Test codes: 7600, 91716, 92053, 92052, 14852, 92061, 19543, 8293, 91723

Clinical use

• Assess risk for coronary heart disease (CHD; primary or secondary)
• Monitor lipid-lowering therapy

Clinical background

Low-density lipoprotein cholesterol (LDL-C) testing is an important part of a CHD prevention strategy. Test results are used to assess the risk of CHD and also to monitor patients who have an increased risk of CHD due to diabetes, prior CHD, other atherosclerotic disease(s), or other risk factors. The risk of CHD can be reduced through lifestyle changes and medical therapy.1-3 Alternative pharmacotherapy may be recommended if statins are not tolerated or do not sufficiently lower LDL-C.2,3

LDL-C is recommended as a primary target of lipid-lowering therapy for CHD prevention.2,3 However, approaches to LDL-C monitoring during therapy vary. Some guidelines recommend targeting percent reductions in LDL-C from baseline,2 while other guidelines recommend targeting absolute LDL-C values.3 Regardless of the guidelines followed, LDL-C targets depend on a patient’s atherosclerotic cardiovascular disease (ASCVD) risk, and absolute LDL-C values are used as thresholds for therapy intensification.2,3 Thus, accurate measurement of LDL-C is important for patient management.

Because of the complexity of direct measurement, LDL-C levels have traditionally been calculated using the Friedewald equation, which incorporates the results of 3 separate measurements (all units are in mg/dL): (1) Total cholesterol (the sum of all forms of cholesterol, including very low-density lipoprotein cholesterol [VLDL-C]), (2) high-density lipoprotein cholesterol (HDL-C), and (3) triglycerides (TG):

LDL-C = total cholesterol – HDL-C – TG/5

“TG/5” is an estimate of VLDL-C. The fixed factor of 5 represents a presumed “constant” ratio of TG to VLDL-C cholesterol. However, for patients with high TG and/or low LDL-C levels, the equation may yield artificially high VLDL-C and artificially low or nonreportable LDL-C values. Therefore, Quest Diagnostics calculates LDL-C using an alternative method that allows greater personalization to a patient’s specific TG and non-HDL-C levels: the Martin-Hopkins calculation.4

The Martin-Hopkins calculation uses an adjustable factor to estimate VLDL-C instead of a fixed factor of 5 but is otherwise similar to the Friedewald equation. This adjustable factor was derived from an analysis of TG to VLDL-C ratios in nearly 1.4 million people.4 The factor is chosen from a matrix table of 180 possible factors, which range from 3.1 to 11.9, corresponding to an individual’s TG and non-HDL-C (total cholesterol – HDL-C) levels. It is lowest (3.1) for patients with very low levels of TG (7 to 49 mg/dL) and high levels of non-HDL-C (≥220 mg/dL), and highest (11.9) for those with very high levels of TG (≥400 mg/dL) and low levels of non-HDL-C (<100 mg/dL).

Compared with the Friedewald equation, the Martin-Hopkins calculation provides many advantages, including better correlation with direct LDL-C measurements,4-8 better concordance with guidelines-based risk classification, especially at high TG and low LDL-C,4-8 and tracking more closely with total atherogenic burden, assessed by apolipoprotein B and non-HDL-C levels.9 The ability of the Martin-Hopkins calculation to adjust for high TG levels may also make LDL-C estimates more reliable in nonfasting patients.10 This can be convenient for risk assessment, especially for patients who have difficulty fasting (eg, young children and people with diabetes).10 The improved accuracy at lower LDL-C (≤70 mg/dL) allows more accurate categorization of patients in very high-risk categories undergoing aggressive treatment with low LDL-C goals.

Compared with other LDL-C equations, the Martin-Hopkins calculation provides the most accurate estimate. Large-scale studies have shown that it provides better correlation with LDL-C reference values determined by a “gold standard” beta-quantitation isotope dilution mass spectrometry method, which has traceability to the International System of Units.11 The Martin-Hopkins calculation also has better concordance with guideline-based LDL-C categorization determined using methods validated against beta-quantitation.12

Assays using calculated LDL-C include Lipid Panel (test codes 7600 and 91716), ASCVD Risk Panel with Score (test codes 92053 and 92052), Lipid Panel with Reflex to Direct LDL (test codes 14852 and 92061), and Lipid Panel with Ratios (test code 19543). Panel components can be ordered separately: total cholesterol (test codes 334 and 91717), HDL-C (test codes 608 and 91719), and TG (test codes 896 and 91718).

The direct LDL-C assay (test codes 8293 and 91723) provides an alternative to calculated LDL-C. Direct measurement provides a reliable result even when TG levels are up to 1,290 mg/dL or LDL-C values are low (10 to 40 mg/dL) and calculation is less accurate.7