Metabolism S10 - The Thyroid Gland

Question 1

Describe the position of the thyroid relative to adjacent structures

Answer 1

Gland located in the neck

Anterior to the lower larynx and upper trachea

It is inferior to the thyroid cartilage

The recurrent laryngeal and the external branch of the superior laryngeal nerves lie close to the thyroid.

Question 2

Describe the vasculature associated with the thyroid gland

Answer 2

Highly vascularised with 2 arteries and 3 veins supplying and draining it.

Superior and anterior arteries

Superior, middle and anterior veins

Question 3

Describe the shape, size and weight of the thyroid gland

Answer 3

Two lateral lobes joined by a central isthmus

2-3cm across and weights 15-20g making it one of the largest endocrine glands.

Question 4

Describe the two major cell types found in the thyroid

Hints: What structures are the cells associated with? What do they secrete?

Answer 4

Follicular cells:

Arranged in units called follicles separated by connective tissue.

Follicles are spherical and lined by epithelial follicular cells.

Surrounding a central lumen containing protein - ‘Colloid’

Cells secrete Thyroxine and Tri-iodothyronine

Parafollicular (C-cells):

Found in the connective tissue

Secrete calcitonin

Question 5

What is the active hormone secreted by follicular cells?

Which of the hormones secreted by follicular cells is more stable?

Answer 5

T3 - Tri-iodothyronine is active

T4 - Thyroxine is inactive, however is more stable

Question 6

What is Calcitonin?

Answer 6

A polypeptide hormone involved in calcium metabolism.

Question 7

How are T3 and T4 synthesised?

Answer 7

Iodine is transported into follicular cells from the blood stream against the concentration gradient (and in conjunction with 2 Na+ ions) via the Sodium Iodide Symporter

Tyrosine rich protein (thyroglobulin) produces by follicular cells

Thyroglobulin then secreted into the colloid

Iodide is oxidised to produce and iodinating species.

Iodination of the side chains of tyrosine residues in thyroglobulin leads to production of:

MIT - Monoiodotyrosine

DIT - Di-iodotyrosine

Coupling of DIT and MIT forms T3 within the thyroglobulin

Coupling of DIT and DIT forms T4 within the thyroglobulin

T3:T4 production ratio is ~1:10

Question 8

How are T3 and T4 stored?

How much of each is stored?

Answer 8

Stored extracellularly in the lumen of the follicles as part of thyroglobulin residues

0.4uM of T3 stored
6uM of T4 stored

These amounts are considerable and would last several months of normal rates of secretion

Question 9

Describe how T3 and T4 are transported in the blood

Hint: Relative affinities, half lives should be mentioned

Answer 9

T3 and T4 and hydrophobic so are transported bound to transport proteins (Thyroxine binding globulin, pre-albumin, albumin)

<1% free and active in blood

T3 has less affinity for transport proteins so has a greater % total free and shorter half life

T3 half life is ~2 days
T4 half life is ~8 days

Question 10

What happens to T3 and T4 levels in circulation during pregnancy and why does this change occur?

Answer 10

During pregnancy Oestrogen increases synthesis of Thyroxine binding globulin (TBG) and there is a fall in free T3/T4 as more is bound to transport proteins.

This decreases negative feedback of T3/T4 on TRH and TSH so these stimulate the thyroid gland to produce more T3/T4 and the amount of free T3/T4 returns to normal

Total amount of circulating hormone increases though.

Question 11

What controls T3/T4 secretion?

Hint: Organs, Hormones

Answer 11

Controlled by the hypothalamus and anterior pituitary gland

Thyrotrophin releasing hormone (TRH) released from the dorsomedial nucleus of the hypothalamus

TRH travels in the hypothalamic/pituitary portal system to stimulate secretion of Thyroid stimulating hormone (TSH) from thyrotrophs in the anterior pituitary gland

TSH travels in blood and affects the follicular cells.

Question 12

What is Thyrotrophin releasing hormone (TRH) and what controls its release?

Answer 12

TRH is a tri-peptide hormone

Stress stimulates TRH release

Drop in temperature stimulates TRH release

T3/T4 inhibit TRH release (negative feedback)

Question 13

What is Thyroid stimulating hormone (TSH) and what controls its release?

Answer 13

TSH is a glycoprotein consisting of two non-covalently linked subunits (alpha and beta).

TRH stimulates

T3/T4 inhibits (negative feedback)

Question 14

Describe the rhythm of TSH release and it’s method of action

Answer 14

Released in low amplitude pulse throughout the day following a circadian rhythm (High during the night, low in the early morning).

TSH interacts with receptors on the surface of follicle cells and stimulates all aspects of synthesis and secretion of T3/T4

Question 15

What long term effects can TSH have on the thyroid gland?

