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A Physiology > 7.3. Production and effects of thyroid hormones (T3/T4). The regulation of their secretion. > Flashcards

7.3. Production and effects of thyroid hormones (T3/T4). The regulation of their secretion. Flashcards

1
Q

I. Thyroid gland
1. Describe the anatomy of thyroid gland

A
  • 2 lobes connected by an isthmus and sit in front of the trachea
  • Weight 15-20g (physiological weight)
  • Follicle size: 200-300μm
  • Lumen of follicle contains a homogenous eosinophilic material = colloid material (contains thyroglobulin – secreted from epithelial cells)
  • Synthesis of thyroglobulin by endocytosis of colloid (thyroglobulin) in the interfollicular area
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2
Q

I. Thyroid gland
1B. What is the position of thyroid gland?

A

2 lobes connected by an isthmus and sit in front of the trachea

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3
Q

I. Thyroid gland
3. What is the physiological weight of thyroid gland?

A

15-20g

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4
Q

I. Thyroid gland
4. What does the lumen of follicle contain?

A

Lumen of follicle contains a homogenous eosinophilic material = colloid material
(contains thyroglobulin – secreted from epithelial cells)

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5
Q

I. Thyroid gland
5. Where does synthesis of thyroglobulin occur?

A

Synthesis of thyroglobulin by endocytosis of colloid (thyroglobulin) in the interfollicular area

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6
Q

II. Thyroid hormones
1. Where are thyroid hormones produced and secreted?

A

Thyroid hormones are produced in and secreted by thyroid follicle epithelial cells

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7
Q

II. Thyroid hormones
2. What are the 2 active thyroid hormones?

A

Thyroxine (T4) and tri-iodothyronine (T3) are the two active hormones

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8
Q

II. Thyroid hormones
3. What are characteristics of T3 and T4?

A
  • T3 has one iodine missing on its 5’ position (outer ring)
    (If one iodine is missing from inner ring = loss of hormone activity)
  • T3 is more active than T4, but far more T4 is secreted
  • They are derived from 2 tyrosine molecules, which provides benzyl rings that make the hormones hydrophobic and able to diffuse through the PM
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9
Q

II. Thyroid hormones
4. What happen if 1 iodine is missing from the inner ring of thyroid hormones?

A

Loss of hormone activity

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10
Q

II. Thyroid hormones
5. Draw the structure of thyroxine

A
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11
Q

II. Thyroid hormones
6. Draw the structure of triiodothyronine

A
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12
Q

II. Thyroid hormones
7A. What does thyroid hormone synthesis require?

A

Thyroid hormone synthesis requires iodine – without it = no proper hormone synthesis

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13
Q

II. Thyroid hormones
7B. How does thyroid hormone synthesis occur?

A

The synthesis consists of 2 main processes:
1) Iodination: when iodine is built into the hormone molecule (occurs in AAs which are peptide bound, because they are a part of thyroglobulin)
2) Coupling: When 2 modified tyrosine’s are coupled together to form a hormone

(Thyroid hormone synthesis requires iodine – without it = no proper hormone synthesis)

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14
Q

II. Thyroid hormones
7C. How does iodination occur within thyroid synthesis?

A
  • Iodination: when iodine is built into the hormone molecule (occurs in AAs which are peptide bound, because they are a part of thyroglobulin)
  • Single iodination -> mono-iodo-tyrosine (MIT)
  • Double iodination -> di-iodo-tyrosine (DIT)
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15
Q

II. Thyroid hormones
7C. How does thyroid coupling occur?

A
  • DIT + DIT -> T4 (condensation reaction)
  • T4 is still peptide bound – part of thyroglobulin molecule
  • MIT+DIT -> T3
  • DIT + MIT -> rT3 (reverse T3) – 1 iodine in inner ring = inactive product => no hormone activity
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16
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8A. List 6 steps of mechanism of thyroid synthesis

A
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17
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8B. What does the follicular cell produce?

A

a tyrosine-rich glycoprotein, thyroglobulin (TG), which is
sent to the colloid space

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18
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8G. What is the fate of MIT and DIT after thyroid hormone synthesis?

A

MIT and DIT will be deiodinated inside the cell by a deiodinase
=> iodide and tyrosine will be recycled

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19
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8C. How does iodine oxidation occur?

A
  1. I- is pumped into the colloid via pendrin (Cl-/I—antiporter).
  2. I- is oxidized into I2 (iodine) by TPO (thyroperoxidase) with the help of Duox2, an apical membrane-bound enzyme which produces H2O2 needed for oxidation
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20
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8D. What is the role of TPO (thyroperoxidase)?

