C cells are known as?
Parafollicular cells
What do c cells do?
Secrete calcitonin, a peptide hormone
What does c cells cause?
Medullary corcinomas.
A neuroendocrine tumour that comprises ±5% of thyroid cancers,
arising in the C (parafollicular)
cells
Thyroid epithelial cells are also known as?
Thyrocytes
Thyrocytes are organised in what kind of shape?
spherical follicles
Follicular cells secrete?
Thyroid hormone
The thyroid secretes what 3 hormones?
T3, T4 and calcitonin
Differences between T3 and T4?
T4 is secreted in greater amounts than T3. Small amount in reverse T3 form. T3 is more potent than T4.
How is T4 converted to T3?
By a deiodinase enzyme found in many peripheral tissues
How is T3 more potent than T4? (ie greater chemical action)
Binds with a higher affinity to T3 receptors
Name the 3 types of deioninases?
Type 1 Type 2 Type 3
Type 1 deioninases?
Low affinity Converts to T4 to T3. Supply circulating T3
Type 2 deionisases?
High affinity Expressed by glial cells of CNS. Provides T3 even when T4 levels are low.
Type 3 deioniases?
Highly expressed in pregnancy. Role in regulating thyroid hormone inactivation. Convertes T4 to inactive T3
Biosynthesis of Thyroid hormone?
add pic. Iodide in uptake from the blood by thyroid follicular cell. This iodide is excreted to the follicle colloid to be oxidised to be iodine. This iodine is added to thyroglobulin (also excreted by the thyroid follicular cell by exocytosis into follicle colloid). Couple this I2-thyroglobulin and endogenesis back into the thyroid follicular cell. Thyroglobulin lysosomal degradation is the enzyme that degrades the I2-thyroglobulin to T4, T3, MIT & DIT subunits. T3 & T4 are taken up by the blood system.
What is the follicle colloid?
The space surrounding thyroid follicles.
What enzyme is responsible for the iodination and conjugation reactions?
Peroxidase enzymes
Thyroglobulin
Synthesised by thyroid epithelial cells Secreted into the lumen of the follicle.
What pump is used to take up the iodide from the blood?
the sodium-iodide symporter
Na is transported into the follicular cell down its conc gradient while iodide into the cell against its conc. gradient.
Colloid
Colloid is ingested by thyroid epithelial cells by endocytosis. Laden endosomes fuse with lysosomes, which contains enzymes that digest thyroglobulin.
DIT (diodotyrosine)
Intermediate of the biosynthesis of thyroid hormone.
MIT (monoiodotyrosine)
Iodinated amino acid involved in the synthesis of T4 &T3.
What much iodide is ingested & excreted each day?
400micrograms
How much iodide is taken up by the thyroid gland
70-80 micrograms
What is the total iodide content in the humans body and additionally and what is the consequence of having this number very high?
7500 micrograms 1% released each day. Need a few days to express iodide depletion
Regulation of thyroid hormone secretion?
Important in controlling basal metabolic rate.
Regulation of the production of thyroid hormone PKA, PKC and Cai and what does that effect in the body?
Structural domains of thyroid receptor
What is TR (thyroid receptor)?
Functions as a heterodimer with Retinoic Acid X receptor (RXR). TR-RXR binds to TRE (thyroid response element) on target gene.
What happens when Thyroid hormone (TH) isnt present?
TR-RXR represses gene trancription Recruitment of a corepressor complex HDAC containing.
What happens when thyroid hormone is present?
Corepressor complex is released. Coactivator are recruited. HAT- containing complex increase HDAC to promote transcription
Physiological effects of Thyroid hormones?
1) Accelerated metabolism (by T3 and T4 production 2) Important during growth and development 3) Sympathomimetic action (increase response to catecholamines (neurotransmitters)) 4) Cardiovascular & respiratory effects- enhances sensitivity to adrenoceptors. 5) Effects the Autonomic nervous system and catecholamine action (increase b-adrenergic receptors and intracellular second messengers) 6) Effects the nervous system (enhances wakefulness, alertness etc)
Hyperthyrodism is due to what 3 causes?
Autoimmune disease (graves disease)
Autoantibodies stimulate thyrotrophin receptors on thyroid gland follicle cells. Leading to continual stimulation of thyroid hormone synthesis.
