Dr. Fondel - Thyroid Physiology

Question 1

WHich cell makes thyroid hormone?

Answer 1

Follicular cells

Question 2

Where is thyroid hormone stored?

Answer 2

Colloid

Question 3

Parafollicular cells / C cells

Answer 3

Secrete calcitonin

Question 4

How is thyroid hormone made?

Answer 4

Start with a tyrosine and add an iodine to the 3’ or 5’ position. Then add multiple of the diiodotyrosines together to make T4 or add a diiodotyrosine to a monoiodotyrosine to make T3.

Question 5

How is it exactly that follicular cells aid in the creation of thyroid hormone?

Answer 5

They use an Na/I symporters in order to make what is called thyroglobulin, which is made in the cell and then secreted out of the follicular cell. Iodine is then oxidized (catalyzed by TPO) And is prepared to join up with thyroglobulin. The thyroglobulin is then iodinated (also by TPO) outside of the follicular cell. They are then joined together, called coupling (also by TPO). The molecules then come back into the follicular cell via endocytsis and then there is a proteolytic process to free T3/T4 from the larger Molecule. They are then secreted out of the basal side of the cell as T3 and T4.

Question 6

Hashimotos

Answer 6

Autoimmune disease in which you develop antibodies against either TPO or thyroglobulin.

• gland becomes inflamed and thyroid hormone production is halted.
• Because of this, your T3/4 levels will be quite low it your TSH levels will be quite high because no negative feedback.

Question 7

How do we convert T4 into T3?

Answer 7

5’deiodinase. This is why we might have a lot more T4 than T3 but we are able to easily convert it into T3 when we need it.

Question 8

What is the difference between 5’ Deiodinase and 5. Deiodinase?

Answer 8

5' = T4-->T3
5 = T4-->reverse T3

Question 9

What are the carrier proteins that carry TH?

Why is it necessary that TH has Carrier proteins?

Answer 9

• Albumin, TBG, transthyretin. AT&T
• It is necessary to have these carrier proteins because TH has a very small molecular weight and would otherwise be filtered through the kidney and excreted. Also, TH is hydrophobic and is insoluble in blood so it needs the carrier proteins.

Question 10

Why do you think that T4 has a longer half life than T3?

Answer 10

T4 has a higher affinity for the carrier molecules.

Question 11

Hypothalamic-Pituitary-Thyroid (HPA) axis

Answer 11

TRH–>TSH–>T3/4
Environmental stressors such as cold, Leptin, increased caloric intake will stimulate the release of the peptide, TRH. TRH is secreted into the Hypophyseal portal vein where it targets thyrotrophic cells in the anterior pituitary. Activation of these cells cause release of TSH from the anterior pituitary. TSH then goes through the blood stream and eventually binds to receptors on follicular cells that stimulate the production of T3/T4. T3/T4 can exert a negative feedback on TRH and TSH.

Question 12

How exactly does TSH binding to receptors on follicular cells cause T3/T4 production?

Answer 12

1) TSH binds to G-protein linked receptor.
2) Adenylate Cyclase is activated
3) Increase in cAMP
4) This leads to an increase in TPO and thyroglobulin

1) TSH biding causes glucose reuptake and oxidation.
2) oxidation of glucose supplies H2O2 necessary for T3/4 production.

1) TSH binding causes stimulation of Na+/K+ ATPases
2) This causes a gradient to be formed for Na import into the cell. (Remember that Na and I work in a symporter so there needs to be a gradient)

1) TSH also causes the size and number of follicular cells to rise, so chronic stimulation can cause the thyroid to balloon.

Question 13

Graves’ disease

Answer 13

Antibodies constitutively activate the TSH receptor on the follicular cells so that you get hyperthyroidism. If you think about it, your T3/T4 levels will be quite high, but because of the negative feedback mechanism, TSH levels will be quite low.

Question 14

Hyperthyroidism and Hypothyroidism

Answer 14

Both of these occur at the level of the pituitary gland as opposed to what we saw in Hashimotos and Graves’ disease where the issue was at the level of the receptor. You will have either increase or decreased TSH, which will cause an increase or decrease in T3/4. So, in summary there will be a direct correlation between the two whereas in Graves and Hashimotos there will be an inverse relationship.

Question 15

What are the names of the thyroid receptors and where are they located?

Answer 15

TRalpha and TRbeta - these receptors are found in the nucleus, and once T3/4 bind to them, they bind to DNA At what are termed “Thyroid Hormone Response Elements.” They generally bind as a heterodimer with RXR. These receptors and RXR can bind to the TRE’s even without the hormone - T3/4 - but in that case, they act as silencers instead of activators.

