L15-16 Thyroid Gland Flashcards
What is the largest endocrine gland
Thyroid
When you’re a little baby growing in your mommy’s tumtum, when does your thyroid gland start secreting thyroid hormone and why?
12 weeks gestation
Thyroid hormone helps myelinate the CNS and is critical in the growth of the fetus
What will happen if the fetus doesn’t have thyroid hormone?
Cretinism
What is the functional unit of the thyroid?
Follicular cell
What kind of cells release calcitonin?
Parafollicular cells
Where in the thyroid are hormones stored?
Colloid
In hyperthyroidism, what happens to the colloid?
Colloid gets reabsorbed
=increased production and release of TH into plasma
What happens to the colloid in hypothyroidism?
Decreased colloid reabsorption and thyroid hormone synthesis
What are the 4 main steps in the synthesis of thyroid hormones, and what hormone must be present for them to happen?
- Uptake of iodide from plasma
- Incorporation/Organification- putting iodide and tyrosine together
- Coupling of iodinated tyrosine to form the thyroid hormone
- Diffusion of T3 and T4 into blood
TSH is critical for every one of these steps!!!*****
NO TSH= THESE THINGS ARE NOT GONNA HAPPEN
Where are thyrotrophs?
In the pituitary gland
Which organ releases TRH?
Hypothalamus
What kind of cells does TRH target
Thyrotrophs in the pituitary
What cells are the target of TSH
Follicular cells in thyroid
TSH receptor activation results in _____________
Stimulation of all steps in thyroid hormone synthesis
Uptake, organification, coupling, and release of thyroid hormones
Biological effects of TSH
Stimulation and gene transcription of:
1. Na-Iodide symporter
- Thyroglobulin (Tg)
- Thyroid peroxidase (TPO)
- Synthesis of T3 and T4
What does the Na-Iodide symporter do?
Sucks up iodide from blood
What does thyroglobulin (Tg) do?
Its a glycoprotein that serves as a scaffold for tyrosine iodination as well as storage of thyroid hormone
(Tg contains all the tyrosine the thyroid needs)
What does thyroid peroxidase (TPO) do?
Enzyme involved in the oxidation of iodide and its incorporation into tyrosine residues of Tg
Where does synthesis of T3 and T4 occur?
In the cytosol of follicular cell AND the colloid
**synthesis is both intracellular and extracellular*
Which is a prohormone: T3 or T4
T4. It is not the most active form of thyroid hormone
Where does iodide come from?
Diet
What is the average daily intake of iodide
400μg
How much iodide is in the thyroid and what form is it in?
2 month supply (7500μg) in the form iodothyronine (or thyronines)
What is the purpose of having such a large pool of iodide in the thyroid?
Protects from iodide deficiency for about 2 months
Where does tyrosine come from?
It is endogenous
What are the ingredients of thyroid hormone
Tyrosine
Iodide
How does iodide get into the cytosol of the follicular cell?
Na-Iodide symporter (NIS) brings in 2 Na+ ions with 1 iodide molecule
The Na+ is moving down its concentration gradient which was set up by the Na/K/ATPase
(Secondary active transport)
After iodide is brought into the cytosol of the follicular cell, how does it get to the colloid?
Efflux through the iodide channel **Anoctamin-1 on the apical membrane
What allows the anoctamin-1 iodide channels to open and allow iodide into the colloid?
TSH
Which channel will be upregulated you have a low iodide diet
NIS (the Na-Iodide Symporter)
What will the kidneys do in respsone to a low iodide diet
Will reduce excretion of iodide
What two things can cause hypothyroidism?
Mutations in NIS
No iodide in diet
Why do people get goiter when they have no iodide?
WAY too much TSH, which causes growth.
No negative feedback to hypothalamus/ant pituitary from T3 or T4 to turn off the TSH flow.
What causes congenital iodide transport defect (ITD)
Mutation of the NIS gene
Na-Iodide Symporter
Hypothyroidism, goiter, and reduced uptake of radio-iodide are symptoms of____________
Iodide transport defect (ITD)
Do you have NIS (Na-Iodide Symporter) anywhere else in the body other than they thyroid?
Gastric mucosa
Placenta
Lactating mammary gland-concentrates iodide in milk to give to newborns
Are the Na-iodide symporters in the gastric mucosa, placenta, and lactating mammary gland also regulated by TSH?
NO!
Graves’ disease hormone levels:
TSH
T3 and T4
TSH: low
T3 and T4: High
What happens with Grave’s disease?
Autoantibodies are produced that ~mimic~ TSH and stimulate NIS.
