What is the phenotype of heterozygous lipoprotein lipase deficiency?

Abstract

Purpose of review: Genetic testing of patients with severe hypertriglyceridemia often identifies a single heterozygous pathogenic variant in the LPL gene. The complex and variable phenotype associated with this genotype is the topic of this review.

Recent findings: Previous research showed that heterozygosity for lipoprotein lipase deficiency is associated with reduced but variable post heparin lipolytic activity alongside inconsistent plasma lipid phenotypes ranging from normal to mild-to-moderate to severe hypertriglyceridemia. Recent research confirms and extends these observations, showing that a heterozygous individual can express a highly variable phenotype over time, depending on the presence of secondary factors. About 10% (range 8-20%) of patients with severe hypertriglyceridemia or multifactorial chylomicronemia syndrome are heterozygous for a rare pathogenic LPL variant, and a clinically relevant minority of these has recalcitrant or sustained hypertriglyceridemia.

Summary: Heterozygosity for lipoprotein lipase deficiency predisposes to hypertriglyceridemia, which is sometimes severe depending on secondary factors, but is typically quite responsive to routine interventions such as diet, lifestyle and existing lipid-lowering therapies. However, many heterozygotes for pathogenic variants in LPL have completely normal plasma lipids.

Keywords: chylomicronemia; familial chylomicronemia syndrome; hyperlipoproteinemia type 1; hyperlipoproteinemia type 4; hyperlipoproteinemia type 5; hypertriglyceridemia; lipoprotein lipase; lipoprotein lipase deficiency; multifactorial chylomicronemia syndrome; pathogenic variant.

Box 1

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FIGURE 1

Schematic overview of biochemical consequences of heterozygous and homozygous LPL deficiency. (a) An adult carrier of a single copy of pathogenic LPL gene variant is shown, with heterozygosity signified by the striped sweater. In the absence of secondary factors – such as increasing age, obesity, poor diet, inactivity, alcohol use, impaired glucose tolerance, insulin resistance, diabetes or use of triglyceride-raising medications – such an individual often shows normal plasma triglyceride levels, carried within VLDL and without fasting chylomicronemia. In this scenario, the genetically compromised lipolytic capacity is unstressed and sufficient to manage the influx of triglyceride (TG)-rich lipoproteins. Bi-directional arrows signify that such individuals can transition to mild-to-moderate hypertriglyceridemia (HTG), formerly known as hyperlipoproteinemia (HLP) type 4 with increased VLDL but not chylomicrons, with increasing age and accumulation of secondary factors. The bidirectionality signifies that individuals in this state can revert to normal with lifestyle modification, diet and existing medications. But also possible is progression to (b), namely multifactorial severe HTG or multifactorial chylomicronemia syndrome (MCS), formerly known as hyperlipoproteinemia (HLP) type 5 with increased VLDL and chylomicrons. This phenotype occurs in a heterozygote who has significant secondary factors. Chylomicrons accumulate secondarily as compromised lipolytic capacity becomes saturated with liver-derived VLDL. (c) A young patient with biallelic pathogenic LPL variants (with homozygosity signified by the solid sweater) has familial chylomicronemia syndrome (FCS), formerly known as hyperlipoproteinemia (HLP) type 1 or LPL deficiency. Lipolytic capacity is essentially absent from birth. Chylomicrons cannot be catabolized and accumulate pathologically. The blockade prevents dietary triglyceride from reaching the liver, reducing production of VLDL.