Endocrinology 5- HPT Axis Flashcards
Where does the thyroid gland sit
Above cricoid cartilage
Blood supply for thyroid gland
Superior (ext. carotid) and inferior (thyrocervical trunk) thyroid arteries; venous plexus on surface gives rise to suerior, middle, and inferior thyroid veins which drain into jugular
ANS innveration of thyroid gland
Middle and inferior cervical ganglion (sympathetic nevous system)
Thyroid follicle
epithelial cells surrounding lumen (lumen filled with colloid, 30% of thyroid mass, thyroglobulin is a major cmponent)
parafollicular cells (C Cells)
produce calcitonin, other proteins that maintain follicle
Do parafollicular cells touch colloid?
No
Effect of TSH on epithelial cell sof thyroid gland
becme cuboid in shape (they are active)
What kind of hormone is thyroid hormone
AMine
They are called iodothyronines
What are the 2 precursors to thyroid hormone
thyroglobulin (TG) and iodide
Where is most exccess iodide excreted?
urine
Wolf-Chaikoff effect
An intrathyrodial response that ensures consistence of iodide storage in face of changes in dietary iodide. increases in iodide intake decrease gland transport and hormone synthesis. Therefore, in clinic, high iodide doses can be used to rapidly shut down thyroid hormone production in hyperthyroid patients.
Thyroxine – Which “T” is it, half life length, how does it travel in blood, binds to receptor with what kind of affinity
T4
Long half life in plasma (7-8 days due to tight binding to transport protein)
binds to receptor with low affinity
Triiodothyronine – which “T” is it, what is significant about this vs thyroxine and how do we get it, binding with receptor is like what?
T3
Primary active form, most is converted intracellularly from T4, binds with high affinity and low capacity to receptor
Reverse triiodothyronine – Which “T” is it, and what is significant about it?
rT3, biologically inactive
HPT axis overview
Hypothalamus releases TRH from PVN (this area experiences negative feedback by T4/T3, impacts synthesis). This goes to pituitary thyrotropes and leads to release of TSH (which can be negatively fed back on by T3 and acts as “thyroid sensor). These can also be inhibted by somatostatin and dopamine. Then the TSH will go to thyroid gland cells and lead to increasng every aspect of thyroid hormone synthesis and release
Negative feedback in HPT axis
T4/T3 will stop PVN from releasing TRH
T3 will stop thyrotropes from releasing TSH
Other inhibition in HPT axis (not T3/T4 directly)
Somatostatin and dopamine will tonically inhibit thyrotropes
What kinds of cells in thyroid gland does tsh stimulate
follicular cells
Where is the receptor for TSH
Cell surface on follicular cells
Where does thyroid hormone synthesis take place in thyroid gland
in colloid space
where does iodide come from for thyroid gland and how is it brought into follicular cells
blood, brought in through a sodium-iodide symporter, transported through folicular epithelial cell against electrochemical gradient (requires energy)
Step 1 in thyroid hormone synthesis
Iodide trapping
TSH stimulates iodide trapping by increasing the symporter activity, transporting against electrochemical gradient and trapping the iodide in the cell.
What can impact the use-ability of the sodium iodide cotransporter
lithium - it can be taken up by sodium channel and gets stuck there
Step 2 in thyroid hormone synthesis
Transport - iodide transported to follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine – the thyroglobulin is then transported to lumen.
Step 3 in thyroid hormone synthesis
iodination - iodination of tyrosyl residues on thyroglobulin.
TG has tyrosines hanging off. Iodination/organification adds on the iodination through creating MIT/DIT
Step 4 in thyroid hormone synthesis
Conjugation
You must conjugate iodinated tyrosines
Step 5 in thyroid hormone synthesis
Endocytosis - conjugated thyroglobulin with T4/T3 enters follicular epithelial cell again and is packaged into endosomes.
Step 6 in thyroid hormone synthesis
Proteolysis - Thyroglobulin, MIT, DIT, T3/T4 area all released from vesicle and you get step 7
Step 7 in thyroid hormone synthesis
Secretion - T3/T4 are yeeted into circulation
7 Steps of thyroid hormone synthesis
- iodide trapping
- transport
- iodination
- conjugation
- endocytosis
- proteolysis
- secretion
If you put 2 DIT’s together and conjugate them what is the result
T4
If you take 1 DIT and 1 MIT together hat is the result
T3 or reverse T3
What is the diffrence between T3 and reverse T3
Reverse T3 has the second iodination (the DIT) on the outer ring. T3 has MIT as the outer ring.
