S2: Thyroid Gland

Question 1

What are the 2 broad classes that thyroid function can be split into?

Answer 1

1. Developmental
   Essential for normal development especially in CNS and bone during early life
2. Metabolic
   Essential for normal metabolism of many body tissues also CVS function

Question 2

Define Euthyroid, Hypothyroid and Hyperthyroid

Answer 2

Euthyroid = Thyroid function in normal range
Hypothyroid = Thyroid function below normal (TH deficiency)
Hyperthyroid = Thyroid function is above normal (TH excess)

Question 3

Anatomy of thyroid gland

Answer 3

• 2 lobes (L and R)
• Sometimes a third pyrimidal lobe
• Rich blood supply - has more blood per weight than the kidney
• Supplied by the inferior thyroid artery from the thyrocervical trunk of subclavian
• Superior thyroid artery as a branch of the external carotid artery

Question 4

What is the functional unit of thyroid tissue?

Answer 4

Follicle

Question 5

Structure of a follicle

Answer 5

A follicle consists of a mass of colloid (a protein rich storage material, contains a lot of hormones available for release). The colloid is surrounded by a single layer of follicular cells.

Follicular cells synthesise the thyroid hormones and release them into the colloid and then take them back up from the colloid when there is need for release.

Between the follicles there are capillaries with the basal membrane of follicular cells facing the capillary and the apical membrane facing the colloid.

Question 6

What do C cells in the thyroid do?

Answer 6

C cells secrete calcitonin. Calcitonin is involved in calcium regulation but thought to be minor role.

Question 7

How are thyroid hormones derived?

Answer 7

Thyroid hormones are derived from the joining of two iodinated tyrosine molecules.

Question 8

What is T4 and T3?

Answer 8

They are the two types of thyroid hormones.

T4= Thyroxine, has 4 iodines
T3= Triiodothyronine, has 3 iodines

There is also a reverse T3, which has the iodines in the opposite arrangement. This is inactive/has no activity.

Question 9

Which is less active:

T4 or T3?

Answer 9

T4 is less active than T3, i.e. T3 is more active at the thyroid receptor. However T4 is the major form that is released into the blood, so in many ways T4 is like a prohormone, with possible conversion of T4 -> T3 that can happen in target tissue.

Question 10

What hormones stimulates TH synthesis and release?

Answer 10

Thyrotropin stimulating hormone (TSH)

Question 11

Describe TH synthesis

Answer 11

The process begins with the uptake of iodide, it is present in relatively low concentration in the plasma and it is higher in the follicular cell so it has to be taken up against its concentration gradient. This requires secondary active transport. The sodium gradient (generates Na+/K+ ATPase) is used to transport iodide into follicular cell via Na+/I- symporter (NIS).

Once iodide is inside the cell, it can diffuse out of the cell through apical membrane into colloid through an exchanger called pendrin (PDS).

Iodide is then oxidised into iodine by an enzyme thyroid peroxidase (TPO). This also requires hydrogen peroxide and a large protein called thyroglobulin.

What thyroid peroxidase does is it oxidises iodide to iodine and then iodinates these tyrosine residues, (by covalently binding iodine to them) if it iodinates them in one place you get mono-iodotyrosine (MIT), if in two you get di-iodotyrosine (DIT).

f you combine a MIT and a DIT you get T3
If you combine a DIT and a DIT you get T4

Question 12

What exchanger takes iodide into colloid?

Answer 12

Pendrin (PDS)

Question 13

Why is needed to oxidise iodide to iodine in the colloid?

Answer 13

• The enzyme Thyroid peroxidase (TPO).
• Hydrogen Peroxide
• Large protein thyroglobulin (synthesised in follicular cell and it is a type of protein store which contains many tyrosine residues)

Question 14

Describe TH release

Answer 14

There is endocytosis/pinocytosis into the follicular cell. There is then combining of the colloid droplet with lysosomes and via lysosomal enzymes there is freeing of the T3/T4 from the protein store as well as hydrolysis of thyroglobulin.

