterol can also crystallize, transiently, as needle-, spiral- and tubule-shaped crystals of anhydrous cholesterol. A lengthy list of promoters, and a shorter list of inhibitors, has now been defined. There are many situations where GB stasis in humans is associated with an increased risk of gallstone formation--including iatrogenic stone formation in acromegalic patients treated chronically with octreotide (OT). As well as GB stasis, however, OT-treated patients all have 'bad' bile which is supersaturated with cholesterol, has excess cholesterol in vesicles, rapid microcrystal mulceation times and a two-fold increase in the percentage DCA in bile. This increase in the proportion of DCA seems to be due to OT-induced prolongation of large bowel transit time (LBTT). Thus LBTT is linearly related to (i) the percentage of DCA in serum; (ii) the DCA pool size; and (III) the DCA input or 'synthesis' rate. Furthermore, the intestinal prokinetic, cisapride, counters the adverse effects of OT on intestinal transit, and 'normalizes' the perce

Topics: Acromegaly; Animals; Bile Acids and Salts; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Gallbladder; Gastrointestinal Transit; Humans; Mice

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.. 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.. 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).. 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.

Topics: Acromegaly; Adult; Cholelithiasis; Cholic Acid; Cisapride; Constipation; Cross-Over Studies; Deoxycholic Acid; Double-Blind Method; Female; Gallbladder Emptying; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Male; Middle Aged; Octreotide; Prospective Studies; Regression Analysis

Topics: Acromegaly; Constipation; Deoxycholic Acid; Gallstones; Gastrointestinal Transit; Humans; Intestinal Absorption; Octreotide

Acromegalic patients have slow colonic transit, increased rates of deoxycholic acid formation, and an increased prevalence of cholesterol gall stones, especially during long term octreotide treatment. However, the effects of this prolonged large bowel transit time on the numbers of faecal anaerobes and the activities of the enzyme systems which biotransform conjugated cholic acid into unconjugated deoxycholic acid (cholylglycine hydrolase and 7alpha-dehydroxylase) are unknown.. Therefore, in 10 non-acromegalic controls, 11 acromegalic patients not treated with octreotide, and 11 acromegalics on long term (8-48 months) octreotide (100-200 mug three times daily subcutaneously), we measured large bowel transit time and, in freshly voided faeces, the activities of the two bile acid metabolising enzymes, and related the results to the proportion of deoxycholic acid in fasting serum. Moreover, in patients with acromegaly, we measured quantitative bacteriology in faeces.. Mean large bowel transit time in acromegalics not treated with octreotide (35 (SEM 6.5) hours) was 66% longer than that in non-acromegalic controls (21 (3.1) hours; NS) and became further prolonged during octreotide treatment (48 (6.6) hours; p<0.001). These octreotide induced changes in transit were associated, in acromegalic patients, with more total (15.0 (2.5) v 6.3 (1.3)x10(9) colony forming units (cfu)/g; p<0.05) and Gram positive (6.3 (2.3) v 3.2 (1.0)x10(9) cfu/g; p<0.05) faecal anaerobes. Mean faecal cholylglycine hydrolase activity in the long term octreotide group (22.0 (6.0)x10(-2) U/mg protein) was 138% greater than that in non-acromegalic controls (12.0 (6.0)x10(-2); p<0.01). Similarly, mean 7alpha-dehydroxylase activity in octreotide treated acromegalics (11.1 (1.18)x10(-4) U/mg protein) was 78% greater than that in patients not receiving long term octreotide (6.3 (0.5)x10(-4); p<0.001). The mean proportion of deoxycholic acid in fasting serum also increased from 18.0 (2.88)% in the untreated group to 29.6 (2.3)% during long term octreotide (p<0.05). There were significant linear relationships between large bowel transit time and: (i) faecal 7alpha-dehydroxylase activity; and (ii) the proportion of deoxycholic acid in fasting serum and between 7alpha-dehydroxylase activity and the proportion of deoxycholic acid in serum.Summary/interpretation: These data suggest that increased deoxycholic acid formation seen in acromegalics during octreotide treatment is due not only to the greater numbers of faecal anaerobes but also to increased activity of the rate limiting enzyme pathway (7alpha-dehydroxylation) converting cholic acid to deoxycholic acid.