A
  1. Oxidation of I- to I2
  2. Inducing iodination and coupling to form T4, T4, MIT and DIT – all bound to TG
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21
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8C. What is the fate of The TG-hormone complex?

A

5) The TG-hormone complex will get endocytosed by the epithelial cell when the thyroid is stimulated
6) Inside the cell, the complex fuses with lysosome and the T3, T4, MIT and DIT are hydrolyzed by a protease

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22
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8E. What is the fate of the hydrophobic T4 and T4?

A

The hydrophobic T4 and T4 will easily diffuse to the blood circulation by simple diffusion

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23
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8B. What does the follicular cell produce?

A

a tyrosine-rich glycoprotein, thyroglobulin (TG), which is
sent to the colloid space

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24
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8C. What are the position and role of Na+-iodide symporter (NIS)?

A

Na+-iodide symporter (NIS) on the basolateral side of the epithelial cell pumps I-(iodide) into the cell from the blood

25
Q

II. Thyroid hormones - mechanism of thyroid synthesis
8H. What is the fate of thyroglobulin after the synthesis of thyroid hormone?

A

Thyroglobulin degrades to AAs, which are re-used for synthesis of TG

26
Q

II. Thyroid hormones - Summary of the iodide metabolism
9A. What is the Minimal iodine required of human body?

A

Minimal iodine required = 50 – 100 μg/day
- If not: the thyroid function↓ => hypothyroidism
- Average uptake = 400μg

27
Q

II. Thyroid hormones - Summary of the iodide metabolism
9B. Why are there regions that people add iodine supplements to table salt?

A

In some regions (like the Swiss alps, South America, Asia), the iodide content of the soil is low
-> the iodide content in vegetables and animal meat will also be low = iodine deficiency (hypothyroidism)
-> endemic iodine deficiency = effects all people who live in that region
=> Solution: add iodine supplements to table salt

28
Q

II. Thyroid hormones
10. What is the structure and role of The Na+-I symporter (NIS) ?

A

The Na+-I symporter (NIS) is a 12 TM domain glycoprotein which performs an electrogenic transport (electrically imbalanced), moving 2 Na+-ions and 1 I—ion into the cell

29
Q

II. Thyroid hormones - Inhibition of hormone synthesis
11A. The NIS is not specific for iodide – it can transport other ions as well. This will inhibit the thyroid hormone synthesis.
-> How?

A

The NIS is not specific for iodide – it can transport other ions as well:
1. Thiocyanate (SCN-) competes with I-, thus, inhibiting hormone synthesis
-> SCN- is formed from foods rich in glycosides (cabbages, broccoli, cauliflower,
mustard, cassava)  hypothyroidism
2. Perchlorate (ClO4-): environmental pollutant
-> inhibits uptake of I- at NIS
-> The thyroid gland can transport both the physiological and isotope form (I131) -> dangerous!!
- Example: Chernobyl disaster = a lot of I131 formed
-> got into air, vegetables etc. Thyroid gland would accumulate this toxic radioisotope, which lead to mutations + cancer
SOLUTION: eat high amount of non-radiant iodide, to reduce the amount of the toxic radioisotope

30
Q

II. Thyroid hormones - Inhibition of hormone synthesis
11B. What are examples of TPO inhibitors?

A

Thiouracil and propylthiouracil inhibit hormone synthesis (used as medication against hyperfunction)

31
Q

II. Thyroid hormones - Inhibition of hormone synthesis
12. What is the Wolff-Chaikoff effect?

A

If high amount of iodide is consumed (>2mg/day-intake), it will lead to inhibition of hormone synthesis
-> inhibits enzymes involved (Duox2, etc)

32
Q

II. Thyroid hormones
13. How are thyroid hormones transported?

A
  • The thyroid hormones have a hydrophobic nature = lipid-soluble.
  • In the blood, the solubility is increased by transport proteins -> can bind T4/T3.
33
Q

II. Thyroid hormones
14. Major of thyroid hormones are bound to transport proteins.
-> What are the percentages of protein-bound thyroid hormone and free thyroid hormone?

A
34
Q

II. Thyroid hormones
14. Major of thyroid hormones are bound to transport proteins.
-> What are the percentages of transport proteins that bound to thyroid hormones?

