Thyroid Physiology and Intro to Endocrinology Flashcards
Where does the thyroid sit?
Anterior to the third tracheal ring
Between C5- T1
What are the three main arteries supplying the thyroid and their origins?
Superior thyroid artery (first branch of external carotid)
Inferior thyroid artery (thyrocervical trunk)
(10%) Thyroid ima (brachiocephalic trunk, arch of aorta)
What are the three main veins draining the thyroid and where do they drain into?
Superior thyroid vein (internal jugular vein)
Middle thyroid vein (internal jugular vein)
Inferior thyroid vein (brachiocephalic vein)
Why is it possible to remove part of the thyroid?
Because it has numerous blood supplies that can take over if arteries/veins are removed
Which parts of the thyroid does the superior thyroid artery supply?
Superior and anterior parts
Which parts of the thyroid does the inferior thyroid artery supply?
Posterior and inferior parts
What three hormones does the thyroid make and secrete?
Thyroxine (T4)
Tri-iodothyronine (T3)
Calcitonin (calcium homeostasis)
What are T4 and T3 derivatives of?
Tyrosine
T4 has 4 molecules of ___
Iodine
T3 has 3 molecules of ___
Iodine
Which cells make calcitonin?
Parafollicular (C) cells in the thyroid
Where are thyroid hormones made and stored?
Inside the follicular cells of the thyroid
What are the six steps of thyroid hormone synthesis?
Thyroglobulin synthesis
Uptake and concentration of iodide
Oxidation of iodide to iodine
Iodination of thyroglobulin
Coupling of 2 iodinated tyrosine molecules
Secretion
Are T3 and T4 fat soluble?
Yes
How is T3 and T4 transported in the blood?
By plasma proteins -
Thyronine Binding Globulin (70%)
Albumin (30%)
How does iodide enter the thyroid cell?
Iodide trapping
Draw the diagram (slide 11)
By a Na Iodide symporter (NIS) (both move in together)
Can move into the cell against a concentration gradient.
Uses energy provided by Na/K ATPase pump that moves Na+ out of cell and K+ in
Allows the thyroid to concentrate iodide.
What are some dietary sources of iodine?
Why do we need to trap iodide?
Milk and dairy Seafood Sea salt Fruit and vegetables Sauerkraut Supplemented salts
Need to trap iodide because it is rare in our diet
Which transporter is used to get iodine from the follicle cell into the follicular lumen?
Pendrin
Which transporter is used to get iodine from the blood into the follicle cell?
Na Iodide symporter (NIS)
What converts iodide to iodine?
dirty to clean
An enzyme called thyroid peroxidase (TPO)
Where does thyroglobulin synthesis take place?
Follicle cell
What does iodine join with?
Tyrosine on the thyroglobulin chain
What is MIT?
Mono-iodotyrosine
1 iodine joined to a thyroglobulin chain
What is DIT?
Di-iodotyrosine
2 iodine molecules joined to thyroglobulin chain
What makes T3?
MIT + DIT = T3
What makes T4?
DIT + DIT = T4
How is the thyroglobulin backbone with MIT, DIT, T3 and T4 taken into the follicular cell from the colloid?
Engulfed by microvilli on follicular cell and make vesicles out of colloid
What attaches to the vesicles of TG chain when it is in the follicular cell?
Lysosomes
What do lysosomes release when they attach to vesicles?
Protease
What does protease do in the follicular cell?
Breaks down molecules:
Releases thyroglobulin + MIT & DIT that did not attach properly back into the colloid via pendrin
Releases T3 and T4 into the blood
Where is thyroid peroxidase (TPO) found?
On the luminal membrane of the follicular cell
WHITE BOARD:
Draw out T3 and T4 synthesis on a whiteboard and use PowerPoint slide/hand drawing to mark
See slide/drawing
Where is TSH released from?
Anterior pituitary gland
WHITE BOARD:
Regulation of secretion of T3 and T4
negative feedback loop, endocrine glands
Hypothalamus - TRH
TRH —> Anterior pituitary
Anterior pituitary - TSH
TSH —> Thyroid
Thyroid - T4, T3
Increase in T4 and T3 decreases production of TRH from hypothalamus and TSH from anterior pituitary
Where is TRH released from?
Hypothalamus
Out of TRH, TSH, T4, and T3, which are tropic and which are trophic?
