Thyroxine-binding globulin (TBG) is an acidic glycoprotein consisting of a single polypeptide chain with a molecular mass of 54,000 daltons. It is one of three principal carrier proteins for both thyroxine (T4) and 3,5,3-triiodothyronine (T3); the other thyroid hormone carrier proteins are thyroxine-binding prealbumin (TBPA) and albumin. TBG, though present in significantly lesser amounts than TBPA and albumin, has a higher affinity for the thyroid hormones and is therefore the chief carrier protein. In healthy subjects, under 0.05 percent of total circulating T4 is present as unbound (free) hormone. The bound fraction is distributed among the carrier proteins as follows: TBG, 70–75%; TBPA, 15–20%; and albumin, 5–10%.
Both bound and unbound T4 are present in an equilibrium that tends to reassert itself in the face of altered levels of the carrier proteins by inducing a corresponding alteration in the total level of T4 in circulation, while leaving the free T4 level relatively unchanged. Hence the free T4 concentration may be expected to correlate more closely than the total T4 concentration with clinical thyroid status, for an abnormal total T4 result may signify either an abnormality in thyroid function or simply a variation (physiological or pathological) in the carrier proteins.
Thus, for example, the TBG elevations typical of pregnancy, oral contraceptives and estrogen therapy will cause the total T4 level to increase, often beyond the limits of normal, without inducing a corresponding elevation in the free T4 level. Again, alterations in the TBG level sometimes mask the effects of abnormal thyroid function by elevating the total T4 level of a hypothyroid patient — or lowering that of a hyperthyroid patient — into the euthyroid reference range. Here, too, the free T4 concentration will typically reflect the patient's actual thyroid status more reliably than the total T4 concentration.
Historically, estimation of free T4, often via the free thyroxine index (FT4I), has been the most frequently used test for thyroid dysfunction. Calculation of the FT4I typically involves multiplying a total T4 result by a T3-uptake (or T4-uptake) result. The T3 uptake test yields a relative measure of the unsaturated binding sites on TBG, rather than a direct, quantitative estimate of the concentration of this carrier protein. The TBG saturation index (TBG- SI) has been used, under various names, e.g. thyroid hormone binding ratio (THBR), as a substitute for the FT4I. The TBG-SI is essentially just the ratio of total T4 to TBG, multiplied by some factor (depending on the units) so as to achieve a standard reporting scale. When total T4 and TBG are both expressed in molar units as nmol/L and the factor is taken as 100, the TBG-SI represents the fractional occupation of TBG binding sites by T4, expressed as a percent.