Lack of response to chenodeoxycholic acid in obese and non-obese patients. Role of cholesterol synthesis and possible response to ursodeoxycholic acid.
This paper describes seven patients with radiolucent gallstones in functioning gallbladders who did not respond to chenodeoxycholic acid (CDCA). Despite large doses (greater than or equal to 19 mg CDCA/kg/day), CDCA-rich bile (CDCA conjugates 70-97% of total biliary bile acids) and greater than or equal to one year's treatment, their fasting duodenal bile remained supersaturated with cholesterol and their gallstones did not dissolve. Five patients came to cholecystectomy, gallstone analysis and liver biopsy for measurement of hepatic cholesterogenesis (HMGCoAR activity). In three who stopped CDCA before surgery, the mean HMGCoAR (pmol/mg microsomal protein/min) of 50.2 was higher than in our untreated gallstone controls (32.2 +/- SEM 2.0; P less than 0.05). Two patients who took CDCA until surgery had a mean HMGCoAR of 33.5--more than twice that in CDCA-treated gallstone controls. These findings suggest that non-response to CDCA may be related to high or unsuppressed hepatic cholesterogenesis. In one patient who did not respond to CDCA, treatment with 19 mg ursodeoxycholic acid/kg/day did desaturate his bile.
D000328:Adult; D000368:Aged; D001646:Bile / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000627:therapeutic use*; D002769:Cholelithiasis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D012995:Solubility; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases