Disorders of bile acid metabolism in cholesterol gallstone disease.

Abstract

The aim of the study was to evaluate the metabolism of individual bile acids in patients with cholesterol gallstone disease. Therefore, we determined pool size and turnover of deoxycholic (DCA), cholic (CA), and chenodeoxycholic acid (CDCA) in 23 female gallstone patients classified according to their gallbladder function and in 15 healthy female controls. Gallstone patients had normal hepatic bile acid synthesis, but, depending on gallbladder function, differed with respect to turnover and size of the bile acid pools: Patients with well-emptying gallbladder (group A, n = 9) had enhanced turnover and reduced pools of CA (-46%; P < 0.01 vs. controls) and CDCA (-24%; P < 0.05), but normal input and size of the DCA pool. With reduced gallbladder emptying (< 50% of volume; group B, n = 6), turnover and pools of CA, CDCA, and DCA were similar as in controls. Patients with loss ofgallbladder reservoir (group C, n = 8) had increased input (+100%; P < 0.01) and pool size of DCA (+45%; P = 0.07) caused by rapid conversion of CA to DCA, while the pools of CA (-71%; P < 0.001 vs. controls) and CDCA (-36%; P < 0.05) were reduced by enhanced turnover. Thus, in patients with cholesterol gallstones, the pools of primary bile acids are diminished, unless gallbladder emptying is reduced. Furthermore, in a subgroup of gallstone patients, who had completely lost gallbladder function, the CA pool is largely replaced by DCA owing to rapid transfer of CA to the DCA pool. This probably contributes to supersaturation of bile with cholesterol. (J. Clin. Invest. 1992. 90:859-868.) Key words: bile acid metabolism * cholesterol gallstone disease * deoxycholic acid -gallbladder emptying . cholesterol saturation of bile IntroductionIn most nonobese patients with cholesterol gallstones, the pools of cholic acid (CA)' and chenodeoxycholic (CDCA) are reduced ( 1-6), and deoxycholic acid (DCA) is often increased in bile (7). Both changes could contribute to supersaturation of bile with cholesterol ( 1, 7, 1. Abbreviations used in this paper: CA, cholic acid; CCK, cholecystokinin; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FTR, fractional turnover rate. circulation (9), the increase ofDCA by raising biliary secretion of cholesterol ( 10).The small pools ofCA and CDCA may be caused by a small gallbladder reservoir ( 1 1), by enhanced turnover (2, 5), or by inhibition of bile acid synthesis by an oversensitive feedback mechanism ( 1 2) or by elevated levels of DCA ( 13,14). An increased fraction ofDCA in bile could be caused by high input and large pool size of DCA. CA is nearly completely 7a-dehydroxylated to DCA by anaerobic bacteria in the colon (7,15,16), but only 30-40% of this DCA is absorbed from the intestine ( 17 ). The DCA pool could be expanded by increased input of DCA owing to increased synthesis ofthe precursor CA or to an increased fraction of CA transferred to the DCA pool.It is still unclear which of the above factors account(s) for the reduction in CA and CDCA pool size and which for an increase in biliary DCA. ...

Reduced ileal expression of OSTα-OSTβ in non-obese gallstone disease

“…There is consensus that in most gallstone patients, the proportion of deoxycholate in bile is increased (19,20) and the bile acid pool size is diminished (19,21). In experimental animals, deoxycholate is a strong inhibitor of bile acid synthesis (22), compatible with a low rate of bile acid formation in some gallstone patients (23).…”

“…In experimental animals, deoxycholate is a strong inhibitor of bile acid synthesis (22), compatible with a low rate of bile acid formation in some gallstone patients (23). On the other hand, the effect of deoxycholate in humans is controversial (24,25) and most studies in gallstone patients report an increase in both bile acid turnover (19,26) and synthesis (27,28). Increased biliary deoxycholate levels, bile acid turnover, and synthesis may all occur as a response to an increased ileal loss of bile acids.…”

Apical sodium bile acid transporter and ileal lipid binding protein in gallstone carriers

“…Furthermore, evidence is available that c) alterations of intestinal bile acid recycling (5), d) prolonged intestinal transit (5), e) altered bile salt synthesis, and f ) gallbladder motility defects are important in human gallstone formation and biliary pain (6). Accordingly, the pools of cholic and chenodeoxycholic acid have been found to be reduced in most normal weight gallstone patients, whereas that of deoxycholic acid is often increased (7). Cholic acid is almost completely 7-a-dehydroxylated to deoxycholic acid by anaerobic bacteria in the colon (8), and z30-40% of this deoxycholic acid is absorbed from the intestinal lumen (7).…”

“…Accordingly, the pools of cholic and chenodeoxycholic acid have been found to be reduced in most normal weight gallstone patients, whereas that of deoxycholic acid is often increased (7). Cholic acid is almost completely 7-a-dehydroxylated to deoxycholic acid by anaerobic bacteria in the colon (8), and z30-40% of this deoxycholic acid is absorbed from the intestinal lumen (7). The expansion of the deoxycholic acid pool observed in gallstone patients (7) could possibly result from increased cholic acid synthesis, small intestinal spill of cholic acid into the colon, bacterial overgrowth, or a change in bacterial flora favoring cholic acid deconjugation.…”

Ebselen Protects against the Reduction in Levels of Drug‐Metabolizing Enzymes in Livers of Rats with Deoxycholic Acid‐Induced Liver Injury

“…Man and most animal species have deoxycholic acid in their enterohepatic circulation. Increases in serum or biliary concentrations of deoxycholic acid have been found in patients with gallstones (Berr et al 1992), colon cancer and adenomas (Bayerdorffer et al 1993). Deoxycholic acid has a strong detergent action against the cell membranes (Miyazaki et al 1984;Scholmerich et al 1984;.…”