LabMed

Familial Hypoalphalipoproteinemia

At a Glance

Hypoalphalipoproteinemia, or low levels of high-density lipoprotein cholesterol (HDL-C), is quite prevalent in the United States, according to the third National Health and Nutrition Examination Survey (NHANES III). Approximately 35% of adult men have HDL less than 40 mg/dL and 39% of women have HDL less than 50 mg/dL.

The common, mild forms of hypoalphalipoproteinemia have no characteristic physical findings, but patients may have premature coronary heart or peripheral vascular disease, as well as a family history of low HDL cholesterol levels and premature coronary heart disease (CHD).

Reduced HDL-C levels may be accompanied by increased triglyceride and remnant lipoprotein levels and are associated with increased risk for CHD at all levels of LDL-C. This is because HDL has the ability to promote the efflux of cholesterol from atherogenic foam cells in the arterial wall and to mediate reverse cholesterol transport from the tissues back to the liver.

In most cases, the genetic basis for the familial hypoalphalipoproteinemia is unknown, but it is usually inherited in an autosomal dominant fashion. In rare instances, it may be due to mutations in the ApoA-1, ApoC-III, ApoA-IV gene complex or from the disorders Tangier Disease or LCAT deficiency. A growing number of quantitative trait loci (QTLs) for low HDL-C are also being identified, and the condition may be purely environmental in origin. Some patients with severe low HDL-C levels manifest corneal opacities and xanthomas.

Hypoalphalipoproteinemia is often found in patients with CHD, and research indicates that about 60% of patients with CHD have HDL levels below the 10th percentile of normal values. Prevalence of low HDL-C is higher in certain ethnic groups, such as those of South Asian Indian descent. The levels of atherogenic lipoproteins may significantly contribute to the impact of hypoalphalipoproteinemia on CHD in humans (i.e. low HDL only appears to be a risk factor in the context of an accompanying atherogenic trigger).

Low HDL-C is a common feature in type II diabetes and is frequently associated with high triglyceride and remnant lipoprotein levels. When present with high triglyceride levels, low HDL-C may be an early symptom of (and sensitive biomarker for) impaired glucose tolerance and increase lipolysis. Very low plasma levels of HDL-C are also found in patients with genetically disturbed metabolic pathways indirectly linked to HDL metabolism (e.g. lipid storage diseases, such as Gaucher's disease and Nieman-Pick disease).

Other secondary conditions associated with hypoalphalipoproteinemia include obesity, physical inactivity, cigarette smoking, end-stage renal disease, dysglobulinemia, severe liver disease, malabsorption, malnutrition and severe inflammatory disease.

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

Criteria for the definition of familial hypoalphalipoproteinemias are a low HDL-C level (below the 10th percentile) in the presence of normal VLDL-C and LDL-C levels, an absence of diseases or factors to which hypoalphalipoproteinemia may be secondary, and the presence of a similar lipoprotein pattern in a first-degree relative. Familial hypoalphalipoproteinemia is a relatively common disorder and is often associated with decreased apo A-I production or increased apo A-I catabolism. The molecular diagnosis can be made by electrophoresis of the plasma apolipoproteins and/or DNA analysis to identify the specific mutation.

Test Results Indicative of the Disorder

Hypoalphalipoproteinemia has no clear-cut definition. The US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) redefined the HDL-C level that constitutes a formal CHD risk factor to a minimum desirable level of 40 mg/dL (from 35 mg/dL) for both men and women. For patients with metabolic syndrome, the designated levels of HDL-C that contribute to the syndrome are gender-specific: for men, a desirable HDL-C level is greater than 40mg/dL, but for women the desirable level is greater than 50mg/dL to satisfy the definition of metabolic syndrome.

HDL in plasma is almost undetectable in persons with the familial apo A-I deficiency caused by deletions of the APOA1 gene, the HDL level being less than 10 mg/dL. Heterozygotes tend to have less severe reductions in HDL.

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?

Treatment with the following drugs may affect plasma HDL levels: probucol, androgens or progestins, high-dose thiazide diuretics, and high-dose beta-blockers. A very low-fat diet will also contribute to low HDL levels.

What Lab Results Are Absolutely Confirmatory?

Criteria for the definition of familial hypoalphalipoproteinemias are a low HDL-C level (below the 10th percentile) in the presence of normal VLDL-C and LDL-C levels, an absence of diseases or factors to which hypoalphalipoproteinemia may be secondary and the presence of a similar lipoprotein pattern in a first-degree relative.

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