56 - Iodine Metabolism and Thyroid Hormones

Question 1

Amount of iodine in a healthy adult

Answer 1

15-20 mg

Question 2

Amount of iodine in the body that is stored in the thyroid

Answer 2

70-80%

Question 3

Recommended daily intake of iodine

Answer 3

150 micrograms per day (1100 micrograms as the upper limit)

Question 4

Health consequences of low iodine at all ages
1
2
3

Answer 4

1) Goitre
2) Hypothyroidism
3) Thyroid gland displays increased susceptibility to nuclear radiation

Question 5

Foetal consequences of low iodine 
1
2
3
4

Answer 5

1) Spontaneous abortion
2) Stillbirth
3) Congenital abnormalities
4) Perinatal mortality

Question 6

Childhood, adolescent consequences of low iodine

Answer 6

Impaired mental function

Delayed physical development

Question 7

Adult consequences of low iodine
1
2
3

Answer 7

• Impaired mental function
• Reduced work productivity
• Iodine-induced hyperthyroidism

Question 8

Goitre

Answer 8

Physiological adaptation to chronic iodine deficiency.
Excessive TRH released, leading to excessive TSH stimulation (from anterior pituitary gland) of thyroid gland, leading to hypertrophy, hyperplasia.

Question 9

Negative feedback regulation of thyroid gland

Answer 9

Hypothalamus releases thyroid stimulating hormone releasing hormone (TRH)
Anterior pituitary gland releases thyroid stimulating hormone
Thyroid gland releases T4/T3, which negatively feedback on pituitary gland and hypothalamus.

Question 10

What do T3 and T4 refer to?

Answer 10

Number of iodine atoms joined to thyroid hormone (T3 has three, T4 has four)

Question 11

Where do the cell bodies of neurons communicating with the posterior pituitary lie?

Answer 11

In the paraventricular nucleus of the hypothalamus

Question 12

Protein transporters involved in moving TRH into pituitary gland cells

Answer 12

Monocarboxylate transporter 8 (MCT8) and organic anion transporter of polypeptides (OATP)

Question 13

Nucleus involved in negative regulation of TRH release

Answer 13

Paraventricular nucleus

Question 14

Structure of thyroid gland

Answer 14

Follicular glands, which is where most thyroid hormone is synthesised.
Follicles have lumens, into which hormone is secreted.

Question 15

How does iodine enter thyroid follicular cells?

Answer 15

Through Na+/I- symporter

Question 16

How does iodine travel into follicular lumen?

Answer 16

Through pendrin channel

Question 17

What catalyses the iodination of thyroglobin?

Answer 17

Thyroperoxidase

Question 18

Steps of biosynthesis of thyroid hormone 
1
2
3
4
5
6

Answer 18

Involves iodination of tyrosine residues in thyroglobulin.
Iodination catalysed by thyroperoxidase.
If iodinated in one position, called monoiodotyrosine (MIT).
If iodinated in two positions, called diiodotyrosine (DIT)

• At the basolateral membrane of thyroid follicular cells, iodide is taken up by the sodium/iodide symporter (NIS). Sodium gradient of the cell is created by the Na+/K+-ATPase
• At the apical membrane, iodide enters the lumen of thyroid follicles via an anion exchanger termed pendrin.
• At the cell-lumen interface, iodide is oxidised by the thyroid peroxidase (TPO) and H2O2 to atomic iodine (I).
• Thyroglobulin (TG) is synthesised in the follicular cells and secreted into the lumen. TPO catalyses iodination of TG by the atomic iodine (I) to form mono- and di-iodotyrosines.
• TPO also catalyses coupling of the iodinated tyrosine residues to form the T3 and T4-moieties in TG which is then stored in as colloid in the lumen.
• Upon stimulation by TSH for secretion, the iodinated TG is internalised into the follicular cells where it is digested in lysosome to generate T3 and T4.
• T3 and T4 is released into the blood circulation by an unknown mechanism (possibly by monocarboxylate transporter).

