Lipid Composition Of Gallbladder Bile Research Articles

Gallstone Formation Follows a Different Trajectory in Bariatric Patients Compared to Nonbariatric Patients.

Since obese patients form cholesterol gallstones very rapidly after bariatric surgery, in patients who did not form gallstones during preceding years, we hypothesized that gallstone formation follows a different trajectory in bariatric patients compared to nonbariatric patients. We therefore analyzed the lipid composition of gallbladder bile derived from 18 bariatric gallstone patients and 17 nonbariatric gallstone patients (median (IQR) age, 46.0 (28.0–54.0) years; 33 (94%) female) during laparoscopic cholecystectomy using an enzymatic and lipidomics approach. We observed a higher concentration of total lipids (9.9 vs. 5.8 g/dL), bile acids (157.7 vs. 81.5 mM), cholesterol (10.6 vs. 5.4 mM), and phospholipids (30.4 vs. 21.8 mM) in bariatric gallstone patients compared to nonbariatric gallstone patients. The cholesterol saturation index did not significantly differ between the two groups. Lipidomics analysis revealed an interesting pattern. Enhanced amounts of a number of lipid species were found in the gallbladder bile of nonbariatric gallstone patients. Most striking was a fivefold higher amount of triglyceride. A concomitant ninefold increase of apolipoprotein B was found, suggesting secretion of triglyceride-rich lipoproteins (TRLs) at the canalicular pole of the hepatocyte in livers from nonbariatric gallstone patients. These findings suggest that gallstone formation follows a different trajectory in bariatric patients compared to nonbariatric patients. Impaired gallbladder emptying might explain the rapid gallstone formation after bariatric surgery, while biliary TRL secretion might contribute to gallstone formation in nonbariatric patients.

The role of dietary fats in the pathogenesis of gallstones.

Gallstone disease is exceptionally common, occurring especially in Western populations, with cholesterol gallstones predominating. Currently, it is believed that one of the essential factors in the pathogenesis of cholesterol gallstones is a physical-chemical event that results primarily from alterations in the lipid composition of gallbladder bile. Cholesterol supersaturation is due principally to excessive secretion of cholesterol into the bile. Several biochemical defects, as well as diet, might cause hypersecretion of cholesterol. The precise effects of diet on cholesterol supersaturation of bile have not been clearly established, although epidemiological, clinical, and animal studies indicate that diet plays an important role in cholesterol gallstone formation. This review summarizes current information on the role of dietary fat in the modulation of cholesterol gallstone formation.

Effect of Terminal Ileal Transposition on Gallbladder Bile Composition Following Proctocolectomy

Enterohepatic circulation of bile acid is impaired and the percentage of secondary bile acids in bile decreases after proctocolectomy and ileo–anal anastomosis. Moreover, the site-specific function and morphology of the terminal ileum are likely to be damaged by acute and chronic inflammation because the ileum is being used as a reservoir in this procedure. A jejunal segment was interposed between the terminal ileum and the anus to spare the terminal ileum from being used as a reservoir following proctocolectomy in dogs. We performed this study to investigate the effects of this procedure on gallbladder bile lipid composition. Adult mongrel dogs underwent either terminal ileal transposition procedure (n= 7) or conventional ileo–anal anastomosis (n= 7) following two-stage proctocolectomy. The animals were laparotomized and gallbladder bile was collected 12 weeks later. In the terminal ileal transposition group, the total bile acid concentration significantly decreased (P< 0.01), while the secondary bile acid percentage did not. In the conventional group, the percentage of secondary bile acid significantly decreased (P< 0.05), while the total bile acid concentration remained unchanged. Proximal transposition of the terminal ileum may have an advantage in preserving the percentage of secondary bile acid in gallbladder bile. This procedure effects bile lipid metabolism differently than conventional ileo–anal anastomosis.

