LabMed

Familial Hyperalphalipoproteinemia

At a Glance

High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with risk for coronary heart disease (CHD): an increase of 1 mg/dL of HDL-C is associated with a 2% and 3% decrease in risk for CHD in men and women, respectively. Hyperalphalipoproteinemia, or increased circulating levels of HDL-C, are commonly due to genetic mutations. Familial hyperalphalipoproteinemia is thought to coexist with longevity, and higher HDL-C levels have been found in healthy elderly individuals.

Among the genetic factors identified thus far, including scavenger receptor class B type 1 (SR-B1), apolipoprotein CIII (ApoC-III) deficiency, homozygous deficiency of cholesteryl ester transfer protein (CETP) can lead to dramatic elevations of HDL-C and ApoA-I. This is often accompanied by the accumulation of large cholesteryl ester (CE)- and ApoE-rich HDL particles.

Subjects with CETP mutations and intermediate-to-high levels of HDL-C have been reported to be at increased risk for CHD. However, the relationship between CETP mutations to CHD appears complex, as subjects who have them, and also have higher HDL-C levels greater than 60 mg/dL, show a very low prevalence of CHD. The increase in CHD in CETP-deficient heterozygotes with normal HDL levels probably reflects a defect in reverse cholesterol transport, and is consistent with this function of HDL being central to its anti-atherogenic properties. Heterozygous deficiency of CETP lead to milder increases (10-30%) in HDL-C and is the cause of increased HDL-C levels in 5-7% of the Japanese population.

Rare null or missense mutations in the hepatic lipase (HL) gene can also cause increased HDL-C, ApoA-I, and triglyceride (TG) levels and decreased levels of classical LDL species, with an accumulation of large, buoyant LDL, representing VLDL remnants. In some HL-deficient individuals with additional metabolic defects, there may be increased accumulation of beta-VLDL, which can stimulate foam cell formation and predispose to CHD.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

CETP null mutation homozygotes (an intron 14 splicing defect is common in the Japanese population) have no detectable CETP in their plasma, massively elevated HDL-C (2-6 times normal levels), moderately increased ApoA-I (1.8 times normal), increased TG levels, and decreased plasma ApoB levels (about 60% of normal). Immunoaffinity analysis will reveal an increase in CE and ApoA-I levels, reflecting the role of CETP in regulating clearance of HDL CE in humans, increases in HDL size and apoprotein content occurring as a result of delayed clearance of HDL CE from the plasma. There is an increase in the larger HDL2 species, which are enriched in cholesteryl esters and depleted of TG. With the complete absence of CETP, CE levels in VLDL, IDL, and LDL may be reduced up to one-third of normal values.

Individuals heterozygous for the intron 14 splicing defect have plasma CETP about 35% of normal levels. Mean HDL-C level equals 67 mg/dL.

In affected families, ApoA-1 levels and HDL-2/HDL-3 ratios are also elevated in heterozygotes, but ApoB and LDL-C levels are unchanged.

Other CETP mutations that still produce some active CETP will have less severe effects: mean increases of about 10% in HDL-C and significant decreases in mean plasma TG and blood glucose levels.

Rare null or missense mutations in the hepatic lipase (HL) gene can also cause increased HDL-C, ApoA-I, and triglyceride (TG) levels, decreased levels of classical LDL species, with an accumulation of large, buoyant LDL, representing VLDL remnants.

(Table 1)

Table 1

Test results Indicative of the Disorder
HDL-C > 68 mg/dL

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Although environmental and hormonal influences play into the variance in HDL-C levels in the general population, genetic factors are important (e.g. variants in the HL gene, lipoprotein lipase (LPL) gene and lecithin cholesterol acyltransferase (LCAT) genes).

What Lab Results Are Absolutely Confirmatory?

Increased HDL cholesterol concentration in multiple family members may be used to identify familial hyepralphalipoproteinemia. Apo AI measurement may also be useful. Increased HDL-C is generally considered atheroprotective; however, some care should be given, as genetically increased values could in rare cases be associated with increased risk.

Although mutations in the CETP gene resulting in decreased CETP activity result in increased HDL-C concentrations, the HDL particles may be large and cholesterol laden and may not be functional in reverse cholesterol transport. The recent failure of the CETP inhibitor torcetrapib suggests this may be the case. Patients who received torcetrapib therapy had marked increases in HDL-C values but actually had poor cardiovascular outcomes.

The clinical utility of CETP inhibitors has not yet been ruled out, as other influences of torcetrapib could have attributed to the poorer outcomes. Other CETP inhibitors have been produced by pharmaceutical companies and are now in clinical trials. Results from these trials should answer the question as to whether CETP inhibition will be a viable clinical tool.

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