Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.
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...
Low density lipoprotein (LDL) apheresis provides a safe and effective means of treating patients with homozygous familial hypercholesterolaemia (FH). It also has a role in preventing the progression of coronary artery disease in heterozygotes and others with severe dyslipidaemia who are refractory to or intolerant of high doses of lipid-lowering drugs. Established methods involve either adsorption of apolipoprotein B-containing lipoproteins by affinity columns containing anti-apolipoprotein B antibodies or dextran sulphate, or their precipitation at low pH by heparin, in each instance after first separating plasma from blood cells with a cell separator. The most recently developed method enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate columns. All 4 methods have proved to be similarly efficient when used weekly or biweekly to lower LDL cholesterol and Lp(a) without unduly reducing HDL cholesterol. Economic constraints restrict the use of LDL apheresis to the treatment of potentially fatal disorders such as FH, where there is clear evidence of benefit compared with conventional therapy. Widening the indications to include the treatment of other dyslipidaemic disorders such as steroid-resistant nephrotic syndrome, post-transplant donor vessel disease, stroke and prevention of re-stenosis after coronary angioplasty requires evidence from controlled trials that is currently lacking.
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