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Thyroid Hormone Metabolism Flashcards

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1
Q

What is iodine?

A

A crucial element for the production of thyroid hormones, which is essential for mammalian life

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2
Q

Why is an adequate supply of iodide necessary in early life?

A

To prevent iodide deficiency disorders, because thyroid hormones are crucial for embryonic and postembryonic development

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3
Q

Particularly for which organs or systems is iodine crucial?

A

CNS
Lungs
Musculoskeletal system

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4
Q

What are thyroid hormones master regulators of?

A

Cellular metabolism in virtually all tissues at all stages of life

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5
Q

Where can iodine (as iodide) come from?

A

Only from external sources - mostly food, but also water

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6
Q

Is iodine widely distributed in nature, what is the result of that?

A

It is not widely distributed in nature, thus, in the past iodine deficiency was common among people in every continent

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7
Q

What is the main national and international effort to incraese iodine intake?

A

Voluntary or mandatory iodination of salt

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8
Q

What is goiter (goitre)?

A

A reflection of chronic iodine deficiency

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9
Q

When does goiter become an endemic issue?

A

In populations where the intake of iodine is less than 10μg per day

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10
Q

What is the long term effects of persistent iodine deficiency?

A

Can affect growth and mental development in all age groups

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11
Q

What can severe iodine deficiency in mothers and fetuses lead to?

A

Pregnancy loss and cretinism with:
1. Irreversible mental retardation
2. Neurologic dysfunction
3. Growth retardation

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12
Q

What are the likely clinical manifestations in severe cases of goiter? (3)

A
  1. Difficulty in swallowing or breathing
  2. Loss of voice
  3. Myxedematous cretinism
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13
Q

What is the likely cause of hoarseness of the voice in severe cases of goiter?

A

This is likely due to damage to the recurrent laryngeal nerves

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14
Q

What does mild iodine deficiency in school-age children result in?

A
  1. Learning disability
  2. Poor growth
  3. Diffuse
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15
Q

What does mild iodine deficiency in adults present as?

A

Mild iodine deficiency is also associated with goiter. Thyroid gland enlargement is often seen with no disturbance in the thyroid function (nontoxic nodular goiter)

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16
Q

What is dietary iodine normally ingested as?

A

Form of iodide

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17
Q

What is the first step of iodide metaolism?

A

Iodide absorption in the GIT, and particularly the small intestine

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18
Q

What is the sodium/iodide symporter?

A

Key glycoprotein on the plasma membrane that actively transports iodide into cells, such as enterocytes and thyroid follicular cells

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19
Q

What is the primary site of iodide storage in the human body?

A

The thyroid gland contains about 70 to 80% of the body’s total iodine

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20
Q

What is the first step in the metabolism of iodine? How does it begin?

A

Iodine trapping: this process commences with the uptake of iodide from the capillary into the follicular cells of the gland by an active transport system

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21
Q

Why is there an active transport system for the transport of iodide?

A

The concentration of iodide in the plasma is so low, the active mechanism is required for the thyroid cell to concentrate the required amounts of this element

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22
Q

What is the active process of iodide transport dependent on? Why?

A

The presence of sodium gradient across the basal membrane of the thyroid cell, Na+/K+ ATPase.
Sodium is required so that when 2 Na+ ions are transported it results in the entry of one iodide atoma gainst an electrochemical gradient (soidum/iodide symporter)

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23
Q
A
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24
Q

What is the role of NIS in the lactating mammary gland?

A

Important role by concentrating iodide in the milk, thereby supplying newborns with iodide for thyroid hormone synthesis

