Thyroxine-binding globulin (TBG) deficiency is a nonharmful condition that is either acquired or inherited. The only known complications associated with TBG deficiency are those stemming from the primary disorders that cause the acquired form of this condition. Complications could also potentially result from erroneously administered treatment if TBG deficiency is misdiagnosed as another disorder.
The thyroid hormones (THs)—thyroxine (T4) and 3,5,3′-triiodothyronine (T3)—circulate in blood by reversibly binding to carrier proteins. Although only 0.3% or less of T3 and T4 circulates unbound, it is this free hormone fraction that is metabolically active at the tissue and cellular level.
The 3 main proteins that carry the majority (>95%) of THs are thyroxine-binding globulin (TBG), transthyretin (TTR, or prealbumin), and albumin. A minor proportion of the THs is bound on serum lipoproteins. Very rarely, and in the context of anti-TH antibodies in autoimmune thyroid disease, immunoglobulins also may bind TH. TH binding to TBG is characterized by low capacity but high avidity; the converse is true, ie, high capacity but low avidity, for TH binding to TTR and albumin.
Inherited or acquired variations in the concentration and/or affinity of these proteins may produce substantial changes in serum total TH levels measured by commercially available assays.
Notably, these changes do not result in illness (ie, hypothyroidism or hyperthyroidism), because the concentration of the free TH does not change.
A deficiency in TH-binding proteins is suspected when abnormally low serum total TH concentrations are encountered in clinically euthyroid subjects in the presence of normal serum thyrotropin (ie, thyroid-stimulating hormone [TSH]). More specifically, low TBG is suggested because this protein carries the majority of the serum TH.
Several states of deficiency of this protein have been described that are either inherited or acquired. Thyroid function tests (TFTs) in patients with TBG deficiency show normal TSH and free T4, but low total T4 and, occasionally, low total T3 serum concentrations. The most important clinical aspect of TBG deficiency states is recognition of these disorders and avoidance of unnecessary and potentially harmful TH replacement therapy.
Causes of TBG deficiency
Inherited causes of TBG deficiency include the following:
TBG gene defects – Partial deficiency (X linked) and complete deficiency (X linked)
Other genetic defects – Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1), which is autosomal recessive
Acquired causes of TBG deficiency include the following:
Chronic liver disease
Severe systemic illness (but not in human immunodeficiency virus/acquired immunodeficiency syndrome [HIV/AIDS] or acute intermittent porphyria)
Acromegaly (in very rare cases only)
Drugs (eg, androgens, glucocorticoids, L-asparaginase)
TBG deficiency does not lead to phenotypic features and no morbidity or mortality is directly associated with it. As mentioned above, patients with acquired TBG deficiency may have morbidity and mortality secondary to their underlying illness (usually severe). In addition, morbidity may be associated with misinterpretation of the TFTs as representing a hypothyroid state, with resultant unnecessary, potentially harmful treatment.
Patients with inherited TBG deficiency should be aware of their condition in order to notify their health-care providers and avoid misdiagnosis.