Bengin tumour of the thyroid cells
causing enlargment glands
Increase hormone production
Excussive secretion of TS from a TSH-producing tumour
Hypothyrodism is caused due to?
Inflammatory/autoimmune disease (Hasimoto disease)
antibodies attacking specific thyroid cellular components.
Defective hypothalamic and pituitary function
Dietary iodine deficiency
Goitre
Enlarged thyroid gland (Swelling in the front of the neck)
90% causes are because of iodine deficiency.
Unnormal production of TH.
Other causes could be: graves dsease or excess production of TSH
Hyperthyrodism is when?
What does it do the body?
Too much T4 produced.
Makes everything go faster but the resistance in peripheral vascular resistance
Hypothyrodism is when?
What does it do to the body?
When too little T4 is produced.
Slows everything down. Increase resistance in peripheral vascular resistance
Graves Disease?
Weight loss despite increased intake of food.
Increase heat production (causing excessive sweating and difficulty breathing and swallowing).
Clinical signs of graves disease: protrusion of the eyeball (exphthalmia) and puffy eye (periorbital edema)
TSH levles are low (the hypothalamus and pituitary are inhibited by the high levels of T4 and T3)
Differences between Graves disease and Pituitary adenoma?
Graves is a primary endocrine disease while pituitary adenoma is a secondary endocrine disease.
Graves increase in TSI and decrease in serum TSH while pituitary is the opposite
Treatment for Hyperthyroidism?
Surgery (partial or complete removal of gland)
Drugs (thioureylene)
What is thioureylene?
It is an antithyroid drug
Effects of Thioureylenes?
Orally active (inhibits thyroid hormone synthesis)
Prevents iodination by interfering with peroxidase enzyme action.
Hormone synthesis inhibited rapidly but fall in hormone levels and effects takes several weeks since the glands have large pre-existing hormone stores and because T4 is tightly bound to binding proteins- leads to slow T4 metabolism.
Radioiodine?
Major method of treating hyperthyroidism.
Taken orally as capsules of radioactive sodium iodide.
Produces gamma-rays and b-particles: causing localized cell damage to thyroid follicular cells.
Used as single administration and half life of about 8 days.
May produce hypothyroidism if too much gland damage.
Potassium iodide and iodine as treatment?
Intake of iodide exceeds 2mg/day: intraglandular conc. reaches a level to surpress NADPH oxidase activity.
Autoregulatory phenomenon known as Wolff-Chaikoff effect.
Hence giving a mixture of potassium iodide and iodine (lugol's solution)
Inihibitory effects for up to 2 weeks.
Used as short-term thyroid suppression. (few days before surgery)
Where is the iodine converted to iodide in the body?
Ingested iodine is converted to iodide by the liver
Propraolol use?
No direct effect on thyroid hormone sythensis or release
Used to block noradrenaline overstimulation.
Used for patients awaiting gland surgery.
Treatment of hypothyroidism?
Replacement therapy: synthetic T4 and T3 injected.
T4 is obviously the first choice but takes a while to build up as it binds to blood plasma proteins.
T3 in emergencies: due to rapid action compared to T4.
Source and Transport of T3 in the brain?
T4 enters a glial cell and is converted to T3 by D2 (type 2 dioioninase).
T3 exits the cell and is transported into a neurone my MCT8.
add pic
MCT8 mutations?
Located on the X chromosome.
Therefore more severe effects on males as they only have one X chromosome. Deleterious mutations results in Allan-Herndon-Dudley syndrome. Neurological abnormalities.
Females have 2 copies: heterozygous. Mild thyroid phenotype 50% of passing it onto son.
What intracellular components produced thyroglobulin?
Endoplasmic reticulum and golgi complex
What has to occur for bound T3 and T4 to be detached from the thyroglobulin molecule.
Internalise a portion of the thyroglobulin-hormone complex into the thyroid follicular cell.
The membrane-enclosed droplets of colloid coalesce with lysosome, whose enzymes chop T3 and 4 as well as MIT and DIT.
How can T3 and T4 freely pass into the blood stream from follicular cells?
They are lipophilic
Recycle of iodide to produce more T3 and T4? HOW?
Iodinase swiftly removes the iodide from MIT and DIT, allowing the freed iodide to be recycled for synthesis of more hormone.
What plasma proteins do T3 and T4 bind to in the blood?
Thyroxine-binding globulin
Selectively binds to only thyroid hormone.