Thyroid Gland

Question 1

What does the thyroid gland produce?

what is the functional unit of the thyroid gland? what is it surrounded in?

where’s the lumen of the thyroid gland?

Answer 1

produces prohormone tetraiodothyronine (T4) and the active hormone triiodothyronine (T3)

Thyroid follicle –> surrounded by a single layer of epithelial cells

in the follicle called “colloid”

Question 2

Of T3 and T4, which one is active?

Answer 2

T3 –> this one is the most active and biologically relevant.

Question 3

What cells are seen in the thyroid?

Answer 3

C cells –> which produce calcitonin!

C cells are also called “parafollicular cells”

Question 4

What is colloid have inside it?

what stimulates this colloid to release stuff?

Answer 4

newly synthesized thyroid hormones attached to the thyroglobulin.

so an internal pool of thyroid pool.

TSH!

Question 5

How do we get to produce T4 and T3?

How does it start from circulation?

What’s the difference between the two products?

what’s to note about these two initial products? (differences and activity)

What combination of these creates T3 or T4?

Answer 5

2 Iodide(I-) (trapped from circulation) + H2O2 –> Iodine (I2)

Iodine + Tyrosine –> MIT and DIT.. the only difference is the location of the iodine molecule on the molecule (this happens in the thyroglobulin)

MIT and DIT is NOT biologically active.

MIT has only 1 Iodine, DIT has 2 iodine.

depending on the conjugation of those molecules we’re generating either T3 or T4.

2 DIT –> T4

1 DIT + 1 MIT –> T3

Question 6

What’s to note about the structure of T4 vs T3?

Answer 6

T4 has 4 Iodine ions off of it, or (2 on each benzene ring)

T3 has one Iodine on 1 (outer) ring, and 2 on the inner ring

Question 7

What is the major secretory product of the TSH?

of T3 and T4, which one usually free?

Answer 7

T4… even though it’s not biologically active! (T4 can be conjugated to T3)

T3.

Question 8

What are the relative levels of T3/T4?

Answer 8

around 90% of the thyroid hormone is going to be the T4.. 10% is T3, and then there’s going to be 1% of “reverse T3”.

The reverse T3 is the inner ring having only one iodine rather the outer… this is the INACTIVE form of T3.

Question 9

What can happen to T4?

what enzyme does most of the peripheral conversion? where is it found?

What about the other one?

Answer 9

it can be converted!

80-90% of the conversion of T4-T3 is going to be happening peripherally.

the enzyme that’s doing this is the Deiodinases type 1 –> this does most of the conversion. (found on skeletal muscle)

Deiodinases 2 is going to be localized in the brain in the anterior pituitary –> adds another sensor for T3 levels, which helps put breaks on TSH and this deiodinase is unaffected by starvation

Question 10

what’s the importance of Deiodinase 2 in the brain?

Answer 10

It can help tell the brain to stop sending out TSH. It will not be affected by starvation.

also if the body is in starvation, it won’t be taken up at all by starving cells so it can still regulate even in starvation.

Question 11

in starvation, do we want the thyroid to be activating metabolic stuff, oxygen consumption?

so what happens to the T4?

what catalyzes this then?

Answer 11

no. we don’t want to affect the brain so that’s done by shifting to create more of the reverse T3 which is INACTIVE, than the active T3.

this is catalyzed by Deiodinase type 3.

Question 12

Fasting, Medical and surgical stress, catabolic disease… what do these have in common with the thyroid?

Answer 12

you’re going to have a reduction of conversion of T4 into T3 because you don’t want T3 affecting basal metabolism, heat, or anything like that.

Question 13

What is on the basolateral membrane of the follicular epithelial cells of the thyroid??

Answer 13

So you have the follicular epithelial cells

on the basolateral membrane:

Na/K ATPase –> keeping the concentration gradient going

“I Trap” –> it’s a symporter called NIS that sends iodide into the cell at the expense of sending 2 Na into the cell, which is going with the gradient.. but the Iodine is going against the gradient.

Question 14

How is Thyroglobulin synthesized?

what’s on the thyroglobulin?

what happens once iodide is in the follicular cell?.. what is this site called?

What catalyzes the Iodide to Iodine? Where is this happening?

What happens once you have Iodine?

Final step before thyroglobulin can move around freely in the colloid region?

Answer 14

it’s formed in the rough ER, processed by the golgi, and secreted into the lumen.

Thyroglobulin has several molecules of tyrosine and some of those are going to be iodized.

