Percentage Of Deoxycholic Acid Research Articles

Octreotide increases the proportions of arachidonic acid-rich phospholipids in gall-bladder bile.

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.

Composition of cecal bile acids in ex‐germfree mice inoculated with human intestinal bacteria

Germfree (GF) mice were orally inoculated with human fecal suspension or various components of human fecal microbiota. Three weeks after the inoculation, cecal bile acid composition of these mice was examined. More than 80% of total bile acids was deconjugated in the cecal contents of ex-GF mice associated with human fecal dilutions of 10(-2) or 10(-6), or anaerobic growth from a dilution of 10(-6). In these ex-GF mice, deoxycholic acid accounted for about 20% of total bile acids. In the cecal contents of ex-GF mice associated only with clostridia, unconjugated bile acids made up less than 40% of total bile acids, about half of those in other ex-GF groups. However, the percentage of deoxycholic acid in these mice was the same as that in the other groups. These results indicate that dominant anaerobic bacterial combination is efficient for deconjugation of primary bile acids, and that clostridia in the human feces may play an important role in 7alpha-dehydroxylation of unconjugated primary bile acids in the intestine.

Review: pathogenesis of gallstones.

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 percentage of DCA in serum/bile. Patients with spontaneous gallstone disease also have prolonged LBTTs, more colonic gram-positive anaerobes, increased bile acid metabolizing enzymes and higher intracolonic pH values, than stone-free controls. Together, these changes lead to increased DCA formation, solubilization and absorption, Thus, in addition to the 'lithogenic liver' and 'guilty gall-bladder' one must now add the 'indolent intestine' to the list of culprits in cholesterol gallstone formation.

Deoxycholic acid is not related to lithogenic factors in gallbladder bile

The influence of deoxycholic acid (DCA) on the factors in gallbladder bile responsible for cholesterol gallstone disease has been a controversial subject of discussion. This might be partially due to patient selection or inappropriate methods. Therefore, we investigated the relationship between the percentage of DCA and lithogenic factors in the gallbladder bile of patients with cholesterol gallstones and with normal or moderately impaired gallbladder contractility. Patients with pigment stones served as a control group. The percentage of DCA in the gallbladder bile of 20 patients with cholesterol stones (23.2% ± 6.5%; mean ± SD) was comparable to the DCA percentage in the gallbladder bile of 11 patients with pigment stones (26.5% ± 8.5%). No correlation was seen between the DCA percentage of total bile acids and the crystal observation time, cholesterol saturation index (CSI), total protein value, mucin level, and amount of cholesterol in vesicles or crystals in the total group of patients or in the subgroups with cholesterol or pigment stones, respectively. The lack of correlation between DCA percentage and CSI was determined in native bile (r = 0.048) as well as in crystal-free bile after ultracentrifugation (r = 0.107). Our findings demonstrate that in patients with gallstones, the percentage of DCA in gallbladder bile is not related to any of the known biliary factors associated with cholesterol gallstone disease. We conclude that in patients with normal or moderately impaired gallbladder function, an elevated DCA level in the gallbladder bile is of minor pathophysiologic significance for the formation of cholesterol gallstones.

Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile

Little is known about the effects of biliary deoxycholic acid on the partitioning of biliary cholesterol between vesicles and micelles and on the rate of nucleation of cholesterol microcrystals, key steps in gallstone formation. Therefore, 43 samples of fresh gallbladder bile were obtained from a heterogeneous group of patients with and without stones. Univariate and multivariate analyses were then applied to determine the inter-relationships between biliary cholesterol saturation, total lipid concentration, and bile acid species and (1) the distribution of biliary cholesterol between vesicles and micelles and (2) the cholesterol microcrystal nucleation time. The percentage of deoxycholic acid in bile was shown to be linearly related to the cholesterol saturation index ( r = .54; P < .001), the vesicular cholesterol:phospholipid molar ratio ( r = .53; P < .001), and the molar concentration of cholesterol in the vesicles ( r = .59; P < .001). The mean proportion of biliary deoxycholic acid conjugates was also greater in patients with rapid nucleation times (23.4 ± SEM 1.1%) than in those with slow nucleation times (17.3 ± 1.9%; P < .05). As total bile lipid concentration increased, the proportion of total biliary cholesterol in vesicles decreased ( r = .53; P < .001), whereas the molar concentration of vesicular cholesterol increased ( r = .42, P < .01). The cholesterol saturation indices, total bile lipid concentration, and proportion of biliary deoxycholate were independent determinants of the molar concentration of cholesterol in vesicles. We conclude that relative increases in the percentage of deoxycholic acid and in bile lipid concentration, favor the partitioning of cholesterol into vesicles. In turn, this leads to an increase in the vesicular cholesterol : phospholipid molar ratio and thus to a decrease in the cholesterol microcrystal nucleation time.

Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile

Little is known about the effects of biliary deoxycholic acid on the partitioning of biliary cholesterol between vesicles and micelles and on the rate of nucleation of cholesterol microcrystals, key steps in gallstone formation. Therefore, 43 samples of fresh gallbladder bile were obtained from a heterogeneous group of patients with and without stones. Univariate and multivariate analyses were then applied to determine the inter-relationships between biliary cholesterol saturation, total lipid concentration, and bile acid species and (1) the distribution of biliary cholesterol between vesicles and micelles and (2) the cholesterol microcrystal nucleation time. The percentage of deoxycholic acid in bile was shown to be linearly related to the cholesterol saturation index (r = .54; P < .001), the vesicular cholesterol:phospholipid molar ratio (r = .53; P < .001), and the molar concentration of cholesterol in the vesicles (r = .59; P < .001). The mean proportion of biliary deoxycholic acid conjugates was also greater in patients with rapid nucleation times (23.4 +/- SEM 1.1%) than in those with slow nucleation times (17.3 +/- 1.9%; P < .05). As total bile lipid concentration increased, the proportion of total biliary cholesterol in vesicles decreased (r = .53; P < .001), whereas the molar concentration of vesicular cholesterol increased (r = .42, P < .01). The cholesterol saturation indices, total bile lipid concentration, and proportion of biliary deoxycholate were independent determinants of the molar concentration of cholesterol in vesicles. We conclude that relative increases in the percentage of deoxycholic acid and in bile lipid concentration, favor the partitioning of cholesterol into vesicles. In turn, this leads to an increase in the vesicular cholesterol:phospholipid molar ratio and thus to a decrease in the cholesterol microcrystal nucleation time.

The role of bile composition and physical chemistry in the pathogenesis of octreotide-associated gallbladder stones

Background/Aims: 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. Methods: 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 μg/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. Results: 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). Conclusions: 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.

Composition of biliary lipids and kinetics of bile acids after cholecystectomy in man

Postcholecystectomy biliary lipid composition and bile acid kinetics were studied in 24 women and 4 men. Hepatic bile was collected periodically for as long as 4 months without interrupting the enterohepatic circulation and without infecting the biliary system. In 23 patients with cholesterol gallstones, fasting biliary cholesterol made up 10.2% of total lipids in the steady state; in 5 patients with bilirubinate stones, saturation of fasting hepatic bile with cholesterol was lower (8.7% of total lipids). The percentage of deoxycholic acid after cholecystectomy was not higher than that of seven healthy, noncholecystectomized controls. Postcholecystectomy studies of diurnal variation of biliary lipids (7 patients) showed that postprandial hepatic bile had a significantly lower cholesterol saturation than fasting bile. Pool sizes of cholic and chenodeoxycholic acids were low (average 0.4 g/70 kg, each); total synthesis for both bile acids was normal (average 460 mg/day/70 kg), but fractional turnover rates of the two primary bile acids increased after cholecystectomy, probably due to more frequent recycling of the small bile acid pool.

Patterns of Bile Acids and Microflora in the Human Small Intestine

Bile acids were studied in the intestinal content of 12 control subjects, 8 patients with ileal resection, and 3 patients with intestinal stasis. Intestinal fluids were aspirated from the duodenum after cholecystokinin stimulation and from four additional sites in the small intestine, 50 cm apart, 4 to 7 hr after a meal. The total concentrations of bile acids and their conjugates were determined by enzymatic assay. The distribution of bile acids was measured by gas liquid chromatography. The results were examined in relation to the intestinal microflora cultured from the same samples, described in a separate paper. Bile acid concentrations were lower in the duodenum of patients with ileal resection. Throughout the small intestine there was a marked decrease in bile salts conjugated with taurine and a smaller decrease of glycine-conjugated bile salts. In addition, the percentage of chenodeoxycholic acid was clearly increased at all levels, while the percentage of deoxycholic acid was decreased. In the 2 patients with any deoxycholic or lithocholic acid, anaerobic organisms, such as bacteroides, were abundant in most areas in the small intestine. In the 3 patients with intestinal stasis the total duodenal bile acid concentrations were similar to those in the control subjects, but throughout their small intestine there was a modest decrease in taurine-conjugated bile acids and a definitely increased proportion of deoxycholic and lithocholic acids. The proportion of unconjugated bile acids was not clearly increased in any patient studied.