What does the thyroid gland develop from?
Invagination of the floor of the pharynx , it tracks down as the thyroglossal duct into the neck.
Describe the gross anatomical structure of the thyroid gland.
Two main lobes, connected in the centre by the thyroid ishmus.
Usually has a pyramidal lobe which usually arises from the left of the isthmus and represents the final termination of the thyroglossal duct.
The whole gland sits on the thyroid cartilage and upper rings of the trachea.
Very well vascularised gland with one of the highest rates of blood flow of any organ in the body
Which part of the thyroid microscopic structure is responsible for hormone production?
- Follicles, and follicular acini.
- Each follicle is a single layer of epithelial cells which surround protein rich COLLOID.
- The colloid is basically full of the glycoprotein thyroglobulin.
- Each thyrocytes features a large endoplasmic reticulum and lots of small secretory granules which contain thyroglobulin
What happens to the structure of the follicles in the active and inactive states of hormone production?
- ACTIVE: the follicles are small, with larger epithelial cells of cuboid shape. Colloid is dense and small and being actively absorbed into the thyrocytes
Microvilli lining the interior surface of the follicle from the thyrocytes interact with the colloid.
- INACTIVE: follicles very large with a thin flat layer of thyrocytes surrounding them
What is the primary hormone secreted by the thyroid gland?
Thyroxine (T4).
Small amounts of triiodothyronine (T3)
Remember, T4 is less biologically active whilst the smaller amount of T3 is highly biologically active. T3 is generally made at the site of action where free T4 is deiodinated.
What is the main substrate for thyroid hormone production?
Iodine.
Describe homeostasis of iodine
- Dietary absoprtion in the small intestine primarily
- Minimum daily intake for sufficient thyroid hormone production in 150micrograms, supplementation usually comes in the form of table salt which gives people more than enough, around 500micrograms TOTAL INPUT
- The two main organs which use free circulating iodine are the thyroid gland, and the kidney which uptakes it for absorption.
120 micrograms are absorbed with about 80 micrograms used to make hormone and the remaining 40 micrograms being excreted back into ECF. - Free T3 and T4 is metabolised in the liver and thus release a further 60micrograms of iodine into the ECF
- A small amount of thyroid hormone leaves through the GIT via bile, and through enterohepatic circulation is reabsorbed. Overall 20 micrograms are lost in the stool.
How much iodine, on average, enters the ECF per day?
500 from dietary intake
40 from diffusion from the thyroid gland
60 from hepatic breakdown of thyroid hormone
= total 600micrograms per day
The thyroid uptakes 120micrograms for hormone production (20%) whilst the remaining 80% is excreted in urine and a tiny bit in stools.
How is iodine transported into thyrocytes?
- Basolateral membrane of thyrocytes contains a sodium / iodine symporter (NIS) which actively transports 2Na+ and 1I- int the cell against the concentration gradient.
- The iodide must exit the thyrocyte to access the colloid via the apical membrane, mediated by the chloride-/iodide- exchanger PENDRIN
What other glands contain the sodium/iodine symporter (NIS)?
Salivary glands Gastric mucosa Placenta CIliary body Choroid plexus Mammary glands Malignancies from these tissues - They do not contain TSH receptors though
How is T3/T4 formed?
- Iodide ions undergo ORGANIFICATION and become iodine (I), they enter the colloid by means of the pendrin exchanger which pouts one iodine ion into the collid in exchange for one chloride ion.
- Iodine is attached to tyrosine residues present on secreted thyroglobulin, a reaction catalyzed by thyroid peroxidase
- The thyroglobulin comes from the thyrocytes and is secreted into colloid by means of exocytosis
- Thyroid peroxidase is a membrane bound molecule found in the apical membrane of thyrocytes - The hormones produced are stuck onto thyroglobulin until they are required
- When thyroid hormone is required, thyroglobulin is endocytosed into thyrocytes and broken down by lyzosomes
- The bonds on thyroglobulin holding on to T3/T4 are broken down and thus they can be released into the cytosol and subsequently diffuse into the capillary bed
How much of each hormone is released per day?
- T4 - around 80 micrgrams with a half life of 1 week
- The majority is bound to thyroid binding globulin in the blood, with 20% to thyroid binding pre-albumin (TBPA or transthyretin) and 10% to albumin. A tiny amount is free circulating in serum. - T3 - 4micrograms released only, with a half life of m1-2 days. Half is bound to thyroid binding globulin with the remainder being bound to albumin. Once again a tiny amount is freely diffused into the serum.
So more T4 produced, but more T4 albumin bound in plasma than T4.
What factors increase thyroid binding globulin levels?
TBH is increased in states of increased oestrogen such as in patients receiving supplementation or those who are pregnancy.
What factors decrease thyroid binding globulin levels?
- Drugs that compete for the binding site such as aspirin, phenytoin and clofibrate
- Steroids
- Androgens (work in opposite effect to oestrogens)
- Severe liver disease
- Nephrotic syndrome
Basically, drugs who compete, and diseases which cause a state of stress to the body.
What are the main effects of the thyroid hormones?
They have a wide range of effects which essentially cause increase in metabolic rate. by means of stimulation of oxygen consumption.
Circulating thryroid hormones (T3) enter cells and bind to nuclear thyroid receptors. Remember T4 can also bind but it is not as active.
How does calcium function in the body?
99% in bone
1% in intracellular fluid
0.1% in ECF 0 either bound to albumin or free and active
Its main functions in the body is as a hormone which acts on coagulation, muscle contraction, nerve depolarisation and as a second messenger mainly.
How is calcium regulated in the body?
3 hormones involved:
- Parathyroid hormone
- 1, 25 dihydroxycholecalciferol (calcitriol)
- Calcitonin
1: Low calcium in the plasma causes PTH release from the parathyroids.
2: PTH affects two organs:
- BONE: causes increase bone resorption and decreased bone formation
- KIDNEY: Increases conversion of 25, hydroxy Vit D to 1, 25 dihydroxyvitamin D (1 alpha hydroxylase). Calcitriol has a negative feedback mechanism on PTH which decreases its production
- DCT in kidney which increases calcium resorption
3: Active vitamin D (calcitriol) has further effects on its own on the kidney by increasing calcium resorption from the PCT.
How does parathyroid hormone affect bone?
Regulates osteoblast and osteoclast activity.
Osteoclasts are essentially monocytes.
Osteoblasts express the receptor activator for nuclear factor kappa beta ligand (RANKL).
Osteoclasts express RANK. When they come into contact with cells that express the RANKL, there are two pathways initiated:
- RANK/RANKL interaction
- Mononuclear phagocytes colony stimulating factor (MCSF)
What happens when these cells come into contact is that pre-osteoclasts are matured into osteoclasts.
How is calcium resorbed from bone?
Osteoclasts erode previously formed b one. They attach to the surface with integrins and form what is called a SEALING ZONE.
This sealing zone is like a pseudolysozyme where protons are released creating a highly acidic environment of pH 4.0. In this environment, the hydroxyapetite is resorbed, the minerals being transferred from the bone to the cytosol to the interstitial fluid.
What are the main cells in the parathyroid gland?
- Chief cells which produce PTH
2. Oxyphil cells which contain oxyphil granules - function unknown
How is PTH synthesized?
Initilaly produced as part of the larger precursor: preproPTH. Prepro PTH is cleaved to form proPTH in the ER
How is PTH synthesized?
Initilaly produced as part of the larger precursor: preproPTH. Prepro PTH is cleaved to form proPTH in the ER, this is then cleaved in the golgi apparatus to form PTH.
PTH are then packaged up into secretory granules and released as the main product of the chief cells.