.Most of it will be T4, less will be T3. Some T4 will be converted to T3 before it is secreted.

Question 15

How is some iodine recycled in the follicular cell?

Answer 15

Deiodinising enzymes (shown as DEHAL-1)

Question 16

How do T4/T3 exist in circulation?

Answer 16

T4/T3 are quite lipophilic so most exist in plasma bound to the plasma protein

• 70% bound to thyroid binding globulin
• Rest bound to either albumin or transthyretin

Question 17

Why is T3 important?

Answer 17

So most of circulating hormone is as T4. But with regards to actual hormone action, T3 is more important and it is the free thyroid hormone that counts as it has to be free to stimulate its receptors.

There are more free T3 than T4.

Question 18

Explain the metabolic regulation of thyroid hormones (TH)

Answer 18

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

There are the family of the three iodothyronine selenodeiodinases, D1-3 (which is why the trace element selenium is essential in diet).

These enzymes de-iodinate the thyroid hormones in various ways, they have the option of converting T4 to T3 (more active form) or converting T3 to an inactive form.

The thyroid hormone receptor is a nuclear receptor (in the nucleus of the cell), meaning the thyroid hormones need to enter the cell, it does this via specific thyroid hormone transporters.

So T3 that enters the cell can bind to its nuclear receptor, or if you want to upregulate T4 that enters the cell can be converted by D2 into the more active T3 which itself can then bind to its nuclear receptor, thus increasing T3 binding to its receptor.
So the deiodinases have shown to be important tissue-specific (through varying expression of the deiodinases) of way of regulating the amount of T3 actually available to bind with the receptor.

D1 can remove an iodine from the 5 and 5’ position
D2 only from the 5’ position (T4 to T3 - activating)
D3 can remove iodine from position 5 (T4 to T2 - deactivating)

Question 19

How is the synthesis, release and circulating concentration of TH controlled?

Answer 19

There is negative feedback control of thyroid synthesis and secretion, via the hypothalamo-pituitary axis.

• Hypothalamic neurosecretory cells release thyrotrophin releasing hormone (TRH) into portal capillaries (capillaries between hypothalamus and pituitary).
• TRH stimulates thyrotrophs of the anterior pituitary to secrete thyroid stimulating hormone (TSH).
• TRH stimulates pituitary.
• TSH release from pituitary stimulates thyroid gland to release T3/T4.

Levels of T3/T4 rise, these rising levels have a negative feedback effect and shut down synthesis and secretion of TRH and TSH.
Factors such as cold and stress can also influence release of TRH by acting on the hypothalamus.

Question 20

What is TSH?

Describe its receptor

Answer 20

Thyroid stimulating hormone (TSH).

It is a glycoprotein and its receptor is a surface transmembrane receptor. which is part of the GPCR family.

Most of the TSH receptor appear to be via the adenylate cyclase pathway

Question 21

What are the various actions of TSH?

Answer 21

• Increase iodide uptake by increasing the sodium iodide symporter
• Stimulates other reactions involved in TH synthesis
• Stimulates uptake of colloid (back into follicular cell for release)
• Induces growth of thyroid gland (can lead to goitre)

Question 22

How can iodine deficiency lead to goitre?

Answer 22

Less Iodine –> Less T3/T4 synthesis –> More TRH by hypothalamus and TSH released by pituitary (neg. feedback) –> Growth of thyroid gland induced

Question 23

Describe Thyroid Hormones (HR) receptors

Answer 23

• TH receptors belong to the nuclear receptor superfamily
• Nuclear receptors are ligand activated transcription factors
• They have higher affinity for T3 and their activation requires dimerisation with another T3 receptor or retinoic acid receptor. The dimer constitutes the receptor for TH and will then do its effects.
• There are certain domains on the receptor which bind to the hormone and bind to the DNA.

