Screening for Dysbetalipoproteinemia by Plasma Cholesterol and Apolipoprotein B Concentrations

Abstract

Dysbetalipoproteinemia (type III hyperlipidemia) is a highly atherogenic mixed hyperlipidemia characterized by the accumulation of remnants of triglyceride-rich lipoproteins (chylomicrons and VLDL) (1). The binding of these remnants to hepatic lipoprotein receptors is mediated by apolipoprotein E (apoE). At the apoE gene locus, there are three common alleles: e2, e3, and e4 (2). ApoE2 binds poorly to hepatic lipoprotein receptors, leading to impaired remnant clearance. Consequently, remnants become enriched with cholesterol and migrate abnormally on electrophoresis. More than 90% of dysbetalipoproteinemic patients are homozygous for apoE2, but only a minority (1 in 20) of apoE2 homozygotes will be overtly hyperlipidemic. Remnant accumulation sufficient to cause hyperlipidemia usually occurs only when a second metabolic hit increases lipoprotein production (e.g., diabetes) or further decreases remnant clearance (e.g., hypothyroidism) (3). Dysbetalipoproteinemia is highly atherogenic but responds well to lifestyle changes and lipid-modifying medications. Genetic counseling is important, particularly in areas where there is a high local prevalence of autosomal dominant apoE mutations (4)(5). Dysbetalipoproteinemia is often suspected when both the total cholesterol (TC) and triglyceride (TG) concentrations are increased and the TC/TG molar ratio approximates 2:1. Clinically, pathognomonic palmar crease xanthomata are found in only ∼20% of patients (4)(6)(7). There are no simple diagnostic tests for dysbetalipoproteinemia. Diagnostic tests are based either on the demonstration of remnant accumulation or characterization of apoE. Electrophoretic techniques include serum agarose gel electrophoresis, but a broad β band is found in less than one half of patients (8)(9). Ultracentrifugation is required to demonstrate β-migrating VLDL. Nondenaturing polyacrylamide gradient gel electrophoresis is an effective screening technique (9). Cholesterol-enriched VLDL is diagnostic of dysbetalipoproteinemia (10)(11)(12), but sample preparation requires ultracentrifugation, which is not available in routine diagnostic laboratories. ApoE phenotyping requires isoelectric focusing, and genotyping is …