HDL laboratory test
Synonyms and keywords: HDL-C, HDL-P

# Overview
The association between HDL concentration and cardiovascular outcomes, especially in statin treated high-risk patients with residual cardiovascular risks, has triggered a large interest in the evaluation of HDL lowering drugs.  HDL is one of the most complicated and heterogeneous among the different lipoproteins; in fact, HDL subfractions vary largely in function, structure, size, cholesterol and triglyceride contents.  The widely used method of measurement of HDL is based on the chemical measurement of HDL-cholesterol (HDL-C); however, recent evidence suggests that HDL-C might not be the best method to measure the functionality of HDL and assess its relationship with cardiovascular outcomes among statin treated patients. Recent studies postulate that HDL-particles (HDL-p) might be a better measure for HDL's effect on residual cardiovascular risks.

# HDL Measures

## HDL-C
- HDL-cholesterol (HDL-C) has long been used to quantify HDL; in fact, HDL-C is measured according to its density on ultracentrifugation which ranges between 1.063 and 1.21 g/L.
- HDL is very heterogeneous in structure, size, and proportion of cholesterol and triglycerides; in fact, different HDL subtypes have different physiochemical and functional characteristics.  Although several studies demonstrated an inverse relationship between HDL-C and cardiovascular risks, this association was not demonstrated in some circumstances probably because the number of HDL-C might not have reflected the actual functionality of HDL.  Hence, it has been hypothesized that HDL-C may not be the best method to measure HDL functionality and assess its association with cardiovascular risk factors.

## HDL-P
- HDL-particles (HDL-P) refers to the sum of the concentration of all the subfractions of HDL. HDL-P can be measured by nuclear magnetic resonance spectroscopic analysis or by ion mobility.  However, these two modalities of measuring HDL-P have not been proven to give identical results; and hence there is no standardized modality to measure HDL-P yet.
- A recent study published in September 2013 suggests that HDL particle number (HDL-P) might be a better tool to assess HDL levels and its association with residual cardiovascular outcomes in patients treated with statin.  This study relied on data from the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) where HDL size, HDL-P, HDL-C, and apolipoprotein A-I level were measured in a population of 10,886 participants.  HDL-P was better associated with coronary vascular disease than HDL-C in statin-treated participants.  HDL-P and HDL-C equally correlate with coronary vascular disease in patients not treated with statin.  In addition, the MESA trial (Multi-Ethnic Study of Atherosclerosis) reported that decreased levels of HDL-P is associated with an increased risk of higher intima-medial thickness of the carotid artery.  HDL-C was no longer associated with intima-medial thickness of the carotid artery after adjustment for LDL-P and each other.
- The identification of an accurate method to clinically measure HDL has tremendous importance, especially that a lot of trials investigating new HDL increasing therapies are ongoing.

## HDL-P as an Alternative to HDL-C
Few studies have evaluated the association between HDL-P and CHD risks, and we know of none that evaluated it jointly with HDL-C and LDL-P.
- Multi-Ethnic Study of Atherosclerosis (MESA) study on multi-ethnic men and women without clinical CVD or lipid-lowering medication use at baseline showed HDL-C associations with carotid intima-media thickness (cIMT)  and its CHD incidence to be substantially attenuated by adjusting for atherogenic lipoproteins, particularly LDL-P.  In contrast, HDL-P (particle concentrations) associations with cIMT and incident CHD were relatively unaffected by adjusting for atherogenic lipoproteins, HDL-C, and mean HDL particle size.
- Multiple Risk Factor Intervention Trial (MRFIT) : Low HDL-P levels predicted CHD death over 18 years of follow-up among men with metabolic syndrome in the MRFIT cohort.  In the MRFIT, high levels of HDL-P and especially medium HDL-P were associated with a reduced risk of CHD
- EPIC-Norfolk Study : In this study lower HDL-P levels predicted incident events independent of age, sex, apoB, triglycerides, mean HDL particle size, smoking, myeloperoxidase, paraoxonase-1, and hsCRP.
- VA-HIT Study : In this study lower levels of baseline and on-trial HDL-P predicted CHD events among men with low HDL-C randomized to gemfibrozil vs. placebo.
- Womens Health Study : This large study showed the inverse association of HDL-P with incident CVD over an 11 year follow-up was not significant.  However, HDL-P was inversely associated with incident CHD among postmenopausal women in the Womens Health Initiative Hormone Trial, adjusted for treatment arm, and the inverse association of HDL-P with cIMT was statistically significant for women in the current study.

# HDL Measurement Modalities
The available modalities for the measurement of HDL are:
- Covalent chromatography
- Chemical precipitation
- Cross immune electrophoresis
- Ion mobility assays
- NMR
- One dimension gel electrophoresis
- Ultracentrifugation

## Chemical Measurements
Chemical measurements can be used to estimate HDL concentrations present in a blood sample, though such measurements may not indicate how well the HDL particles are functioning to reverse transport cholesterol from tissues. HDL-cholesterol (HDL-C) is measured by first removing LDL particles by aggregation or precipitation with divalent ions (such as Mg++) and then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate.

## Electrophoresis Measurements
Since the HDL particles have a net negative charge and vary by size, electrophoresis measurements have been utilized since the 1960s to both indicate the number of HDL particles and additionally sort them by size. Larger HDL particles are carrying more cholesterol.

## NMR Measurements
The newest methodology for measuring HDL particles, available clinically since the late 1990s uses nuclear magnetic resonance fingerprinting of the particles to measure both concentration and sizes.  This methodology was pioneered by researcher Jim Otvos and the North Carolina State University academic research spinoff company and dramatically reduced the cost of HDL measurements.