Thyroid

Question 1

Where does thyroid hormone come from?

Answer 1

Thyroid gland

Question 2

What connects the thyroid gland lobes together at the ventral side of the trachea?

Answer 2

Isthmus. side note: Thyroid hormone is innervated by ANS and fed by thyroid arteries. You can literally touch it by palpating your neck.

Question 3

What lines up the thyroid tissue? Why are these cells important? Where do they store excess TH? How DO follicular cells retrieve stored TH?

Answer 3

Follicular cells, responsible for making TH. The TH is then stored in the follicle lumen called a Colloid (can stay there for up to 3 months…comprises of 1/3 of the weight of the thyroid gland). Follicle cells retrieve the TH by endocytosing it through the cell and back to the basal membrane surface and into circulation.

Question 4

What is the job of parafollicular (C) cells? Where are they located?

Answer 4

Makes calcitonin. C cells are located next to the follicular cells.

Question 5

How does one make TH?

Answer 5

1. Take tyrosine
2. Add Iodine to the 3 position OR add Iodine to the 3 and 5 position (in both cases, you add it to the tyrosine benzene ring)
3. Fuse one iodinated ring of tyrosine with another ring that was iodinated. If a double iodinated tyrosine fuses with a single iodinated tyrosine, you get T3 (3,5,3’-Triiodothyronine). If 2 doubles fuse, you get T4 (thyroxine.)

Question 6

Besides amount of I’s the tyrosine gets, what is the difference between T3 and T4?

Answer 6

T3 is the active form, and only comprises of 7% of the population. T4 is inactive, and takes up 91 percent of the population. The last 2% comprises of an unusable (to researcher knowledge), reverse form of T3.

Question 7

What does the thyroid follicular cell need in order to make TH? How does it obtain it?

Answer 7

Needs source of Iodine. Does this with a Na/I SYNporter, which shuttles Na and I into the follicular cell (more that 90% of the body’s Iodine concentration is stored in the thyroid).

Question 8

What are the steps used to incorporate Iodine into TH? What enzyme catalyzes all of this?g

Answer 8

1. Oxidation (needs H2O2), which covelently attaches to the phenol ring of tyrosine.
2. Iodination
3. Coupling
   All of the reactions are catalyzed by TPO (Thyroid peroxidase), which is nearly entirely found in the APICAL membrane of the follicular cells.

Question 9

Where does TPO add Iodines?

Answer 9

Adds them specifically to tyrosine residues called Throglobuline. Thyroglobulin (exclusively made in follicular cells) is then shuttled to the follicle lumen to be used as a substrate for TPO

Question 10

How does the thyroid follicle cell activate colloid?

Answer 10

Upon shuttling colloid into the follicular cell, it is fused with lysosomes, which break up the colloid into free T3 and T4 molecules, which passively flows into the bloodstream.

Question 11

What is Hachimoto disorder?

Answer 11

Autoimmune antibodies attack thyroglobulin or TPO or both. This is associated with severe inflammation of the gland and structural damage to the gland. Patient presents as a patient with HYPOthyroidism because the disease inhibits TH synth.

Question 12

The active thyroid hormone is T3, but the most abundant form is T4. How do you convert T4 to T3? What happens if you use 5-deiodinase instead of 5’-deiodinase?

Answer 12

5’-deiodinase (so legit, to activate T4, you remove the iodine on the 5’ position). If you use 5-deiodinase, you remove the 5 from the other benzene ring. Problem is that this is still an inactive form…actually, it become reverse T3!!!

Question 13

How do most of the T3’s come into existance?

Answer 13

You convert it from T4 using 5’-deiodinase

Question 14

What are the 3 binding proteins used for TH? Why are binding proteins used?

Answer 14

Use Thyroxine-Binding Globulin (TBG), Transthyretin, or Albumin (Albumin it the most chosen). Binding proteins are used to transport TH because TH is insoluble in blood. Binding proteins are used to transport TH to destination. They also prevent TH from being excreted from the kidneys (because TH has a really low molecular weight), effectively extending the half-life of TH in the body.

Question 15

T3 or T4 has the highest affinity to binding proteins, and thus the longer half life in the body?