Question 16

Why is it that T4 is mostly biologically inactive?

Answer 16

Because T3 binds with a much higher affinity to TRalpha/beta than does T4.

Question 17

What does thyroid hormone even do?

Answer 17

• Increase basal metabolic rate
• increase CO
• increase linear bone growth
• increase body temp
• Increase metabolic turnover
• maturation of the CNS

Question 18

How does TH cause increased BMR?

Answer 18

It upregulates the respiratory mitochondrial enzymes, thus increasing the amount of mitochondria in the cell. In order to do this, we need O2, so increased Cardiac Output.

Question 19

How does TH increase CO in order to keep up with the ATP demands?

Answer 19

It has both direct and indirect effects.
Direct - Upregulate actin, myosin, myosin dependent ATPases, and Ca dependent ATPases, which pump Ca into the cell in order for the heart to beat more rapidly.
Indirect - Upregulate the beta adrenergic receptors in order to enhance the SNS activity on the heart.

Question 20

TH caused increased energy consumption, so in order to accompany that we need to increase ATP usage. How does this happen?

Answer 20

• TH upregulates the production of Na/K Pumps, which maintain sodium gradients and uses up a massive amount of energy. With this is also heat production.
• TH also cause futile cycling to occur. This causes either anabolism or catabolism of fat, carbs, or protein. Depending on the dosage of T3/T4 either anabolism or catabolism will occur.
• facultative thermogenesis (on a later slide)

Question 21

What physical characteristics will people with hyperthyroidism exhibit? Why?
What about hypothyroidism?

Answer 21

Hyperthyroidism - They will tend to lose a lot of weight and experience muscle atrophy because futile cycling will occur and catabolism will dominate so there will be breakdown of lipids, glycogen, and protein concentrations over time. Increased metabolic turnover.
Hypothyroidism - The opposite will occur in that there will be decreased metabolic turnover and therefore with regards to futile cycling, anabolism will tend to occur. This is because there tends to be excess glycogen and lipids.

Question 22

Facultative thermogenesis

Answer 22

Occurs in brown adipose tissue (BAT). T3/4’s ability to increase O2 consumption and generate body heat. T3/4 will cause the upregulation of UCP-1 (uncoupling protein), which acts in mitochondria to leak out protons, which short circuits the respiratory chain. Therefore, O2 is continually made, but much less ATP is produced, but rather most of the energy is lost as heat.

Question 23

How does T3/T4 promote bone growth?

Answer 23

Through upregulating GH and IGF-1

Question 24

How does T3/T4 affect CNS development?

Answer 24

Myelinogenesis, neuronal outgrowth, synapse formation

- has to occur during. The perinatal period (immediately before and after birth).

Question 25

How do you Treat hyper/hypothyroidism?

Answer 25

Hyper - thyroidectomy, thyroid ablation, TPO inhibitor

Hypo - Thyroxine (T4)

Question 26

How is the thyroid gland Innervated?

Answer 26

SNS

Question 27

COmmo symptoms of hyperthyroidism

Answer 27

Weight loss, muscle atrophy, profuse sweating, intolerance to heat, elevated body temp, bulging eyes, diarrhea, restlessness, rapid heart rate,

Question 28

Giving a thyroid replacement Therapy to someone who is Hypothyroid As a child will help some things but not others. What will it help? What won’t it help?

Answer 28

Will help - height age and bone age

Won’t help - mental age

Question 29

What stimulates the hypothalamus to secrete TRH?

Answer 29

Cold temps (makes sense because TH raises body temp)
Increased caloric intake (make sense TH increased metabolic turnover) 
Leptin (some sort of GI hormone)

Question 30

How does Thyroid hormone alter thermogenesis?

Answer 30

Either through facultative thermogenesis in brown fat or through the use of ATP in order to drive the Na/K pump.

Question 31

In hyperthyroidism will systolic or diastolic BP be high?

Answer 31

Systolic - The heart will pump very heart because of the affects on the heart we discussed to increase CO. The arteries will then dilate in order to warm up the skin (remember that hyperthyroidism is responsible for being warm). Also remember that systolic is the pressure of the blood as it is being ejected from the heart.

Question 32

If someone is hypothyroid will their systolic or diastolic BP be high?

Answer 32

Their diastolic because their heart will not be pumping as hard but they will vasoconstrict in order to keep the heat in and you will be cold. Therefore, the pressure in the arteries will be high. Diastolic measures the pressures in the arteries.