Tropic - TRH, TSH
Trophic - T3, T4
What is the relationship between TSH, LH and FSH?
All are glycoproteins with alpha and beta chains
Alpha chains are identical to each other
Beta chains are protein specific (individual to each hormone)
How does TSH increase production of thyroid hormones?
Increases every step of production and secretion of T3 and T4
Why can’t thyroid hormones dissolve in blood?
They are lipophilic (fatty)
Which of the thyroid hormones is active and which is inactive?
Which one is produced more?
T3 - active, body produces less
T4 - inactive, body produces more
Thyroxin binding globulin (TBG) has a higher affinity for ____
T4
Why can diseases of the liver affect thyroid hormone circulation?
30% of thyroid hormones in the blood are bound to albumin which is made in the liver
What does T3/T4 have to do to enter the target cell?
Be unbound from plasma proteins
T4 has to change to T3 to bind to the receptor
What is the name given to the enzymes that convert T4 to T3?
Deiodinases
How many types of deiodinases are there?
3 types
They are tissue specific
Why can different tissues produce different responses to circulating thyroid hormones?
There are tissue specific enzymes called deiodinases that either activate or deactivate thyroid hormones
What is the name of the transporter that allows thyroid hormones into a target cell?
MCT8(10)
How do thyroid hormones have an effect on target cells?
They bind to receptors inside the target cell.
Receptor-hormone complex moves to the nucleus where it binds to DNA and alters protein synthesis
This will then produce a thyroid hormone response.
What 4 broad effects to thyroid hormones have?
Metabolism - affects basal metabolic rate (BMR)
Maturation and differentiation
Neurological function
Growth
By which week of gestation does a fetus make and secrete its own thyroid hormones?
Week 12
Define Cretinism
Impaired physical and neurological development due to iodine deficiency during foetal or postnatal development
How do we screen newborns for TSH?
Heel prick test
Explain why an excess of T3 will increase ventilation rate
T3 increases the amount of mitochondria respiratory enzymes and basal metabolic rate.
More O2 is needed to meet the demand.
Hyperventilation occurs, alongside increased HR and blood flow to supply the O2 to tissues
Why does hyperthyroidism increase the patient’s temperature?
Because their metabolic rate has increased due to excess T3
Why does hyperthyroidism increase the patient’s appetite?
Because the patient is ingesting substrates for O2 consumption as a result of the increased metabolic rate caused by excess T3
e.g. proteins/lipids/carbohydrates
What can cause clinical problems of the thyroid (2 broad categories)
Thyroid gland function
- gland formation/function
- iodine supply
- signalling pathways
- congenital or acquired
Response to T3/T4
-thyroid hormone resistance (T3R defect)
What does a thyroid function test (TFT) measure?
TSH
T4 (free)
T3 (sometimes, free)
What blood results would you expect to see in hypothyroidism?
TSH - high
T4 - low
What blood results would you expect to see in hyperthyroidism?
TSH - low
T4 - high
List some common symptoms of hyperthyroidism
Palpitations/rapid pulse Diarrhoea Heat intolerance Tiredness Weak muscles Nervousness Thirst Polyuria Goitre
What is the name for a sever form of hyperthyroidism?
Grave’s disease
Exophthalmos
List some common symptoms of hypothyroidism
Fatigue Tiredness Sensitivity to cold Constipation Dry skin and hair Alopecia (outer 1/3 of eyebrow) Low mood Goitre
What is the name of the autoimmune disease that can cause hypothyroidism?
Hasimotos thyroiditis
How does hypothyroidism cause a goitre?
Low levels of iodine decrease the amount of T4 produced
Decrease in T4 signals anterior pituitary gland to secrete more TSH.
The thyroid is still unable to make T4 because of the iodine deficiency
The thyroid hypertrophies because the number of cells increases in an effort to increase levels of T4 in response to an increase in TSH
How does Grave’s disease (hyperthyroidism) cause a goitre?
The autoimmune disease produces thyroid stimulating immunoglobulin (TSI) which mimics TSH
TSI will increase the amount of T4 produced by the thyroid
Increase T4 will decrease TSH production from anterior pituitary.
However decreased TSH will not decrease T4 because there is still TSI working to increase T4.
This causes hypertrophy of the gland, causing a goitre
What are the 3 treatments for hyperthyroidism?
