Recent developments in the measurement and application of small dense LDL-cholesterol

Low-density lipoprotein (LDL) and its cholesterol (LDL-C) play a crucial role in the pathophysiology of atherosclerotic cardiovascular disease (ASCVD). The LDL particles consist of subfractions of different sizes and densities. Among the LDL subfractions, small dense LDL (sdLDL) particles have been reported to be associated with ASCVD as a residual risk factor.^1,2 Various laboratory methods to measure sdLDL exist, including density gradient ultracentrifugation, gel electrophoresis, gel-filtration chromatography, and nuclear magnetic resonance^1,2; thus, the analysis of sdLDL is a matter of concern for clinical biochemists. In this issue of Annals of Clinical Biochemistry, Nakamura et al. present a reference interval for serum concentrations of sdLDL-cholesterol (sdLDL-C) in healthy Japanese adults. ³ They used a direct homogeneous assay that permits rapid and easy measurement of cholesterol on sdLDL particles. Establishing this method is a welcome development since various other laboratory methods for measurement of sdLDL are difficult to standardise and apply in a routine clinical setting.^1,2

This development comes in the wake of other recent developments that may permit wider application of sdLDL in clinical practice. First, an equation for calculating sdLDL-C from a standard lipid panel (i.e. without additional costs) has been published. ⁴ This calculation was validated against the direct sdLDL-C measurement used by Nakamura et al. ³ There are solid grounds for expecting the equation to be useful in the routine clinical setting. For example, in the Multi-Ethnic Study of Atherosclerosis population, sdLDL-C calculated by this equation had a stronger association with ASCVD than all other lipid parameters, including directly measured sdLDL-C. ⁴ This observation has led to speculation that measured sdLDL-C may simply be a marker for a pro-atherogenic condition, rather than causally related to atherosclerosis ⁵ ; the increased risk of patients with mixed hyperlipidaemia, who have high concentrations of triglycerides and LDL-C, may be causally related to other unmeasured factors that more closely associated with calculated rather than measured sdLDL-C.

Second, directly measured sdLDL-C is highly correlated with LDL-C also measured by direct homogenous assay.^5,6 This may help to explain why the impact of measured sdLDL-C on ASCVD-related outcomes is attenuated after adjustment with LDL-C.^5,6 Perhaps considering such an adjusted attenuation of the impact of sdLDL-C, Nakamura et al. also presented reference data on the sdLDL-C/LDL-C ratio in their cross-sectional population. ³ However, changes in sdLDL-C do not parallel those of LDL-C under lipid-modulating therapy in an ‘interventional’ condition, ⁷ so the ratio must be applied cautiously for patient monitoring in the clinical setting.

Finally, it is important to recognise that there is still no gold standard for the measurement of sdLDL.^2,6 A good – albeit not always excellent – correlation between sdLDL-C and sdLDL, as measured by polyacrylamide gel electrophoresis, has been shown as well as a different relationship with cardiometabolic parameters of values measured by the respective methods. ⁶ This suggests that the different methods for the determination of sdLDL have somewhat different relation to ASCVD. Determining the reference interval for sdLDL-C is meaningful as the first step for clinical use, ³ but it will be necessary to accumulate more data on sdLDL-C in the clinical setting using other methods to measure sdLDL.