So once the Iodide is in the cell, it’ll be exported through a transporter in the luminal site called “Pendrin”

Within the membrane of the luminal membrane we have peroxidase (TPO).. this is important for catalyzing Iodide to Iodine. (all this is happening as it goes through the luminal (apical) membrane.

This peroxidase also helps catalyze the iodine into MIT and DIT and helps put it on the Thyroglobulin.

Finally, peroxidase helps the conjugation of MIT and DIT to either T3 or T4. (NOTE.. YOU WILL STILL HAVE EXTRA MIT/DIT.. IT’S GOING TO BE RECYCLED)

Question 15

What happens when you have the completed Thyroglobulin molecule out in the lumen.. how does it get back into the follicular cell and what happens?

what happens to the leftover MIT/DIT?

What’s on thyroglobulin usually? just in general

Answer 15

There is Pinocytosis then of the TG with bounded stuff on it.

then you’ll have lysosomal proteases that breaks the thyroglobulin into different components… T3 and T4 are going to be cleaved into circulation (by proteases of lysosomes), and MIT and DIT are going to be recycled.

MIT and DIT (on the thyroglobulin) are going to recycle the MIT And DIT through “Intrathyroidal deiodinase”!

T3, T4, MIT, DIT.. you can have multiple of each

Question 16

Through the entire synthesis of. thyroid hormones… what’s going to mediate most of the steps?

what specific step in the pathway is it most typically seen (in her slide)

what’s to note about this and growth? what happens if we have excess TSH

Answer 16

TSH!

pinocytosis of the Thyroglobulin (with T3+T4 bound).

TSH is a growth factor, so when we have excess of this around, the thyroid gland will tend to be enlarged –> goiter.

Question 17

What happens if we have a deficiency of intrathyroidal deiodinase?

what happens if we don’t have iodide? What’s favored?

what about too much iodide?

Answer 17

it can mimic dietary Iodide deficiency in our diet.. so it’s important to have it intracellularly! because it’s not able to get rid of iodine off of the MIT/DIT, so no iodide can even come through.

T3 is favored

too much? prevent too much thyroid hormone… T4 or reverse T3.

Question 18

What is the Wolff-Chaikoff effect?

what’s being effected?

Answer 18

inhibiting peroxidase (TPO), which will decrease the production of thyroid hormone.

this is happening due to high levels of Iodide which inhibit organification (abundance of iodide is going to inhibit MIT and DIT production..

its not permanent, it’s transient!!

Question 19

What different ions competitively inhibiting the Na/Iodide symporter?

Answer 19

Perchlorate… Thiocynate

these alter Thyroid hormone creation.

no iodide coming in, affecting thyroid production.

Question 20

PTU:

what does it help treat?

what does it do?

Answer 20

used in the treatment of hyperthyroidism.

it inhibits TPO!

Question 21

What are the levels of iodine/iodide in the thyroid gland? What’s happening between the ECF and the thyroid gland?

what’s the most important aspect to remember about iodine and where it’s stored?

Answer 21

the iodide trap is going to take extracellular fluid iodide and shove it into the thyroid gland

there’s also an iodide leak going from thyroid gland back to the ECF

most important is to remember that iodide is going to be stored in the colloid.. it’s stored as IODINE on tyrosine of thyroglobulin (iodinated tyrosine)

Question 22

in case of an issue, how much iodine is stored in the thyroglobulin in the follicular colloid?

Answer 22

2-3 months worth

Question 23

What populations tend to have an iodine deficiency?

Answer 23

populations away from the coast… the seaweed and fish have iodine in it

Question 24

how can you assess thyroid gland activity?

what are two types of disease that increase the uptake of iodine?

main message?

Answer 24

radioactive iodine uptake!

you’re measuring how much 123 iodine uptake.. hyperactive thyroid gland uptakes more of the radioactively labelled iodine.

Hyperthyroidism
Extreme stimulation of the thyroid gland (grave’s disease associated thyrotoxicosis)

so hyperthyroid uptakes way more iodine.

This explains why when we have a ton of Iodine we don’t see more T3 made… rather we see the Wolff chaikoff effect.

Question 25

how is most thyroid bound in circulation? where is this synthesized? what does it have affinity for? how does this relate to half life? why is this good?

Answer 25

1) most thyroid hormone is bound by Thyroxine binding globulin (TBG) (70% of those) synthesized by the liver! this binding protein has a higher binding affinity for T4 than T3... helps in having a longer half life! (T4 is 6-8 days, T3 is 1 day) it's good to have a pool connected to the TBG.

