Which protein are thyroid hormones not bound to in circulation?

Thyroid Hormones in Circulation: Binding Proteins

In normal circulation, thyroid hormones are bound to albumin, thyroxine-binding globulin (TBG), and thyroxine-binding prealbumin (TBPA), but not to thyroglobulin.

Thyroid Hormone Transport Proteins

Thyroid hormones in the bloodstream are primarily bound to three carrier proteins:

1. Thyroxine-binding globulin (TBG) - The major transport protein with highest affinity for T4 and T3
2. Albumin - Lower affinity but high capacity carrier due to its abundance in serum
3. Thyroxine-binding prealbumin (TBPA) - Also called transthyretin, serves as an additional carrier

Role of Thyroglobulin

Thyroglobulin is not a transport protein for circulating thyroid hormones. Instead, it serves a fundamentally different role:

• Thyroglobulin is the precursor protein synthesized exclusively within the thyroid gland 1
• It functions as the matrix for thyroid hormone synthesis within the thyroid follicles 2
• Thyroglobulin contains specific hormonogenic sites where iodination and coupling of tyrosine residues occur to form T3 and T4 1
• After hormone synthesis, proteolysis releases T3 and T4 from thyroglobulin into circulation 3

Importance of Thyroid Hormone Transport Proteins

The binding proteins in plasma serve critical physiological functions:

• Only a minute fraction (0.03% of T4 and 0.3% of T3) circulates unbound as free hormone 4
• Free hormone is metabolically active at tissue level and responsible for thyroid status 4
• Transport proteins ensure uniform distribution of thyroid hormones among cells 5
• They provide a large reservoir of hormone that can be readily available 4
• They protect against sudden fluctuations in hormone levels 5

Clinical Significance

Understanding thyroid hormone binding is clinically important because:

• Abnormalities in binding proteins can alter total thyroid hormone levels without affecting free hormone concentrations or thyroid status 4
• This can lead to misdiagnosis of thyroid dysfunction if only total hormone levels are measured
• Conditions that alter binding protein levels (pregnancy, oral contraceptives, liver disease) can affect interpretation of thyroid function tests

Common Pitfalls in Clinical Practice

• Relying solely on total T3/T4 measurements without assessing free hormone levels
• Failing to consider binding protein abnormalities when total hormone levels don't match clinical presentation
• Not recognizing that thyroglobulin in circulation is used as a tumor marker for thyroid cancer but is not involved in hormone transport

By understanding the distinction between thyroglobulin (the precursor within the thyroid) and the actual transport proteins in circulation (TBG, albumin, and TBPA), clinicians can avoid misinterpreting thyroid function tests and provide appropriate management.