Overstimulation of the thyroid gland causes high amounts of T3 and T4, and goiter.
(Low amounts of TSH since there’s so much T3, T4 causing negative feedback to hypothalamus and anterior pituitary)
What test can be done if you suspect your patient has hyper/hypothyroidism
Radioactive iodine uptake (RAIU)
What is the tracer used in Radioactive iodine uptake test
123 I
Iodine Isotope 123
Under normal conditions, how much of the 123 I should be taken up by the thyroid after 6 hours
15%
What is an organification defect?
When iodine cant be incorporated into tyrosine
If you do the radioactive iodine uptake (RAIU) on someone who has hyperthyroidism, what will you see?
A very high uptake of the tracer iodine (123 I)
What effect do perchlorate and thiocyanate have on the thyroid?
They inhibit NIS and iodide uptake, thus causing a goiter
These can be contaminants in water!
Once inside the cell, iodide is transported to the apical membrane by ________
Pendrin
At the apical luminal membrane, iodide is oxidized to iodine by _______
Thyroid peroxidase (TPO)
Oxidizing agent is H2O2
As well as secreting iodide into the follicular lumen, what else does Pendrin do
It is critical to hearing
What is Pendred Syndrome?
Mutations in the gene for Pendrin causes:
Goiter during childhood
Hearing loss
What does Tg do?
It is a long string of tyrosine residues that TPO sticks iodines onto to make DIT and MIT
In the lumen, tyrosine residues within Tg are ___________.
This reaction is catalyze by _____.
Iodinated
TPO (thyroid peroxidase)
Which carbon on tyrosine does iodine bond to
3 only or both 3 and 5
If iodine bonds to the 3 carbon on tyrosine, what molecule is made
Monoiodotyrosine (MIT)
If iodine bonds to the 3 and 5 carbons on tyrosine, what molecule is made
Diiodotyrosine (DIT)
What keeps you from making a shitload of T3/T4 when you eat a shitload of iodine?
The Wollf-Chaikoff effect.
Organification of iodine gets shut down in the colloid, independent of how much TSH you have.
=less thyroid hormone is released for a few days until intrathyroidal levels of iodine drop and the normal thyroid hormone synthesis resumes.
What enzyme couples MIT and DIT residues together?
Thyroid Peroxidase (TPO)
MIT + DIT=
T3
DIT + DIT=
T4 (Thyroxine)
Have you watched this video:
https://youtu.be/2qYBzjtm2SA
“Thyroid Hormone Production” by Handwritten Tutorials
Watch it at 1.5 speed
How do T3/T4 and (some) Tg get from the colloid to the bloodstream?
What is the name of the molecule that helps?
Follicular cells use ~endocytosis~ to engulf it and then secrete it into the bloodstream
The molecule that helps the endocytosis is called MEGALIN****
(I’m sorry I’m not totally clear on what megalin is but it’s bold and underlined on slide 20)
What happens to any leftover MIT and DIT in the follicular cell?
It is deiodinated by intrathyroidal deiodinase and the free iodine is recycled for de novo synthesis of T3/T4
Under normal conditions, does any Tg get into the blood stream?
Yes, small amounts leak out.
Hyperthyroidism causes (increased/decreased) levels of Tg in the blood
Increased
What is the name of the substance that inhibits Thyroid peroxidase?
Propylthiouracil
If you give someone propylthiouracil, what events of thyroid hormone synthesis will be inhibited?
All the things Thyroid Peroxidase does:
Oxidation of iodide
Organification
Coupling
Where does thyroid peroxidase act?
At the apical membrane (luminal)
(Does these things:
- Oxidation of iodide
- Organification
- Coupling)
What enzymes snip T3 and T4 off the Tg before they get secreted?
Proteases
Which side of the follicular cell does endocytosis to eat the T3/T4 and Tg
The apical membrane (luminal)
Which is released more: T3. T4, or rT3?
T4 is the main product 90%
T3 is 10%
And rT3 is less than 1%
What does rT3 do?
Nothing it is inactive
In the plasma, what do T3 and T4 bind to?
Thyroxine-binding globulin
Albumin
Transthyretin
Lipoprotein
How much free T3 and T4 is in the blood?
Less than 1% of the hormone is free
Almost all of it is bound to proteins
T4 is not very active and is considered a prohormone. Where does it become activated?
In the “periphery”
What type of deiodoniases act on the outer ring?
Type 1 and type 2
When T4 gets deiodinated in the outer ring, what does it become?