A

1) 85% bound to TBG (thyroxine binding globulin – synthesized in liver)
2) 10% bound to TBPA (thyroxine binding pre-albumin)
3) 5% bound to albumin (not specialized for TH transport)

35
Q

II. Thyroid hormones
15. What are the characteristics of the presence of thyroid hormones?

A
  • Since only the free hormone is active (biological effect), the transport proteins act as a ‘’circulating hormone pool’’ of thyroid hormones
  • They can be readily utilized by dissociation from the bound proteins
  • Hormone binding proteins will ↓ renal loss of hormones (not filtrated in kidney)
  • When the [T4]total↑, the [T4]free will be unchanged, because the transient decrease will be immediately corrected by regulating mechanisms
36
Q

II. Thyroid hormones - Metabolism of thyroid hormones
16A. What are the 3 enzymes that are responsible for the metabolism of thyroid hormones?

A
  • Type 1 deiodinase
  • Type 2 deiodinase
  • Type 3 deiodinase
37
Q

II. Thyroid hormones - Metabolism of thyroid hormones
16B. How does Type 1 Deiodinase work?

A
  • Remove an iodide from the outer ring (5’), T4 -> T3 (activating step)
  • Usually in high blood flow organs like kidney, liver and skeletal muscle – releases T3 to the blood for the low-flow organs
38
Q

II. Thyroid hormones - Metabolism of thyroid hormones
16C. How does Type 2 Deiodinase work?

A
  • Same as type 1, T4 -> T3
  • Expressed in the pituitary, HT, CNS, brown adipose tissue
  • T3 will stay inside the cells – will not enter the blood
39
Q

II. Thyroid hormones - Metabolism of thyroid hormones
16D. How does Type 3 Deiodinase work?

A

Will remove iodide from the inner ring (5), T4 -> rT3 (inactivation = hormone activity lost)

40
Q

II. Thyroid hormones - Mechanism of T4 and T3 action
17A. What is the general mechanism of T4 and T3 action?

A

Thyroid hormones have IC receptors (in nucleus) -> TH can enter through diffusion/transporters
- IC receptor work in form of dimers
- Thyroid hormone receptor (TR) in dimer with retinoid X receptor (RXR)
- Together they bind to a DNA sequence, the thyroid response element (TRE)

41
Q

II. Thyroid hormones - Mechanism of T4 and T3 action
17B. What are the 4 detailed step of mechanism of T4 and T3 action?

A

1) T4 + T3 are released from the transport proteins into the bloodstream and enter the cytosol by diffusion or by carrier-mediated transport (MCT8 - monocarboxylate transporter)
2) T4 + T3 enter the cell
3) In the cell, most of T4 is metabolized into T3 by 5’iodinase -> T3 is the final active
form
4) T3 binds to TR -> conformational change of the TR-RXR complex -> binding to TRE occurs -> gene transcription activated
-> The effects of thyroid hormones are mediated through gene transcriptions

42
Q

II. Thyroid hormones - Effects of thyroid hormone
18A. How is Basal metabolic rate (BMR) stimulated?

A

Thyroid hormones will stimulate the BMR (= minimal energy expenditure required at complete rest)
- TH will ↑O2-consumption by ↑synthesis + activity of Na+/K+-ATPases and ↑mitochondrial enzymes
- The increased O2-consumption will increase the BMR -> ↑heat production
- TH will also stimulate uncoupling proteins that make adipocytes burn fuel for purpose of heat production

43
Q

II. Thyroid hormones - Effects of thyroid hormone
18B. What happen if there is an increasing BMR?

A

BMR↑ (heat production)metabolites↑ (vasodilators) -> TPR↓ (lose heat = vasodilation)
=> Decreased TPR -> ↓Pdia
=> Overall effect: ↑CO + ↓TPR = ↑Psys + ↓Pdia = ↑Ppulse (patient with
hyperthyroidism)

44
Q

II. Thyroid hormones - Effects of thyroid hormone
19. How does Intermediate metabolism work?

A
  • Blood glucose↑ (by ↑glucose absorption, glycogenolysis, gluconeogenesis)
  • Cholesterol level↓
  • Protein synthesis↑
    +) But if concentration of T4/T3↑↑ = protein degradation (muscle weakness)
  • lipolysis↑ (because TH stimulate β-AR = permissive effect – a physiological level of TH is necessary for these reactions)
45
Q

II. Thyroid hormones - Effects of thyroid hormone
20. What are the cardiovascular effects of thyroid hormones?

A

Since there is a high demand for oxygen to fuel the high metabolic activity, there will also be a need for ↑CO through ↑HR and ↑SV.
This is done by permissive effects: TH cannot directly stimulate the HR, but will ↑expression of signaling proteins -> gene expression change -> catecholamines (NE/E) which f.ex. can stimulate HR

46
Q

II. Thyroid hormones - Effects of thyroid hormone
21. What are the respiratory effects of thyroid hormones?

A
  • Rate of respiration (frequency) ↑
  • Minute ventilation (𝑉 ) ↑
  • Erythropoietin (EPO) production↑
    -> RBC↑ (more RBC can carry more O2)
47
Q

II. Thyroid hormones - Effects of thyroid hormone in grow and development
22A. How can thyroid hormone affect CNS development?

