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Lesson 2, Topic 1
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Thyroid Hormone Synthesis

January 24, 2021
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We will review thyroid hormone synthesis and some essential clinical correlates.

A thyroid follicular unit is represented in this illustration. The central colloid is surrounded by a circumferential array of thyroid follicular cells. The perifollicular capillaries transport iodide from the periphery to the thyroid follicular cells, and active thyroid hormone from the follicular cells to the general circulatory system.

This is an expanded illustration of a thyroid follicular cell.

Iodide is transported from the perifollicular capillary into the thyroid follicular cell by the basal sodium-iodide symporter, under a sodium electrochemical gradient facilitated by the sodium-potassium pump

Thyroglobulin (Tg) is synthesized from tyrosine residues, a process that occurs in the nucleus and rough endoplasmic reticulum. Thyroglobulin undergoes further posttranslational modification in the Golgi apparatus of the follicular cell. It is then secreted into the follicular lumen, which happens to be the site of colloid storage through a process of exocytosis.

Iodide is transported to the apical membrane of the thyroid follicular cell by an apical channel protein called pendrin. At the apical membrane, thyroid peroxidase enzyme catalyzes the oxidation of iodide into iodine. This oxidation step requires hydrogen peroxide.

Tyrosyl residues on the thyroglobulin molecule undergo iodination by the previously oxidized iodine molecule. This process of “organification” is facilitated by thyroid peroxidase and results in the formation of monoiodothyronine (MIT) and diiodiothyronine (DIT) residues. If one iodine molecule combines with one tyrosyl residue on thyroglobulin, monoiodothyronine is formed, if iodine molecules with two tyrosyl residues, dioiodothyronine is formed.

Triiodothyronine (T3) and tetraiodothyronine (T4) are then formed in a final coupling reaction, which involves the formation of ester linkages between “donor” and “acceptor” iodothyronine (MIT or DIT) residues. The thyroid peroxidase enzyme also facilitates this step.

The thyroid follicular cell ingests colloid through a process of receptor-mediated pinocytosis, facilitated by megalin. Proteolysis of the colloidal substrate in the thyroid follicular cell yields thyroglobulin, free amino acids, MIT, DIT, T3, and T4. Deiodinases present in the cytoplasm of the follicular cell convert some T4 into active thyroid hormone (T3) and removes iodine from MIT and DIT residues. Iodine can then be recycled for additional thyroid hormone synthesis, and free amino acids can also be rechanneled into thyroglobulin synthesis. Thyroid hormone is then actively transported across the basolateral plasma membrane of the thyroid follicular cell into the perifollicular capillaries by active transport. T4 and T3 are bound to carrier proteins called thyroid binding globulins to facilitate transport throughout the human body.

Now we will review some essential clinical pearls

What is the mechanism underlying cutaneous hyperpigmentation in Graves’ disease?

Hyperthyroxinemia, which refers to excess circulating thyroid hormone, leads to accelerated metabolism of cortisol. Low serum cortisol causes a compensatory increase in adrenocorticotrophic hormone (ACTH) due to the loss of negative feedback inhibition of cortisol on ACTH production.

ACTH subsequently binds melanocortin-1 (MCR-1) receptors in the skin to trigger melanogenesis.

The role of the sodium-iodide symporter in radioactive iodine therapies for thyroid cancer

Iodide uptake occurs across the membrane of the thyroid follicular cells through an active transporter process mediated by the sodium iodide symporter.

Decreased sodium-iodide symporter expression accounts for the reduced iodide uptake in some thyroid carcinomas. Thus, by targeting sodium iodide symporter expression in cancer cells, we could enable these cells to concentrate iodide.

Gene transfer of the sodium iodide symporter into the thyroid follicular cell confers increased radioiodine uptake by up to several hundred-fold. It stands to reason that gene transfer can allow patients with radioactive iodine non-avid differentiated thyroid cancer an opportunity to gain therapeutic benefit from radioactive iodine treatment.

This is the end of the presentation on thyroid hormone synthesis.