Estimating LDL ApoB: infomania or clinical advance?

Epidemiological and clinical studies have consistently demonstrated that increased concentrations of LDL cholesterol in plasma are associated with increased risk of atherosclerotic cardiovascular disease (CVD). The reference method for LDL cholesterol is -quantification, a method developed by the CDC that requires ultracentrifugation and is accordingly labor intensive, time consuming, and expensive. Thus, in routine clinical laboratory practice, LDL cholesterol is estimated by the Friedewald formula (1 ). This equation requires the measurement of total cholesterol, HDL cholesterol, and triglycerides, together with a calculation factor that estimates the concentration of cholesterol in very-lowdensity lipoprotein (VLDL). However, this formula is not valid for nonfasting patients, when plasma triglyceride concentrations are 4.5 mmol/L (400 mg/dL), in familial dysbetalipoproteinemia, or when there is abnormal VLDL composition. Direct measures of LDL cholesterol are available, but they are not standardized and are expensive. Apolipoprotein B (apoB), a large amphipathic glycoprotein, plays a central role in human lipoprotein metabolism (2 ). The APOB gene is located on chromosome 2 and produces, via a unique mRNA editing process, two forms of apoB in circulating lipoproteins, apoB-48 and apoB-100 (3 ). ApoB-48 is the truncated form of apoB-100 consisting of the N-terminal 48% of full-length apoB-100. ApoB-48 is synthesized in the intestine and is essential for the formation and secretion of chylomicrons. ApoB-100 is synthesized in the liver and is an essential structural and functional component of VLDL and its metabolic products, intermediate-density lipoprotein (IDL) and LDL, being the ligand for the LDL receptor. Essentially all circulating apoB is associated with lipoproteins, and unlike most other apoproteins, apoB cannot exchange freely among lipoprotein particles (2, 3 ). VLDL, IDL, LDL, and lipoprotein each contain one molecule of apoB-100. Similarly, chylomicrons and their remnants contain a single molecule of apoB-48. Hence, plasma apoB concentrations reflect the total number of atherogenic particles present in the circulation (4, 5 ). Moreover, like LDL cholesterol, an increased plasma concentration of apoB has been shown to be key risk factor for the development of atherosclerotic CVD. In a series of prospective epidemiological studies, plasma apoB has been shown to be superior to LDL cholesterol, and has been the topic of recent reviews (5, 6 ). The largest prospective study is the Apolipoprotein-related Mortality Risk (AMORIS) study (7 ), in which 175 553 individuals from Sweden were recruited and followed for an average of 5.5 years. The relationships between fatal myocardial infraction, apoproteins, and other lipid measures were examined in multivariate analyses (after adjusting for age, total cholesterol, and triglycerides), and apoB, apoA-I, and apoB/apoA-I ratio were all significant predictors of myocardial infarction in both sexes. Moreover, apoB was more significant than LDL cholesterol in prediction of myocardial infarction in both men and women. ROC analysis showed that apoB had greater sensitivity and specificity than LDL cholesterol as a predictor variable in both sexes, especially in those with normal/low LDL cholesterol. Importantly, the results from several large statin trials show that change in plasma apoB concentrations in response to treatment may be a better predictor of cardiovascular benefit than change in LDL cholesterol (5, 6 ). Achieving a target level of apoB may therefore be a more important therapeutic objective than a target level of LDL cholesterol. In routine clinical laboratory practice, total apoB is measured in plasma, by immunoturbidimetric or immunonephelometric methods, thereby avoiding ultracentrifugation (8, 9). The measurement of apoB has been standardized by the IFCC/WHO, is automated, and can be performed on nonfasting samples (10). Although apoB-48 may be recognized by apoB-100 antibodies owing to cross-reactivity, apoB-100 is by far the predominant apoB molecule ( 90%) present in plasma, even in the nonfasting state. However, light-scattering techniques can be unreliable in lipemic samples from hypertriglyceridemic individuals. Increased concentrations of LDL apoB may identify patients with greater numbers of LDL particles in whom atherosclerotic CVD risk is increased (9 ). These patients may not necessarily have increased concentrations of LDL cholesterol. Unfortunately, LDL apoB cannot be calculated by a process equivalent to the Friedewald formula. Moreover, direct measurement of LDL apoB requires ultracentrifugation, making it labor intensive, time consuming, and expensive, limiting its 1 Nonstandard abbreviations: CVD, cardiovascular disease; VLDL, very-low-density lipoprotein; apoB, apolipoprotein B; IDL, intermediate-density lipoprotein. Clinical Chemistry 54:5 782–784 (2008) Editorial