Total Thyroxine (TT4) and Total Triiodothyronine (TT3) Methods

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Thyroxine (T4) is the principal hormone secreted by the thyroid gland. All the T4 in the circulation is derived from thyroidal secretion. In contrast, only about 20% of circulating triiodothyronine (T3) is of thyroidal origin. Most of the T3 in blood is produced enzymatically in nonthyroidal tissues by 5'-monodeiodination of T4.[121] In fact, T4 appears to function as a pro-hormone for the production of the more biologically active form of thyroid hormone, T3. In the circulation, most (~99.98%) of the T4 is bound to specific plasma proteins, thyroxine-binding globulin (TBG) (60-75%), TTR/TBPA (prealbumin/transthyretin) (15-30%) and albumin (~10%).[12,16] Approximately 99.7% of T3 in the circulation is bound to plasma proteins, specifically TBG. This represents a 10-fold weaker protein-binding than seen for T4.[12] Protein-bound thyroid hormones do not enter cells and are thus considered to be biologically inert and function as storage reservoirs for circulating thyroid hormone. In contrast, the minute free hormone fractions readily enter cells by specific membrane transport mechanisms to exert their biological effects. In the pituitary, the negative feedback of thyroid hormone on TSH secretion is mediated primarily by T3 that is produced in situ from the free T4 entering the thyrotroph cells.

Technically, it has been easier to develop methods to measure the total (free 1 protein-bound) thyroid hormone concentrations, as compared with tests that estimate the minute free hormone concentrations. This is because total hormone concentrations (TT4 and TT3) are measured at nanomolar levels whereas free hormone concentrations (FT4 and FT3) are measured in the picomole range and to be valid, must be free from interference by the much higher total hormone concentrations.