Drugs (inhibit production)
Radioactive iodine (destroy gland)
Surgery
What are the treatments for hypothyroidism?
Levothyroxine (synthetic T4) - aim for normal TSH in response to treatment
Liothyronine (synthetic T3)
What type of gland is the thyroid gland?
An endocrine gland
Define endocrinology
The study of the endocrine glands and the substances they secrete
Define endocrine gland
A gland that makes and secretes hormones into the BLOODSTREAM, through which they travel to affect DISTANT targets
Define hormone
A chemical substance produced by cells and released especially into the blood and having a specific effect on cells or organs usually at a distance from the place of origin
Define exocrine gland
A gland that secretes its products through DUCTS opening into an epithelium rather than the blood
Define paracrine
Acts on adjacent cells
Define autocrine
Acting on surface receptors of the same cell it is secreted from
What type of signalling to neurotransmitters display?
Paracrine (adjacent cell)
What type of input does the endocrine system receive?
Chemical and physical stimuli
What type of response does the endocrine system display?
Chemical response
Name some endocrine organs
Hypothalamus Pituitary Thyroid Thymus Adrenal glands Pancreas Kidneys Ovary Uterus Testes
List the main endocrine hormones
Glucocorticoids
Insulin, glucagon
Thyroid hormones
Gastric hormones (CSK, gastrin)
Enteric hormones
ADH, RAAS hormones
What are the three major molecular types of hormones?
Polypeptides (chains of amino acids)
Modified amino acids (proteins)
Steroids
Name some hormones derived from amino acids
Serotonin (single)
Thyroid hormones (dipeptides)
Insulin
FSH, TSH, LH (complex polypeptides)
Name some hormones derived from lipid precursors
Cholesterol (sex steroids, vitamin D)
Fatty acids (prostaglandins)
Where on the cell do amino acid-derived hormones have their receptors?
Cell membranes
Where on the cell do lipid-derived hormones have the receptors?
Intracellular
sex hormones
Why do lipid hormones have intracellular receptors?
Because they are usually hydrophobic
How are protein and peptide (amino acid) hormones released from cells?
Exocytosis in secretory vesicles
How are steroid hormones released from cells?
Diffusion
Define primary endocrine dysfunction
Too much of the effector hormone (trophic) from endocrine organ
Define secondary endocrine dysfunction
Overstimulation of the effector endocrine organ by excessive tropic hormone
What is Cushing’s Syndrome?
Excess of glucocorticoid
List the 6 steps of protein and peptide hormone synthesis:
A. Gene transcription
B. mRNA to rER
C. Translation on rER
D. Post-translational processing
E. Packaging into secretory vesicles
F. Exocytosis
List the 4 steps of steroid hormone synthesis:
- Hydrolysis of esters and release of cholesterol/Ch. uptake
- Cholesterol to pregnenolone
- Processing
- Diffusion
List some key differences between protein/peptide and steroid hormone synthesis:
Protein + peptide
1. Involves gene transcription
- Translation on the rER
- Undergoes exocytosis in secretory vesicles
Steroid hormones
1. No gene activation/ transcription
- Cholesterol is changed to pregnenolone in the mitochondrion
- Processing happens on the sER
- Hormones diffuse through the plasma membrane
- Type and activity of enzymes determines type and amount of hormones
- Indirect genetic control of production of steroid hormones - enzymes that help with the process are controlled by genes
What subunits can a G-protein coupled receptor have?
Alpha
Beta
Gamma
What do protein kinases do?
Add phosphate groups
Draw the pathway from activation of a G-protein to release of Ca2+ from the endoplasmic reticulum
Binding to G-protein coupled receptor
Activated G protein stimulates activity of phospholipase C
Stimulates IP3
Release of Ca2+ from endoplasmic reticulum
Draw the pathway from activation of a G-protein to release of protein kinases
Binding to G-protein coupled receptor
Activated G protein stimulates activity of adenylate cyclase
Adenylate cyclase takes ATP and cyclizes it to cAMP (removes 2 phosphates, energy gain)
This produces a second messenger which stimulates protein kinases (+ phosphate groups to things, usually activating them)
Describe the tyrosine kinase receptor system
Signalling molecule binds to receptor which brings the 2 halves of the receptor together
The receptor uses energy from ATP –> ADP and the spare phosphate groups to phosphorylate the receptor into an active form (Dimer)
Proteins recognise the phosphorylated form and they become active (phosphorylate)
Active proteins bring about cellular changes
List some major features of water soluble hormones
Are large and hydrophilic
Cannot pass through membranes
Bind to cell surface receptors (GPCR/tyrosine kinase)
List some major features of fat soluble hormones
Steroids and thyroid hormones
Large and hydrophobic (lipid soluble)
Bind to intracellular and cell surface receptors
What is a tropic hormone?
