Lecture 7: Thyroid and HPT Axis Flashcards
Where is the thyroid?
anterior to the cricoid cartilage
Describe the morphology of the thyroid
2 symmetrical lobes fused by isthmus
What is the blood supply to the thyroid?
superior (ext. carotid) and inferior (thyrocervical trunk) thyroid
How is the epithelium arranged in the thyroid?
in follicles that contain large storage of thyroglobulin (colloid)
Inactive, flattened follicles are __________ epithelium
squamous
Once stimulated by _____, follicles become active
TSH
Active follicles transform to ____________ epithelium
cuboidal
The lumen of the thyroid is filled with ___________ (30% of mass)
colloid
Parafollicular cells (C cells) produce ____________
calcitonin
Describe the morphology of the follicular cells
cuboidal shape
microvilli extend into colloid
close to fenestrated capillaries
Do the parafollicular cells touch the colloid?
NO
What are the 2 precursors of thyroid hormones (or iodothyronines?)
1) thyroglobulin (TG)
2) iodide
What is the bare minimum of iodide intake to avoid thyroid hormone deficiency?
20ug/day
If the average iodide intake is 400ug/day and we only need 20, where does the rest go?
excreted into urine
What is the Wolf-Chaikoff Effect?
intrathyroidal response that assures constancy of iodide storage in the face of changes in dietary iodide\
AUTOREGULATION OF IODIDE INTAKE
Increases in iodide intake __________ (increases/decreases) gland transport and hormone synthesis
decrease
What is a clinical tool to rapidly shut down thyroid hormone production in hyperthyroid patients?
Very high iodide doses
basically at really high doses of iodide, the thyroid does not take up a lot of it
What are the 3 thyroid hormones?
1) Thyroxine (T4)
2) Triiodothyroinin (T3)
3) Reverse triiodothyronine (rT3)
Which thyroid hormone binds to its receptor with low affinity? With high?
T4 –> low affinity
T3 –> high affinity
What form of thyroid hormone is found circulating?
T4 (tightly bound to transport proteins in blood)
Where is T3 found?
intracellularly (converted from T4)
What is the active form of thyroid hormone?
T3
What does rT3 do?
nothing, biologically inactive
Which hormone has a long half life, T4 or T3?
T4
7-8 days
What is the HPT axis?
Hypothalamus (TRH) - Pituitary (TSH) -Thyroid (T3/T4)
Where in the hypothalamus is TRH made?
PVN
gets negative feedback by T4/T3
What is the thyroid sensor in the pituitary?
intracellular T3 (imposes negative feedback)
Type II deiodinase
What inhibits TSH in the pituitary?
somatostatin, dopamine
Describe the functional polarization of the thyroid follicle?
Apical: exposed to lumen (colloid) where hormone synthesis occurs; iodination of TG
Basolateral: exposed to blood; iodine uptake “trap”
where thyroid hormone is released
Where are the thyroid hormones made?
colloid
Where are hormones iodinized?
follicle
Describe the first step of thyroid hormone synthesis
1) Iodide trapping: TSH stimulates iodide trapping by increasing activity of NIS co-transporter in basal membrane of follicular epithelial cell
What carries iodide into the follicular epithelial cell?
NIS co-transporter
stands for sodium, iodide symporter
Once iodide has been taken up by the cell, what is the second step in thyroid hormone synthesis?
2) I- is transported to the follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine (I)
What oxidizes iodide to iodine?
thyroid peroxidase (TPO)
All steps in thyroid hormone synthesis are mediated by ____
TSH
What inhibits NIS? the symporter responsible for iodide uptake?
lithium
can be used to treat hyperthyroidism
After iodide is transported to the apical membrane and converted to iodine, what happens?
tyrosyl residules on thyroglobulin are iodinated
ORGANIFICATION
What does MIT and DIT mean?
MIT = one thyroid residue iodinated DIT = two thyroid residues iodinated
What happens after iodination?
conjugation of iodinated tyrosines to form T4 and T3 linked thyroglobulin
What inhibits thyroid peroxidase (TPO)?
carbimaxole (cannot convert iodide to iodine –> cannot iodinate hormones)
What is the chemical make up of T4? (in terms of DIT/MIT)
2 DIT
What is the chemical make up of T3?
