Sex differences in the size of bile acid pools.

In view of the excess prevalence of gallstones among women and the association of gallstones with diminished bile acid pool size, we measured bile acid pools in 27 male and 25 female healthy human volunteers. The average bile acid pool in the women was significantly smaller than in the men (2.25 +/- .12 g versus 2.88 +/- .16 g; p = 0.003). Chenodeoxycholic acid pool size, computed from bile acid composition data available in 43 of these subjects, was also smaller in women than men (0.94 +/- 0.06 versus 1.22 +/- 0.07 g; p = 0.004). Age, race, and body size bore no statistically significant relationship to bile acid pool size. Biliary cholesterol saturation was positively correlated with weight and obesity and showed a significant inverse correlation with chenodeoxycholic acid pool size, but not with total bile acid pool size. These findings suggest a possible mechanism for the higher prevalence of gallstones among women.

Effect of phenobarbital on biliary lipid metabolism in normal man.

The efficacy of phenobarbital in altering biliary lipid composition in normal man was investigated by determining parameters of biliary lipid metabolism in 8 human subjects without biliary tract disease before and after oral phenobarbital administration at a dose of approximately 3 mg per kg per day for 25 to 54 days. In 8 subjects studied, phenobarbital did not produce any statistically significant changes in the following parameters: bile lipid composition, cholesterol saturation index, total bile acid pool size, daily fractional turnover rate of cholic acid, hepatic secretion rates of cholesterol, bile acids, or phospholipids, and the fraction of the total bile acid pool represented by individual bile acids. Therefore, phenobarbital is not an effective agent, at least when used alone, in inducing changes in bile lipid composition during a short term of administration in normal man. This would indicate that phenobarbital would not be a useful modality in the prevention of the development of cholesterol gallstones, but its prophylactic value in subjects with bile of higher lithogenicity cannot be predicted from these studies.

Hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity in hamsters on a lithogenic diet.

The activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme for liver cholesterol biosynthesis, has been determined in young hamsters given a diet known to produce cholesterol gallstones in this species and compared to the activity found in chow-fed hamsters. None of the hamsters fed the lithogenic diet for 15 days or less developed gallstones but 74 percent of those on the diet for 26 to 49 days had cholesterol gallstones. None of the chow-fed animals developed gallstones. The mean HMG CoA reductase activity of hamsters on the lithogenic diet at 4 to 6 hours after the onset of the dark period was 20 times greater than in hamsters in the fasting state and 12 times that of fed hamsters on the chow diet. These greatly elevated enzyme activities were found as early as 2 to 15 days on the lighogenic diet and thus long before the gallstones appeared. The percentage of the bile acid pool represented by chenodeoxycholic acid was significantly higher, and that cholic acid correspondingly lower on the gallstone-inducing diet. This shift in bile acid composition may have contributed to gallstone formation. No significant accumulation of cholesterol was noted in liver or carcass. Increased synthesis of cholesterol induced by the greatly stimulated enzyme activity in hamsters on the lithogenic diet could account for the increased secretion of cholesterol in bile noted by others with subsequent supersaturation of gallbladder bile with respect to cholesterol, and then gallstone formation.

Effects of fasting on bile acid metabolism and biliary lipid composition in man.

The effects of a four to six day fast on gallbladder bile lipid composition, bile acid pool size, bile acid composition, and cholic acid metabolism have been determined in normal human subjects. Total bile acid pool size and cholic acid pool size were measured before and after fasting by a one-sample technique previously validated in our laboratory. The rate of synthesis of cholic acid and its fractional turnover rate before fasting were measured using standard techniques. Estimates of fasting cholic acid synthesis rate and fractional turnover rate were calculated as daily averages from the change in cholic acid pool size, in combination with the change in cholic acid specific activity, during the fasting period. Since these estimates are approximate, a maximum value for cholic acid synthesis rate during fasting was also determined by assuming that the entire change in cholic acid specific activity during the fasting period occurred instantaneously. The molar percent of cholesterol in gallbladder bile was reduced in eight of nine subjects after a four to six day fast (p less than .01; mean reduction 30.5%). The molar percents of bile acid and phospholipid were not significantly altered by fasting. The cholesterol saturation index, calculated on the basis of these data, was reduced by an average of 31.0% after a four to six day fast (p less than .02). The average daily cholic acid synthesis rate and the fractional turnover rate were reduced in all six subjects on whom isotope kinetic studies were carried out. The mean decrease in synthesis rate was 68.5% (p less than .05; range 55.2-79.8%) while the mean decrease in fractional turnover rate was 64.4% (p less than .05; range 30.2-100%). Reduction in synthesis rate was confirmed by the determination of maximum fasting synthesis of cholic acid, which averaged 61.1% lower than synthesis in the fed period. Fasting had no consistent effect on total bile acid pool size, cholic acid pool size, or bile acid species composition.

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.

PIP: The reported association between use of oral contraceptives (0C) and gallbladder disease led to a study of the effects of OCs on lipid compos ition of gallbladder bile on 22 healthy women between the ages of 19 and 39. Subjects were observed during routine OC use and during normal medication-free cycles. Cholesterol saturation was significantly higher in gallbladder bile during OC use than during normal menstrual cycles (125 versus 92%, p less than .001). During daily ingestion of OCs the p roportion of cholic acid was significantly higher (50 versus 41%, p less than .001) and the proportion of chenodeoxycholic acid significantly lower (35 versus 42%, p less than .001) than during the normal menstrual cycle. These data show that routine administration of OCs induce alterations in the composition of human gallbladder bile and suggest a biochemical basis for the increase in gallbladder disease observed among women ingesting OC steroids.

Determination of bile acid pool size in man: a simplified method with advantages of increases precision, shortened analysis time, and decreased isotope exposure.

A simplified isotope dilution method for measurement of the bile acid pool size in normal subjects is described and compared with the traditional method of Lindstedt (Acta Physiol. Scand. 40: 1-9, 1957). Advantages of this simplified method include a four- to eightfold reduction of isotope dose, facilitation of analytical procedures, and a reduction in the required number of duodenal intubations. In 15 human subjects who had two separate estimates of pool size by this method, precision averaged 2.6 percent. In 16 comparisons, pool size measured by this method averaged 13.7 percent higher than simultaneous estimates by the Lindstedt method. Factors affecting accuracy (as opposed to precision) in both methods are discussed.