In addition to the difficulties with the LDL-C approximation, there are further problems with the use of LDL-C in general, even if it is directly measured. Since LDL-C is proportional to the number of LDL particles, one might expect the two to change in the same direction, even if the magnitude of change were to vary widely. Unfortunately, there are certain situations in which an increase in LDL-C may signal a decrease in LDL particle number.

Theoretical Problems Relating LDL-C to Particle Number

The cholesterol content of LDL depends on other variables, such as the volume of the LDL particles and the ratio of cholesterol to TGs within the particle. The following statement presents a simplified form of the relationship:

~LDLC « [ Particle Number ^ Particle Volume ^ Cholesterol ] - HDLC - TGs

LDL TG 5

IDL LP(a) VLDL HDL

We have expressed the relationship mathematically not only to illustrate its complexity, but also to convey which variables are directly, as opposed to inversely, proportional to ~LDL-C. It is natural to expect that increased ~LDL-C represents an increased number of lipoprotein particles. However, the statement given reveals that the overall cholesterol mass would also increase if the particles were larger, or even if the ratio of cholesterol to TG increased. On the other hand, there are several conditions in which lipoproteins are enriched with TGs (e.g., metabolic syndrome or type 2 diabetes). Note that TGs appear in the statement twice, potentially magnifying their influence. Because TGs are inversely proportional to ~LDL-C, hypertriglyceridemia may be associated with lower ~LDL-C levels, thereby underestimating the LDL particle number. Likewise, if the LDL particles tend to be smaller than usual, the ~LDL-C might underestimate the LDL number, even if the particles were more numerous than usual.

Many clinicians assume that ~LDL-C correlates with the number of LDL particles. The presumption of a stable relationship rests on the questionable assumption that all the other variables are constants or that their collective effects cancel each other out. In practice, the complex changes can actually result in retrograde changes in ~LDL-C with respect to LDL particle number. When treatment favorably increases LDL particle size or increases the ratio of LDL cholesterol:TGs, ~LDL-C may rise, despite a fall in the number of LDL particles (44). This may lead the clinician to assume that treatment was deleterious, when in all likelihood, it was beneficial. This renders the relationship between ~LDL-C and LDL number unpredictable, because we cannot assume that these variables will change in the same direction.

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