5. EUTHYROID HYPERTHYROXINEMIA AND HYPOTHYROXINEMIA

5.1.Euthyroid hyperthyroxinemia (table 9)

This term is used when the serum T4 concentration is increased, due to binding protein abnormalities, medications, associated illness or hormone resistance, without thyroid dysfunction. An apparent abnormality may be caused by artefacts such as tracer misclassification in assay separation methods (127, 132) or binding competitors, either present in the sample, or generated during sample storage or incubation prior to free hormone estimation (117). Qualitative and quantitative changes in thyroid hormone binding proteins (114) are a common cause of euthyroid hyperthyroxinemia. Structural TBG variants with altered binding affinity usually affect T4 and T3 similarly, but albumin variants may show selective affinity for either T4 or T3. In general, the various methods of serum free T4 estimation give a useful correction for TBG abnormalities. In contrast, albumin variants such as familial dysalbuminemic hyperthyroxinemia (FDH) are prone to methodological artefacts because of increased affinity for T4-analog tracers, resulting in spuriously high serum free T4 estimates (127, 138). Of the multiple known variants in TTR structure, two result in euthyroid hyperthyroxinemia (191).

Circulating T3 or T4-binding autoantibodies can cause methodological artefacts of both total and free T4 and free T3 measurement (131, 132), either falsely low or high values, depending on the assay separation method (115). Tracer bound to the endogenous antibody will be falsely classified as bound in adsorption methods or free in double antibody methods, leading respectively to falsely low or falsely high values (115, 132). Assay after ethanol extraction of serum will establish the true total hormone concentration. Antibodies are only occasionally sufficiently potent to increase T3 or T4 binding in vivo sufficient to elevate the true total hormone concentration (192). Mild hyperthyroxinemia, both total and free, with normal serum TSH and T3 concentrations is common in patients receiving T4 replacement therapy (170, 193), with a small variation depending on the time interval between ingestion and blood sampling (171).

5.2 Euthyroid Hypothyroxinemia

Any thyromimetic compound such as T3 or triiodothyroacetic acid (Triac), inhibits TSH and, therefore, T4 secretion. Serum T4 concentrations may be low in the face of normal or even elevated serum T3 concentrations in patients with iodine deficiency (198), and in situations of partial thyroid failure in which organification of iodide is impaired (199).

Inhibition of TSH secretion, decreased production of binding proteins, and accelerated T4 clearance may each contribute to lowering of the serum total T4 concentration in patients with severe nonthyroidal illness. Free T4 estimates can vary widely, depending on the method that is used. Free T4 estimates that use diluted serum are particularly likely to give subnormal values in the presence of binding inhibitors (see above).