Question 26

What is TSH more sensitive to? bound hormone or free hormone

Answer 26

free T4 / T3

Question 27

Other than TBG, what else binds T3 and T4?

Answer 27

Transthyretin (TTR) Albumin

Question 28

Hypothalamus secretes TRH --> Pituitary signals TSH --> Thyroid makes T3 and T4 and it sends it to circulation where it can be bound in equilibrium with bound and free T3 and T4. which is biologically active?

Answer 28

the free t4 and t3!

Question 29

T3 resin uptake test?

Answer 29

You'll have a sample of an individual and you're going to have TBG w/bound T4 from the serum (predominately T4) the sample is going to be exposed to a fixed amount of free, labeled T3. whenever there's a free binding space on TBG it'll now be bound to TBG.. whatever isn't bound is going to bind to a resin. so given a fixed amount of resin you can get an estimate of how much TBG they have in the system.

Question 30

In individuals with Hyperthyroidism, what would you expect their total levels of T3 and T4 be for the resin test?

Answer 30

hyperthyroidism = more T3 and T4 made.. so the total T4 is more, and because more T4 is in the system, there will be more free as well. T3 is going to be elevated because there's too much T4 so there aren't going to be any spots available on TBG.

Question 31

In individuals with Hypothyroidism, what would you expect their total levels of T3 and T4 be for the resin test?

Answer 31

hypothyroidism = low T3 and T4 so you'll have a low total, low free T4.. Because there's low T3, it'll bind. to the empty spots on TBG. so the resin will be decreased because there's none bound to it really.

Question 32

If you have high TBG.. what can you expect for total levels of T4 (free and bound) and T3?

Answer 32

High TBG means your normal amounts of T4 will be bound.. because of this, the once normal free amounts are low and your body says "oh shit we don't have enough" so it produces more.. so free will be normal again, but the TOTAL amount will be more! more TBG will mean that more empty spots, so T3 will bind to it and you won't have as much resin uptake of T3.

Question 33

Low TBG?

Answer 33

Low total TBG.. so total is lowered, there will be normal T4 increased T3 resin uptake because its not binding to TBG, there's too little of it, so the spillover will bind to the resin!

Question 34

What is hepatic failure with TBG and levels of T3 and T4?

Answer 34

TBG is made in the liver.. so we're going to have low TBG.. so you're going to expect low T4 and lower T4 free, and high T3 resin uptake

Question 35

Pregnancy and TBG? T3 and T4 levels? what is this clinical term called?.. free levels are "normal"

Answer 35

Higher TBG! so high total TBG and normal levels of T4 because the body is saying hey, we need more hormone wake up.. and higher total T4. lower T3 resin uptake because its binding to the unregulated levels.. this means less free T3 so there will be a transient increase in T3, normalizing it! so the female is going to have normal levels.. called "clinically euthyroid"

Question 36

Explain why having a high TBG is going to give you high total T4, but normal levels of free T4. also why will it have low T3 resin uptake?

Answer 36

having high total T4 bound reduces it from the free pool.. that's enough to tell the axis hey.. we don't have enough FREE thyroid hormone.. so with time those levels will be normalized. that's why the normal TOTAL is high because you're counting bound and FREE! more T3 is binding to empty spots so it won't be binding to the resin.. lower T3 resin uptake.

Question 37

what is the pathway of Thyroid hormone? Once you create T3 and T4, what does that do? what other inhibitor is seen and what is the indirect and direct changes?

Answer 37

TRH through the hypothalamus --> releases TSH from the anterior pituitary the thyroid gland brings T4 and T3 out into the bloodstream. the free levels of T4 and T3 are telling the anterior pituitary to quit sending out TSH when there is too much. presence of deiodinase 2 (sensor for free t4 and t3) is going to determine if there's peripheral conversion to T3 and if we have too much it'll have direct (changes to pituitary) and indirect (inhibit production of TSH alpha and beta chain to not make TSH) changes.

Question 38

What is the receptor within the thyroid gland for TSH? what does TSH do for the thyroid gland then?

Answer 38

the receptor for the TSH in the thyroid is a G protein that is a Gs complex... it's going to produce adenyl cyclase, generate cAMP which is going to be helpful for mediating gene transcription (modulating transcription in the nuclei). some of that transcription is the synthesis of thyroglobulin. 1) increases synthesis and secretion of thyroid hormones 2) trophic effect on thyroid gland

Question 39

what are the 3 stimulating factors that affect thyroid hormone secretion?

