FREE THYROID HORMONE MEASUREMENT
2001; Elsevier BV; Volume: 30; Issue: 2 Linguagem: Inglês
10.1016/s0889-8529(05)70187-0
ISSN1558-4410
Autores Tópico(s)Ion channel regulation and function
ResumoMore than 60 years ago, it was shown that thyroid hormones are extensively bound to plasma proteins.73 In humans, 0.02% to 0.03% (about 1 part in 4000) of T4 and 0.2% to 0.3% of T3 circulates in the free or unbound state in undiluted normal plasma at 37°C. In normal human serum, approximately 75% of the total circulating T4 concentration of 60 to 140 nmol/L, or 4 to 11 μg/dL, is carried on thyroxine-binding globulin (TBG), with about 10% to 15% attached to prealbumin (transthyretin or TTR) and 10% to 15% bound to albumin. Carriage of T3 is similar, except that a smaller proportion is bound to TTR. A minor fraction (<5%) of circulating T4 and T3 is associated with lipoprotein.7 When binding to TBG is altered, total serum T4 and T3 tend to change so as to restore the preexisting concentration of free hormone, as determined by the set point of the feedback relationship with thyroid-stimulating hormone (TSH). In contrast to binding proteins for corticosteroids, vitamin D, and sex hormones, which seldom show genetic structural variation and are highly specific for a single family of ligands, many qualitative and quantitative variations occur in the iodothyronine-binding proteins, which also have affinity for unrelated hydrophobic ligands, such as numerous drugs and nonesterified fatty acids (NEFA). At least theoretically, free concentrations of thyroxine (T4) and triiodothyronine (T3) are diagnostically more relevant than the total serum level because of the many binding protein variations that can alter total iodothyronine concentrations, independent of thyroid status. As well as the common causes of acquired changes in the concentration of TBG, there are dozens of known hereditary variants in the structure of TBG, TTR, and albumin, many of which change the binding protein concentration or binding affinity, resulting in large changes in total serum T4 (Fig. 1).69 Binding to plasma proteins is noncovalent and rapidly reversible; the bound moiety of hormone functions as a reservoir. A rigid distinction between bound and free hormone moieties is somewhat artificial because dissociation and reassociation are so rapid that the free and bound hormone fractions interchange several million times per day.23 Dissociation of bound hormone almost instantaneously replenishes the free hormone concentration as this minute fraction is taken up by tissues or irreversibly cleared. Dissociation also occurs in vitro when serum is progressively diluted; the free hormone concentration is at first well maintained by progressive dissociation of the large store of bound hormone until that reservoir eventually becomes depleted. In general, many approaches to free T4 estimation, including the time-honored technique of T3 resin uptake, give useful diagnostic information when the concentration of TBG is abnormal; however, it is difficult to establish valid free T4 methods that accommodate the full range of binding protein variants. Furthermore, no method, including equilibrium dialysis and ultrafiltration, which are often regarded as the gold standard or reference methods, gives a true indication of the effects of binding competitors that inhibit binding of T4 to TBG, whether present in vivo or generated during sample processing and storage. These problems can be so troublesome in critically ill subjects that measurement of total T4, which is generally free of artifact, is likely to give more accurate diagnostic information than a free T4 estimate. All of the current methods of thyroid hormone measurement are comparative. As is true for all immunoassays, they rely on the assumption that the sample and standard are identical in all measured characteristics other than the concentration of assay analyte. Assays become invalid when plasma protein binding of tracer differs between the sample and standard. If less tracer is available for competition with the assay antibody in the samples than in the standards, results will be spuriously high, and vice versa.
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