The role of low density lipoprotein (LDL) receptors in the pathogenesis of hereditary and acquired forms of hypercholesterolemia has been investigated in vivo by simultaneously determining total and receptor-independent LDL catabolism with "MI-labeled LDL and "'I-labeled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL, determined as the difference between the turnover of 125I and 1311, was found to be virtually absent in two homozygotes with familial hypercholesterolemia and markedly reduced in a hypothyroid patient. Treatment of the latter with L-thyroxine markedly stimulated receptor-mediated catabolism and reduced LDL levels as did cholestyramine administration in a control subject. Reduction of LDL levels by plasma exchange in a control subject and homozygote had no such effect. These results demonstrate the existence of an intrinsic and almost total defect of receptor-mediated LDL catabolism in homozygous familial hypercholesterolemia and demonstrate an analogous but reversible abnormality in hypothyroidism.Hypocatabolism of low density lipoprotein (LDL) characterizes both familial hypercholesterolemia (FH) and hypothyroidism (1, 2). Studies with cultured fibroblasts have revealed an inherited deficiency of LDL receptors in FH, more marked in homozygotes than in heterozygotes, which has been assumed to be the cause of the catabolic defect in vivo (3, 4). Stimulation of high affinity binding and degradation of LDL in normal fibroblasts by triiodothyronine (5) suggests the possibility of an analogous but acquired deficiency of LDL receptors in hypothyroidism. Recently, Shepherd et al. (6) provided in vivo evidence of a decrease in receptor-mediated LDL catabolism in FH heterozygotes, using the technique developed by Mahley et al. (7). This involves the simultaneous administration of 125I-labeled native LDL (l2I-LDL) and '311-labeled LDL (131I-LDL) treated with 1,2-cyclohexanedione (Chd); the latter modification blocks arginine residues and thus inhibits binding of LDL to receptors on fibroblasts and smooth muscle cells (8). Using this approach, we have been able to demonstrate the virtual absence of receptor-mediated LDL catabolism in homozygous FH and the presence of a similar but reversible abnormality in hypothyroidism. Our observations, published previously only as abstracts (9, 10), help validate a novel method ofquantitating receptor-mediated LDL catabolism and illustrate the importance of that pathway in regulating serum cholesterol levels in man.SUBJECTS AND METHODS Two male FH homozygotes (M.M., D.L.), both ages 16 years and with receptor-defective fibroblasts on established criteria (11), whose clinical details are given elsewhere (12), were studied after having discontinued cholesterol-lowering drugs and plasma exchange for 5-6 wk. A 30-year-old woman (E. P.) with overt primary hypothyroidism was studied twice, before and after being rendered euthyroid by a 6-wk treatment with L-thyroxine (0.2 mg/day). Two of the authors, both normolipidemic men, aged 34 and 47, act...

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1. The lipids and lipoproteins of lymph obtained from the dorsum of the foot were examined in seven human subjects. 2. The concentration of total cholesterol in lymph was about one-tenth that in plasma and was significantly correlated with the plasma total cholesterol concentration. The ratio of esterified to total cholesterol in lymph was similar to that in plasma. 3. Triglyceride was detectable in lymph, but the concentration was less than one-tenth that in plasma and was unrelated to the plasma triglyceride concentration. 4. No lipase activity was detectable in lymph, either before or after intravenous injection of heparin. 5. Cholesterol-esterifying activity was detected in four samples of lymph. 6. The major lipoprotein antigens of human plasma (apo-A, apo-B and apo-C) were present in whole lymph, but their distribution in fractions of different density was different from that in plasma. 7. [14C]Cholesterol, injected intravenously, appeared in lymph within 30 min of the injection, indicating that some of the cholesterol in lymph is derived directly from plasma. 8. At intervals greater than 29 days after a single intravenous injection of [14C]-cholesterol, the specific radioactivity of lymph cholesterol was greater than that of plasma cholesterol, indicating that some of the cholesterol in lymph is derived from tissue pools of cholesterol with slow turnover.

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suMMARY The effectiveness of repeated plasma exchange with 2 to 4 litres of plasma protein fraction as long-term treatment for familial hypercholesterolaemia has been evaluated in six severely affected patients receiving conventional cholesterol lowering treatment. Cell-separator mediated exchange at monthly intervals for one to two years reduced mean serum cholesterol levels from 18 5 mmol/I (715 mg/dl) to 12-4 mmol/l (480 mg/dl) in two female homozygotes but failed to influence xanthomata or prevent a two-to threefold increase in their left ventricular aortic systolic pressure gradients. More effective reduction of mean serum cholesterol levels from 15 7 mmol/l (608 mg/dl) to 8-6 mmol/l (333 mg/dl) in two male homozygotes by plasma exchange at fortnightly intervals for two to three years was accompanied by resolution of xanthomata and by stabilisation of aortocoronary lesions. In two male heterozygotes with angina, coronary angiographic appearances were unaltered or improved after one to two years of thrice-monthly plasma exchange, which reduced mean serum cholesterol levels from 6-4 mmol/I (248 mg/dl) to 4 7 mmol/I (182 mg/dl). We conclude that plasma exchange every one to two weeks, combined with oral nicotinic acid and/or cholestyramine, retards the rate of progression of atheroma in homozygotes and possibly induces regression in heterozygotes.Familial hypercholesterolaemia is a dominantly inherited defect of beta-or low-density lipoprotein metabolism which affects approximately 1 in 500 persons in Britain' and North America.2 The great majority of affected subjects are heterozygotes in whom the disorder is characterised by hyperbetalipoproteinaemia (type II hyperlipoproteinaemia) from birth, appearance of tendon xanthomata in early adult life, and the premature onset of coronary heart disease. Men