Physiology - Endocrinology of the Thyroid Gland Flashcards
What are the 2 iodotyrosils?
MIT and DIT
What is MIT?
Monoiodotyrosine
What is DIT?
Diiodotyrosine
Where is the 1st iodide added onto to Tyr?
3’
Where is the 2nd iodide added onto to Tyr?
5’
What is T3?
MIT + DIT
What is T4?
DIT + DIT
How many iodides does T3 have on the outer ring?
1
How many iodides does T4 have on the outer ring?
2
Which thyroid hormone is the active one in the body?
T3
What are T3 and T4 bound to? Which one is more bound that the other?
Thyroid hormone binding globulin (TBG) (~70% of it)Higher percentage of T4 is bound (99.97% T4 bound vs. 99.7% T3 bound)
What is reverse T3? When is it created? What is it a sign of?
It has 2 iodides on the outer ring and 1 on the inner ringCreated by improper conversion of T4 to T3 in the peripheryUsually a sign of illness, carb starvation, and in the fetus
Where are the thyroid hormones produced? Describe their structure.
In the follicles of the thyroid gland in the neck made of single layer of follicular cells surrounding the follicular space containing colloid (made by follicular cells)
What are the 3 roles of the follicular cells of the thyroid gland?
- Bring in iodide2. Transport iodide to the follicular space3. Makes enzymes for thyroid hormone production
What are the 3 effects of TSH on the thyroid gland?
- Stimulation of hormone production/secretion2. Increase in size3. Stimulation of iodide uptake
What type of receptor is the TSH receptor on the thyroid gland? How many membrane spanning regions does it have?
G-protein coupled receptor7 membrane-spanning regions
Where is the TSH receptor located in the thyroid gland?
Basolateral surface of the follicular cells
How does the TSH receptor in the thyroid gland work to increase thyroid hormone production?
Activates adenylyl cyclase which increases cAMP in the cells, which accelerates ALL hormone producing processes
What is the major inhibitor of thyroid hormone production?
Propylthiouracil (PTU)
What is the precursor of thyroid hormones?
Tyr
How is iodide pumped into the follicular cells of the thyroid gland?
I-/Na+ symporter on basolateral membrane through secondary active transport as the Na+/K+ ATPase provides the concentration gradient of sodium
What are the 4 competitive inhibitors of the I-/Na+ symporter of the follicular cells of the thyroid gland? What do these inhibit exactly? How?
- Thyocyanate: SCN-2. Perchlorate: ClO4-3. Perrhenate: ReO4-4. Pertechnetate: TcO4-Inhibit the UPTAKE of iodine, not the pump itself because they are transported instead (indirect inhibition)
How does iodide leave the follicular cells of the thyroid gland?
Simple diffusion
What is the ratio of iodide inside a thyroid follicular cell to that of serum in humans?
25:1
How do we treat thyroid tumors? What can this damage as collateral?
Radioactive iodide therapy to ablate the tumorSalivary glands can be damaged also
What happens to the iodide once it has entered the follicular cells of the thyroid gland? How? To what end? What does this require?
It is transported through the apical membrane in the follicular space (on the luminal surface) through which it travels due to the electrochemical gradient (the follicular space has similar ectrochemical characteristics to the exterior of the cell) to be oxidized by thyroperoxidase (TPO), which requires NADPH
How is TPO activated to oxidize iodide once it has entered the follicular cells of the thyroid gland? What inhibits it?
Stimulated/Activated by TSHInhibited by PTU
Is the thyroid the only place where iodide can be oxidized?
Yes
How is thyroid storm treated during pregnancy? Why?
With PTU only during the first trimester (because it also causes liver damage) and then methimazole
In what food is thyocyanate found in?
Cassava (from Zaire, central Africa)
What does eating cassava cause in people from Zaire?
They already are not ingesting enough iodide and by eating cassava they cannot pump iodide into the follicular cells of the thyroid gland, so this causes:1. Low iodide2. High amounts of TSH: thyroid gland growth = goiter
What is cretinism due to? Symptoms?
