The Thyroid (Part 1) – Synthesis & Secretion of Thyroxine

The Thyroid

Iodine is an essential part of the Thyroid hormones.
Without iodine the thyroid hormones cannot be synthesized.
Requirement of iodine is about 150–200 mg/day.
Sources of iodine are drinking water, fish, cereals, vegetables & iodinated salt.
Total body contains 25–30 mg of iodine
80% of the total iodine is stored in the thyroid gland.
Iodine level in blood is 5–10 μg/dl.
Goitrogens are seen in cassava, maize, millet, bamboo shoots, sweet potatoes and beans.
Cabbage and tapioca contain thiocyanate, which inhibits iodine uptake by thyroid.
Mustard seed contains thiourea, which inhibits iodination of thyroglobulin.
The only biological role of iodine is in formation of thyroid hormones, thyroxine (T4) and tri-iodo thyronine (T3).

Thyroid gland takes up and concentrates iodine (iodide).
This step is inhibited by thiocyanate and perchlorate, which compete for the carrier mechanism.
This step is stimulated by TSH.
The congenital defect, iodine trapping defect, may be treated by large doses of iodine.

The iodide taken up by the thyroid cell is oxidized to active iodine.
The thyroid is the only organ which can perform this oxidation step.
This step is catalyzed by the enzyme Thyroperoxidase.
Reaction needs hydrogen peroxide, which is produced by an NADPH-dependent reaction.

In this step the Thyroglobulin, that is synthesized by the thyroid follicular cells, is iodinated.
There are 115 tyrosine residues in the Thyroglobulin (Tgb).
Out of these 115 only 35 residues can be iodinated (follicular space).
Thus 3-monoiodotyrosine (MIT) and 3,5-di-iodotyrosine (DIT) are produced.

In this step, some of the tyrosine residues in the thyroglobulin are aligned opposite to each other, and are coupled.
When two DIT molecules couple, one molecule of tetra-iodothyronine (T4) is formed.
Tri-iodothyronine (T3) may be formed by de-iodination of outer ring of T4 by 5’-deiodinase.

The thyroid gland is unique in that it is the only endocrine gland to store appreciable amounts of the hormone.
The thyroglobulin contains about eight T4 residues per molecule.
It is stored as colloid in the thyroid acini.

When necessity arises, thyroglobulin is taken up from the acinar colloid into the cell by pinocytosis.

The T4 is liberated by hydrolysis by specific proteases.
This activity is markedly enhanced by TSH.
This is depressed by iodide and therefore potassium iodide (KI) is used as an adjuvant in hyperthyroidism.
In a genetic disorder, abnormal Tgb is synthesized, resulting in deficient proteolysis and deficiency of thyroxine.

The T4 is released into the bloodstream.
The T3 is produced by de-iodination at 5’ position, either inside the thyroid cell or in the peripheral tissues.
Reverse T3 (rT3) is formed by the inner ring de-iodination by 5-deiodinase. Its biological activity is negligible.

The MIT and DIT that are not utilized are de-iodinized and salvaged for re-utilization inside the cell itself.
Deiodinase defect is the inborn error of metabolism affecting this step.
In such cases, DIT and MIT are seen in urine.
Since iodine is excreted, iodine deficiency is manifested. Treatment is to give iodine.

Thyroid hormones are transported in plasma by proteins.
The bound form is biologically inactive, but they can be rapidly released.
Total protein bound iodine (PBI) is about 10 µg/dL; out of which T4 constitutes 8 µg/dl.
The thyroxine binding globulin (TBG) (54 kD) carries about 80% of T4 and 60% of T3.
The rest of thyroid hormones are loosely bound with Transthyretin (TTR-prealbumin) and albumin.

T4 has a half-life of 4–7 days, while T3 has about 1 day.
T3 is biologically more active.
T4 is a prohormone which is de-iodinated to T3.
In the peripheral tissues, de-iodination takes place. This is done by a de-iodinase.
Part of the T3 and T4 are conjugated with glucuronic acid & excreted through bile, and to a lesser extent, through urine.