Carbimazole
Drug which inhibits thyroid peroxidase (TPO)
What is the enzyme that adds iodine to tyrosine
tyrosine peroxidase
Radioactive iodide uptake scan
Thyroid hormone is very fucking good at taking up iodine –>
Put radiolabeled iodine in blood and look at it on an image after allowing 24h for uptake –> what you see is an outline of the two lobes in the thyroid gland.
You can also use other anions to determine function of thyroid gland too
Hot nodule on radioactive iodide test for thyroid gland would mean
You could have one follicle or a cluster of follicles which are overactive and not responding to wolf-chaikoff effect anymore
Cold nodule on radioactive iodide test
Area not responsive of iodine – predictive of malignancy
Normal uptake of thyroid gland of iodide after 24h
25%
Percent iodide uptake for hyper or hypothyroidism
Hyper = >60% (uptake of iodide will seem continuous)
Hypo <5% (uptake of iodide will seem to be very low and plateau quickly)
Extreme situation of thyroid gland with high turnover – what would we see as far as iodide uptake over 24h
Rapid uptake, dip, and if we add more it would be rapid uptake again – this is what we see in Grave’s disease, because follicles are overactive and takes iodide up as fast as possible, makes it, spits it out as fast as i can, and ten starts over (rapid turnover of thyroid hormones)
Organification defects look like what for iodide uptake over 24h and how you test for it
IOdide cannot be put onto the tyrosine residue, so if it can’t be put on we say this is an organification defect – how do you test that? You inject radioactive iodide into patient and let thyroid gland take it up, then block the symporter with perchlorate. If you block this symporter all radioactive stuff in blood cannot get in and anything taken up before is already there - if there is no organification defect, it should be stufck in there and you continue to see it. However, if there is an organification defect it isn’t stuck because electrochemical gradient is opposite way you should see nothing after blocking sympoter because iodine will leave via diffusion through cell membrane.
Type 1 peripheral conversion of thyroid hormone
Outer and inner ring deiodinase
liver, kidney, thyroid, and skeletal muscle
primary source of T3 in circulation
If we take off outer ring, we’re making active T3 – if we take off inner, we make inactive T3 (rT3) – this one can make both
Type II peripheral conversion of thyroid hormone
Outer ring deodinase
Brain, pituitary, placenta, cardiac muscle
This one ONLY makes active T3– this is referred to as the thyroid sensor of the pituitary gland because it is highly expressed in thyrotrophs and we need T3 for negative feedback - therefore, this ensures signal gets around to pituitary to shut off system.
This is very important for development
Type 3 peripheral conversion of thyroid hormone
Inner ring deiodinase, only makes inactive form
brain, placenta, skin
high expression in brain and placenta where we have to control expression of TH and T3. Reverse T3 is a biological safety mechanism–so tissues can make it if we have too high levels of TSH and active TH
How is thyroid hormone transported in blood (ex. how is 99% of itgoing?)
Bound to transport proteins, especially TBG (thyroxine binding globulin) and transthyretin (TTR), with some bound to albumin
where are thyroid hormone binding proteins made
liver
Do changes in binding proteins change the amount of free thyroid hormone in plasma
not really because there’s never really any free thyroid hormone in circulation, its almost always tightly bound. If you think about it this makes sense; it would otherwise be degraded very fast. The binding proteins also deliver the TH to the taget cell, get cleavage, and then can be reused, unlike other binding proteins
When thyroid binding globulin has the thyroid hormone it carries cleaved, what happens to it?
It binds another thyroid hormone immediately after
Half lives of T4 and T3 when bound
T4- very long, like a week
T3- a day
Unbound they die almost immediately
What kind of receptor is the thyroid hormone receptor
nuclear receptor - dimerizes with retinoic x receptor (same family as steroid hormones, means thyroid hormone goes inside cell)
Thyroid hormone receptor interaction with T3 - affinity, capacity?
High affinity low capacity
Thyroid hormone interaction with T4- affinity?
Low affinity- very little biological activity at physiological concentrations
In the cell, how do you get T4 –> T3?
