Thyroid Hormones

Question 1

Describe Myxoedema

Answer 1

The condition is diagnosed from a combination of abnormal thyroid function, physical examination findings of severe hypothyroidism, and altered mental status. Bradycardia, hypothermia, and hyponatremia are often present as well. Treatment is often administered intravenously, since there may be edema of the gut wall that limits oral absorption.

Question 2

What hormones are associated with the thyroid glands

Answer 2

The iodothyronines:
Tri-iodothyronine (T3) and tetra-iodothyronine (T4, Thyroxine)
Also calcitonin is produced which is concerned with calcium metabolism.

Question 3

What are the properties of these hormones

Answer 3

They are amines, and hence share a mixture of properties of both steroid and polypeptide hormones.

Question 4

How many lobes does the thyroid have

Answer 4

2 lobes- left and right

Question 5

Describe the general structure of the thyroid

Answer 5

Consists of single cell layers of follicular cells surrounding a central region filled with a yellowish protein rich gel called colloid. Between 20 and 40 follicles are grouped together by surrounding connective tissue to form lobules, each lobule receiving its own blood supply and having the ability to function independently of other lobules. Interspersed between the follicular cells are small clumps of very different cells called parafollicular cells.

Question 6

What is the role of the parafollicular cells

Answer 6

These cells operate completely independently of the main thyroid tissue and produce calcitonin.

Question 7

Describe how the follicles vary in shape and size depending on the degree of their stimulation

Answer 7

Highly active follicles consist of thick columnar follicular cells.
Relatively inactive cells would have thinner more cuboidal follicular cells

Question 8

What separates the two lobes

Answer 8

The isthmus

Question 9

What is found on top of the isthmus

Answer 9

The pyramid

Question 10

How much does the adult thyroid gland weigh

Answer 10

Between 15-20g.

Question 11

Where is the thyroid gland found

Answer 11

The trachea

Question 12

Describe the uptake of inorganic iodide into the follicular cells

Answer 12

The concentration of inorganic iodide is greater in the follicular cell than it is in the general circulation.
Also the anion has to enter against its electrical gradient, as living cells have a negative interior with respect to the exterior.
Iodide therefore has to move against an impressive electrochemical gradient.
It does this by means of the sodium-iodide symporter (NIS) in the basolateral membrane which transports two sodium ions and one iodide ions into the cell down the sodium gradient. The energy needed to drive this process is provided by the Na+/K+ ATPase pump.

Question 13

Describe Thyroglobulin synthesis

Answer 13

Binding of TSH to TSHR also stimulates the transcription of genes in the nucleus that will synthesise thyroglobulin. Thyroglobulin is a large glycoprotein homodimer. Thyroglobulin is secreted into the colloid through the apical membrane

Question 14

How are the iodide ions transported into the colloid

Answer 14

They reach the apical membrane where they are transported into the colloid by the pendrin transporter

Question 15

Describe the iodination and organification reactions that form mono- and di-iodotyrosines

Answer 15

Binding of TSH to TSHR also activates TPO.
Along the apical membrane colloid border the inorganic iodide gets oxidised to a highly active, short-lived form of iodide known as ‘reactive iodine’. This iodination reaction is catalysed by TPO (Thyroidal peroxidase) in the presence of hydrogen peroxide.
In this form it immediately gets ‘organified’ by binding to positions 1 and 2 of certain tyrosyls which are incorporated into the thyroglobulin, forming the mono- and di-iodotyrosyls (MIT and DIT).

Question 16

Describe the coupling reaction

Answer 16

The thyroglobulin undergoes a configurational change, known as the coupling reaction, in which the molecule undergoes a structural realignment such that specific di-iodotyrosyls link up with either mono- or di-iodotyrosyls to form tri- and tetra-iodothyronines. This reaction is also under control of TSH.

