High-density lipoprotein (HDL-C), long considered the “good” cholesterol because of its association with a lower risk of atherosclerosis is being re-examined in light of new research. HDL-raising drugs have not been shown to offer protection against cardiovascular disease (CVD), and some studies have even shown increased risk of CVD in individuals with high HDL levels. “These findings have prompted clinical lab researchers to ask whether HDL is being measured in the right way—and how those measurements should be interpreted,” writes Kristin Harper in November’s Clinical Laboratory News.

Clinicians typically rely on cholesterol levels associated with ApoA1, a major protein component of HDL particles (HDL-P) to measure HDL levels in patients. While most experts view HDL-C as a valid biomarker, it can mask variations in HDL-P. “HDL carries more than 200 different species of lipids and 80 different proteins,” says Alan Remaley, MD, PhD, a senior investigator and section chief of the lipoprotein metabolism laboratory at the National Heart, Lung and Blood Institute in Bethesda, Maryland. “Two people can have identical HDL-C levels, but it doesn’t mean their particles are the same in size or function.”

Direct HDL-C assays don’t always do the job, especially on patients with CVD or dyslipidemia. To address analytical performance issues with these tests, some manufacturers have taken steps to minimize interference by other cholesterol fractions. Still, other experts insist that HDL-C is a poor method for quantifying these particles.

“HDL-P number is better, and some studies show marginally better predictions with HDL-P than HDL-C,” says W. Sean Davidson, PhD, professor of pathology and laboratory medicine and vice chair of research at the University of Cincinnati College of Medicine in Ohio. Nuclear magnetic resonance (NMR) spectroscopy of plasma or serum samples, which breaks down the distribution of subspecies by size, is an alternative that shows promise. Current research suggests that smaller HDL-P are associated with CVD, and learning more about how particle size changes in response to disease could yield important insights into the role that HDL plays in atherosclerosis.

Despite this advantage, NMR spectroscopy has yet to catch on. Although it’s already been approved by the Food and Drug Administration, NMR is rarely used, and “we don’t really know what the large, medium, and small HDL particles mean,” admits Remaley. The test also hasn’t received sufficient validation as a metric for HDL-P in the peer-reviewed literature.

Other methods of measuring HDL-P and its size subspecies are under evaluation. Researchers have taken a specific interest in measuring cholesterol efflux capacity, which potentially predicts both incident and prevalent CVD risk, according to Jay Heinecke, MD, professor of medicine and Karasinski Endowed Chair in metabolic research at the University of Washington in Seattle.

As the article emphasizes, these emerging methods need to be studied further before they’re ready for clinical use. “As novel HDL tests are refined and become more widely used, the research community will learn more about how these particles function in atherosclerosis,” writes Harper.

Pick up November’s CLNto learn what the future holds for refining HDL tests.