Abnormalities of cholesterol turnover in hypercholesterolemic (type II) patients.

Cholesterol turnover was measured in 5 normal subjects and 14 familial hypercholesterolemic (Type II) patients. All patients were fed eucaloric cholesterol-free or very low cholesterol formula or mixed-food diets. They were given single doses of cholesterol-1,2-3H and cholesterol-4-14C simultaneously, one isotope intravenously (IV), and the other orally. Plasma cholesterol specific radioactivity decay curves for 3H and 14C isotopes in each patient conformed to the short-term (10 to 12 weeks) kinetics of the two-pool model. In type II patients, the total mass of cholesterol in pool A was significantly larger by about 17 Gm. (by the IV method) and 27 Gm. (by the oral method) as compared with normal subjects. The increase in size of pool A in Type II patients occurred equally in plasma and tissues comprising pool A (probably liver and intestine). The rate constant for the excretion of cholesterol from pool A was significantly reduced in the Type II patients. The rate constant for the transfer of cholesterol from pool A to pool B was also reduced in the Type II patients. Furthermore, the metabolic clearance fraction was decreased by 50 per cent as compared with normal subjects. In normal subjects and in Type II patients, the size of pool A was significantly larger by about 5 Gm. and 15 Gm., respectively, by the oral method as compared with the IV method. This difference in the size of pool A probably reflects differences in isotopic equilibration with the intestinal mucosal cholesterol pool. All other parameters of cholesterol turnover by the IV method as compared with the oral method were similar. Our results suggest that the expanded rapidly exchangeable pool of cholesterol (pool A) is due to a defect in cholesterol transport and excretion in familial hypercholesterolemia (Type II). The decreased rate of removal of cholesterol from the plasma and/or catabolism in tissues could be one important cause of familial hypercholesterolemia in man.