Effect of Chronic Ursocholic Acid Administration on Bile Lipid Composition and Bile Acid Pool Size in Gallstone Patients

We assessed the effect of chronic (4-6 weeks) administration of ursocholic acid (UCA) (15 mg/kg/day), a natural bile acid with poor detergent capacity, on biliary lipid composition of gallbladder bile (n = 26) and bile acid pool size (n = 5) in gallstone patients. During treatment the biliary molar percentage UCA increased from trace values to 28% (p less than 0.001). This effect was accompanied by an increase in molar percentage deoxycholic acid from 16% to 33% (p less than 0.001). Total bile acid pool size remained unchanged during UCA administration; cholic acid and chenodeoxycholic acid pool sizes decreased from 1.0 to 0.6 mmol (p less than 0.05) and from 1.6 to 0.9 mmol (p less than 0.05), respectively. The molar percentage cholesterol of gallbladder bile decreased from 9.8% to 7.0% (p less than 0.001) during UCA, but bile remained supersaturated with cholesterol in 21 patients. The weak effect on biliary lipid composition and the increase of potentially toxic deoxycholic acid in bile suggest that UCA is unlikely to replace ursodeoxycholic and chenodeoxycholic acid for medical treatment of gallstones.

Biliary lipid composition in patients with cystic fibrosis.

Lipid composition of gallbladder bile was determined in 20 patients with cystic fibrosis (CF) (9 females and 11 males, ranging in age from 3 to 18 years). The results were compared with 47 normal subjects matched for age, sex, and pubertal stage. In patients with CF, bile was undersaturated with cholesterol before puberty in both sexes and no differences with normal controls could be observed. After puberty, a similar increase in cholesterol saturation was noted in females with CF (85 +/- 15% vs. 130 +/- 38%, p less than 0.01) and normal controls (82 +/- 11% vs. 138 +/- 31%, p less than 0.01). No change in cholesterol saturation could be observed in male patients and controls after puberty. Molar percentage of chenodeoxycholic acid (CDCA) was lower (p less than 0.05) in postpubertal females (31 +/- 9%) and males (36 +/- 7%) with CF compared to controls (42 +/- 8% and 40 +/- 5%, respectively), while cholic acid (CA) was higher in all patients with CF. In females with CF, lithocholic acid (LCA) increased after puberty (2.2 +/- 0.8% vs. 5.3 +/- 2.6%, p less than 0.05) and was higher compared to controls (2.2 +/- 0.8%, p less than 0.001). An increase was also noted for deoxycholic acid (DCA) in postpubertal females with CF (1.7 +/- 2.6% vs. 10.8 +/- 7%, p less than 0.05), but it was lower in both sexes after puberty than in respective controls. The present results suggest that cholesterol saturation of bile in patients with CF is not different from respective controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of tauroursodeoxycholate feeding, with or without taurine supplementation on hepatic bile acids and cholesterol metabolism in the hamster

This study reports the effect of short-term tauroursodeoxycholic acid (TUDCA) and of TUDCA with addition of taurine on the lipid composition of gallbladder bile, on cholesterol and bile acid synthesis and intestinal excretion, in the female hamsters. After either one or two weeks, the percentage of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in bile of treated hamsters significantly increased. Both treatments (TUDCA alone or TUDCA + taurine) decreased the percentage of cholic acid without affecting 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase or cholesterol 7 alpha-hydroxylase activities. Sterol and bile acid content of the feces collected during the period of the study did not show any difference. Bile acid glycine to taurine conjugation ratio (G/T ratio) in TUDCA treated animals was significantly higher in respect to controls after only one week of treatment. On the contrary, bile acid G/T ratio significantly decreased in the group of animals supplemented with taurine, but only after two weeks of treatment.

Biliary cholesterol saturation in non-obese women and non-obese men before and after puberty.

The lipid composition of gallbladder bile was determined in forty-seven normal, non-obese subjects (twenty females and twenty-seven males) without gallstones ranging in age from seven months to twenty-nine years. Before puberty, bile was undersaturated with cholesterol in both sexes to the same extent. After puberty a marked increase in cholesterol saturation was observed in females but not in males (138% vs 88%; P less than 0.01). A significant correlation between age and cholesterol saturation could be observed in females (r = 0.546; P less than 0.05) but not in males. In addition a significant correlation between absolute weight and cholesterol saturation in all females (r = 0.827; P less than 0.001) and those after puberty (r = 0.659; P less than 0.05) could be demonstrated. In neither sex was saturation related to body mass index or ideal body weight. These findings suggest that saturation of bile raises in women during puberty but not in men, and this sex-related difference in cholesterol saturation probably contributes to the more common occurrence of gallstones in women than in men.