Question 24

What two genes encode for TH receptors?

Answer 24

TR alpha and TR beta

Question 25

How do TH receptors activate or repress transcription?

Answer 25

The receptor can and does bind in the absence of the ligand, but in this case the combination of cofactors present results in a suppressive effect, i.e. transcription is repressed.
Conversely when the ligand binds (T3) in this case, the combination of the receptor and cofactors present results in an activating effect, i.e. transcription is activated.

Question 26

What do thyroid hormones need to cross to access TH receptors?

Answer 26

TH must cross the cell membrane in order to access the nuclear receptor.

Transporters are required despite them being lipophilic.

e.g. MCT8

Question 27

What is Allan-Herndon-Dudley Syndrome?

Answer 27

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

Question 28

Functions of Thyroid Hormone (TH)

Answer 28

1. Increased metabolic rate
   - Number and size of mitochondria, enzymes in metabolic chain, Na+/K+ ATPase activity
   - Positive inotropic and chronotropic effect on heart
   - Syntergizes with SNS
2. Energy Metabolism
   - Partially antagonises insulin signalling
   - Gluconeogenesis, Lipolysis
3. Role in growth and development

Question 29

What are the two types of hypo/hyper thyroidism?

Answer 29

Primary hypo-/hyperthyroidism is where there is a problem with the thyroid gland itself
Secondary hypo-/hyperthyroidism is where there is a problem the pituitary regulation of the thyroid gland

Question 30

Describe Congential Hypothyroidism

Answer 30

Congenital Hypothyroidism associated with retarded growth and learning impairment, linked to iodine deficiency. So congenital hypothyroidism can be easily avoided by monitoring iodine levels during pregnancy. Thyroid problems in an adult aren’t really fatal but can make your life miserable. Lack of thyroid in early life can lead to irreversible neurological damage. However, if detected at birth, it can be corrected. It is now simply preventable with a simple neonatal heel prick test that sees TSH levels. Low TSH should be investigated for congenital hypothyroidism.

Question 31

What is primary hyperthyroidism?

Answer 31

Primary hyperthyroidism, would mean the thyroid gland itself is over producing TH. This would negatively feedback onto the hypothalamus and pituitary gland leading to a decrease in TRH and TSH.
In primary hypothyroidism (e.g. due to iodine deficiency), the thyroid gland isn’t producing enough TH, means there is an absence of negative feedback so TSH and TRH release is up-regulated and levels increase.

Question 32

What is Secondary Hyperthyroidism?

Answer 32

Secondary hyperthyroidism may be caused by a tumour for example in the pituitary gland effecting the thyrotrophs. There would be increased synthesis and secretion of TSH so levels will increase. Hence so T3 and T4 will increase. There will still be the negative feedback, but everything now is working at a higher level.
So high TSH and T3/T4 would indicate secondary!

Question 33

Describe Grave’s Disease

Answer 33

Is an autoimmune disease, because it is primary hyperthyroidism there will be high circulating levels of TH and low TSH.
Symptoms include weight loss, tachycardia and fatigue. There also tends to be a diffuse goitre and opthalmopathy.

The pathology is due to stimulating auto-antibodies. Normally the TSH receptor binds TSH and TH synthesis and secretion is stimulated in the normal way. There is then also negative feedback on levels of TSH.
What occurs is that auto-antibodies get generated by the body and these bind to the TSH receptor as agonists. This results in the receptor being permanently activated/overactivated.
The high levels of T3/T4 will negatively feedback on TSH decreasing its levels, but T3/T4 will continue to be released as the problem is with the antibodies stimulating the TSH receptor.

Question 34

Describe Hashimoto’s disease

Answer 34

Is another autoimmune disease, but this time characterised by low circulating TH but high TSH.
- Primary Hypothyroidism
Symptoms would reflect a lack of TH activity and include lethargy and an intolerance to cold, lack of growth and development and diffuse goitre.