Thyroid gland

Question 1

How does the thyroid help with development?

Answer 1

It is essential for normal development, especially CNS and bone

Question 2

How does the thyroid help with metabolism?

Answer 2

Essential for normal metabolism of many body tissues

Question 3

What kind of blood supply does the thyroid gland have?

Answer 3

A rich blood supply from to major arteries
Inferior thyroid artery from subclavian.
Superior thyroid artery from carotid

Question 4

What is excessive production of thyroid hormone called?

Answer 4

Thyrotoxicosis. This can lead to a thyroid storm. (Excess sympathetic activity)

Question 5

Explain the histology of the thyroid gland

Answer 5

Large colloid nodules surrounded by follicular cells (the hormonally active thyroid cells). There are also c-cells (parafollicular cells)

Follicular cells synthesize and secrete TH
C-cells secrete calcitonin

Question 6

What is thyroid hormone?

Answer 6

It comes in two forms:
Triiodothyronine (T3) and Thyroxine (T4)
They are made by condensing two tyrosine residues and attaching covalently either by three or four iodine atoms.

Question 7

What is T3?

Answer 7

The active form converted at target cells

Question 8

What is T4?

Answer 8

The major form released to blood, less active (prohormone)

Question 9

How is TH synthesised and released?

Answer 9

1. Active uptake of I- across basolateral membrane, against concentration and electrical gradient, by Na/I symporter (NIS). Stimulated by TSH.
2. Iodide efflux (diffusion) across the apical membrane via exchanger known as pendrin (PDS).
3. At extracellular apical membrane, iodide is oxidized to iodine and covalently bound to tyrosine residues within the thyroglobulin (TG) macromolecule. Requires thyroid peroxidase (TPO) and H2O2.
4. Tyrosine residues may be iodinated in one (mono-iodotyrosine, MIT) or two (DIT) positions. Coupling of iodotyrosine residues (catalysed by TPO) produces T4 (DIT-DIT) and a smaller amount of T3 (MIT-DIT).
5. Under the influence of TSH, colloid droplets consisting of thyroid hormones within the thyroglobulin molecules are taken back up into the follicular cells by pinocytosis.
6. Fusion of colloid droplets with lysosomes causes hydrolysis of thyroglobulin and release of T3 and T4.
7. About 10% of T4 undergoes mono- deiodination to T3 before it is secreted. The released iodide is reutilized. Several-fold more iodide is reused than is taken from the blood each day but in states of iodide excess, there is a loss from the thyroid.
8. Approximately 100 μg TH secreted per day (90% T4 and about 10% T3). Secretion probably relies on membrane transporter

Question 10

How are thyroid hormones circulated?

Answer 10

Over 99% bound to plasma protein

Mainly thyroid-binding globulin (~70%), also transthyretin (10-20%), albumin (10-20%)

Question 11

What kind of receptors are TH receptors?

Answer 11

TH receptors (TRs) belong to the nuclear receptor family
-Ligand-activated transcription factors (nuclear receptors) which cause transcription of target genes or repress transcription. 

They have a high affinity for T3

• Activation requires dimerization with another TR or retinoid X receptor (RXR)
• TRs encoded by two genes: TR alpha and TR beta

Question 12

How do thyroid hormone receptors work?

Answer 12

A TR dimerises with either another TR or an RXR. Both their DNA binding regions bind to the DNA, specifically to thyroid hormone response elements (TRE) in the promoter regions of target genes. In the absence of hormone, TR binds co-repressor (CoR) proteins that silence gene expression. (1) T4 or T3 enters the nucleus; (2) T3 binding dissociates CoR from TR; (3) Coactivators (CoA) are recruited to the T3-bound receptor; (4) gene expression is altered.

Question 13

How are THs regulated metabolically?

Answer 13

Relative levels of T3, T4 and inactive forms controlled in target tissues

Three iodothyronine selenodeiodinases, D1-3

Tissue-specific expression

Regulate the amount of T3 actually available to bind with the receptor

D2 activates T3 by converting T4 into T3 and allowing plasma T3 to pass through into nuclear T3 pool.

D3 inactivates T3 and T4 by converting them into T2 and rT3 respectively.

Question 14

How are THs transported across the cell membrane?

Answer 14

• TH previously thought free to diffuse across the cell membrane
• In fact, transporters are required, some recently identified, e.g., MCT8, OATP1C1

Question 15

What happens when mutations occur in the gene for MCT8?

Answer 15

MCT8: mutations in gene discovered to underlie an X-linked condition, Allan–Herndon–Dudley syndrome, which is associated with psychomotor retardation.

Normally, glial cells, via the enzyme D2, convert D4 to D3 which can either bind to the nuclear receptor or be transported to adjacent neurons via MCT8 transporter.

Question 16

What are the functions of TH?

Answer 16

Increase metabolic rate

• Number and size of mitochondria, enzymes in the metabolic chain, Na/K exchange ATPase activity
• Positive inotropic and chronotropic effects on heart
• Synergizes with sympathetic nervous system

Energy metabolism

• (Like GH and cortisol) Partially antagonizes insulin signalling
• Gluconeogenesis, lipolysis

Growth and development

Question 17

Explain the negative feedback control of thyroid hormone synthesis and secretion, via the hypothalamic-pituitary axis

Answer 17

Stimuli like stress or cold temperatures are detected by the hypothalamus and then hypothalamic neurosecretory cells release thyrotropin-releasing hormone (TRH) into the portal capillaries.
TRH stimulates thyrotropes of anterior pituitary to secrete thyroid stimulating hormone (TSH)
TSH binds to TSH receptors on the thyroid follicular cells and stimulates synthesis and release of TH.
As T3 and T4 levels rise, this activates negative feedback, the hypothalamus and anterior pituitary will be turned down.

Question 18

What is congenital hypothyroidism?

Answer 18

It is a cause of intellectual disability. Easily preventable with a simple neonatal heel prick. Test TSH levels.
Possible hypothyroidism if TSH levels are high.

Question 19

What kind of receptor is a TSH receptor?

Answer 19

Found in the thyroid gland, they are part of the G-protein coupled receptors.

Question 20

What does TSH do?

Answer 20

Increased iodine uptake
Stimulates other reactions involved in TH synthesis.
Stimulates uptake of colloid
Induces growth of thyroid gland (which can lead to goitre)

Question 21

What is hyperthyroidism?

Answer 21

TH excess
Primary: the problem is thyroid gland itself
Secondary: the problem is pituitary regulation

Primary means low TRH and TSH. If only TSH and TH are high, then it is secondary, possibly tumour on the anterior pituitary.

Question 22

What is Th deficiency called?

Answer 22

Hypothyroidism

Question 23

What is Grave’s disease?

Answer 23

Primary hyperthyroidism
Autoimmune
High circulating TH, low TSH
Weight loss, tachycardia, fatigue
Diffuse goitre (TSH receptor stimulation)
Ophthalmopathy 

Happens when antibodies are developed to the TSH receptor. Act as pharmacological agonists so lots of TH is produced leading to low TSH levels.

Question 24

What is Hashimoto’s disease?

Answer 24

Primary hypothyroidism
Autoimmune against the thyroid gland
Low circulating TH, high THS
Lethargy, intolerance to cold
Lack of growth and development
Diffuse goitre