Hypertriglyceridemia Workup

Updated: Jul 23, 2021
  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Approach Considerations

Rule out secondary causes of hypertriglyceridemia, including diabetes mellitus (fasting or random glucose levels), hypothyroidism (thyroid-stimulating hormone [TSH] levels), chronic renal failure (urinalysis, creatinine, and microalbumin), alcohol abuse, hormone replacement therapy, and/or oral contraceptives. [45, 46]

Measure plasma lipid and lipoprotein levels while the patient is on a regular diet after an overnight fast. The Endocrine Society also recommends using fasting triglyceride levels over nonfasting triglyceride levels for the diagnosis of hypertriglyceridemia. [46]

Abnormal lipoprotein patterns can often be identified after determining serum cholesterol and triglyceride levels and visual inspection of the plasma sample (stored at 4°C). In some cases, performing electrophoresis and ultracentrifugation of whole plasma specimens may be necessary to help establish a diagnosis.

If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious lesions will reveal accumulations of fat (not cholesterol). A biopsy of cutaneous lesions suspected to be either planar or tuberous xanthomas will reveal cholesterol deposition.

Although some studies have shown that tests such as C-reactive protein (CRP) and total homocysteine levels have some predictive value in screening for vascular disease, and thus are emerging as nontraditional risk factors for coronary heart disease, further investigation is needed to determine their value. [45] Nonfasting triglyceride levels may reflect the level of atherogenic remnant lipoproteins and may even be stronger predictors of cardiovascular events than traditional fasting lipids. [47]


Lipid Analysis

Elevated triglycerides are determined by direct laboratory analysis of serum or plasma after a 10- to 12-hour fast. Determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.

Moderately elevated total cholesterol and triglyceride levels accompanied by the presence of palmar crease xanthomas confirm the diagnosis dysbetalipoproteinemia. Further laboratory workup may not be necessary.

Very low-density lipoproteins (VLDLs) are increased and chylomicrons are absent when triglyceride levels are elevated but below 1000 mg/dL. If triglyceride levels are above 1000 mg/dL, both VLDL and chylomicrons are usually present.

A standard lipid profile using the Friedewald equation to calculate the LDL cholesterol is not useful if the triglyceride level is more than 400-500 mg/dL. The excess cholesterol present in beta-VLDL is included in the LDL cholesterol value. If the triglycerides are elevated but less than 1000 mg/dL and the total cholesterol is elevated, the lipoprotein abnormality may be caused by either: (1) elevations of both low-density lipoprotein (LDL) and VLDL, which is type IIb or mixed hyperlipoproteinemia, or (2) increased remnant VLDL or intermediate-density lipoprotein (IDL), which is type III hyperlipidemia or dysbetahyperlipoproteinemia (total cholesterol levels, about 300-600 mg/dL; triglyceride levels, about 400-800 mg/dL). The 2 disorders may be distinguished by obtaining a direct LDL cholesterol analysis (enzymatic analysis), which is available at most commercial laboratories. If the direct LDL cholesterol is significantly lower than the calculated LDL cholesterol, a diagnosis of type IIIhyperlipoproteinemia is likely. Furthermore, if the cholesterol-to-triglyceride ratio in isolated VLDL is greater than 0.3, dysbetalipoproteinemia is likely (normal ratio, 0.2).

The only procedure that reliably distinguishes between a mixed hyperlipoproteinemia (increased LDL cholesterol and triglycerides) and type III hyperlipoproteinemia (increased IDL) is beta quantification (lipoprotein electrophoresis). This expensive analysis involves ultracentrifugation followed by electrophoresis. However, it is not performed by most commercial or hospital laboratories. Studies that can isolate and measure VLDL and IDL include density-gradient ultracentrifugation and nuclear magnetic resonance spectroscopy. These tests are reliable in helping diagnose dysbetalipoproteinemia, but they may be available only at lipid specialty laboratories.

Specialized lipid centers should be contacted if type IIb or III must be confirmed. In most clinical settings, however, distinguishing between these entities is rarely necessary, because the treatment of both conditions is essentially the same. Diet modification, exercise, and appropriate weight loss improve both. Type IIb and III also respond to the same medications—niacin and/or fibric acid derivatives. [48] Therefore, no matter which diagnosis applies to a given patient, the treatment is the same.

The Endocrine Society does not recommend routinely measuring lipoprotein particle heterogeneity in patients with hypertriglyceridemia, suggesting that although apolipoprotein B (apo B) or lipoprotein(a) [Lp(a)] levels may be useful, results of other apolipoproteins are generally not clinically useful. [46] However, apo E genotyping or phenotyping can be used to determine if the patient is homozygous for apo E-2, but this finding is not sufficient for the diagnosis of dysbetalipoproteinemia without clinical or lipid abnormalities consistent with the disorder.


Chylomicron Determination

If the triglyceride levels are greater than 1000 mg/dL and the presence of chylomicrons must be confirmed, the simplest and most cost-effective test involves overnight refrigeration of an upright tube of plasma or serum. If a creamy supernatant is seen the next day, chylomicrons are present. If the infranatant is cloudy, high levels of very low-density lipoprotein (VLDL) are present (type V hyperlipidemia). If the infranatant is clear, the VLDL content is normal and type I hypercholesterolemia (elevated chylomicrons only) should be suspected.

Type I hyperlipoproteinemia (pure hyperchylomicronemia)

To make a definitive diagnosis of type I hyperlipidemia, a deficiency of either lipoprotein lipase or apo C-II must be confirmed. The presence of lipoprotein lipase activity may be measured in plasma following intravenous heparin administration (50 IU of heparin per kg body weight) or by analysis of muscle or adipose tissue biopsy samples.

Defective or absent apo C-II must be determined at a lipid center that performs 1 of the 3 following assays: (1) gel electrophoresis, (2) radioimmunoassay, or (3) confirmation that lipoprotein lipase added to the patient's plasma is not active.