Session 10: The Thyroid Gland Flashcards
Location of thyroid gland.
Neck in front of the lower larynx and the upper trachea. You can start by palpating your thyroid cartilage which is you Adam’s apple. Work your way down until you find another part of cartilage, this is your cricoid cartilage. Just below this is the isthmus of the thyroid gland.
Structure of thyroid gland, macro and micro.
Butterfly shape with two lateral lobes joined by a central isthmus. There are two nerves which lie in close proximity to the gland which are the recurrent laryngeal nerve and the external branch of the superior laryngeal. Also the thyroid is highly vascularised with three arteries supplying it and three veins which drains it. They are called the superior, middle and inferior thyroid arteries/veins.
There are two major cell types: follicular cells and parafollicular cells.
Follicular cells are found surrounding or rather making up. follicles. The follicles are then separated by connective tissue.
Parafollicular cells are found in the connective tissue which separate the follicles
The follicles are spherical and lined with epithelial follicular cells surrounding a central space which is the lumen.
What is found in the lumen?
Colloid
What is colloid?
A hormone which is rich in the protein thyroglobulin.
What type of epithelium are the follicular cells?
Single cuboidal epithelium
What hormones are produced in the thyroid? By which cells?
T4 thyroxine and Triiodothyronine (T3) are produced by the follicular cells. Calcitonin is produced by the parafollicular cells.
What is T3 and T4 derived from?
Tyrosine.
Synthesis of T3 and T4.
- Transport of iodide into epithelial cells against a concentration gradient. Oxidation of iodide to iodine occurs by thyroid peroxidase (TPO) with help of H2O2
- There is also synthesis of tyrosine rich protein which is called thyroglobulin in the follicular cells.
- Exocytosis of thyroglobulin occurs from the follicular cells into the lumen of the follicles.
- Iodination by thyroid peroxidase of the side chains of tyrosine residues in* thyroglobulin forms MIT which is *mono*-iodotyrosine and also forms DIT which is *di-iodotyrosine. Thyroglobulin acs as a scaffold on which the thyroid hormones are formed.
- Coupling occurs of DIT with either MIT or DIT to form T3 and T4 within the thyroglobulin. This is done by thyroid peroxidase.
DIT + DIT = T4 (4 iodines)
MIT + DIT = T3 (3 iodines)
Explain the embryological development of the thyroid gland.
First endocrine gland to develop.
At 3-4 weeks of gestation thyroid gland appears as an epithelial proliferation in floor of pharynx at base of the tongue* and at the *middle of it.
It descends as diverticulum through thyroglossal duct and migrates downwards passing in front of hyoid bone.
During this migration it remains connected to the tongue by the thyroglossal duct but this duct will later on degenerate.
The detached thyroid will continue to its final position over the following two weeks.
Briefly explain the absorption and uptake of dietary iodine.
Dietary iodine is reduced to iodide before the absorption which happens mostly in the small intestines.
The reduced iodide is then taken up into small intestines and further into the blood. Well in the blood it will be taken up by thyroid epithelial cells (follicular cells) which have a sodium-iodide symporter or ‘iodine trap’ on them.
Where is most of iodine in the body contained?
In the thyroid gland (90-95%)
Storage of T3 and T4.
Stored extracellularly in the lumen of the follicles as part of the thyroglobulin molecules.
Ratio of T3 to T4 production/storage.
1:10 in favour of T4.
How long would the storage of T3 and T4 last assuming no more is produced and a normal secretion rate?
Several months (2-3 months)
Explain secretion of T3 and T4.
Thyroglobulin is taken up by the follicular cells from the lumen by endocytosis.
Proteolytic cleavage ensues of the thyroglobulin to release T3 and T4.
T3 and T4 then diffuses into circulation.
Transport of T3 and T4.
Transported in the blood. T3 and T4 are both hydrophobic so they are transported bound to proteins. Usually thyroxine binding globulin but also pre-albumin and albumin.
There is only a small amount T3 and T4 that is free in solution and therefore biologically active.
What is more free in the blood, T3 or T4?
Why?
A higher percentage of T3 is free in the blood, this is because it has a slightly lower affinity for the transport proteins than T4.