Answer 39

TSH Thyroid stimulating immunoglobulins increased TBG levels (e.g. pregnancy -- transitory increase to normal)

Question 40

What are the 6 factors that inhibit thyroid hormone secretion?

Answer 40

Iodide deficiency deiodinase deficiency excessive I- intake (Wolff-Chaikoff effect) --> inhibiting TPO activity (transitory remember, not full blown inhibitor) Perchlorate, thiocyanate (inhibit iodide trap) PTU --> inhibits TPO decreased TBG levels (e.g. liver disease)

Question 41

What do thyroid hormones bind to? What is this complex? why is T3 more biologically more active? what happens when T3 binds?

Answer 41

dependent on the thyroid hormone receptor...this has a retinoid receptor bound to it. the reason that T3 is more biologically active than T4 is that it has more affinity for the thyroid hormone receptor. upon the binding of T3 we are going to have the complex working as a transcription factor. we have sequences in the DNA that are going to trigger gene transcription or inhibit transcription.

Question 42

What does the thyroid hormone receptors synthesize because of the direction of T3/T4?

Answer 42

Na-K ATPase --> key... the activity of this is going to be consuming ATP and oxygen.. the indirect product of this is producing heat. so it affects the metabolism. (IT'S BOTH CREATING MORE NA/K ATPASE AND ACTIVATING THEM) transport proteins B1 adrenergic receptors. others

Question 43

What is stimulated in most tissues because of the thyroid hormones? what about in cardiac muscle cells? (3 things) what do these 3 things lead to the increase in?

Answer 43

synthesis of Na/K ATPase and the activity of them too change of myosin, more sensitivity to b adrenergic receptors, production of Ca ATPase. --> all leading to difference in cardiac output.

Question 44

What does the thyroid hormone do for growth? CNS? BMR?

Answer 44

Growth formation and bone formation ----- maturation of the CNS ---- Na/K ATPase production increased O2 consumption Increased Heat production, Increased basal metabolic rate

Question 45

What does the thyroid hormone do for Metabolism (5)? what's to note about proteins? Cardiovascular? (2)n

Answer 45

increasing absorption of glucose, Glycogenolysis, GNG*** , Lipolysis, Protein synth and degradation Proteins = mostly catabolic though for proteins.. normally if an increase in thyroid hormones, promotes catabolic, so muscle wasting for excess) heart = increased cardiac output and up regulation of B1 adrenergic receptors.

Question 46

How do thyroid hormones increase basal metabolic rate? how can we test it?

Answer 46

the increased activity of Na/K ATPase accounts for most of the increase in metabolic rate. leads to higher O2 consumption and heat production. we can inject thyroxine (T4) it increases the BMR and long term change too (like a month)

Question 47

Hyper / Hypothyroidism and BMR?

