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Clinical Chemistry, Vol 33, 2137-2144, Copyright © 1987 by American Association for Clinical Chemistry
R Ekins
Department of Molecular Endocrinology, Middlesex Hospital Medical School, University of London, England.
I have briefly illustrated the way in which the main features of analog methods may be readily predicted by consideration of elementary physicochemical laws. (Editorial limitations on the length of this presentation have prevented exploration of other issues such as the reasons for, and effects of, the hitherto unexplained inclusion by manufacturers of large amounts of albumin (12, 18) in kit reagents.) The main implication of our analysis is that, to conform genuinely to the principles of "unbound analog" free hormone immunoassay, an analog must bind to serum proteins to a maximal extent of approximately 10% (but preferably less) in the absence of antibody. The notion that an analog is suitable for use in this context merely if it binds to serum proteins with lower affinities than does the native hormone (6) is demonstrably fallacious. Current analog methods thus neither adhere to the principles of unbound analog free hormone assay nor do they survive classic dilution tests of free hormone assay validity. Demonstrably they do not, in a general sense, measure the free hormone in serum. They may nevertheless yield roughly "correct" values in pregnancy (and thus, arguably, possess clinical value) if the analog fortuitously distributes in an optimal manner between serum proteins, implying approximate balance between the biasing effects caused by the protein changes occurring in pregnancy. However, such methods yield incorrect estimates in all other situations in which the binding characteristics of test samples are disturbed (e.g., by the presence of binding competitors, drugs, abnormal proteins, etc. or when "unbalanced" changes in protein concentration occur), this being the fundamental cause of their diagnostic unreliability. Wilkins, Midgley, and their colleagues have consistently opposed these conclusions, although they have never (using their computer model or by other rigorous means) demonstrated them to be incorrect, nor indeed have they ever formally substantiated the physicochemical propositions on which they themselves claim the methodology rests. Furthermore, they have repeatedly misinterpreted experimental results yielded by the Amerlex kits (such as the effects thereon of serum dilution, NEFA, drugs, etc.), discreetly abandoning (and even totally reversing) their original claims (though not withdrawing them) when these appeared no longer tenable. Perhaps the most serious consequence of these events is the resulting confusion in the literature. This is of major importance in physiological research (28), but it also clearly has major implications in clinical chemistry.(ABSTRACT TRUNCATED AT 400 WORDS)
The following articles in journals at HighWire Press have cited this article:
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  J. Jonklaas, N. Kahric-Janicic, O. P. Soldin, and S. J. Soldin Correlations of Free Thyroid Hormones Measured by Tandem Mass Spectrometry and Immunoassay with Thyroid-Stimulating Hormone across 4 Patient Populations Clin. Chem., July 1, 2009; 55(7): 1380 - 1388. [Abstract] [Full Text] [PDF]
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J. E.M. Midgley and N. D. Christofides Point: Legitimate and Illegitimate Tests of Free-Analyte Assay Function Clin. Chem., March 1, 2009; 55(3): 439 - 441. [Full Text] [PDF]
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L. M. Thienpont A Major Step Forward in the Routine Measurement of Serum Free Thyroid Hormones Clin. Chem., April 1, 2008; 54(4): 625 - 626. [Full Text] [PDF]
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B. Yue, A. L. Rockwood, T. Sandrock, S. L. La'ulu, M. M. Kushnir, and A. W. Meikle Free Thyroid Hormones in Serum by Direct Equilibrium Dialysis and Online Solid-Phase Extraction-Liquid Chromatography/Tandem Mass Spectrometry Clin. Chem., April 1, 2008; 54(4): 642 - 651. [Abstract] [Full Text] [PDF]
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L. M. Thienpont, K. Van Uytfanghe, J. Marriot, P. Stokes, L. Siekmann, A. Kessler, D. Bunk, and S. Tai Metrologic Traceability of Total Thyroxine Measurements in Human Serum: Efforts to Establish a Network of Reference Measurement Laboratories Clin. Chem., January 1, 2005; 51(1): 161 - 168. [Abstract] [Full Text] [PDF]
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R. Rej Clinical Chemistry through Clinical Chemistry: A Journal Timeline Clin. Chem., December 1, 2004; 50(12): 2415 - 2458. [Abstract] [Full Text] [PDF]
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J. E.M. Midgley Direct and Indirect Free Thyroxine Assay Methods: Theory and Practice Clin. Chem., August 1, 2001; 47(8): 1353 - 1363. [Abstract] [Full Text] [PDF]
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N. D. Christofides and R. C. Hawkins Furosemide Interference in Newer Free Thyroxine Assays • Dr. Hawkins responds: Clin. Chem., August 1, 1999; 45(8): 1315 - 1315. [Full Text] [PDF]
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N. D. Christofides, E. Wilkinson, M. Stoddart, D. C. Ray, and G. J. Beckett Assessment of Serum Thyroxine Binding Capacity-dependent Biases in Free Thyroxine Assays Clin. Chem., April 1, 1999; 45(4): 520 - 525. [Abstract] [Full Text] [PDF]
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