Which plasma protein has the highest affinity for thyroxine (T4)?

• A. Thyroxine-Binding Globulin (TBG)
• B. TBPA/Transthyretin
• C. Albumin
• D. Transferrin

Answer: (A)

Thyroxine binding in plasma is dominated by carrier proteins, and the one that binds T4 most tightly is thyroxine-binding globulin. Its very high affinity means most circulating T4 is held in a tightly bound form by this protein, creating a small, tightly regulated pool of free hormone that can diffuse to tissues as needed. The other carriers bind T4 as well but with weaker affinity—transthyretin (TBPA) binds but not as tightly as TBG, and albumin binds even more loosely, though it contributes to overall transport because it is abundant. Transferrin binds iron, not T4, so it’s not a primary T4 transporter. Because of this strong affinity, changes in TBG levels will alter total T4 in the blood but usually leave free T4 concentrations relatively stable, which is why TBG is the correct answer.