Insufficient amounts of thyroid hormones during development causing short stature and stunted brain development
How are thyroid hormones produced at the laminal surface?
TPO adds iodide to the tyrosine portions of thyroglobulin (TGB) to form MIT and DIT and then TPO fuses them to form T3 or T4
What protein can inhibit the fusion of MIT and DIT?
PTU
What causes the release of thyroglobulin complex from the colloid surrounding the follicular cells of the thyroid gland? How?
TSHInvagination of follicular membrane into vesicles
What happens to the thyroglubulin complex containing vesicles inside the follicular cells of the thyroid gland?
They fuse with lysosomes to give rise to secondary lysosomes: phagolysosomes where the complex is completely hydrolyzed by proteases into AAs, DIT, MIT, T3/T4
What happens to the non-T3/T4 products in the lysosomes inside the follicular cells of the thyroid gland? Why?
Recycled because there is no tRNA to incorporate them into new proteins
What happens to the iodide in the lysosomes inside the follicular cells of the thyroid gland?
Has to go through the whole oxidation process all over again
What is the predominant form of the thyroid hormone produced in the thyroid gland?
T4: inactive
Which has more affinity for thyroid hormone receptors on target cells: T3 or T4? By how much?
T3x10
What happens to T4 once it binds to thyroid hormone receptors on target cells?
Converted to T3 by 5’ thyroxine deiodinase
Can T4 be converted to T3 in the plasma?
Yes, a small amount is
What 2 enzymes block the conversion of T4 to T3? How?
- Methimazole2. PTUInhibit the deiodinase
What feedback do thyroid hormones have on the hypo and pit? Do both T3 and T4 have these effects?
Hypo: -TRHPit: -TSHYUP
How will an increase in GH affect thyroid hormone production?
Inhibit it because IGF-1 will +SS, which inhibits TSH production by pit
What is newborn hypothyroidism caused by? How is it treated? Symptoms if not treated?
Inability to make thyroid hormones at birthTreatment: administer thyroid hormones to prevent cretinism and growth defects (downturned mouth and dead eyes) FOR THE REST OF THEIR LIVES
What is endemic goiter caused by? 3 symptoms?
Not enough iodide in diet1. Increased TRH2. Increased TSH3. Thyroid growth
What is Grave’s disease caused by? More prevalent in what patients? Symptoms? Treatment? Side effects?
Autoimmune disease where antibodies (TSI: Thyroid Stimulating Igs) attack the TSH receptor of the thyroid gland stimulating it and causing high thyroid hormone production = hyperthyroidism and sometimes diffuse goiterMore common in women10% of patients also have Symptom: big eyes (proptosis), heat intolerance, tremor, weight loss, perspiration, diarrhea, oilier skinTreatment: thiourea drugs (methimazole, not PTU), surgery, and/or radioactive iodine (I131)Side effects: weight gain
What is Hashimoto’s thyroiditis caused by? Symptoms?
Autoimmune disease where antibodies attack thyroglobulin and break down the thyroid gland = hypothyroidismSymptoms: cold intolerance, weight gain, cold clammy skin, slow reflexes and reactions, constipation
What causes inhibition of thyroid hormone release in the blood?
Lithium
What is the Wolff-Chiakoff effect? How long does it last? Why? What is it often used to manage/prevent (2 things)? In what form?
Short-term effect of excess levels of iodide exerting negative feedback on the production/release of thyroid hormones at the point of thyroglobulin release of T3/T4 (vesicle formation). Relieved after 48 hrs due to increased export of iodide.Solution of K+I- can be used to:1. Manage or prevent thyroid storm 2. Decrease size (therefore vasculature) of thyroid and amount of THs
How does ouabain affect thyroid hormone production?
It inhibits the Na+/K+ ATP-ase, therefore inhibiting iodide transport into the follicular cells of the thyroid gland, thereby inhibiting TH production
What is used for radiographic imaging of the thyroid?