Topics: Acromegaly; Adult; Aged; Amidohydrolases; Analysis of Variance; Bacteria, Anaerobic; Colon; Colony Count, Microbial; Deoxycholic Acid; Fasting; Feces; Female; Gastrointestinal Transit; Humans; Hydroxysteroid Dehydrogenases; Male; Middle Aged; Octreotide

Octreotide treatment of acromegalic patients induces cholesterol gallstone formation, in part by impairing cholecystokinin release and gall-bladder contraction. However, there are few data on the effect of octreotide on biliary arachidonic acid-rich phospholipids or mucin glycoprotein, factors which also influence cholesterol gallstone formation.. In acromegalic patients studied before and during 3 months of octreotide treatment, we measured mucin glycoprotein concentrations and the molecular species of phosphatidylcholine, and related the results to the cholesterol saturation and percentage of deoxycholic acid in gall-bladder bile.. The relative proportions of the major arachidonic acid-rich phosphatidylcholine species, PC 16:0-20:4 and PC 18:0-20:4, increased significantly during octreotide treatment. These changes were associated with a rise in the cholesterol saturation index and a non-significant twofold increase in mucin glycoprotein concentration. There were significant correlations between PC 16:0-20:4 and the cholesterol saturation index, percentage of vesicular cholesterol and percentage of deoxycholic acid in gall-bladder bile.. In acromegalic patients, octreotide increases the proportions of arachidonic acid-rich phospholipids, with associated rises in: (a) the cholesterol saturation index and percentage of vesicular cholesterol, and (b) the percentage of deoxycholic acid in gall-bladder bile-changes similar to those found in patients with cholesterol-rich gall-bladder stones.

Topics: Acromegaly; Adult; Arachidonic Acids; Case-Control Studies; Cholelithiasis; Deoxycholic Acid; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Mucins; Octreotide; Phosphatidylcholines; Phospholipids

Prolonged large bowel transit, and an increase in the proportion of deoxycholic acid (DCA), have been implicated in the pathogenesis of cholesterol gallstones-including those developing in acromegalics treated with octreotide. However, there are few data on the effects of intestinal transit on bile acid kinetics.. We therefore measured the kinetics of DCA and cholic acid (CA) using stable isotopes, serum sampling, and mass spectrometry. The results were related to mouth-to-caecum (MCTT) and large bowel transit times (LBTTs) in 4 groups of 8 individuals: (1) non-acromegalic controls, (2) acromegalics untreated with octreotide, (3) acromegalics on long-term octreotide, and (4) patients with constipation. Paired, before and during octreotide, studies were performed in 5 acromegalics.. In the unpaired and paired studies, octreotide significantly prolonged MCTT and LBTT. In the paired studies, the octreotide-induced prolongation of LBTT caused an increase in the DCA input rate (6.4 +/- 2.8 to 12 +/- 2.6 micromol. kg. d, P < 0.05) and pool size (18 +/- 12 to 40 +/- 13 micromol/kg, P < 0.05), and a decrease in CA pool size (45 +/- 15 to 25 +/- 11 micromol/kg, P < 0.05). Furthermore, during octreotide treatment, the mean conversion of 13C-CA to 13C-DCA (micromoles) was greater (P < 0.05) on study days 3, 4, and 5. There were also positive linear relationships between LBTT and DCA input rate (r = 0.78), pool size (r = 0.82, P < 0.001), and a weak (r = -0.49) negative linear relationship between LBTT and CA pool size (P < 0.01).. These data support the hypothesis that, by increasing DCA formation and absorption, prolongation of large bowel transit is a pathogenic factor in the formation of octreotide-induced gallstones.

