Metabolism S10 - The Thyroid Gland Flashcards
Describe the position of the thyroid relative to adjacent structures
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.
Describe the vasculature associated with the thyroid gland
Highly vascularised with 2 arteries and 3 veins supplying and draining it.
Superior and anterior arteries
Superior, middle and anterior veins
Describe the shape, size and weight of the thyroid gland
Two lateral lobes joined by a central isthmus
2-3cm across and weights 15-20g making it one of the largest endocrine glands.
Describe the two major cell types found in the thyroid
Hints: What structures are the cells associated with? What do they secrete?
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
What is the active hormone secreted by follicular cells?
Which of the hormones secreted by follicular cells is more stable?
T3 - Tri-iodothyronine is active
T4 - Thyroxine is inactive, however is more stable
What is Calcitonin?
A polypeptide hormone involved in calcium metabolism.
How are T3 and T4 synthesised?
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
How are T3 and T4 stored?
How much of each is stored?
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
Describe how T3 and T4 are transported in the blood
Hint: Relative affinities, half lives should be mentioned
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
What happens to T3 and T4 levels in circulation during pregnancy and why does this change occur?
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.
What controls T3/T4 secretion?
Hint: Organs, Hormones
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.
What is Thyrotrophin releasing hormone (TRH) and what controls its release?
TRH is a tri-peptide hormone
Stress stimulates TRH release
Drop in temperature stimulates TRH release
T3/T4 inhibit TRH release (negative feedback)
What is Thyroid stimulating hormone (TSH) and what controls its release?
TSH is a glycoprotein consisting of two non-covalently linked subunits (alpha and beta).
TRH stimulates
T3/T4 inhibits (negative feedback)
Describe the rhythm of TSH release and it’s method of action
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
What long term effects can TSH have on the thyroid gland?
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.
What effects do T3/T4 have on metabolism?
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
What effects do T3 and T4 have on growth, development and normal body function?
- 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
What is the effect of hypothyroidism on a child’s development?
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.
What is the effect of hypothyroidism on adults?
Poor concentration and memory and lack of initiative.
What is T3/T4’s mechanism of action and effect on cells?
Hint: Describe how hormone binding brings about the effect on cells
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.
How does De-iodination affect T4?
What does this process regulate?
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
What is the most common cause of Hypothyroidism in adults?
Hashimoto’s disease
Affecting 1% of the population, mostly women
What is the cause of Hashimoto’s disease?
How is it treated?
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)
What are the other causes of adult hypothyroidism? (excluding Hashimoto’s)
Post surgical Radioactive iodine Anti-thyroid drugs Secondary (lack of TSH) Congenital Iodine deficiency
What are the signs and symptoms of hypothyroidism?
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)
What is the main cause of hyperthyroidism in adults?
Grave’s disease
Affects ~1% of the population, mostly women
What is the cause of Grave’s disease?
Antibodies are produces that stimulate TSH receptors on follicle cells resulting in increased production/release of T3/T4
How is Grave’s disease treated?
What is it’s method of action?
Carbimazole that inhibits the addition of iodine into thyroglobulin.
What might be the other causes of hyperthyroidism? (Excluding Grave’s disease)
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
What are the signs and symptoms of hyperthyroidism?
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