Answer 15

T4. It lasts long in the blood, it is where 80% of T3 comes from, and it has the highest binding affinity to binding proteins, all reasons to consider T4 (thyroxine) a prohormone. Essentially, you prescribe thyroxine (T4), not T3!

Question 16

What summons TH? What releases TSH? Where does the thing that releases TSH live?

Answer 16

Thyroid stimulating hormone (TSH). Thyrotropin-releasing hormone (TRH), which lives in the hypothalamus.

Question 17

What causes TRH to be released?

Answer 17

Increased caloric intake, cold temps, and Leptin.

Question 18

Describe the pathway for T3, T4 release.

Answer 18

1. Hypothalamus is stimulated (calories, leptin, cold)
2. Hypthalamus summons TRH
3. TRH cummons TSH
4. TSH stimulates Thyroid follicular cells to endocytosis the colloids.
5. T3 and T4 are released to blood stream.

Question 19

How do you stop T3 and T4 release?

Answer 19

T3 and T4 release inhibits TSH and TRH, stopping T3 and T4 releases (hypothalamic-pituitary-thyroid axis)

Question 20

How does TSH act in a cell?

Answer 20

1. It binds to a TSH receptor on the cell…just so happens to be a G-protein coupled receptor.
2. cAMP is activated. cAMP acts as secondary messenger
3. cAMP activates TPO upregulation and thyroglobulin production.

Question 21

What does TSH upregulation do INSIDE the cell?

Answer 21

1. TSH enhances the uptake of glucose intot the cell. The glucose is oxidized to make H2O2, which is for the oxidation step of TSH synth
2. ACtivates upregulation of Na/K atpases, which shoves Na OUTSIDE of the cell, making a large Na gradient so that it can go back in again with Iodine in the I/Na synporter.
3. Causes the endocytosis of colloid into the thyroid follicle cell, which which is then broken down by lysosomes into T3 and T4

Question 22

What does the presence of TSH do for the cell overall? What is the consequence of overstimulation of thyroid by TSH?

Answer 22

1. Increases the size of the follicular cell
2. Increases the blood flow to the follicular cell
   * **Note that if this is over upregulated, the thyroid gland will swell up like a balloon (GOITER!)

Question 23

What can lead to Goiter?

Answer 23

1. Hypothyroid condition: TH levels go down (loss of feedback which telling it to stop producing TH), so TSH goes up and stays up. Thyroid ends up going though hyperplasia…making more thyroid cells.
2. HYPERthyroid conditions (Grave’s disease)

Question 24

What is Graves disease? Note that this is a primary issue. Anything pit is a secondary issue

Answer 24

Hyperthyroidism autoimmune disease in which the antibodies are directed at the TSH receptor and constituitarily ACTIVATE it, even in the absences of TSH. Thyroid does not know that the stimulation is caused by antibodies. Patient presents with GOITER. TSH levels will be LOW). Patient’s bloodwork will show TH is Up, TSH is DOWN, presents of thyroid stimulating antibodies.

Question 25

Primary hypothyroidism relationships

Answer 25

Hashimoto’s disorder, TH (T3 and T4) is low. TSH is high (because thyroid senses a lack of TH)

Question 26

Primary hyperthyroidism

Answer 26

Grave’s disorder: TH (T3 and T4) is high (receptor attacked and is always on). TSH is low.

Question 27

Hypo-pituitarism

Answer 27

Hypo-TSH secreting adenoma….TH (T3 and T4) is low. TSH is also low

Question 28

Hyper-pituitarism

Answer 28

Hyper-TSH secreting adenoma…TH (T3 and T4) are UP, TSH is also UP

Question 29

Why are TH and steroid hormones special?

Answer 29

They are hydrophobic, and so pass through the membrane and act in the nucleus to nuclear hormone receptors directly. The receptors are ligand activated transcription factors.

Question 30

Where do TH bind in the nucleus?

Answer 30

Hormone Response Elements in promoter or enhancer region of the given gene they are turning on.

Question 31

Which TH receptor is more expressed in the heart and which is more expressed in the pituitary gland? How do the two receptors tend to operate?

