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Letters |
1
Department of Pathology, Saint Louis University, School of Medicine, St. Louis, MO 63104,
2
Pathology and, Laboratory Medical Service, John Cochran Veterans Affairs, Medical Center, St. Louis, MO 63106
a Address correspondence to this author at: Clinical Laboratories, 3635 Vista at Grand, St. Louis, MO 63110-0250. Fax 314-289-7073; e-mail ritterdg{at}slu.edu.
To the Editor:
Total plasma homocysteine consists of free homocysteine and homocysteine that is complexed with itself or with other amino acids or proteins. Free homocysteine has been measured previously as part of a biochemical screen for inherited metabolic disorders. More recently, increased total plasma homocysteine has been suggested as an independent risk factor for atherosclerotic coronary artery disease [reviewed in Ref. (1)]. In addition, increased total homocysteine is associated with a poor prognosis in patients with angiographically demonstrated coronary artery disease(2). These studies have prompted clinicians to include total homocysteine analysis as part of the risk assessment profile of patients with premature coronary artery disease. However, it has yet to be shown that reducing total plasma homocysteine concentration leads to a decrease in cardiovascular risk, although vitamin supplementation may effectively lower or normalize circulating homocysteine concentrations(3).
From a laboratory standpoint, problems exist in homocysteine analysis. External quality-assurance programs for total homocysteine (proficiency testing) are not available at present, and interlaboratory correlations of total homocysteine measurements have not been evaluated formally. We have contacted many of the reference laboratories in the US that offer this assay and have found that the reference ranges vary considerably between laboratories. Although most laboratories offer reference intervals based on in-house studies, a few base reference intervals on a review of the literature. Other laboratories offer a "target range" based on prospective studies, which correlate total homocysteine concentrations with risk for cardiovascular disease or with mortality(2).
To evaluate laboratory variability of total homocysteine
analysis, we sent five samples of frozen plasma in EDTA tubes, all
drawn and pooled from the same fasting subject, to five different
reference laboratories. The analytical variation of the results
produced a wide range of possible risk estimates for that subject
(Table 1
).
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We evaluated the extent of variability attributable to inherent test imprecision as opposed to bias between laboratories. The variance of the reported homocysteine test results is composed of the sum of variance within the laboratories and variance between laboratories. To estimate variance within the laboratories, we obtained the coefficients of variation (CVs) for homocysteine testing from the five reference laboratories. At homocysteine concentrations ranging from 8 to 15 µmol/L, the participating laboratories reported CVs of 4.9–11%. The variances of homocysteine test results within each reference laboratory were estimated to be between 0.44 and 1.46 (µmol/L)2, with an average variance of 0.96 (µmol/L)2. By subtracting the average variance within laboratories from the total variance of 3.25 (µmol/L)2, we found the variance between laboratories to be 2.29 (µmol/L)2. Thus, bias between the laboratories contributed more than random error to the observed variability.
Multiple factors could account for the interlaboratory variability, including different methodologies (most common methods are based on fluorescence polarization immunoassays and HPLC), different approaches to test calibration, lack of availability of reference materials for the various forms of homocysteine, or varying efficiencies for the dissociation of homocysteine-containing complexes. The observed variability makes it difficult to interpret the laboratory result in terms of patient risk for development or progression of cardiovascular disease.
References
The following articles in journals at HighWire Press have cited this article:
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  N. L. Duarte, X. L. Wang, and D. E. L. Wilcken Effects of Anticoagulant and Time of Plasma Separation on Measurement of Homocysteine Clin. Chem., April 1, 2002; 48(4): 665 - 668. [Full Text] [PDF]
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