T3
Deiodinases Type 1 and Type 2 remove the iodine in position (5/5’)
5’
Happens in the outer ring and turns T4 into T3
What type of deiodinase works on the inner ring?
Type 3
When T4 gets deiodinated in the inner ring, what is the product?
rT3 (inactive)
Deiodinase Type 3 removes the iodine in position (5/5’)
5
Happens in the inner ring to produce rT3
Which deiodinase type(s) deactivate T3?
Type 3
Removes the Iodine on the inner ring to make T2
What type(s) of deiodinase turn rT3 in to T2?
Type 1 and Type 2
What is T2?
The deactivated form of T3 and rT3
What are the two mechanisms we have for controlling the levels of T4?
- Deiodinating it into rT3/T2
2. Conjugating it in the liver with sulfa or glucuronide to become more soluble and then excreted
Thyroid hormones have genomic and nongenomic effects. What does genomic mean?
They regulate the transcription of target genes
What are the nongenomic effects of Thyroid hormones?
Rapid effects on ion fluxes, mostly in the cardiovascular system
(Increased oxygen consumption, increased calcium channel activity to increase contractility, etc)
What are the 4 main channels for T3/T4 to get into cells?
MCT prefers T3
OATP prefers T4
LAT
NTCP
(Dont know if the last 2 are important)
What effect would mutations in the gene that codes for MCT have?
Thyroid hormone resistance
Psychomotor retardation
(T3 will not be able to get INto the cells. MCT is the transporter it uses to get in)
OATP transporter prefers (T3/T4)
T4
MCT prefers (T3/T4)
T3
Does it require energy for OATP and MCT transporters to bring T3/T4 into the cells?
Yes usually needs ATP
Once inside the cell, how do thyroid hormones regulate gene transcription?
T3/T4 will bind to thyroid hormone receptors that are in the promoter region of genes regulated by thyroid hormones.
Intracellular thyroid hormone receptors (TRs) have a greater affinity for (T3/T4)
T3. 90% of TRs are occupied by T3
Increased oxygen consumption has what 2 effects?
Increased basal metabolic rate (BMR)
Increased body temperature
How does thyroid hormone increase oxygen consumption?
Increasing activity of the Na-K-ATPase pump
The calorigenic effects of T3/T4 occurs in all tissues except:
Brain
Gonads
Spleen
What are the effects of T3/T4 on metabolism?
Increased glucose absorption from gut
Increased gluconeogenesis
Increased lipolysis
Increased protein synthesis and proteolysis (futile cycling)
Net degradation of tissue protein (negative nitrogen balance)
The cardiovascular system only responds to (T3/T4)
T3*****
What are the effects of T3 on the cardiovascular system?
Increased output and ventilation
Increased HR and contractility
Reduced vascular resistance
What are the effects of T3/T4 on the sympathetic nervous system?
Increased synthesis of β receptors in cardiac/skeletal muscles and adipocytes
What are the effects of T3/T4 on fetal development/maturation/growth?
REQUIRED for normal growth and development
Acts synergistically with GH to promote bone formation
Anabolic- stimulates protein synthesis
Normal maturation of CNS
What happens if a child is deficient in thyroid hormon?
Development is delayed
Bones do not grow
If a child has a thyroid deficiency and isn’t developing normally, can we give them artificial thyroid hormone and make them start growing?
Yes, but must be done EARLY ****
Which one (T3 or T4) feedsback to regulate the release of TRH and TSH from the hypothalamus and anterior pituitary?
T3 only!!!***
What effect will hyperthyroidism have on basal metabolic rate?
Increased
What effect does hyperthyroidism have on gluconeogenesis and glycogenolysis?
What effect does this have on blood glucose?
Increased
Blood glucose stays normal
What effect does hyperthyroidism have on protein synthesis and proteolysis?
Both are increased!
Overall effect is muscle wasting
What effect does hyperthyroidism have on lipogenesis and lipolysis?
What does this do to serum cholesterol?
Both are increased
Serum cholesterol decreased!
True or false:
Catecholamine levels reman normal in both hypo and hyper thyroidism
True!!!
BUT in hyperthyroidism you have increased expression of β receptors so you’re hypersensitive to catecholamines
What are the treatment options for hyperthyroidism?
Remove thyroid
Radioactive iodine to destroy gland
β-blockers to decrease effects of excessive adrenergic stimulation
Propylthiouracil (PTU): inhibits oxidation, coupling, decreases conversion of T4 to T3
Do you see goiter in hypothyroidism or hyperthyroidism?
Sometimes in hypo
Always in hyper
Graves’ disease is a form of hypo or hyperthyroidism
Hyper 👀