This means also that T3’s half-life in the cirulcation is shorter.
Explain the control of thyroid hormone secretion.
Factors that either increase or decrease secretion.
It is mainly governed by negative feedback. An increase in thyroid hormones inhibits release of TRH and TSH. TSH inhibits release of TRH.
Synthesis and secretion of T3 and T4 is under the control of hypothalamus and anterior pituitary gland.
TRH (Thyrotropin-Releasing Hormone) is released under the influence of circulating levels of T3 and T4 due to negative feedback. Stress also increases release and a fall in temperature increases release.
TRH stimulates synthesis and release of TSH (Thyroid stimulating hormone). TSH then travels into blood and affects the follicular cells of the thyroid gland.
Structure of TSH.
Glycoprotein consisting of two non-covalently linked subunits. One alpha subunit and one beta subunit.
Assuming thyroid function is normal. How would you expect the TSH levels to vary throughout the day?
TSH is released in pulses.
It follows a diurnal rhythm meaning it is of higher levels in the night and lower levels in early hours of morning.
Action of TSH.
TSH interacts with GPCR receptors. They stimulate both GalphaS and GalphaQ.
The GPCRs are found on the surface of the follicle cells and the binding stimulates synthesis and secretion of T3 and T4.
What effect does TSH have on the thyroid gland itself?
(Think macro)
It has a trophic effect on the gland which results in increased vascularity, increased size and increased number of cells.
This can result in goitre.
What happens to T3 and T4 in pregnancy?
What are the effects of this?
Oestrogen in pregnancy increases the synthesis of TBG. TBG is the thyroxine binding globulin. This means that the amount of T3 and T4 that is free in the circulation will therefore be reduced as more TBG binds to T3 and T4.
This causes negative feedback to occur. The fall in free T3 and T4 removes the inhibition of TSH and TRH so more TSH will be released to the thyroid gland to produce more T3 and T4.
This results in the free T3 and T4 returning to normal but the total amount in the blood is increased.
Major physiological actions of T3 and T4.
Increases metabolic rate. Stimulates glucose uptake and glucose metabolism. Stimulates mobilisation of fatty acids and oxidation of them. It also stimulate protein metabolism.
The metabolic effects are mostly catabolic so there is an increase in basal metabolic rate.
Increased heat production and oxygen consumption.
T3 and T4 is also important for normal growth and development.
Affect bone mineralisation.
Increased synthesis of heart muscle protein.
CNS is affected because T3 and T4 is required for the development of cellular processes of nerve cells, hyperplasia of cortical neurons and myelination of nerve fibres.
T3 and T4 also stimulate hormone and neurotransmitter receptor synthesis. (Mainly heart and GI-tract.)
Also permissive roles in actions of hormones such as FSH and LH where if there are low levels of T3 and T4 ovulation fails.
What happens if T3 and T4 are low/almost absent from birth?
The absence from birth the child will become mentally and physically retarded. This is called cretinism or more formally Congenital hypothyroidism.
This is because T3 and T4 are needed for normal growth and development and the CNS will not develop correctly if T3 and T4 are not present.
Mechanism of action of T3 and T4.
T3 and T4 enter the cell through thyroid hormone transporters even though they are lipid soluble.
Well in they interact with high affinity receptors loctaed in the nucleus and possible in the mitochondria.
These receptors have a 10x higher affinity to T3 than T4.
Binding of T3 to hormone-binding domain is thought to produce a conformational change in the receptor that unmasks the DNA-binding domain.
Interaction of the hormone-receptor complex with DNA increases rate of transcription.
Rate of transcription leads to increased rate of protein synthesis. This stimulates oxidative energy metabolism to provide the extra energy required for protein synthesis. This also leads to increased cell activity and increased demand for energy.
Give examples of genes that are activated by thyroid hormone.
PEPCK for gluconeogenesis
Ca2+ ATPase
Na+/K+-ATPase
Cytochrome oxidase (Electron transport chain)
6-phosphogluconate dehydrogenase (Pentose pathway)
How might plasma levels of T3 and T4 change due to factors other than thyroid disease.