Answer 31

TR-alpha is more in the heart
TR-beta is more in the pituitary gland. Note that both receptors are present in all tissue is the body and both receptors regulate the same genes.
The two receptors ink together to forma hetero-dimer. They bind to RXR receptor, which facilitates the binding of TR heterodimber to TRE DNA. When TR and RXR are linked on TRE DNA, they are joined with Co-Repressor in the absence of TSH. When TSH is present, the co-repressor is replaced with co-activators.

Question 32

Which form of the TR does RXR prefer to bind to?

Answer 32

T3

Question 33

What does TH do to the body overall?

Answer 33

Stimulates production of ATP over a long period of time. Specifically:

1. It elevates basal metabolic rate (BMR)!!!!!!!!
2. Increase cardiac output
3. Increase metabolic turnover
4. Increase body temp
5. Linear growth in infants and kiddies
6. Maturation of the CNS during perinatal period. (Hypothyroidism, poor bone development (epipheseal plates are abnormal), along with neuro deficits)

Question 34

How does TH elevate the basal metabolic rate?

Answer 34

It upregulates the mitochondrial respiratory enzyme, increasing the size and number of mitochondria per cell. TH increases the demand of O2 to the body by increasing cardiac output. This is done by upregulating actin and myosin (heart structure), increasing Ca and myosin stimulating ATPases, in addion increasing beta receptors (increasing inotropy and chronotropy.)

Question 35

How do TH get rid of the excess energy they create?

Answer 35

1. The upregulate the presence of high energy consuming enzymes (Na/K atpase….takes up 80% of energy of some cells)
2. Na/K atpase generates a heat, which the body uses to regulate body temp

Question 36

What is annoying about TH?

Answer 36

It is both anabolic and catabolic in the same tissues “futile cycling”. It leads to metabolic (carbohydrate) turnover, which leans more catabolic than anabolic (hyperthyroidim patients lose muscle mass and bone mass). In hypo conditions, there is not enough metabolic turnover, so they accumulate fat and gain weight.

Question 37

How does low temp affect hypothalmus?

Answer 37

Triggers TRH, which stimulates TSH, which stimulates thyroid to make T3 and T4, which increases BMR, which creates Heat. T3 and T4 still inhibit TSH and TRH, acting like a thermostat, but in hyperthyroid disorder, the thermostat is wrecked, so these patients have high temps and may sweat perfusely.

Question 38

What is cretinism?

Answer 38

Issue is a lack of Iodine. The thyroid is normal, but the body is not getting enough iodine in their normal diet. These patients have low TH and HIGH TSH. Directly related to mother’s thyrpoid hormone and iodine levels. We (US) get most of our iodine from bread.

Question 39

How does TH stimulate growth?

Answer 39

It upregulates growth factors in SOME tissues. Specifically GH, IGFF1 both in bone. All TH growth and skeletal maturation properties are seen in infants and kiddies only. In adults, TH is associated with osteoporosis and bone breakdown, leading one to believe that there is a specific window allotted for bone growth. E2 and testosterone are also strong stimulators of GH. TH also affects nervous system by affecting brain development by promoting myolingenesis, which protects neurons. Also promotes synapse formation and neuronal outgrowth. Significant deficiency immediately before and after birth will be mentally retarded. Bone development can get back on rate, but mental growth will NEVER recover. Note that maternal TH is used for the 1st and 2nd trimester of the baby. The baby takes over in the 3rd trimester. If mom is low on TH, the baby will suffer, either through c section or through mental L. Lower infant IQ and low birth rate. If woman is hyporthyroid, doc will double TH dose.

Question 40

What are the similarities of hyper and hypothyroidism?

Answer 40

Menstral irregularities and Goiter.

Question 41

What causes hyperthyroidism? How does one treat it?

Answer 41

Graves disease, thyroid neoplasms/hyperplasia, excess TSH secretion (Pit tumor). Treat with TPO inhibitor, thyroid ablation, or thyroidectomy.

Question 42

What causes hypothyroidism? How does one treat it?

Answer 42

Hashimoto, thyroidectomy, iodine deficiency, insufficient TSH secretion (pit tumor), or congenital TR-Beta mutations (GRTH). Treate with T4 (thyroxine)