Inherited Dyslipidemic Splenomegaly: A Genetic Macrophage Storage Disorder Caused by Disruptive Apolipoprotein E (APOE) Variants

Abstract

Background: Persistent splenomegaly, often an incidental finding, can originate from a number of inherited metabolic disorders (IMDs). Variants of APOE are primarily known as risk factors in terms of cardiovascular disease; however, severe dysfunction of APOE can result in a disease phenotype with considerable overlap with lysosomal storage disorders (LSDs), including splenomegaly and gross elevation of N-palmitoyl-O-phosphocholine-serine (PPCS).

Methods: A case study (deep phenotyping, genetic and FACS analysis) and literature study was conducted.

Results: The index patient, with a family history of early-onset cardiovascular disease, presented with splenic infarctions in a grossly enlarged spleen. The identified genetic cause was homozygosity for two APOE variants (c.604C>T, p.(Arg202Cys) and c.512G>A, p.(Gly171Asp); ε1/ε1), resulting in a macrophage storage phenotype resembling an LSD that was also present in the brother of the index patient. A FACS analysis of the circulating monocytes showed increased lipid content and the expression of activation markers (CD11b, CCR2, CD36). This activated state enhances lipoprotein intake, which eventually converts these monocytes/macrophages into foam cells, accumulating in tissues (e.g., spleen and vascular wall). A literature search identified seven individuals with splenomegaly caused by APOE variants (deletion of leucine at position 167). The combined data from all patients identified male gender, splenectomy and obesity as potential modifiers determining the severity of the phenotype (i.e., degree of triglyceride increase in plasma and/or spleen size). Symptoms are (partially) reversible by lipid-lowering medication and energy restricted diets and splenectomy is contra-indicated.

Conclusions: Inherited dyslipidemic splenomegaly caused by disruptive APOE variants should be included in the differential diagnoses of unexplained splenomegaly with abnormal lipid profiles. A plasma lipid profile consistent with dysbetalipoproteinemia is a diagnostic biomarker for this IMD.

Keywords: N-palmitoyl-O-phosphocholine-serine (PPCS); apolipoprotein E; dysbetalipoproteinemia; inherited lipemic splenomegaly; splenomegaly.

Figure A1

Plasma lipid profile of index patient.

Figure 1

The theorized role of APOE in the prevention of atherosclerotic plaques, dyslipidemia and splenomegaly: (A) Under normal conditions, APOE is integrated into VLDL and chylomicrons during hepatic synthesis of these particles and facilitates the removal of “lipids” (converted VLDL components, i.e., LDL) from plasma by functioning as a ligand for LDL receptors (LDLRs) on hepatocytes. Macrophages secrete APOE and simultaneously absorb APOE-containing lipoproteins. (B) In patients with APOE-compromising variants, APOE has decreased affinity for LDL receptors. An elevated amount of lipoproteins in plasma (total cholesterol and triglycerides) result from the impaired clearance of chylomicron and VLDL remnants by hepatocytes. The presence of large quantities of lipids will lead to the increased expression of macrophage-activating surface markers (a.o. CD11b, CCR2, CD36) and stimulate them to actively load lipids (the uptake of lipid particles is depicted by the yellow particles in foam cells), eventually converting into foam cells. Finally, these foam cells accumulate in the bloodstream and various tissues, including the spleen, eventually resulting in splenomegaly.

Figure 2

PRISMA Flowchart meta-analysis.

Figure 3

Lipid droplet count in the monocytes of the index patient and three control subjects: Median and range depicted.

Figure 4

FACS analysis of monocyte surface marker expression: ctrl, pooled healthy control subjects (n = 3) and the index patient (n = 1); Mon, monocyte (mon 1, classical pro-inflammatory monocytes; mon 2, intermediate monocytes and mon 3; non-classical monocytes); CD, cluster of differentiation; CCR, chemokine receptor; TLR, toll-like receptor. Median and range depicted.

Figure 5

Lipid profile before and after splenectomy in cases with inherited dyslipidemic splenomegaly reported in the literature: TG, triglycerides (mmol/L); TC, total cholesterol (mmol/L); HDL, high-density lipoprotein (mmol/L). Lipid profiles shown for four individuals with a deletion of APOE p.(Leu167del) (ε3) before and after splenectomy procedures. Data derived from meta-analysis (cases B, C, E and G, Table 1). Median and range depicted.