Low-density lipoprotein cholesterol (LDL-C) is a lipid particle often called “bad cholesterol” due to its association with cardiovascular risk. LDL-C transports cholesterol throughout the bloodstream, delivering it to cells for structural and hormonal purposes. High levels of LDL-C can contribute to the buildup of plaque in artery walls, a process called atherosclerosis. Assessing LDL-C concentration is a routine part of evaluating cardiovascular health and is typically included in a comprehensive blood test known as a lipid panel.
The Essential Components of a Lipid Panel
A lipid panel provides a snapshot of the fats (lipids) circulating in the bloodstream. Laboratories measure three components to establish the full lipid profile and determine the LDL-C concentration: Total Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C), and Triglycerides (TG).
Total Cholesterol is the sum of all cholesterol carried by lipoproteins, including LDL-C, HDL-C, and Very Low-Density Lipoprotein Cholesterol (VLDL-C). HDL-C is often called “good cholesterol” because it helps remove excess cholesterol from the arteries and returns it to the liver for processing. Triglycerides are a type of fat that serves as a major energy source and are primarily carried by VLDL particles.
Applying the Friedewald Equation
In routine clinical practice, LDL-C concentration is usually estimated using the Friedewald equation, rather than being directly measured. Introduced in 1972, this calculation provides a cost-effective and efficient alternative to complex direct measurement techniques. The equation works by subtracting the cholesterol contained within HDL and VLDL particles from the Total Cholesterol value.
The formula is: LDL-C = Total Cholesterol – HDL-C – (Triglycerides/5).
Laboratories directly measure Total Cholesterol, HDL-C, and Triglycerides, then input these values to solve for LDL-C. The quotient, Triglycerides/5, is used to approximate the cholesterol content of Very Low-Density Lipoprotein (VLDL-C). This approximation relies on the finding that in most people, the ratio of triglycerides to cholesterol within VLDL particles is approximately five-to-one.
When the Calculation Is Not Accurate
The Friedewald calculation relies on the stability of the TG/VLDL-C ratio, which breaks down under certain physiological conditions. The equation is considered unreliable when a patient’s triglyceride level is 400 mg/dL or higher. At these elevated concentrations, the five-to-one ratio is no longer accurate, often causing the Friedewald equation to significantly underestimate the true LDL-C amount. Additionally, the calculation’s accuracy can be compromised if the blood sample is collected soon after the patient has eaten, as the VLDL estimation is based on a fasting sample. In these situations, laboratories must use alternative testing methods.
Alternative Methods for Determining LDL
When the Friedewald calculation is invalidated or for specific clinical needs, laboratories must turn to direct measurement methods. Direct measurement physically isolates the LDL particles in the sample to determine their cholesterol content, unlike the estimation method. The reference standard for this process is ultracentrifugation, which uses high-speed spinning to separate the different lipoprotein particles based on their density. Since ultracentrifugation is time-consuming and requires specialized equipment, most modern laboratories utilize automated homogeneous assays for direct measurement. These assays employ specific chemicals that suppress the detection of other lipoproteins, allowing only the LDL-C to be measured.
Newer Calculation Methods
Newer, more complex calculation methods have also been developed to provide more accurate estimates. One example is the Martin-Hopkins equation, which is particularly useful in patients with moderately elevated triglycerides or very low LDL-C levels.