Topics: Acromegaly; Adult; Aged; Body Weight; Carbon Isotopes; Cholic Acid; Colon; Deoxycholic Acid; Deuterium; Female; Humans; Male; Middle Aged; Octreotide; Postprandial Period

Treatment of acromegaly with octreotide increases the proportion of deoxycholic acid in, and the cholesterol saturation of, bile and induces the formation of gallstones. Prolongation of intestinal transit has been proposed as the mechanism for the increase in the proportion of deoxycholic acid in bile.. To study the effects of octreotide on intestinal transit in acromegalic patients during octreotide treatment, and to examine the relation between intestinal transit and bile acid composition in fasting serum.. Mouth to caecum and large bowel transit times, and the proportion of deoxycholic acid in fasting serum were measured in non-acromegalic controls, acromegalic patients untreated with octreotide, acromegalics on long term octreotide, and patients with simple constipation. Intestinal transit and the proportion of deoxycholic acid were compared in acromegalic patients before and during octreotide.. Acromegalics untreated with octreotide had longer mouth to caecum and large bowel transit times than controls. Intestinal transit was further prolonged by chronic octreotide treatment. There were significant linear relations between large bowel transit time and the proportion of deoxycholic acid in the total, conjugated, and unconjugated fractions of fasting serum.. These data support the hypothesis that, by prolonging large bowel transit, octreotide increases the proportion of deoxycholic acid in fasting serum (and, by implication, in bile) and thereby the risk of gallstone formation.

Topics: Acromegaly; Adult; Aged; Bile Acids and Salts; Cholelithiasis; Deoxycholic Acid; Drug Administration Schedule; Fasting; Female; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Intestine, Large; Male; Middle Aged; Octreotide; Risk Factors

Treatment of acromegaly with octreotide inhibits cholecystokinin release and gallbladder contraction and induces gallbladder stones. However, little is known about the effects of octreotide on bile composition.. Fresh gallbladder bile was obtained from three groups: (1) 11 nonacromegalic patients with cholesterol gallstones, (2) 6 acromegalic patients with octreotide-associated stones (treatment, 300-600 micrograms/day for 3-66 months), and (3) 8 acromogalic patients with no stones before octreotide treatment, 5 of whom were reexamined after 3-24 months of therapy.. Compared with stone-free acromegalic patients untreated with octreotide, bile from patients with cholesterol stones and from acromegalic patients with octreotide-associated stones had greater saturation indices (mean +/- SEM) (1.52 +/- 0.17 and 1.32 +/- 0.14 vs. 0.90 +/- 0.05, respectively; P < 0.01); more cholesterol in vesicles (61.2% +/- 4.5% and 67.7% +/- 7.2% vs. 37.7% +/- 3.5%; P < 0.009); more unstable vesicles (cholesterol/phospholipid ratios, 0.97 +/- 0.12 and 0.81 +/- 0.16 vs. 0.52 +/- 0.05; P < 0.02); more rapid nucleation (< 5 and < 5 days vs. > 18 days; P < 0.003); and more deoxycholic acid (22.8% +/- 2.4% and 23.6% +/- 4.8% vs. 13.9% +/- 1.4%; P < 0.05). In the paired studies, the saturation indices increased from 0.89 +/- 0.07 before octreotide treatment to 1.12 +/- 0.03 during octreotide treatment (P < 0.02), as did the percentage of deoxycholic acid from 13.3% +/- 2.1% to 24.9% +/- 2.7% (P < 0.03).. Acromegalic patients with octreotide-associated gallstones and stone-free acromegalic patients treated with octreotide have similar changes in bile composition to those in patients with "conventional" cholesterol gallstone disease.

Topics: Acromegaly; Adult; Aged; Bile; Chemical Phenomena; Chemistry, Physical; Cholelithiasis; Cholesterol; Crystallization; Deoxycholic Acid; Female; Humans; Male; Middle Aged; Octreotide; Phospholipids

Topics: Acromegaly; Cholelithiasis; Deoxycholic Acid; Female; Gastrointestinal Transit; Humans; Octreotide