Chenodeoxycholic acid normalizes elevated lipoprotein secretion and catabolism in cerebrotendinous xanthomatosis.
Cerebrotendinous xanthomatosis (CTX) is a rare inherited lipid storage disease caused by a defect in bile acid synthesis in which cholesterol and its product cholestanol are deposited in neurological and vascular tissue. Therapy with chenodeoxycholic acid but not with the 7 beta-epimeric ursodeoxycholic acid is usually successful. In an untreated patient, total and low density lipoprotein (LDL) cholesterol were found to be low (134 +/- 11 and 78 +/- 8 mg/dl, respectively). The production rate (PR) and fractional catabolic rate (FCR) of very low density (VLDL) apolipoprotein B (apoB) were, however, both markedly increased (34.7 mg/kg per day and 13.7 pools/day, respectively vs. 15.1 +/- 5.0 mg/kg per day and 6.2 +/- 3.8 pools/day in controls) while the PR and FCR of LDL apoB were moderately elevated (16.3 mg/kg per day and 0.65 pools/day, respectively vs. 12.9 +/- 1.2 mg/kg per day and 0.52 +/- 0.10 pools/day in controls). After 1 month of 750 mg/day of chenodeoxycholic acid, the FCR and PR of both VLDL and LDL apoB became normal while total plasma cholesterol increased significantly to 145 +/- 18 mg/dl. In a second patient who had been receiving 750 mg/day of chenodeoxycholic acid for 6 months lipoprotein kinetics were normal. These parameters did not change when the subject was switched to 750 mg/day ursodeoxycholic acid. We postulate that cholesterol biosynthesis in CTX is derepressed by a diminished hepatic pool of chenodeoxycholic acid and that the elevated secretion of apoB is a response to the increased rate of cholesterol production.
Tint
G S
GS
Department of Medicine, VA Medical Center, East Orange, NJ 07019.
Ginsberg
H
H
Salen
G
G
Le
N A
NA
Shefer
S
S
D000328:Adult; D001927:Brain Diseases / Q000188:drug therapy / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000188:drug therapy / Q000378:metabolism; D013710:Tendons; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use; D014973:Xanthomatosis / Q000188:drug therapy* / Q000378:metabolism
D008074:Lipoproteins; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D002784:Cholesterol