Familial Dysbetalipoproteinemia

At a Glance

Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a genetic disorder characterized by the accumulation of remnants of triglyceride-rich lipoproteins (chylomicrons and very low density lipoproteins or VLDL) in the plasma. The remnant particles are susceptible to uptake by macrophages in peripheral tissues, which may become cholesterol-laden foam cells and lead to atherosclerosis.

The binding of the remnants to hepatic lipoprotein receptors is mediated by apolipoprotein E (apoE). There are three common genetic isoforms of apoE; E2, E3 and E4. The apoE2 allele binds poorly to the lipoprotein receptors, leading to impaired remnant clearance. Remnants thus become enriched with cholesterol and, in about one-half of dysbetalipoproteinemia patients, migrate abnormally on electrophoresis to generate a broad beta-migrating VLDL band in the d less than 1.006 g/ml fraction.

More than 90% of dysbetalipoproteinemia patients are homozygous for apoE2 (where the condition is recessive), but only 5-10% of apoE2 homozygotes (themselves only 1% of the U.S. population) will develop overt hyperlipidemia. Most apoE2 homozygotes are either normolipidemic or hypocholesterolemic (via impaired lipolytic conversion of VLDL to LDL and increased LDL-apoB clearance, leading to lower than normal LDL concentrations).

Remnant accumulation sufficient to cause hyperlipidemia usually only occurs in an apoE2 homozygote when a second metabolic hit or risk factor increases lipoprotein production (e.g. diabetes, obesity, excessive calorie intake) or further decreases remnant clearance (e.g. hypothyroidism, low estrogen levels, decreased LDL receptors due to increasing age). This disease rarely manifests before adulthood and, if it does, is more likely due to a rare, dominantly inherited apoE mutation. Vascular disease is more prevalent and also occurs earlier in men (mean age about 40) than in women (in whom symptoms usually only occur after menopause).

One clinical problem is how to select patients for apoE analysis. Patients most typically present with elevated plasma levels of total cholesterol (TC) and triglycerides (TG), mainly in the VLDL remnants and intermediate-density liproteins (IDL). Some patients with dysbetalipoproteinemia have xanthomas (especially tuberous and tuberoeruptive xanthomas) and/or yellowish lipid deposits in the palmar crease (palmar crease xanthomata), but most do not show signs or symptoms.

Diagnosis of this disorder is also indicated by premature vascular disease (especially of the peripheral arteries). Additional disorders tend to be associated with dysbetalipoproteinemia and may exacerbate the hyperlipidemia (e.g. asymptomatic hyperuricemia, glucose intolerance, obesity and hypothyroidism).

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

A single simple diagnostic test for dysbetalipoproteinemia is not available, but there are some diagnostic markers. Diagnostic tests are based on either demonstration of remnant accumulation (VLDL compositional analysis) and/or apoE genotyping. Defective apoE (commonly apoE2) is essential but not sufficient to cause overt type III hyperlipidemia.

Nearly equal elevations of plasma TC and TG concentrations (>300 mg/dL) are suggestive of dysbetalipoproteinemia but can vary widely. Cholesterol-enriched VLDL is diagnostic of dysbetalipoproteinemia, but sample preparation requires ultracentrifugation to demonstrate beta-migrating VLDL on agarose gel electrophoresis in the d less than 1.006 g/ml fraction.

Tests for various biochemical indices of dysbetalipoproteinemia using common laboratory techniques are subsequently described.

Test Results Indicative of the Disorder

Patients may be classified dysbetalipoproteinemic if they are homozygous for the apoE2 allele and have cholesterol enriched VLDL (i.e. a VLDL-cholesterol (VLDL-C)/TG ratio >0.3 after analysis of VLDL isolated by preparative ultracentrifugation from plasma). Normal VLDL has a cholesterol/TG ratio less than or equal to 0.2.

Other tests are simpler to implement. Dysbetalipoproteinemia may be suspected when both plasma TC and TG levels are increased to approximately the same level. In severely affected patients, plasma TC levels are usually between 300-1000 mg/dL and TG levels tend to equal or perhaps exceed the TC value in a given patient. The diagnosis of dysbetalipoproteinemia should be considered in hyperlipidemic subjects when the TC and TG levels are both elevated and approximately equal.

However, dysbetalipoproteinemia patients will have elevated TC and TG values but lower apoB concentrations than patients without this diagnosis. In general, increased apoB concentrations are associated with higher numbers of circulating atherogenic lipoproteins and higher cardiovascular risk. In dysbetalipoproteinemia, the reverse is true (i.e. apoB levels below the 75th percentile may be associated with very high cardiovascular risk, owing to the very high TC and TG concentrations). Thus, apoB and lipid measurements are not identical, but complementary indices for risk assessment.

The apoB/TC ratio is a simple but effective screening test for dysbetalipoproteinemia in patients with mixed hyperlipidemia. An apoB/TC ratio less than 0.15 identifies dysbetalipoproteinemia with a sensitivity of 89% and specificity of 97%.

The non-HDL-C/apoB ratio is a more novel index that has been shown in a recent Japanese study to help distinguish dysbetalipoproteinemia from other hyperlipidemias, such as combined hyperlipidemia and dyslipidemia of hypothyroidism. Dysbetalipoproteinemia patients have higher values (>2.6) of this index consistent with a greater elevation of cholesterol per lipoprotein particle in the Japanese population.

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?

Additional genetic, hormonal, or envrionmental factors, such as drug effects, renal impairment, obesity, hypothyroidism, low estrogen status, diabetes or age, are required to serve as “cofactors” to develop type III hyperlipidemia in apoE2 homozygotes. It was recently found that mutations in other lipolysis genes (apoC3 3238 G>C, apoA5 -1131 T>C and to a lesser extent the LPL c.27 G>A mutation) are associated with a more severe hyperlipidemia in dysbetalipoproteinemic patients. Laboratory assessment of dysbetalipoproteinemia using cholesterol, triglyceride or lipoprotein/apolipoprotein measurements should not be performed when a patient is taking lipid lowering agents, such as statins, niacin or fibrates. ApoE genotyping can be performed in such cases.

What Lab Results Are Absolutely Confirmatory?

An absolute requirement for expression of the disorder is the occurrence of the mutant form of apoE that is defective in binding to the lipoprotein receptors. However, the only pathognomonic marker of dysbetalipoproteinemia is palmar crease xanthomata, which is found in only about 20% of patients.

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

Useful tests include total cholesterol, triglycerides, apoB and possibly a calculation of non-HDL cholesterol. Less commonly performed testing can be and is used in reference laboratories to make a diagnosis. These include ultracentrifugation and electrophoresis used in combination. A type III lipoprotein phenotype obtained using these methods should be confirmed with apoE genotyping, specifically looking for the presence of the apoE2 homozygous variant (E2/E2). A biochemical phenotype in the absence of an apoE2 allele may represent a more rare inherited apoE mutation, which would require gene sequencing to identify.

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