A

CNS development: a physiological level of TH is necessary, because they are very important for:
- Myelin sheath formation
- Dendrite arborization
- Synapse formation
- Cell migration
=> Lack of TH results in mental retardation/cretinism

48
Q

II. Thyroid hormones - Effects of thyroid hormone in grow and development
22B. How can thyroid hormone affect Bone growth?

A
  • Chondrocyte differentiation
  • Linear growth of bone
  • Bone remodeling
49
Q

II. Thyroid hormones - Effects of thyroid hormone in grow and development
22C. How can thyroid hormone affect connective tissue?

A
  • Degradation of glycoproteins↑
  • Degradation of proteoglycans↑
    2020/2021
    => These molecules are important in binding H2O in CT
    => Absence of TH: degradation↓ = CT binds more H2Oformation of myxedema (hypothyroidism)

GH production↑ (important in normal development of teeth, skin, internal organs)

50
Q

II. Thyroid hormones- Regulation of thyroid hormone synthesis
23. How does hypothalamo-anterior pituitary-thyroid axis work?

A

Increased food intake or decreased temperature can stimulate the HR to secrete TRH:
1. TRH stimulates the anterior pituitary to release TSH
- TSH -> (Gs) -> ↑[cAMP] + ↑[Ca2+]IC
2. TSH stimulates the thyroid to produce T3/T4
- If [TSH] is constantly high -> (positive feedback) -> ↑size of thyroid gland
(goiter)
3. T3 (T4 will be converted to T3) feeds back to inhibit TSH + THR release (negative feedback)

51
Q

III. Tests for thyroid function
1. Why do we test [T3] and [T4]?

A

It is best to measure concentrations of free [T3] and [T4], because hormone-binding globulins can interfere with total hormone concentrations

52
Q

III. Tests for thyroid function
2. Why do we test [TSH]?

A
  • Due to negative feedback mechanism, if TSH is normal, T3/T4 synthesis is likely normal
  • Increased TSH can indicate T3/T4 deficiency or a TSH- producing tumor
  • TSH is routinely measured in newborns, because if there is
    hypothyroidism -> T3/T4↓ -> [TSH]↑ (can detect disorder via [TSH])
53
Q

III. Tests for thyroid function
3. Why do we use thyroid scan?

A
  • Use of Tc (technetium) radioisotope in pertechnetate ion (TcO4-) which is taken up by NIS into thyroid tissues
  • Gamma camera is used to measure radiation from the thyroid (hot spots = tumor cold spots = NIS dysfunction)
54
Q

IV. Disorders
1A. What is the cause of Hypothyroidism?

A

↓[T3/T4]free

55
Q

IV. Disorders
1B. What are the symptoms of Hypothyroidism in infants?

A

In infants: cretinism = mental retardation, decreased height (dwarfism), facial abnormalities

56
Q

IV. Disorders
1C. What are the symptoms of Hypothyroidism in adults?

A
  • Myxedema (because ↑glycoproteins + proteoglycans in CT)
  • Hoarse voice (myxedema of vocal chords)
  • Dry, cool skin (↓BMR)
  • Fatigue
  • Sensitivity to cold
  • Weight gain (less energy burning)
  • Slow speech
  • Bradycardia (↓HR)
  • Depression
    => Pandas are not lazy, they have hypothyroidism (Duox2 mutation)
57
Q

IV. Disorders
2A. What is the cause of Hyperthyroidism?

A

↑[T3/T4]free

58
Q

IV. Disorders
2B. What are the symptoms of hyperhyroidism?

A
  • ↑BMR
  • Weight loss (heat production)
  • Increased appetite
  • Increased sensitivity to heat
  • Sweating
  • Nervousness, anxiety (direct effect on nervous system)
  • Fatigue, muscle weakness (loss of protein due to ↑metabolism)
  • Hyperactivity
  • Tremor
  • Diarrhea (↑GI-tract function)
  • Bulging of the eye (exophthalmos)
  • Tachycardia (↑HR)
    => Detection: ↓cholesterol level (below normal level)

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