Answer 15

TSH has trophic effects on the gland resulting in increased vascularity and increase in the size/number of cells.

These trophic effects can lead to an enlarged thyroid (Goitre) that may be over/under-active.

Question 16

What effects do T3/T4 have on metabolism?

Answer 16

Increased glucose uptake and metabolism

Stimulate mobilisation and oxidation of fatty acids

Stimulate protein metabolism

These catabolic effects lead to:

Increased BMR

Increased Heat production (UCPs)

Increased O2 consumption

Question 17

What effects do T3 and T4 have on growth, development and normal body function?

Answer 17

• Directly affect bone mineralisation and increase synthesis of hear muscle protein
• CNS requires T3/T4 during development of cellular processes of nerve cells, hyperplasia of cortical neurones and myelination
• Stimulate hormone and neurotransmitter receptor synthesis in tissues (i.e. heart muscle and GI) that increases tissue responsiveness to regulatory factors.
• In heart muscle causes tachycardia
• In the GI tract increase motility
• Have a permissive role in the actions of hormones such as LH and FSH
• Ovulation doesn’t occur in the absence of T3/T4

Question 18

What is the effect of hypothyroidism on a child’s development?

Answer 18

In the absence of thyroid hormones the child will remain physically and mentally retarded (Cretinism).

If the deficiency isn’t corrected within a few weeks of birth there is irreversible damage.

For this reason all newborns have thyroid function assessed.

Question 19

What is the effect of hypothyroidism on adults?

Answer 19

Poor concentration and memory and lack of initiative.

Question 20

What is T3/T4’s mechanism of action and effect on cells?

Hint: Describe how hormone binding brings about the effect on cells

Answer 20

T3/T4 and hydrophobic and so will pass through the cell membrane and bind to cytoplasmic and mitochondrial receptors.

T3 binding to the hormone binding domain of a receptor is thought to induce a conformation change that unmasks the DNA-binding domain.

Interaction of the DNA-binding domain increases rate of transcription of specific genes, hence more protein is formed from these genes.

Increase in rate of protein synthesis stimulates oxidative energy metabolism in the target cell to provide extra energy for protein synthesis.

Protein synthesis also produces more specific functional proteins therefore increases cell activity and demand for energy.

Question 21

How does De-iodination affect T4?

What does this process regulate?

Answer 21

T4 is converted to active T3 by the removal of the 5’-iodide

Removal of the 3’-iodide produces inactive reverse T3 (rT3)

De-iodination regulates the amount of active (free) hormone in cells as T3 is 10x more active than T4

Question 22

What is the most common cause of Hypothyroidism in adults?

Answer 22

Hashimoto’s disease

Affecting 1% of the population, mostly women

Question 23

What is the cause of Hashimoto’s disease?

How is it treated?

Answer 23

Auto-immune disease resulting in either:

The destruction of follicle cells

The production of an anti-body that blocks the TSH receptor on follicle cells

Treated with oral thyroxine (T4)

Question 24

What are the other causes of adult hypothyroidism? (excluding Hashimoto’s)

Answer 24

Post surgical
Radioactive iodine
Anti-thyroid drugs
Secondary (lack of TSH)
Congenital
Iodine deficiency

Question 25

What are the signs and symptoms of hypothyroidism?

Answer 25

Cold intolerance and reduced BMR
Weight gain
Tiredness and lethargy
Bradycardia
Skin dry and flaky
Alopecia (hair loss)
Voice deep and husky

Neuromuscular - Weakness, muscle cramps ans cerebellar ataxia (clumsiness)

Question 26

What is the main cause of hyperthyroidism in adults?

Answer 26

Grave’s disease

Affects ~1% of the population, mostly women

Question 27

What is the cause of Grave’s disease?

Answer 27

Antibodies are produces that stimulate TSH receptors on follicle cells resulting in increased production/release of T3/T4

Question 28

How is Grave’s disease treated?

What is it’s method of action?

Answer 28

Carbimazole that inhibits the addition of iodine into thyroglobulin.

Question 29

What might be the other causes of hyperthyroidism? (Excluding Grave’s disease)

Answer 29

Toxic multinodular Goitre (overproducing T3/T4)
Excessive T4/T3 therapy
Excess iodine
Amiodarone treatment
Thyroid carcinoma (Rare - 99% don’t cause hypo/hyperthyroidism)
Ectopic thyroid tissue

Question 30

What are the signs and symptoms of hyperthyroidism?

Answer 30

Heat intolerance, increased O2 consumption and increased BMR
Slight weight gain
Physical and mental hyperactivity
Tachycardia (HR > 100)
Intestinal hyper-mobility
Exopthalmos (bulging of the eye)
Skeletal and cardiac myopathy giving rise to tiredness, weakness and breathlessness
Osteoporosis due to increased bone turnover and preferential reabsorption