Clinical laboratories typically focus on apolipoprotein (apo)E typing of polymorphisms (E2, E3, E4) and less on apoE concentrations, because increased apoE is found in hypertriglyceridemia but correlates less with coronary heart disease. The role of apoE and the importance of splenic macrophages in lipoprotein metabolism are highlighted by this case.
Type III hyperlipoproteinemia (HLP) is inherited either in a recessive or dominant mode. Recessively inherited type III HLP requires homozygosity of apoE2, but E2/2 alleles alone are not enough for development of the lipid and clinical phenotype, because <10% of apoE2/2 homozygotes produce the phenotype. A “second hit” consisting of genetic, hormonal, and environmental factors including obesity, estrogen status, or diabetes are required to develop the phenotype. In contrast, apoE3Δ 149Leu is a rare dominantly inherited form of type III HLP that is attributable to a single defective apoE allele. This phenotype lacks the “classical” tuberous and palmar xanthoma seen in recessive type III HLP, and the lipid profile in apoE3Δ 149Leu depends more on an intact spleen than a second hit.
The spleen plays an important and protective role in clearing the plasma of triglyceride-remnant lipoproteins. Development of hepatosteatosis and splenomegaly appears to occur as a result of hypercatabolism of mutant apoE-containing triglyceride-remnant lipoproteins by splenic macrophages. Enhanced macrophage uptake contributes to the relatively normal plasma lipid concentrations with an intact spleen.
Splenectomy unmasks the remnant lipoprotein defect and leads to the development of hypertriglyceridemia. Then, diet and secondary factors modulate the overproduction of lipoproteins (β-VLDL) concomitantly with the defective removal.
The spleen plays an important role in the abnormal clearance that occurs in other lipid disorders such as Tangier disease. The clinical picture can worsen after splenectomy. Atherosclerosis is accelerated after splenectomy owing to the decreased clearance of remnant lipoproteins, but may take 5–10 years to be clinically apparent. Splenic macrophages may be protective against the development of coronary heart disease.
Grant/funding Support: None declared.
Financial Disclosures: None declared.
- © 2008 The American Association for Clinical Chemistry