A chemical signal released from an endocrine gland that tells another endocrine gland to increase or inhibit secretion
What is an effector hormone?
A hormone released from a gland that has an effect on a target cell
What is a trophic hormone?
A hormone that affects growth and development directly
Use the words tropic and trophic to describe negative feedback
Endocrine organ releases a tropic hormone
Has an effect on another endocrine organ
2nd endocrine organ releases a trophic hormone which stimulates growth and development
Release of trophic hormone inhibits the action or tropic hormones upstream which inhibits the release of the trophic hormone
Give an example of hormones producing a positive feedback cycle
Oestrogen causing increase in luteinising hormone (release of ovum)
What can cause an excess of a hormone?
Neoplasm (CA)
Hyperplasia
Ectopic production
What can cause a hormone deficit?
Gland destruction (trauma, disease, autoimmune)
Undeveloped gland
What can cause hormone resistance (failure to respond)?
Receptor problems
Intracellular signalling defects
Where are glucocorticoids made?
Adrenal glands
What is the plasma half life of a peptide (amino acid) hormone compared to a steroid/thyroid (lipid) hormone?
Amino acid half life is seconds - minutes
Steroid half life is minutes - days
Draw hormone synthesis for protein and peptide hormones, and steroid hormones.
Where on the rER does mRNA bind to to undergo translation?
Slide 18 of intro to endo lecture
Ribosomes on the rER
List some features of a hydrophobic hormone
Transported bound to plasma proteins - binding affinity is important
The hormone when it is bound is considered inactive, is protected from degredation and acts as a reservoir
What type of receptor is the insulin receptor?
Tyrosine-kinase receptor system
What type of receptors do water soluble hormones bind to. Give examples
Cell surface receptors
G-protein coupled receptors
Tyrosine kinase receptors
Outline the typical pathway that a steroid hormone takes to produce new proteins.
Typically transfuses through the cell (although can bind to receptors on cell surface)
Binds to cytoplasmic or nuclear receptor to produce an activated transcription factor
Transcription produces mRMA
Translation on ribosomes of rER
New protein made
Where are ‘releasing hormones’ released from?
Where do they normally go to?
The hypothalamus
Anterior pituitary gland
What is Addison’s disease?
List some symptoms
Hypo-adrenalism
Reduced glucocorticoids (CORTISOL) and mineralcorticoids
Weight loss, anorexia Weakness Fever Depression N + V Diarrhoea/constipation Confusion Abdo/back pain
What is Cushing’s syndrome?
List some symptoms
Glucocorticoid (CORTISOL) excess
Weight gain Moon face Depression, psychosis Insomnia Thin skin, bruising Back pain Polyuria
What, that is attached to thyroglobulin, eventually makes thyroid hormones?
Tyrosines attached to thyroglobulins eventually make thyroid hormones
Where is the majority of iodine found?
Why is this useful?
In the colloid of the follicles
The follicles accumulate iodine from the blood and secrete it into colloid
Useful for imaging - inject radioactive iodine
Describe a type 1 deiodinase
Cell surface of most cells (especially liver, kidney, thyroid, brain)
Inner and outer ring deiodination
ACTIVATING T4 –> T3
Describe a type 2 deiodinase
Intracellular - CNS, brown fat, placenta, skeletal and cardiac muscle
Outer ring deiodination
ACTIVATING T4 –> T3
Describe a type 3 deiodinase
Placenta + CNS
Removes iodine from T4 to make reverse T3.
Inner ring deiodination
INACTIVATING T4 –> rT3 –> T2
Where is T4 converted to T3?
Inside a target cell by deiodinases
What autoantibody does Grave’s disease produce?
Thyroid stimulating immunoglobulin
Acts like TSH
Low TSH
High T4
What is Hasimotos thyroiditis?
Autoimmune destruction of the thyroid gland that leads to hypothyroidism
High TSH
Low T4