1 MIT + 1 DIT
Which hormone has the outer ring DIT and inner ring MIT?
rT3
Once T3/T4 are made and iodinated, what happens?
endocytosis (mediated by MEGALIN)
conjugated thyroglobulin with T4/T3 enters follicular epithelial cell
packaged in endosomes
What happens after endocytosis?
proteolyis (TG, MIT, DIT, T4, and T3 released from vesicle)
then secretion into circulation
How much thyroid hormone is stored in colloid?
2-3 months worth
Which protein assists with endocytosis of conjugated thyroglobulin?
megalin
What is the purpose of radioactive iodide uptake scans?
to measure iodide uptake in thyroid epithelial cell (via NIS)
What do black results indicate on radioactive thyroid scan?
sites of uptake (hot nodule)
more black area –> indicative of Graves
cold nodules are more indicative of thyroid cancer than hot
What is normal iodide uptake?
25% after 24 hours
dont have more because of Wolf Chaikoff
What is iodide uptake in hyperthyroid patients? Hypothyroid patients?
> 60%
hypo:
How do you test for an organification defect?
block NIS (with perchlorate) so iodide cannot be taken up
should still be able to convert iodide to iodine (TPO still functional)
Why do thyroid hormones have different effects on different tissues?
deiodinases
Where are Type I deiodinases?
Liver, kidney, thyroid, skeletal muscle
primary source of T3 in circulation due to their OUTER and INNER ring deiodinase
Where are Type II deiodinases?
brain, pituitary, placenta, cardiac muscle
outer ring deiodinase
Where are Type III deiodinases?
brain, placenta, skin
inner ring deiodinase
What percentage of T4 is deiodinated to T3?
80%
What are the transport proteins for thyroid hormone?
1) thyroxine-binding globulin (TBG) 70%
2) Transthyretin (TTR) 10%
3) Albumin (15-25%)
Which has a longer half life, T4 or T3?
T4 (7-8 days)
T3 (1 day)
What does T4 bind to with the highest affinity?
TBG (but it is in lowest concentration)
What increases TBG?
estrogen, hepatitis
What decreases TBG?
nephrotic syndrome, steroids
How is T4 released at target tissues?
cleaved by protease (reversible reaction)
What kind of receptor is the the thyroid hormone receptor (THR)?
nuclear (same as steroids; forms heterodimers with retinoic acid receptor)
Where is THR expressed?
nearly every cell type
Which hormone does THR have the highest affinity for?
T3 (low capacity thought)
low affinity for T4
What is the physiological function of T3?
1) Increase basal metabolic rate (BMR)
2) Promote brain (CNS) maturation (increases beta-adrenergic receptors)
How does T3 increase BMR?
- stimulates hepatic gluconeogenesis, proteolysis, lipolysis
Increases energy/oxygen consumption; increases thermogenesis (hyperthyroid patients are heat intolerant)
What does T3 do in terms of brain development?
- promotes neuronal cell migration
- myelination
- synaptic transmission
What is cretinism?
iodine deficiency during development
short stature, mental retardation
Why are hyperthyroid patients at risk for arrhythmias?
increased beta-adrenergic receptors (resting heart rate and stroke volume)
T3 increases cardiac output (increases stroke volume and resting heart rate)
Is thyroid cancer more common in women or men?
WOMEN (3:1)
How do goiters form without iodine?
excessive production of TSH, get hyper active follicular cells causing a goiter
Label these hyper or hypothyroid: Graves, Hashimotos thyroiditis, iodine deficiency
HYPER: Graves
HYPO: Hashimotos thyroiditis, iodine deficiency
What is the cause of Graves?
autoimmune - antibodies stimulate TSH receptor (called Long-Acting Thyroid Stimulator - LATS) leading to elevated levels of T4/T3 (thinks it is always on)
What is Hashimotos Thyroiditis?
autoimmune destruction of thyroid follicles (antibodies against TPO (cannot convert iodide to iodine) and TG
cold intolerance
What is thyroid storm??
Hyperthyroid coupled with severe acute illness (tachycardic, altered mental status, circulatory collapse)
treat with carbimazole and beta blockers (restore heart rate)