Question 17

How many thyronines are normally formed on each thyroglobulin

Answer 17

3-4

Question 18

Where are the thyronines stored

Answer 18

In the colloid

Question 19

Describe the uptake from colloid and release into circulation

Answer 19

Binding of TSH also results in the pinocytosis of the colloid, drawing bits of it back into follicular cells. Once the iodinated thyroglobulin is back in the follicular cell cytoplasm, it is taken up by lysosomes directed towards the apical membrane, also in response to TSH. These lysosomes contain various enzymes, including proteases and deiodinases, which break down the thyroglobulin, releasing iodine, tyrosine and thyronines. The iodine and tyrosine residues of MIT and DIT can be recirculated within the cell for reuse. T3 and T4 are secreted through the basolateral membrane into the circulation by means of a transporter mechanism.

Question 20

Describe the transport of the iodothyronines in the blood

Answer 20

Mostly bound to plasma proteins

	a) thyroid-binding globulin: TBG (70-80%)
	b) albumin (10-15%)
	c) prealbumin (aka transthyretin)

Only 0.05% T4 and 0.5% T3 unbound (bioactive components)

Question 21

What is the main hormone product of the thyroid gland

Answer 21

T4

Question 22

Describe the peripheral conversions of the iodothyronines.

Answer 22

T4 plays a role as a pro-hormone in addition to its direct role of a hormone itself. Numerous peripheral tissues contain deiodinases which can deiodinate T4 to the more bioactive T3 by the removal of the iodine atom at position 5’. However, a different deiodinase can deiodinate the 5’ of pro-hormone T4 to form rT3.

Question 23

Describe the differences in metabolic activities of T4,T3 and rT3

Answer 23

While T3 is more biologically active than T4, rT3 is metabolically inactive. Under specific conditions peripheral tissues have the ability to direct the nature of the deiodination pathway depending on their environmental circumstances, either increasing or decreasing the biological activities associated with these thyroid hormones.

Question 24

Describe the differences in half-life and latency periods of the thyroid hormones

Answer 24

Latent period:
T3: ~ 12h
T4: ~ 72h

Half lives:
T4 around 7-9 days
T3 around 2 days

Question 25

What is the main mechanism of action of the iodothyronines on

Answer 25

Gene transcription (upregulation or downregulation).

Question 26

Describe the different mechanisms of action of the iodothyronines

Answer 26

The free, unbound iodothyronines are able to cross peripheral cell membranes by means of specific transporters.
Bind to nuclear receptors- modulate gene transcription.
There are also thyrosine high affinity binding sites on mitochondrial membrane and can influence mitochondrial metabolism directly by acting on mitochondrial DNA.

They also have non-genomic actions on ion channels and pumps

Question 27

What happens once bound to its nuclear receptor

Answer 27

Locates a specific domain on a target chromosome and activate or inhibit a specific gene transcription process resulting in the synthesis or inhibition of a new protein

Question 28

Describe the actions of thyronines in the foetus

Answer 28

Fetal growth & development

Untreated congenital hypothyroidism: cretinism

TH & TSH measured in new-born infant’s heel-prick test
Essential for development of nervous system too

Question 29

Describe the actions of the thyronines in adults

Answer 29

 Basal metabolic rate
Protein, carbohydrate & fat metabolism- weight loss and increased appetite in hyperthyroidism
Potentiate actions of catecholamines
(e.g. tachycardia- patients often present with palpitations , lipolysis)
Effects on the GI (diahhroea, increased bowel frequency , CNS- irritability, restlessness , Reproductive system- irregular periods, subfertility

Question 30

Describe the control of TH production

Answer 30

T4 and T3 have a direct negative feedback on the anterior pituitary gland. They also have an indirect negative feedback on the hypothalamic nuclei. Oestrogens and glucocorticoids stimulate the release of the TSH, somatostatin inhibits it.
Iodide (Wolff-Chaikoff effect) inhibits the release of the thyroid hormones.

High TSH, low TH.