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Letters |
Research and Development, Ortho-Clinical Diagnostics, Cardiff Laboratories, Whitchurch, Forest Farm Estate, Cardiff CF4 7YT, Wales, UK, Fax 44 1222 526635,
To the Editor:
The Technical Brief by Hawkins (1) refers to the
increase in measured serum free thyroxine (FT4)
concentrations by furosemide as "interference", and this deserves
comment. As discussed previously (2)(3), one can
legitimately conclude that an assay is unaffected after the addition of
exogenous substances (such as thyroid hormone-binding proteins or
binding inhibitors) if the assay measures the total amount
of the analyte (such as T4). The situation is,
however, different with assays measuring free analyte (e.g.,
FT4) concentrations. This is because the
FT4 concentration (as dictated by the law of mass
action) depends on the equilibrium that exists between the
protein-bound T4 (PBT4) and
the serum binding capacity (sBC, which is defined as the concentration
of free binding sites times their binding affinity toward
T4):
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One can readily predict from this equation that drugs such as furosemide, which bind to the thyroid hormone-binding sites (4)(5), will cause an increase in the FT4 concentration by reducing the available binding sites (sBC). This effect will be observed irrespective of whether the drug is a true component of the sample or is a contaminant. Hence, the rise in FT4 concentration observed by Hawkins (1) is to be expected by theory and is not the result of assay interference.
It is evident from the data, however, that the degree of response to furosemide depends on the methodology used. The differences in FT4 methods could be related, as Hawkins suggests, to differences in serum dilution in these assays. Increasing the serum dilution in a FT4 assay, especially in an assay containing T4-binding substances (e.g., bovine serum albumin), will greatly disturb the endogenous T4/protein equilibrium and will lead to underestimation of FT4 in sera whose T4 binding capacities are reduced (3). Thus, assays having the highest serum dilution will be expected to show the largest deviation from the true FT4 concentration.
Clearly the statement (1) that clinician awareness of the effect of drugs on FT4 (and other analytes) is of paramount importance. Equally important is the knowledge that the effects of drugs are transient and will persist only as long as sufficiently high concentrations of drug remain in the circulation. For example, in the case of furosemide, it has been documented (6) that regardless the route of administration, 69–97% of the furosemide is removed from the bloodstream in the first 4 h after the drug is given. If a sufficient time period is allowed between drug administration and venipuncture, the effect of the drug on FT4 estimation will be eliminated or greatly diminished.
In summary, furosemide and other drugs capable of binding to the thyroid hormone-binding proteins (e.g., ketoprofen, phenylbutazone, mefenamic acid, phenytoin, probenecid, sulindac, and fenclofenac) should increase the measured FT4 concentration in assays that truly measure FT4, i.e., the resulting increase in FT4 concentration is not caused by interference. The magnitude of the FT4 increase varies with the FT4 assay being used. The variability is likely the result of differences in the degree of disturbance of the endogenous T4/protein equilibrium exerted by the assay reagents. Assays that cause the least disturbance in this equilibrium will best reflect the true FT4 values.
References
Department of Pathology, and Laboratory Medicine, Tan Tock Seng Hospital, Moulmein Rd., Singapore 308433, E-mail Robert_Hawkins{at}notes.ttsh.gov.sg
To the Editor:
Dr. Christofides correctly points out that increased free thyroxine concentrations are expected in the presence of drugs that bind to thyroid-binding proteins and that such increases cannot legitimately be considered "interference". However, clinicians using free thyroxine measurements to assess and monitor thyroid disease might see acute drug effects as a nuisance (a seeming "interference") despite their accurate reflection of in vivo free hormone concentrations.
The following articles in journals at HighWire Press have cited this article:
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  J. Penders, T. Fiers, and J. R. Delanghe Quantitative Evaluation of Urinalysis Test Strips Clin. Chem., December 1, 2002; 48(12): 2236 - 2241. [Abstract] [Full Text] [PDF]
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