Thyroid Function

 The thyroid is a very important endocrine gland that secretes three hormones. Two of the hormones are iodinated (have iodine attached to them) and are called iodothyronines. The three hormones are:

• Triiodothyronine (T3)
• Tetraiodothyronine (T4), also called thyroxine
• Calcitonin (CT)

When studied under the microscope, the thyroid gland is composed of follicles. These follicles are filled with a substance known as colloid where the iodothyronines are stored. Surrounding these cells are the parafollicular cells, which produce the hormone calcitonin, which is involved in calcium metabolism.

The synthesis of T3 and T4

Fig.1: Thyroid hormone synthesisThe synthesis of the iodothyronines is dependent on iodine from the diet. Iodine is found in most foods and is especially prevalent in seafood and dairy products. It's often added to foods in the form of iodised salt, for example. However, some mountainous areas have soil that is low in iodine. As a result, foods grown there are iodine deficient and goitres (enlarged thyroids) are more common.

The follicular cells of the thyroid gland concentrate iodine in the form of iodide using an iodide trap. The iodide trap actively pumps iodide from the blood into the follicles using the sodium / iodide symporter (NIS) which has been cloned (Fig. 1). Once the follicular cells have taken up the iodide, it is activated into a reactive form by a peroxidase enzyme.

Once activated, this reactive iodine associates with a protein rich in the amino acid tyrosine (called thyroglobulin). Initially, the iodine associates with thyroglobulin either singly or in pairs (mono- or di- units). Then, as a result of coupling reactions, units with three or four iodine ions (tri- or tetra- units, hence T3 and T4) are formed. The protein containing the iodothyronines is then stored as colloid in the follicular cells.

The production of T3 (triiodothyronine) and T4 (thyroxine) is regulated by thyrotrophin (Thyroid Stimulating Hormone - TSH) which is secreted from the anterior pituitary. The control of TSH release is by another hormone called Thyrotrophin Releasing Hormone (TRH). The control of this system is by a negative feedback mechanism. TSH stimulates the synthesis of thyroglobulin, the iodide trap, the coupling reactions in the follicular cells and the release of the iodothyronines into the circulation (Fig. 2).

The function of the Iodothyronines (T3 and T4)

Fig.2: Feedback control of thyroid function

Both T3 and T4 are released from the thyroid, but much more T4 is produced than T3. When released into the circulation, they combine with plasma proteins, mainly Thyronine Binding Globulin (TBG). A small proportion of the iodothyronines also bind to albumin and prealbumin (TBPA). Less than 1% of the iodothyronines are free (unbound) in the plasma.

Oestrogens increase the synthesis of TBG and decrease the clearance of the iodothyronines. In states where there are high levels of circulating oestrogens (i.e. pregnancy), there are 30% higher levels of circulating T4, but free serum T4 levels remain normal.

In the peripheral tissues, T4 is converted into the more active iodothyronine T3. This is brought about by a deiodination reaction. T3 is a more potent hormone than T4 but it has a shorter half-life. There is another important conversion in the periphery where T4 is deiodinated to an inactive iodothyronine called reverse T3 (rT3). The precise role of rT3 is not fully understood, but it is thought to regulate the amount of active iodothyronines in the periphery.

T3 and T4 are associated with the same physiological actions:

Drugs that affect thyroid function

There are a number of drugs that can affect thyroid function:

1. Corticosteroids
Very high doses of corticosteroids (e.g.dexamethasone) can decrease the basal production of TSH and TRH and thus decrease thyroid hormone levels.

2. Lithium Carbonate
Lithium carbonate is a commonly used drug for manic depression. This drug inhibits the release of the thyroid hormones and interferes with their peripheral deiodination.

3. Salicylates, furosemide, salicylates, phenytoin, carbamazepine, non-steroidal anti-inflammatory agents
These drugs displace both T4 and T3 from plasma binding proteins, reducing the availability of thyroid hormones in the circulation.

4. Sulphonamides
These drugs result in a slight decrease in the amount of thyroid hormones.

5. Amiodarone
This is an anti-arrhythmic drug that contains iodine, thus delivering a large iodine load to the patient, which may induce a particular type of thyrotoxicosis (see webpage 'Overview' of thyrotoxicosis). A higher TSH in relation to serum free T4 is seen during longterm amiodarone therapy, perhaps because this drug, or its active metabolite, desethylamiodarone, acts as an antagonist at thyroid hormone receptors. This drug can have various effects on thyroid function causing both hyperthyroidism and hypothyroidism, depending on iodine levels and thyroid function.

Replacing thyroid function (see also Thyroxine Treatment)

Any patient with permanent hypothyroidism (low thyroid state) from any cause will need thyroid hormone replacement for the rest of their lives. The treatment of choice is synthetic levothyroxine, which in Australia is either Oroxine or Eutroxsig, both made by Aspen Pharma. The substance in the pill is identcal to the thyroid hormone (T4) produced by the thyroid. Most people will need about 100 to 125 micrograms a day to replace thyroid function completely, which amounts to one or two pills every day, for life.

Levothyroxine (T4) and triiodothyronine (T3) are the thyroid hormones that circulate throughout the bloodstream. The thyroid gland is the sole source of T4. However, only 10% to 20% of T3 is made in the thyroid gland; the remaining 80% to 90% is produced when T4 is broken down into T3 by other organs in the body.

When a patient takes levothyroxine, the level of T4 in the blood rises and falls slowly. On the other hand, when a patient takes medications containing the much more potent T3, the blood level of T3 rises quickly to hyperthyroid levels and falls rapidly. Therefore, preparations containing T3 cause patients to become hyperthyroid several hours a day and are not recommended.

It is important to note:

• If the type, brand, or dosage of levothyroxine is changed, patients should have their blood levels of thyroid hormones checked two to three months later.
• Taking more levothyroxine than prescribed does not speed up recovery and may cause hyperthyroidism and osteoporosis (thinning of the bones).
• Taking the proper dose of levothyroxine will not increase a patient's risk of developing osteoporosis.
• Levothyroxine treatment is not indicated for patients with fatigue, obesity, or infertility unless the patients also have a confirmed diagnosis of hypothyroidism.
• The warning on some non-prescription cold and flu preparations to avoid taking them if the patient has thyroid disease does not apply to hypothyroid patients taking levothyroxine in the prescribed amounts.
• Pregnant women and nursing mothers can safely take levothyroxine. In fact, patients with inadequately treated hypothyroidism have an increased risk of miscarriage.