LETTER TO THE EDITOR
Problems in the measurement of Lp(a) (millimoles per liter versus milligrams percent): Reply
Arnold von Eckardstein, MDa,
Paul Cullen, MDa and
Gerd Assmann, MDa
a Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfalische Wilhelms-Universitat Münster, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany
vonecka{at}uni-muenster.de
We are grateful to Dr. Kottke for raising an important point. Lack of standardization has been a big problem in comparing Lp(a) data from different studies and in defining the threshold value above which cardiovascular risk is increased. A working group supported by the National Institutes of Health/National Heart, Lung and Blood Institute (NIH/NHLBI) evaluated 22 Lp(a) assays using reference material developed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and a reference assay designed as proposed by Dr. Kottke (1). Using a test panel consisting of 30 samples, the coefficients of variation among systems varied from 6% to 31%, with some assays biased toward higher and some toward lower Lp(a) values. In agreement with the point raised by Dr. Kottke, a major source of this bias was heterogeneity in the size of apo(a). Overall, however, results of the various Lp(a) assays correlated well. Nevertheless, this bias is an important factor contributing to discrepancies in the suggested risk threshold values for Lp(a), which vary from 0.2 g/l to 0.3 g/l. To put it another way, at a given Lp(a) risk threshold, some assays will overestimate and some will underestimate the cardiovascular risk, especially in persons whose Lp(a) concentration is close to the suggested cutoff.
Thus, we agree with Dr. Kottke that Lp(a) measurements should be performed with standardized assays to allow comparison of data and definition of a universally acceptable risk threshold value. Calibration of the various assays using common reference material is not sufficient for this purpose, as only 2 of the 22 tests investigated by the NIH/NHLBI/IFCC working group showed good agreement with the reference assay despite identical calibration. Manufacturers should optimize their Lp(a) assays using well-defined antibodies and evaluate their results obtained by comparison with a reference test. One alternative to standardized apo(a) immunoassays might be the measurement of the cholesterol content of Lp(a), a variable identified as a cardiovascular risk factor in the Framingham Heart Study (2).
Standardized tests were not available when we measured Lp(a) in PROCAM more than 15 years ago (3). Despite this, we consider our data to be clinically useful. Even though the levels given are in arbitrary units rather than mass concentrations, our measurements clearly show an elevated level of Lp(a) to be associated with increased cardiovascular risk, particularly when it coincides with other risk factors. As outlined above, the risk threshold value remains to be established and may not be the 0.2 g/l suggested by us, even though this value is close to the 80th percentile in the population, a cutoff suggested by the NIH/NHLBI/IFCC working group.
Finally, Lp(a) does not show a stringent dose-response relationship with cardiovascular events (see Fig. 1 of our article, ref. 3). For this reason, the best way to define a threshold value for cardiovascular risk would be to apply a receiver operating characteristics curve analysis to results obtained using a standardized Lp(a) assay in a prospective study.
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References
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- Marcovina SM, Albers JJ, Scanu AM, et al. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem. 2000;46:1956–1967[Abstract/Free Full Text]
- Seman LJ, DeLuca C, Jenner JL, et al. Lipoprotein(a) cholesterol and coronary heart disease in the Framingham Heart Study. Clin Chem. 1999;45:1039–1046[Abstract/Free Full Text]
- von Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Coll Cardiol. 2001;37:434–439[Abstract/Free Full Text]
Related Article
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Problems in the measurement of Lp(a) (millimoles per liter versus milligrams percent)
- Bruce A. Kottke
J. Am. Coll. Cardiol. 2001 38: 1584.
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