Dysbetalipoproteinemia

Abstract

Elevated plasma triglyceride and cholesterol concentrations (mixed hyperlipidemias) are commonly encountered and dysbetaliproteinemia should be considered in this setting. Dysbetalipoproteinemia (remnant clearance disease, Fredrickson type III hyperlipidemia) is an uncommon dyslipoproteinemia related to mutations in apolipoprotein E that disrupt the clearance of remnants of triglyceride-rich lipoproteins; it may be overlooked because xanthomata of the skin and/or tendons occur in a minority of patients. The diagnosis ideally requires the demonstration of remnant lipoprotein accumulation and a genetic cause. Genotyping for apolipoprotein E2 may not prove the diagnosis as it may be associated with low plasma lipid values. The recent association of remnant lipoproteins with atherosclerosis along with many factors that modulate remnant lipoprotein metabolism underscores the importance of recognising dysbetalipoproteinemia as an extreme state of remnant lipoprotein accumulation. Although there may be some differences between remnants in the general population and dysbetalipoproteinemia, it is clear that remnants promote atherosclerosis. Current treatment strategies are adequate but new strategies could also be of benefit in dysbetalipoproteinemia.

Severe Combined Dyslipidemia With a Complex Genetic Basis

“…1-5 Apolipoprotein (apo) E is a component of chylomicrons and their remnants, very low-density lipoprotein (VLDL), and intermediate density lipoprotein (IDL). 1-5 Apo E mediates clearance of these lipoproteins and also plays an independent role in lipid metabolism in the brain. 6 Three common isoforms of apo E, namely, E4, E3, and E2, differ by single amino acid changes encoded by common polymorphisms within the APOE gene.…”

“…5 The cysteine at residue 176 in E2 leads to reduced binding affinity for cell surface receptors compared with E3. 2-5 E2 allele frequency is ~10%, so that ~1% of people are homozygous for E2/E2. Because only ~10% of E2/E2 homozygotes develop FDBL, 2-5 a second “hit” such as obesity, hypothyroidism, renal disease, estrogen deficiency, diabetes, or another genetic mutation is required for clinical expression.…”

“…2-5 E2 allele frequency is ~10%, so that ~1% of people are homozygous for E2/E2. Because only ~10% of E2/E2 homozygotes develop FDBL, 2-5 a second “hit” such as obesity, hypothyroidism, renal disease, estrogen deficiency, diabetes, or another genetic mutation is required for clinical expression. 2-5 Occasionally, extremely rare missense mutations or deletion-duplication variants that impact on other amino acid residues of apo E can lead to compromised protein function, presenting clinically as FDBL.…”

“…2-5 Occasionally, extremely rare missense mutations or deletion-duplication variants that impact on other amino acid residues of apo E can lead to compromised protein function, presenting clinically as FDBL. 2-5…”

“…Clinical features of FDBL include tuberous and palmar xanthoma, plus increased risk of premature coronary and peripheral artery disease. 2-5 Patients classically show equimolar elevations in serum total cholesterol (TC) and triglyceride (TG), 2-5 due to massively elevated IDL. IDL is a normally a minor lipoprotein fraction but it accumulates in FDBL patients due to compromised particle binding from E2/E2 homozygosity.…”