To explore the mechanisms of the profound plasma
cholesterol elevations in familial homozygous
hypercholesterolemia (type IIa),
cholesterol turnover,
sterol balance,
cholesterol absorption, and
low density lipoprotein studies were carried out under controlled dietary conditions in two sisters (aged 13 and 16).
Cholesterol turnover was prolonged. The half-life of the first exponential of the plasma
cholesterol specific activity decay curve was double that of normal adults. The rate constants for the removal of
cholesterol from pool A (KAA = 0.0652) and for the excretion of
cholesterol from the system (Kaa = 0.0197) were less than half of normal. The production rates of
cholesterol were low, only 6.30 and 6.86 mg/kg per day as measured by
cholesterol turnover and
sterol balance techniques, respectively. Fecal neutral
steroid and
bile acid excretion were 5.22 and 1.64 mg/kg per day, which is remarkably low in comparison to those of normal and heterozygous children.
Cholesterol absorption was within the upper limit of the values reported for normal adults. THE
HDL cholesterol values were extremely low (27 mg/dl) in contrast to profoundly elevated
LDL levels. The fractional catabolic rate of
LDL (0.127 per day) and the rate of synthesis and catabolism of apo-
LDL (15 mg/kg per day) were low in comparison to previously reported values in homozygotes. These composite data indicated that the definable metabolic defects of these two sisters with
homozygous familial hypercholesterolemia were the sluggish clearance of
cholesterol from the body coupled with low total body synthesis of
cholesterol.