Fasting and nonfasting LDL cholesterol: to measure or calculate?

Whether lipid profiles should be measured in the fasting or nonfasting state is a hot topic (1, 2 ). The fasting state is that used conventionally (3, 4 ); however, it would be much simpler for patients worldwide if a lipid profile could be taken at any time of the day, irrespective of the time since and the content of the last meal. In both the US and Europe, LDL cholesterol is currently considered the most important measurement in a lipid profile (3, 5 ). Direct assays for measuring LDL cholesterol are widely available and used in many laboratories; however, even if LDL cholesterol measured with a direct method gives results similar to those calculated with the Friedewald equation, it is unclear how the 2 measurements compare in predicting ischemic cardiovascular disease. In this issue of Clinical Chemistry, Mora et al. report on an evaluation of fasting LDL cholesterol concentrations calculated with the Friedewald equation vs direct measurement of fasting and nonfasting LDL cholesterol concentrations for predicting cardiovascular disease in a prospective study of 27 331 women from the Women’s Health Study (6 ). They also examined misclassification of individuals into the National Cholesterol Education Program risk categories (3 ) with direct measurement of LDL cholesterol, compared with conventional Friedewald calculation of LDL cholesterol. These topics are timely and important. In 1972, Friedewald, Levy, and Fredrickson presented a new method for estimating LDL cholesterol and compared it with the gold standard of preparative ultracentrifugation (7 ). The method required only the measurement of plasma total cholesterol, HDL cholesterol, and triglyceride concentrations—all of which can be measured without the use of laborious and expensive ultracentrifugation. For this reason, the method fundamentally changed clinical practice for risk estimation, made possible epidemiologic studies that included LDL cholesterol as a risk predictor, and later provided a way to easily assess the adequacy of statin treatment aimed at reducing LDL concentrations and cardiovascular disease. The Friedewald equation calculates LDL cholesterol as total cholesterol minus VLDL cholesterol minus HDL cholesterol. According to the Friedewald calculation, LDL cholesterol includes intermediate-density lipoprotein (IDL) cholesterol and lipoprotein(a) cholesterol. VLDL cholesterol is calculated as triglycerides divided by a factor of 5 when lipids are measured in milligrams per deciliter and by a factor of 2.22 when measured in millimoles per liter. The triglycerides/5 ratio as a proxy for VLDL cholesterol is based on the observation that the ratio of the mass of triglycerides to that of cholesterol in VLDL is relatively constant in the fasting state, approximately 5:1 in healthy individuals (7 ); however, this means of estimating VLDL cholesterol introduces the well-known limitations of the Friedewald equation. First, at triglyceride concentrations 400 mg/dL or in the nonfasting state when chylomicrons, chylomicron remnants, or VLDL remnants are present, the triglyceride/cholesterol ratio in VLDL will be greater than 5:1, the VLDL cholesterol concentration will consequently be overestimated, and LDL cholesterol will therefore be underestimated. Second, in rare patients with type III hyperlipidemia (remnant hyperlipidemia, dysbetalipoproteinemia) in which cholesterol-rich -VLDLs are present, the VLDL cholesterol concentration will be underestimated, and LDL cholesterol therefore will be overestimated (7 ). During the 1990s, several methods for direct measurement of LDL cholesterol were introduced, but not until 1998, with the introduction of the homogeneous or third-generation assays, did direct measurement of LDL cholesterol become useful in routine clinical practice (8 ). The homogeneous assays directly measure LDL cholesterol after either blocking or solubilizing other lipoprotein classes. These assays are not or only mildly influenced by the presence of chylomicrons and chylomicron remnants and therefore theoretically should not be influenced by a nonfasting state. Direct homogeneous assays have limitations, however, including (a) varying specificity for the LDL cholesterol fraction, leading in general to underestimation of the LDL cholesterol concentration (87%–105% recovery of LDL cholesterol); (b) often including VLDL cholesterol in the LDL fraction; (c) only measuring 31%– Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark. * Address correspondence to this author at: Department of Clinical Biochemistry, Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. Fax 45 44883311; e-mail [email protected]. Received February 20, 2009; accepted February 25, 2009. Previously published online at DOI: 10.1373/clinchem.2008.123083 Clinical Chemistry 55:5 845–847 (2009) Editorials