Question 19

How do T3 and T4 enter target cell?

Answer 19

Through thyroid hormone transporter.

Question 20

How is T4 activated?

Answer 20

By conversion to T3 within target cell.

Question 21

Cellular site of T3 action

Answer 21

Nucleus

Question 22

What determines bioavailability of thyroid hormones?

Answer 22

Deiodination (of T4)

Question 23

T4 structure

Answer 23

Two benzene rings.

Four iodines, two on each benzine ring.

Question 24

Iodines that can be removed from thyroid hormones

Answer 24

5’ position iodines (2x 5’ position I and 2x 3’ position I)

Question 25

Role of D1 and D2 deiodinases

Answer 25

Convert T4 to T3. | Convert rT3 to T2.

Question 26

Role of D1 and D3 deiodinases

Answer 26

Reverse T3. | Function of rT3 not well understood. Might initiate actin polymerisation in astrocytes.

Question 27

Role of D3 deiodinase by itself

Answer 27

Converts T3 to T2

Question 28

T2

Answer 28

Inactive, rapidly degraded form of thyroid hormones

Question 29

Product of decarboxulation of products of thyroid hormone

Answer 29

3-iodothyronamine

Question 30

3-iodothyroamine role 1 2 3

Answer 30

* Reduce body temperature and cardiac output * Signal through membrane-bound G protein coupled receptor (unknown receptor) * Exact mechanism: unclear

Question 31

``` Major physiological actions of thyroid hormone 1 2 3 4 5 ```

Answer 31

1) Increases O2 consumption of almost all metabolically active tissues 2) Increases energy substrate uptake and utilisation 3) Increases energy consumption 4) Increases cellular respiration rates 5) Increases pulse rate and heart rate

Question 32

Mechanism by which thyroid hormones create effects

Answer 32

Increased expression of genes of structural and functional proteins. Increased expression of proteins involved in thermogenesis and mitochondrial function

Question 33

Examples of genes stimulated by thyroid hormones

Answer 33

Myosin heavy chain SERCA (Ca2+ pump in skeletal muscles, moves Ca2+ from cytoplasm into sarcoplasmic reticulum) Beta-adrenoceptors N+/K+ ATPase

Question 34

How does thyroid hormone affect transcription?

Answer 34

* THR (thyroid hormone receptor) forms dimer with RXR (retinoid X receptor) and bind to the thyroid responsive element (TRE) upstream of the transcriptional start site. * THR/RXR dimer bind to the co-repressor complex (CoR) which prevents transcription of the target gene * Binding of T3 to THR replaces CoR with co-activator complex (CoA) to initiate transcription of the target gene

Question 35

How does T3/thyroid hormone receptor/co-activator complex initiate gene transcription?

Answer 35

Bind to thyroid response element. Replacement of the co-repressor complex with co-activator complex leads to removal of histone acetylation nucleosome removal, de-repressing gene

Question 36

Isoforms of thyroid hormone receptor

Answer 36

Alpha and beta isoforms

Question 37

How does TH affect mitochondria?

Answer 37

Leads to transcription of mRNAs, which lead to translation of transcription factors or co-activators. These form mitochondrial proteins. TH can also enter mitochondria, and binds to TH response elements on miDNA.

Question 38

Mitochondrial protein particularly stimulated by TH

Answer 38

PGC-1alpha. | Transcription factor, particularly involved in thermogenesis, mitochondrial biogenesis.

Question 39

Form of TH which has more genomic effects

Answer 39

T3

Question 40

Form of TH which has more non-genomic effects

Answer 40

T4 (can bind to cell surface receptors)

Question 41

Non-genomic effects of TH (T4 is predominant)

Answer 41

Alterations in ion flux across membrane. | Monocarboxylate transporter modulation (this transporter transports TH across membrane). Aspect of negative regulation.

Question 42

TH cell surface receptor

Answer 42

Integrin alphaV beta3.