Effects of fenofibrate on biliary lipids and bile acid pool size in patients with type IV hyperlipoproteinemia

Lipid-lowering drugs, notably clofibrate, may induce a supersaturation of bile with cholesterol, thus favouring the development of cholelithiasis. In order to see whether or not fenofibrate, a clofibrate analogue, has any influence on biliary cholesterol saturation, we determined the lipid composition of gallbladder bile and the bile acid pool size in 15 patients with type IV hyperlipoproteinemia before and after 6–8 weeks of treatment with a daily dose of 300 mg of the drug. At the end of treatment plasma triglycerides were markedly decreased, whereas no detectable influence on liver cell integrity or bile excretory function could be demonstrated in any patient by comparing the pre- and post-treatment serum levels of liver enzymes, bilirubin and bile acids. The mean bile cholesterol saturation index did not significantly change and cholic acid was the only bile acid to increase significantly. In the 3 patients with an initial saturation index of less than 1, bile became supersaturated with cholesterol. However, in no case were the limits of the metastable phase for cholesterol solubility in bile exceeded. Though only long-term prospective studies may give a definitive answer about the lithogenic potential of fenofibrate, our data on gallbladder bile composition in patients with type IV hyperlipoproteinemia indicate that it is not very likely that fenofibrate administration will increase the risk of gallstone formation in severely hyperlipidemic patients.

Influence of probucol on cholesterol and lipoprotein metabolism in man.

The mechanisms for the hypocholesterolemic action of probucol were examined in 17 patients with various levels of plasma cholesterol and triglycerides (TG). All the patients were studied on a metabolic ward. The first period of 6 weeks was for control. Thereafter, probucol was started, and after 2-6 months of drug treatment, the patients were readmitted for another 6-week period for a repeat study. During treatment with probucol, the cholesterol decreased in total plasma by an average of 12%, in low density lipoproteins (LDL) by 11%, and in high density lipoproteins (HDL) by 9%. The TG in total plasma and in very low density lipoproteins (VLDL) remained unchanged during probucol treatment. Turnover of low density lipoprotein apoprotein (apoLDL) was estimated following injection of 125I-labeled apoLDL. Probucol increased the fractional catabolic rate (FCR) for apoLDL by an average of 23%, but did not change apoLDL synthesis. The drug produced no consistent changes in fecal excretion of cholesterol (neutral steroids) and bile acids, in cholesterol absorption, in lipid composition of gallbladder bile, in biliary secretion of cholesterol and bile acids, or in the activities of lipoprotein lipase and hepatic lipase. These data show that probucol lowers LDL by increasing its catabolism. This effect appears to be independent of any changes in metabolism of cholesterol or bile acids.

The possible role of free fatty acids in the pathogenesis of cholesterol gallstones in man

The lipid composition of hepatic and gallbladder bile was examined in 20 patients with cholesterol gallstones and in 20 control subjects. Lipid fractions other than bile salts, phospholipids and cholesterol were found to be present, i.e., sterol esters, non-identified fractions and, above all, free fatty acids. The latter probably originated from biliary phospholipids via activity of phospholipases, present in the gallbladder wall. No significant difference in amount and pattern of free fatty acids and phospholipids was found in hepatic bile between patients with gallstones and controls. On the contrary, we observed relevant differences in the lipid composition of gallbladder bile. In this way, we consider that the bile becomes lithogenic inside the gallbladder as a consequence of release of free fatty acids, particularly if these are constituted by saturated chains. In fact, these can compete with cholesterol in the solubilization in biliary micelles. On the other hand, free fatty acids can be directly toxic for the gallbladder wall and produce a cholecystitis.

Addition of fiber (wheat bran, bassorin) to the standard food does not influence biliary lipid composition in piglets.

