The Primary Hypercholesterolemias

THE PRIMARY HYPERCHOLESTEROLEMIAS

Familial Hypercholesterolemia

Familial hypercholesterolemia is an autosomal dominant trait. Although levels of LDL tend to increase throughout childhood, the diagnosis can often be made on the basis of elevated umbilical cord blood cholesterol. In most heterozygotes, cholesterol levels range from 260 to 500 mg/dL. Triglycerides are usually normal, tendon xanthomas are often present, and arcus corneae and xan-thelasma may appear in the third decade. Coronary disease tends to occur prematurely. In homozygous familial hypercholester-olemia, which can lead to coronary disease in childhood, levels of cholesterol often exceed 1000 mg/dL and early tuberous and ten-dinous xanthomas occur. These patients may also develop elevated plaque-like xanthomas of the aortic valve, digital webs, buttocks, and extremities.

Defects of LDL receptors underlie familial hypercholester-olemia. Some individuals have combined heterozygosity for alleles producing nonfunctional and kinetically impaired receptors. In heterozygous patients, LDL can be normalized with combined drug regimens (Figure 35–2). Homozygotes and those with com-bined heterozygosity whose receptors retain even minimal func-tion may partially respond to niacin, ezetimibe, or reductase inhibitors.

Familial Ligand-Defective Apolipoprotein B-100

Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholes-terolemia of moderate severity. Tendon xanthomas may occur. These disorders are as prevalent as familial hypercholester-olemia. Response to reductase inhibitors is variable. Up-regulation of LDL receptors in liver increases endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles. Niacin often has beneficial effects by reducing VLDL production.

Familial Combined Hyperlipoproteinemia

As described, some persons with familial combined hyperlipopro-teinemia have only an elevation in LDL. Serum cholesterol is usually less than 350 mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated. It may be necessary to add niacin or ezetimibe to normalize LDL.

Lp(a) Hyperlipoproteinemia

This familial disorder, which is associated with increased atherogen-esis, is determined chiefly by alleles that dictate increased produc-tion of the (a) protein moiety. Lp(a) can be secondarily elevated in patients with severe nephrosis and certain other inflammatory states. Niacin reduces levels of Lp(a) in many patients.

Other Disorders

Deficiency of cholesterol 7α-hydroxylase can increase LDL in the heterozygous state. Homozygotes can also have elevated triglycerides, resistance to reductase inhibitors, and increased risk of gallstones and coronary disease. Autosomal recessive hypercholesterolemia is due to mutations in a protein that normally assists in endocytosis of LDL. Some mutations in the PCSK9 gene also cause isolated elevations of LDL. Niacin, ezetimibe, and reductase inhibitors may be useful, vari-ably, in these disorders.

HDL Deficiency

Rare genetic disorders, including Tangier disease and LCAT (lecithin:cholesterol acyltransferase) deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients. Reductase inhibitors and fibric acid derivatives exert lesser effects.

In the presence of hypertriglyceridemia, HDL cholesterol is low because of exchange of cholesteryl esters from HDL into triglyceride-rich lipoproteins. Treatment of the hypertriglyceri-demia may increase or normalize the HDL level.