The D2 deiodinase primarily
Major functions of thyroid hormone
increase basal metabolic rate (stimulate hepatic gluconeogenesis, stimulate proteolysis,stimulate lipolysis and overall increase energy/oxygen consumption , increasing thermogenesis)
Promote CNS maturation
Increase b-adrenergic receptors (heart, skeletal muscle, adpiose tissue – remember, the receptor is a TF)
in what way does thyroid hormone stimulate basal metabolic rate
stimulate hepatic gluconeogenesis
stimulate proteolysis
stimulate lipolysis
If you are hypothyrid, what would you expect to happen to carb metabolism
less gluconeogenesis and less glycogenolysis, but normal serum glucose
if you are hyperthyroid what would you expect to happen to carb metabolism
increased gluconeogenesis and glycogenolysis
normal serum glucose overall
If hypothyroid what would you expect to happen to protein metabolism
less synthesis, less proteolysis
If you have hyperthyroidism what would you expet to happen to protein metabolism
more synthesis, more proteolysis, but overall mucsle wasting
If you are hypothyroid what would you expect to happen to lipid metabolism
Decreased lipogenesis, decreased lipolysis, overall increase in serum cholesterol
if you are hyperthyroid what do you expect to happen to lipid metabolism
increased lipogenesis, increase in lipolysis, and overall decrease in serum choleserol
Thermal handling in hypothyroid individual
intolerant to cold (decreased)
thermogenesis in hyperthyroid individual
heat intolerant (increased thermogenesis)
What is important to notice about thyroid hormone effects on metabolism
they are futile cycles (ex. when you increase gluconeogenesis you’re also increasing glcogenolysis and there’s no serum glucose changes, protein synthesis and degradation change in same way at same time, etc)
How does T3 affect brain development
required for normal neuronal cell migration/differentiation melination, and synaptic transmission
what happens if you don’t have enough iodine in utero
congenital hypothyroidism - short stature, impaired bone formation, severe cognitive impairment, delayed motor development
How does T3 affect the heart
Increases cardiac output- resting heart rate and stroke volume icrease.
Hyperthyroidism can cause arrhythmias due to increased beta adrenergic receptors
how can hyperthyroidism cause arrhythmias
increased beta adrenergic receptors
What is a goiter, essentially
enlarged thyroid glands
Is goiter necessarily a sign of hyperthyroidism
it can be but you can get a goiter if you have hypothyroidism as well, it is a cause of TSH stimulating the thyroid gland
can you tell if someone is hyper or hypo thyroid based on goiter presence
no
Grave’s disease
Making LOTS of thyroid hormone, this is due to a self-antibody called long acting thyroid stimulator that binds and activates TSH receptor - this is a TSH independent problem (so no TSH is made, but it’s being stimulated as if lots of TSH was made because receptor is the one that sends the message).
You get tachycardia, opthamopathy (bulging eyes), irritability, hyperactivity, heat intolerance, weight lice despite normal or high appetite, muscle wasting, nevousness
Hashimoto’s thyroiditis
Autoimmune destruction of thyroid follicles due to antibodies against TPO or TG. You get a goiter but have hypothyroid symptoms - lethargy, fatigue, hair loss, cold intolerance, brittle nails, decreased appetite, weight gain. You initially have agoiter due to TSH stimulation, but as gland is destroyed you get atrophy (advanced stage of disease)
Thyroid storm
emergency situation with undiagnosed hyperthyroid or untreated hyperthyroid and then you get an infection – must immediately block TPO and use beta blockers to restore heart function. Death is caused by severe circulatory collapse. – cardiac output is high but you can’t perfuse everything
How would we know if someone has a failure at the thyroid gland (primary disease)
Lack of negative feedback, so TSH at baseline should be high. Stimulation with TRH increases TSH and it returns to baseline, which means pituitary is making tSH and responding to TRH correctly. We also know because it’s making a lot of TSH there must be endogenous TRH as well, so we can conclude this patient is failing at level of thyroid gland, but you can also try a test to see iodine uptake or how body responds to T3/T4
how do you know if someone is having a pituitary hypothyroidism and thyrotoxosis?
Measure at baseline - nothing, no T3/T4
Stimulate with TRH - nothing
* it should be since there is no T3/T4 at baseline
Says probably a pituitary issue
How do you know if someone has a tertiary hypothyroid disorder
Normal high baseline, slow response, and then protracted return to baseline when giving TRH to these patients. Tells us pituitary is still working (getting some pituitary TSH release but not as high as we would expect) - can respond to TRH but isn’t doing much - after lack of RH you would get a downstream downregulation of receptor, so you have a long time to recycle recpetors to membrane to get response –> protracted response.
how do you know if someone has euthyroid syndrome
looks a little like tertiary problem, but there’s nothing wrong with thyroid gland at all - reason T3/T4 is low is something to do with something going on in body such as renal failure and anorexia. As soon as you fix the other issues, the thyroid hormone problem resolves. Therefore TSH and thyroid are both normal.
