The thyroid gland consists mainly of follicular cells that produce thyroid hormones thyroxine and triiodothyronine and a small proportion of C cells which play a minor role in calcium homeostasis through their secretion of calcitonin.

The thyroid gland is the only organ in the body to utilise iodine and it uses this to synthesise thyroid hormones, which regulate the body’s metabolic rate. Follicular cells are arranged in clusters in the thyroid gland and surround colloid, a fluid which helps store the thyroid hormones these cells produce.

thyroid-follicleTHYROID HORMONE SYNTHESIS

Iodide ions are absorbed from the GI tract into the blood

 

 

A Na+/I symporter pumps one iodide ion with two sodium ions across the basolateral membrane of the thyroid follicular cell. The energy for transporting iodide ions against a concentration gradient comes from a Na+/K+ ATPase which pumps sodium ions out of the cell, generating a low sodium concentration inside the cell, enabling sodium and iodide ion influx into the cell.

 

 

Iodide ions are transported across the apical membrane into follicles by a Cl/I counter transporter (Pendrin).

 

 

Iodide ions are oxidised by THYROID PEROXIDASE on the apical membrane of follicular cells. This is known as iodide trapping as it prevents the iodide ions from leaving the thyroid gland.

 

 

Thyroid follicular cells also produce THYROGLOBULIN, a large glycoprotein with 70 tyrosine residues.

 

 

Oxidised iodide ions combine with thyroglobulin as it passes into the colloid. This reaction is catalysed by THYROID PEROXIDASE and is known as organification. Iodine binds to around 1/6 of the tyrosine residues on the thyroglobulin glycoprotein.

 

 

Tyrosine residues on thyroglobulin are first iodinised to monoiodotyrosine (MIT) and then another iodide ion is added to form dihydrotyrosine (DIT). MIT and DIT can then conjugate to form triiodothyronine (T3) and two DIT molecules can conjugate to form thyroxine (T4). These reactions are all catalysed by THYROID PEROXIDASE.

 

 

Following these reactions, one thyroglobulin glycoprotein contains around 30 thyroxine molecules and a just a few triiodothyronine molecules which it can store in colloid for around 2 to 3 months.

 

 

T3 and T4 is cleaved from thyroglobulin to release the free thyroid hormones. Thyroid cells pinocytose these and lysosomes then fuse with the vesicles that contain them. Proteases in the thyroid follicular cell digest thyroglobulin to release free T3 and T4 which diffuse through the cell membranes into the blood.

 

 

Almost 75% of iodinated tyrosine never becomes the thyroid hormones T3 or T4 and is instead cleaved from thyroglobulin by DEIODINASE which frees iodine that is then recycled back into follicular cells for the production of more thyroid hormone.

 

 

93% of thyroid hormone released into the blood is thyroxine (T4), whilst only 7% is triiodothyronine (T3). This is because T3 is much more potent than T3, so this acts to carefully control the level of highly active thyroid hormone in the blood.

 

 

In the blood, 99% of T3 and T4 combines with plasma proteins, such as thyroxine binding globulin and albumin. Both thyroid hormones have high affinities for plasma proteins so are released SLOWLY into the tissues. 50% of T4 in the circulation is released as free hormone every 6 days, compared to 50% of T3 which is released every day. Therefore, plasma protein bound stores of T4 in the blood last much longer than T3.

 

Once freed from the plasma protein, T3 and T4 diffuse across cell membranes and bind intracellular proteins where they are stored until they are needed. These are stored for several days and weeks.

T3 is far more potent than T4 as a thyroid hormone. T4 must first lose an iodide ion to become T3, a reaction which is catalysed by DEIODINASE. T3 binds to intracellular thyroid receptors that are attached to, or close to genes on the cell’s DNA. The thyroid hormone receptor forms a complex with Retinoid-X receptor at thyroid hormone response elements on DNA. This alters the expression of a wide range of genes, which therefore influences the function of the cell and body systems as a whole.

NOTES:

–          Plasma proteins that bind to thyroid hormones in the circulation act as a buffer to maintain levels of free T3/T4 and keep their concentration within narrow limits. This ensures that there is enough thyroid hormone available to tissues, but prevents an excess of thyroid hormone from having an excessive effect on gene expression within the cells

–          In hyperthyroidism, the plasma proteins that bind thyroid hormones become saturated by the overwhelming amount of T3 and T4 produced. The extra thyroid hormones that are produced therefore enter the circulation as free hormone, so their action cannot be buffered by the plasma proteins. As a result, there is more free hormone readily available to the body’s tissues, leading to the classic symptoms of hyperthyroidism

thyroid-hormone-synthesis-final-pdf

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