Kinetics of the enterohepatic circulation during fasting: Biliary lipid secretion and gallbladder storage

In both experimental animals and humans, cholesterol saturation of bile increases by varying degrees during interruption of the enterohepatic circulation. Thus, dynamic aspects of the enterohepatic circulation during fasting-including gallbladder filling and emptying, and fasting outputs of biliary lipids-should be important considerations for the pathogenesis of gallstones. Therefore, for the present report, we developed and validated techniques of estimating storage capacity of the gallbladder and hepatic outputs of biliary lipids during fasting. These new methods require the use of bilirubin and [¹⁴C]cholic acid as "endogenous" and "exogenous" bile markers, respectively; with them, amounts of bile acids in the nocturnal gallbladder may be determined and related to total bile acid pool size. In studies on 6 cholecystectomized subjects, we showed that hourly outputs of bilirubin were constant throughout the day, so that in addition to monitoring gallbladder function, this marker may be used to calculate nocturnal outputs of biliary lipids. In 7 subjects with gallstones and radiologically functioning gallbladders, measurements of nocturnal storage of bile acids in the gallbladder preoperatively (bilirubin marker method) and intraoperatively ([¹⁴C]cholic acid method) gave comparable results. These studies were extended to include 14 control subjects without gallstones, 12 subjects with cholesterol gallstones, and 6 subjects with pigment stones. Mean pool size of bile acids in subjects with cholesterol stones was smaller (1818 ± SEM 278 mg) than that in controls (2624 ± 524 mg) or in those with pigment stones (2422 ± 481 mg); however, these differences were not statistically significant. Percentage of the total bile acid pool stored overnight in the gallbladder also was not different in the three groups, being 58 ± 7% for controls, 47 ± 6% for cholesterol, and 54 ± 8% for pigment stone subjects. Volumes of gallbladder contents (bile plus gallstones) were similar in the 2 groups with stones. While subjects with cholesterol cholelithiasis had the highest cholesterol saturation of bile, no inverse correlation could be found between either total bile acid pool or nocturnal gallbladder bile acid mass, and saturation indices of bile for the groups as a whole. During fasting, hepatic bile became increasingly saturated because of a relatively well-maintained secretion of cholesterol. The mean fasting output was 67 ± 3% of the mean 24-hr secretion compared to 51 ± 3% and 54 ± 4%, respectively, for bile acids and phospholipids. The nocturnal increase in biliary cholesterol:phospholipid molar ratio was variable from subject to subject, and the degree of this variability was crucial in determining the subsequent change in bile saturation.