The influence of an additional fiber diet on biliary lipid composition of gallbladder bile was studied in 12 piglets. In addition to the standard feed wheat bran was given for 6 weeks and bassorin for 2 weeks to each of four piglets. A group of four piglets served as controls. Gallbladder bile was obtained by ultrasonically guided puncture of the gallbladder. The results showed no significant alteration of bile acids, lipid composition, and lithogenity of bile for either of the diets. These findings are interpreted in that way that the normally high basic fiber content of the food of piglets does not allow a further decrease of the lithogenic index by addition of wheat bran or bassorin. This conclusion would mean that the basic fiber diet should be known before therapeutic trials with fiber diets are planned or interpreted.

Effects of rifampin on biliary lipids in humans.

Because the action of rifampin induces hepatic microsomal enzymes, a study was carried out in four patients to determine whether this drug alters the composition of biliary lipids. Several different measurements were made while patients were both on and off rifampin therapy for various infective processes. These measurements included multiple determinations of lipid composition of gallbladder bile, the relative proportions f individual bile acids, and kinetics of cholic acid and chenodeoxycholic acid. In all four patients, the saturation of gallbladder bile increased during rifampin treatment, and the bile consistently became supersaturated. The relative portions of chenodeoxycholic acid and cholic acid were essentially unchanged by treatment, but total synthesis of bile acids increased in three tested patients with rifampin therapy. These results indicate that rifampin increases saturation of bile with cholesterol, but this increase is not due to a reduction in bile acid production.

Prolongation of intestinal transit and expansion of bile acid pools by propantheline bromide

Because of alterations in bile acid metabolism known to accompany surgical vagotomy, we assessed the effect of medical cholinergic blockade on bile acid metabolism. Five normal volunteers were studied by standard isotope dilution techniques in a control period and again after 2–3 wk of propantheline bromide (Pro-Banthine) 15 mg four times each day. Cholinergic blockade increased the mean cholic acid pool from 1230 μmol to 1860 μmol (P < 0.005) and increased mean chenodeoxycholic acid pool from 1760 μmol to 2180 μmol (P < 0.005). Mean tool bile acid pool increased from 4100 μmol in the control period to 5590 μmol on Pro-Banthine (P < 0.025). Pool size of the secondary bile acid, deoxycholic acid, did not change during Pro-Banthine treatment. As in the case of surgical vagotomy, these changes in bile acid pools were largely a result of reduction in fractional removal rate which for cholic acid averaged 0.714 day−1 in the control period and 0.451 day−1 during Pro-Banthine (P < 0.05). For chenodeoxycholic acid mean fractional removal rate in the control period was 0.411 day−1 and in the Pro-Banthine period was 0.278 day−1 (P < 0.05). For both bile acids, synthesis was not significantly altered by Pro-Banthine. Part of the mechanism of these changes may have been prolonged small bowel transit which averaged 39 min in the control period and 94 min during Pro-Banthine (P < 0.005). Gallbladder emptying rate slowed from a control mean of 0.027 min−1 to 0.020 min−1 during Pro-Banthine, but this change was not statistically significant. Gallbladder bile lipid composition was not appreciably affected by Pro-Banthine administration.

Effects of oral contraceptives on the gallbladder bile of normal women.

In view of the reported association between use of oral contraceptives and gallbladder disease, the effects of contraceptive steroids on the lipid composition of gallbladder bile were studied in 22 healthy women. Each subject was studied during routine use of oral contraceptives and also during normal menstrual cycles on no medication. Gallbladder bile was significantly more saturated with cholesterol during contraceptive therapy than during normal menstrual cycling (125 versus 92 per cent, P less than 0.001). Chenodeoxycholic acid accounted for a significantly smaller proportion (35 versus 42 per cent P less than 0.001) and cholic acid a significantly greater proportion (50 versus 41 per cent (P less than 0.001) of total bile acids during contraceptive steroid therapy. These findings show that exogenous sex steroids in doses and formulations routinely prescribed induce important alterations in the composition of human gallbladder bile, and suggest a biochemical basis for the increase in gallbladder disease observed among women using oral contraceptives.