Answer 47

``` Hyper = high BMR hypo = low BMR ```

Question 48

thyroid hormone on lipid metabolism? carbohydrates and thyroid hormones for metabolism? --> what does this enhance?

Answer 48

we have stimulation of fat mobilization (for use) --> end result is increasing concentration of fatty acids in the plasma (lipolysis) increased GNG and glycogenolysis to generate free glucose and glycogen formation --> this enhances insulin-dependent entry o glucose into the cells.

Question 49

What is the direct effect of thyroid hormones on the heart? (6)

Answer 49

more muscle myosin heavy chain (alpha chain) is favored sacroplasma Ca ATPase B adrenergic signaling (B1) Ventricular contractility and function Decreasing peripheral vascular resistance

Question 50

What is the indirect effects on the heart from the thyroid hormones (kind of a cascade)

Answer 50

T3 creates increased heat production and CO2 in tissues this leads to a decreased peripheral vascular resistance the decreased vascular resistance leads to decrease diastolic blood pressure this leads to increasing the RAAS system, increasing reflex through adrenergic stimulation

Question 51

Both indirect and direct effects on the heart from the thyroid leads to what 3 things?

Answer 51

increased cardiac rate (chronotropy and inotropy) increased cardiac output increased blood volume (through activated RAAS system, adding to this)

Question 52

What do B1 adrenergic receptors do? what acts on these? what happens when there are elevated thyroid hormones? what is the effect?

Answer 52

thyroid hormones stimulate the synthesis of these sympathetics so they're more sensitive to stimulation by the sympathetic nervous system increased chronotropy/inotropy

Question 53

Thyroid hormones and growth? (what do they work with)

Answer 53

thyroid hormones act synergistically with GH and somatomedin to promote BONE FORMATION

Question 54

Thyroid hormones and the CNS? what happens if you have a deficiency? what does this lead to? how can you stop it from happening?

Answer 54

important for CNS maturation deficiency of thyroid hormones during perinatal period leads to --> abnormal development of synapses + decreased dendritic branching/myelination neural changes from this are IRREVERSIBLE --> lead to cretinism unless replacement therapy is started soon after birth

Question 55

Metabolism: Thyroid Excess symptoms Thyroid Deficiency symptoms

Answer 55

heat intolerance weight loss high BMR cold intolerance weight gain low BMR

Question 56

Bone Thyroid Excess symptoms Thyroid Deficiency symptoms

Answer 56

osteoporosis stunted growth

Question 57

CNS Thyroid Excess symptoms Thyroid Deficiency symptoms

Answer 57

agitation, anxiety, difficulty concentrating, hyperreflexia cretinism (congenital) listlessness, slow movement, somnolence, impaired memory, lower mental capacity

Question 58

Skin Thyroid Excess symptoms Thyroid Deficiency symptoms

Answer 58

sweating dry, myxedema

Question 59

CV system Thyroid Excess symptoms Thyroid Deficiency symptoms

Answer 59

Tachycardia, a-fib, palpitations, high output heart failure Bradycardia, lower contractility, low CO, heart failure

Question 60

Intestine Thyroid Excess symptoms Thyroid Deficiency symptoms

Answer 60

diarrhea constipation

Question 61

what's another word for hyperthyroidism? what is primary hyperthyroidism example Secondary example? if we have too much hormone secreting TSH tumor not on the pituitary what will we notice? what if it's on the anterior pituitary?

Answer 61

thyrotoxicosis? graves disease.. happening directly on the thyroid TSH secreting pituitary tumor TSH will be down due to negative feedback of T3 on the anterior lobe of the pituitary gland. TSH is higher

Question 62

explain grave's disease what would your levels of TSH be? clinical signs? how is it differentiated from an oversecretion?

Answer 62

we have immunoglobulins that are stimulating the TSH receptor without the TSH hormone! this is secreting a bunch of t3 and t4 but all this t3 and t4 is telling the pituitary gland to stop making TSH.. so your TSH will be lower exophthalmos (protrusion of the eyeball from edema or peripheral tissue that are pushing the eyeball forward) look for TSI (thyroid stimulating immunoglobulin)

Question 63

what are some causes of hypothyroidism? what's one gland destruction autoimmune disease to know?

Answer 63

pituitary disease (Sheehan's --> secondary disease) destruction of the thyroid gland (irradiation, autoimmune, atrophy, surgery) (primary hypothyroidism) Hashimoto's thyroiditis

Question 64

what is the treatment for hypothyroidism? what happens with women in menopause?

Answer 64

we don't use T3!!, we use T4. this is because it has a longer half life, and it can bind to TBG to prolong that reservoir and convert it if it needs to. overprescribing T4 can contribute to osteoporosis

Question 65

What is Hashimoto's thyroiditis? what levels are you expecting for TSH? what does this cause?

Answer 65

primary hypothyroidism Thyroid hormone synthesis is impaired by thyroglobulin or TPO antibodies... this leads to lower T3 and T4 secretion HIGH because T3 and T4 is not being secreted. tons of TSH levels create goiters

Question 66

causes of cretinism?

Answer 66

iodide deficiency impaired development of the thyroid gland inherent deficit in the synthesis of thyroid hormones. mom taking anti-thyroid meds

Question 67

how can hypothyroidism be caused due to iodide deficiency? if the transient change maintains normal blood levels of thyroid hormones after that, what happens? if they can't?

Answer 67

low iodide --> low synthesis of thyroid hormone TSH will be higher --> leads to goiter asymptomatic symptoms

Question 68

Where can goiter present?

Answer 68

pretty much TOO MUCH TSH, EITHER FROM DISEASE PROCESS OR AS A REACTIONARY hyperthyroidism (graves, 2* tumor) Primary Hypothyroidism

Question 69

TSH levels, T3/T4, TSI: Graves Hyperthyroidism Thyroid nodules

Answer 69

down, up, + down, up, - down, up, -

Question 70

TSH levels, T3/T4 Hashimoto's disease, pituitary abnormality

Answer 70

up, down down, down