Chapter 119

## Abstract

Abstract

1. Patients with type III hyperlipoproteinemia have elevated concentrations of both plasma cholesterol and triglyceride. A biochemical characteristic of the disorder is the occurrence of β-migrating VLDL (β-VLDL), which are cholesterol-enriched remnants of both intestinal chylomicrons and hepatic VLDL. The β-VLDL are enriched in a variant form of apo E, which, in type III hyperlipoproteinemic subjects, is dysfunctional.

2. Clinical features of the disorder are varied. Many type III subjects have cutaneous xanthomas, particularly tuberoeruptive or tuberous xanthomas and xanthomas of the palmar creases (xanthoma striata palmaris); the latter have not been identified in any other disorder. These patients have a high incidence of premature coronary and (especially) peripheral atherosclerosis. In the most common form of the disease, overt hyperlipidemia is only rarely manifested before adulthood. Type III subjects frequently have other disorders that exacerbate the hyperlipoproteinemia.

3. Apolipoprotein E is a polymorphic protein that results from the existence of multiple alleles at a single gene locus and from varying posttranslational sialylation. The genetically determined polymorphism of apo E has a significant impact on normal variations in lipid, lipoprotein, and apolipoprotein levels in the human population. The primary molecular defect in most patients with type III hyperlipoproteinemia is the presence of a mutant form of apo E (apo E-2) that differs from normal apo E (apo E-3) by only a single amino acid substitution (cysteine for arginine at residue 158). The apo E-2 variant binds poorly to low-density lipoprotein receptors and is associated with a recessive mode of inheritance of type III hyperlipoproteinemia. Other rare forms of mutant apo E causing type III hyperlipoproteinemia appear to be associated with dominant inheritance.

4. The normal catabolism of remnant lipoprotein particles, which is directed by apo E, is altered in type III hyperlipoproteinemia. The presence of the defective apo E results in the accumulation of chylomicron and VLDL remnants (β-VLDL) in plasma. These particles in turn have a propensity for uptake by macrophages in peripheral tissues. As a result of massive cholesterol deposition, these macrophages become foam cells, which may be the progenitors of cholesterol-laden cells in the atherosclerotic lesion.

5. In the recessive form of the disorder, the development of overt hyperlipidemia requires the inheritance of two alleles for the mutant apo E [E-2(Arg 158 → Cys)]. The occurrence of the defective alleles is necessary but not usually sufficient to induce the type III hyperlipoproteinemia. Most E-2/2 subjects are either normolipidemic or even hypocholesterolemic. Thus, the development of the recessive form of the overt hyperlipidemia involves other genetic, hormonal, or environmental influences that, in combination with the defective receptor binding of apo E, precipitate the development of the hypertriglyceridemia and hypercholesterolemia. The secondary factors include hypothyroidism, low-estrogen conditions, obesity, diabetes, and age.

6. In the dominant form of the disorder, subjects possessing a single allele for one of the rare variants of apo E have the overt hyperlipidemia, presumably from birth. Secondary genetic, hormonal, or environmental factors usually are not required to precipitate the accumulation of remnant lipoproteins in the plasma, but secondary factors can sometimes modulate the severity of the disorder.

7. Diagnosis of type III hyperlipoproteinemia is indicated by increased plasma cholesterol and triglyceride, the presence of β-VLDL, xanthomas (especially palmar xanthomas), premature vascular disease (especially of the peripheral arteries), and usually the apo E phenotype E-2/2. The diagnostic hallmark of this disorder is the presence of apo E that is defective in binding to lipoprotein receptors.

8. Type III hyperlipoproteinemia usually responds well to therapy. Dietary control is the preferred treatment, but a drug regimen may also be required to lower lipid levels. Useful drugs for treatment of type III hyperlipoproteinemia include nicotinic acid, fibric acid derivatives, and HMG-CoA reductase inhibitors. In particular, gemfibrozil seems to be the drug of choice in treating this disorder.

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