Methodological changes
Albumin changes
Dilution effect
Diurnal variations of TRH
The pulsatile secretion of TRH
Medications
Most common form of hypothyroidism. Does it most commonly affect men or women?
Hashimotos’ Disease
Most in women 5:1
Explain what happens in Hashimotos’.
It is an autoimmune disease that results either in destruction of thyroid follicles or the production of an antibody that blocks the TSH receptor so the follicular cells can’t respond to TSH.
Treatment of Hashimotos’.
Usually by oral thyroxine (anti-thyroid drugs). It’s usually done by synthetic thyroxine which is called Levothyroxine (T4)
Why is T4 given and not T3?
T4 can convert into T3.
Explain conversion of T4 into T3.
T4 can be converted to T3 in tissue by the removal of 5’-iodide. This usually happens in the liver. This is important for regulating the amount of active hormone in cells as T3 has 10 times the activity of T4.
Usually T4 is converted into T3 by the removal of 5’-iodide. What happens if the 3’-iodide is removed instead?
This creates an inactive reverse T3 which is called rT3.
Action of rT3.
Can bind to thyroid hormone receptors without stimulating them so it works as an antagonist to T3.
Most common form of hyperthyroidism.
Affects most men or women?
Grave’s disease.
Most in women.
Explain Grave’s disease.
Autoimmune disease in which antibodies do not block the TSH receptors but instead stimulate them.
These antibodies are called Thyroid stimulating immunoglobulin or TSI. This leads to an increased production of T3 and T4 and also a fall in levels of TSH due to negative feedback. However the fall in TSH has no effect as the thyroid gland is not stimulated by the TSH in this disease but rather the TSI.
Treatment of Grave’s disease.
Usually by anti-thyroid drugs such as carbimazole.
Action of carbimazole.
Carbimazole is a pro-drug which is the converted into methimazole in the body.
Methimazole inhibits thyroid peroxidase from coupling and iodinating tyrosines on thyroglobulin.
How long does it take for carbimazole to have an effect?
Why?
2-3 months.
Because there is still a storage of T3 and T4 in the follicles.
Causes of hypothyroidism.
Auto-immune (Hashimotos’)
Failure of thyroid gland
Iodine deficiency
TSH or TRH deficiency
Radioactive iodine
Post surgery of thyroid gland
Congenital
Anti-thyroid drugs
Post-partum thyroiditis
Dyshormonogenesis
General signs and symptoms of hypothyroidism.
Obesity
Lethargy
Intolerance to cold
Bradycardia
Dry skin
Alopecia
Hoarse voice
Constipation
Slow reflexes
Symptoms of hypothyroidism in children.
(Cretinism)
Dwarfed stature
Mental deficiency
Poor bone development
Slow pulse
Muscle weakness
GI disturbances
Symptoms and signs of hypothyroidism in adults.
Myxedema
Thick puffy skin
Muscle weakness
Slow speech
Mental deterioration
Intolerance to cold
T3, T4 and TSH levels in hypothyroidism.
Low T3 and T4 and high TSH
T3, T4 and TSH levels in hyperthyroidism.
High T3 and T4.
Low TSH.
Causes of hyperthyroidism.
Autoimmune (Grave’s)
Toxic multinodular goitre
Solitary toxic adenoma
Excessive T4 or T3 therapy
Drugs like amiodarone
Ectopic thyroid tissue
Signs and symtpoms of hyperthyroidism.
Weight loss
Irritability
Heat intolerance, sweating and warm vasodilated hands. Increased oxygen consumption and increased BMR
Tachycardia and heart palpitation
Fatigue and weakness
Increased bowel movements and possible diarrhoea
Increased appetite
Osteoporosis
Possible tremor of outstretched hands
Hyper-reflexive
Breathlessness
Loss of libido
Sweating and tremor
Investigations to test for either hypo or hyperthyroidism.
T3, T4, TSH, TSI
Also TPO antibodies
Also do a thyroid scintigraphy
Explain thyroid scintigraphy.
Technetium-99m used for isotope scanning of the thyroid with a gamma camera.
The radiation exposure is low because of the biological half-life of the technetium 99m.
Why might children get hypothyroidism?
Congenital hypothyroidism
Dyshormonogenesis (No TPO)
Iodine deficient mother