Radioactive derivatives of the competitive inhibitors of the iodide pump
What is the ratio of iodide inside a thyroid follicular cell to that of serum in animals that have been chronically stimulated with TSH?
500:1
What is the ratio of iodide inside a thyroid follicular cell to that of serum in hypophysectomized animals?
5:1
Other than through cAMP levels, how can the TSH receptor on the thyroid increase TH levels?
Phospholipase A activation
What other 4 organs can take up iodide? +?
- Salivary glands2. Mammary glands3. Chorion4. Stomach
Describe the composition of thyroperoxidase.
Heme containing and glycosylated
What does TPO require to function? Where does it come from?
Hydrogen peroxide H2O2 produced by NADPH-dependent enzyme resembling cytochrome C reductase
What is the class of drugs that PTU is part of?
Thiourea drugs
What is the organification of tyrosine?
The ionidation of Tyr
What is the full name of T3?
Triiodothyronine
What is the full name of T4? 2 names
Tetraiodothyronine = thyroxine
What are the 4 thiourea class antithyroid drugs?
- Thiourea2. Thiouracil3. Propyllthiouracil (PTU)4. Methimazole
Does the coupling of MIT and DIT/DIT and DIT cleave the peptide bond? What does it leave behind?
NOPELeaves dehydroalanine behind
Describe the structure of thyroglobulin.
Homodimer with 8-10% carbs, 0.2-1% iodide, 5 MIT, 4.5 DIT, 2.5 T4, 0.7 T3 and close to 5500 AAs
How many Tyr does thyroglobulin contain?
134
How many ATPs are required to produce 1 T3 or T4?
~3,400
How much TH supply does the extracellular colloid contain?
Months supply
Once thyroglobulin is hydrolyzed, how are MIT and DIT deiodinated to be recycled? What does this require?
By deiodinase requiring NADPH
What % of dietery iodide is absorbed?
30%
What are the medium-term effects of excess iodide levels? Why? How long does it take cells to recover?
Increased organification leading to increased MIT and DIT but decreased T3/T4 possibly because of decreased T3/T4 content of TGBTakes cells 7-10 days to recover
What are the long-term effects of excess iodide levels? Why?
Permanent iodide block and a goiter and hypothyroidism develop probably due to some underlying defect in thyroid
What is the role of arachidonic acid in the effects of excess levels of iodide?
Might be involved in recovery mechanism after iodide inhibition
What is the T3/T4 that is not bound to TBG bound to? 2 molecules? What %?
- Thyroxine-binding pre-albumin (TBPA): 10-15%2. Albumin: 15-20%
What is the plasma half life of T3?
1.5 days
What is the plasma half life of T4?
6.5 days
Why is it important to measure free and total thyroid hormone levels?
Because many agents alter TBG levels (total hormone) without altering free hormone levels and those are the only ones that are biologically active ie hyper/hypothyroidism can only be determined by free hormone levels
What organ synthesizes TBG? What stimulates its production? What inhibit its production?
Liver+ estrogen- glucocorticoids
What 2 molecules compete with THs for TBG binding?
- Phenytoin2. Salicylates
Where is the thyroid hormone receptor located?
Nuclear receptor on thyroid response elements (TRE) of the DNA
How does the thyroid hormone receptor bind to DNA? 2 ways. Which form is the most active?
Either as a homodimer or as heterodimer with RXR (most active)
What stimulates TRH release by hypo?
Low T3 levels
What are the 2 genes that encore thyroid hormone receptors?
TRalpha and TRbeta
What do TREs consist of?
Inverted (palindromic) or direct repeats of: AGGTCA
Are direct repeats of TREs one after another?
NOPE, separated by 4 base pairs
Where are TREs found in DNA?
- Growth hormone gene 2. Cardiac sarcoplasmic reticulum Ca2+-ATP gene (SERCA2)3. Isoform of myosin genes 4. Beta-adrenergic receptors of cardiac muscle and arterioles(2 and 3 increase heart rate)
What mediates transcriptional repression of TREs? How?
nTREs: TR binds to them to repress transcription
Where are nTREs found?
TSH subunits genes
What is the effect of TH on oxygen consumption? Why?
Increases O2 consumption by increasing number of Na+K+ ATP-ases
What is the effect of TH on protein synthesis? What does this cause?
Increase in protein synthesis –> positive nitrogen balance = intake of nitrogen into the body is greater than the loss of nitrogen from the body, so there is an increase in the total body pool of protein
What metamorphosis is TH necessary for?
Amphibian metamorphosis: tadpole to frog
How does gene activation happen when TH binds to the TH receptor on DNA?
TH recruits coactivators to the receptor that interact with the initiation complex
What is the most common form of hyperthyroidism?
Grave’s disease
To what family does the TH receptor belong to?
Steroid/Thyroid/Retinoic acid superfamily of nuclear receptors
What is proptosis due to in Grave’s disease? 3 aspects.
- TSIs are attacking receptors on fibroblasts in the eye causing them to proliferate leading to inflammation behind the eye.2. TSIs also cause the accumulation of mycopolysaccharides in the interstitial space leading to an increase in osmotic pressure in IS3. Muscle damage and inability to close eye lids and sometimes eye has to be enucleated because it is so dry.
Does reverse T3 have a function?
No known one
Which membrane is considered the outside membrane of the follicles of the thyroid?
The apical membrane toward the follicular space
What are the 3 types of patients to whom we recommend PTU instead of methimazole?
- First trimester pregnant women2. Thyroid storm3. Allergic to methimazole
What is a thyroid storm? What can it be caused by? What is the main risk? Treatment?
Huge amount of TH entering your system at once.Can be caused during neck surgery (may or may not involve thyroid), by surgeon causing a huge release by touching the colloid space that has months worth of hormonesRisk: ventricular fibrillation and heart attack. Very dangerous.Treatment: PTU, lithium, and methimazole
What is a goitrogen?
Food containing TH production/release inhibiting agent
What does the response of cell to T3 vs T4 depend on?
The amount of tyrosine deiodinase
How long does it take for newborn hypothyroidism to be noticed? How come?
Few days because of T4 half life in newborn blood from mother
Are autoimmune disorders more common in females or males? Why?
Females because of birth process where antibodies are produced by the mother
What other condition is often seen alongside Grave’s disease? Why?
70% of patients also have Hashimoto’s thyroiditis because different kinds of antibodies are being produced: some will activate some will destroy
Can iodide be used to treat hyperthyroidism? When?
Yes, in the short-term
Why does hyperthyroidism cause weight loss and hyperphagia?
Because excess TH causes an increase in the basal metabolic rate causing an increased caloric intake which is then burned fast:1. Na+ is more permeable so the Na+/K+ ATPase channels are doing more work2. Gut motility is increased
Why does hyperthyroidism cause heat intolerance? 2 reasons
- Excess TH increases the basal metabolic rate2. Excess TH causes an increase in uncoupling proteins: mitochondrial inner membrane proteins channels/transporters that are capable of dissipating the proton gradient and use that energy to generate heat
What is the effect of VERY high TH levels? Eg?
Catabolic effect which increases blood glucose levels and breaks down macromoleculesEg: collagen and finger nails fall off
What does a diffuse goieter mean?
Means the size increase is consistent all around the gland
What is NADPH used for during TH synthesis? 2 things
- Oxidizing iodine2. MIT and DIT deiodination when recycled
What does constitutive production of a hormone mean? Eg?
Production without negative feedback. Eg: endemic goitier
What does a bounding pulse mean?
Noticeable/Pulsating
What is the thyroid isthmus?
The tissue connecting the four poles across the trachea
What does exophtalmos mean?
Bulging of the eyes = proptosis
What is cold iodine?
Iodine ingested to inhibit TH
Are THs anabolic or catabolic?
Both depending on amount:Normal amount: anabolic effect (eg: increase in beta adrenergic receptors)Excess: catabolic effect (eg: collagen breakdown)