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24
What is the effect of sodium/iodide symporter (NIS)?
Enables thyrocytes to concentrate iodide roughly 30 to 60 fold within the cytosol of thyrocytes
25
What is the absence of NIS associated with?
Congenital hypothyroidism and goiter unless large quantities of inorganic iodide are provided
25
Where is NIS functionally expressed endogenously in extrathyroidal tissues?
Salivary glands Stomach Intestine Lactating breast
25
In which pathologies is NIS funtionally expressed?
Primary and metastatic breast cancers
26
What is the purpose of the (131) I - treatment?
Targets remnant malignant cells abdominal metastases that actively accumulate the radioisotope via NIS
26
What is the relation between NIS and radioactive iodine therapy?
The molecule at the center of the remarkably successful treatment for thyroid cancer based on (131)I-, which is administered after thyroidectomy
27
Where is iodide stored?
In thyroglobulin After active transport into the thyroid, iodide is stored in the TG protein before undergoing conversion into T3 and T4
28
What is thyroglobulin?
A 2764 amino acid hyperglycosylated protein expressed in thyrocytes and secreted to the follicular lumen where it accumulates
29
What happens to dimeric Thyroglobulin?
It is secreted to the follicular cavity and iodinated at specific tyrosine residues, a process modulated by the dietary iodine intake
30
How does TSH affect virtually all cellular processes involving thyroid hormone production?
Influences: 1. Thyroidal iodine uptake 2. Thyroglobulin iodination 3. Reuptake of iodinated thyroglobulin and thyroid cells growth
31
What is the relation between hypo/hyperthyroidism and TSH?
Both conditions are characterizes by abnormal concentrations of TSH, as well as thyroid hormones in the serum
32
How does TSH mediate its function?
By binding to and activating TSHR which is the receptor expressed in the thyroid
33
What can activated TSHR also be coupled to?
It can also be coupled to stimulatory Gs protein to stimulate the production of the thyroid hormone
34
What can happen to the alpha-subunit of TSHR, and what is the result of it?
It can dissociate from the beta-subunit and become an antigen, which is further recognized by te immune system and results in autoantibody production
35
What is the pathology associated with the binding of TSHR-stimulating antibodies to TSHR on the thyroid cells?
Grave's disease, stimulating the gland to overproduce thyroid hormones and cause thyroid enlargement and orbital fibroblasts, can cause Grave's orbitopathy
36
How many tyrosine residues out of the large number of amino acids in TG are potential sites for iodination?
Around 66 tyrosine residues, of which only a subset is iodinated and couple to form thyroid hormones
37
What are DUOX2 and DUOX1?
They both belong to the NADPH oxidase family, and they are present in the thyroid
38
What is the primary function of NADPH oxidase?
To generate reactive oxygen species (ROS) during a process known as a respiratory burst
39
Where are DUOX proteins localized?
In the apical poles of the thyroid cells exposed to the colloid of thyroid follicles, where they co-localize with thyroid-peroxidase
40
What is thyroid-peroxidase? Where is it found?
A transmembrane protein anchored to the apical membrane of thyroid follicle cells
41
What is the role of thyroid-peroxidase?
It plays an essential role in thyroid hormone synthesis, catalyzing the iodination of tyrosine on thyroglobulin
42
What does thyroid-peroxidase require for the oxidation of thyroidal iodide?
Requires H2O2 generated by the calcium-dependent Dual oxidases (DUOX) enzymes
43
What is iodination facilitated by?
Both DUOX and thyroid-peroxidases
44
How does Carbimzaole work?
By inhibiting the TPO that catalyzes the iodination of tyrosine residues in thyroglobulin and the oxidative coupling of iodinated tyrosines
45
What does the synthesis of T3 and T4 within thyroglobulin involve?
Oxidative coupling betweenn iodinated tyrosine residues on thyroglobulin
46
What is the first step in thyroid hormone release? What is next?
1. The endocytosis of colloid from the follicular lumen by a process known as micropinocytosis 2. Following endocytosis, endocytotic vesicles fuse with lysoymes and proteolysis is catalyzed by proteases, all of which are active at the acidic pH of the lysosome
47
What are T3 and T4 like in circulation?
Bound reversibly and almost completely to carrier proteins
48
How many specific thyroid hormone transporters have been identidied so far?
At least 20 cell-specific thyroid hormone transporters
49
What happens to the concentration of thyroid hormones once inside the cell?
It is tightly controlled by three iodothyronine deiodinase enzymes (DIO1, DIO2, and DIO3)
50
What is the function of DIO1, DIO2 and DIO3?
They catalyze the removal of iodine atoms at the phenolic ring (activation pathway) or at the tyrosyl ring (inactivation pathway) of T4 and T3
51
Why is reverse T3 considered an inactive metabolite?
It cannot bind to the receptor
52
Is T2 involved in the genomic action of T3?
No, but it might exert various metabolic effects
53
Which enzymes are associated with the activation of T4 into T3?
DIO1 and DIO2 of the outer ring deiodinase
54
Which enzymes are associated with the inactivation of T3 into T2?
DIO3 Secondarily by DIO1
55
What is the ideal therapeutic goal for hypothyroidism?
Restore clinical and biochemical euthyroidism via physiologic thyroid hormone replacement
56
What has the standard treatment approach for thyroid replacement in hypothyroidism been?
Administration of levothyroxine (LT4) at doses that normalize the serum TSH --> The iodothyronine deiodinases in peripheral tissues produce most of the circulating active form of thyroid hormone, T3, via conversion from T4
57
What is the hypothesis behind the LT4 "monotherapy"?
It will maintain an adequate serum pool of T4, and the iodothyronine deiodinases will then provide psychologic regulation of T3 availability
58
What is the effect of Cys785Thr (DIO1)?
Decreased deiodinase activity Increased rT3 levels and reduced T3:rT3 ratio
59
What is the effect of Ala1814Gly (DIO1)?
Increased deiodinase activity Increased T3 levels and increased T3:rT3 ratio
60
What is the effect of Thr92Ala (DIO2)?
Decreased deiodinase activity Increased T4 and reduced T3 levels and reduced T3:T4 ratio
61
What is the effect of ORFa-G3A (DIO2)?
Increased deiodinase activity Reduced T4 levels and increased T3:T4 ratio
62
What is the effect of Thr154Gly (DIO3)?
Unchanged deiodinase activity Unchanged thyroid hormone levels
63
How do some polymorphisms of DIOs affect plasma levels of thyroid hormones?
By modifying deiodinase activity or expression
64
In which tissues is TR expressed?
Skeletal muscles Brown adipose Heart Different brain regions
65
How does R3 exert its biological activity?
Either by binding to nuclear receptors and regulating target gene expression (genomic action) or by binding to cytosolic partners and activating intracellular cascades (non-genomic action)
66
Which family do the thyroid receptors belong in?
Superfamily of nuclear hormone receptors that function as ligand-modulated transcription factors
67
What occurs upon binding of the T3 thyroid hormone receptor complexes to thyroid hormone response elements within chromatin?
Transcription of target genes, regulated by an exchange of co-repressor and co-activator complexes
68
What is the net effect of increased thyroid hormones?
Increase in basal metabolic rate
69
How is the binding of the T3/T4 to TR and then TRE of specific genes accomplished?
This is accomplished by increasing the expression of genes that code for enzymes in the catabolic and anabolic pathway of fat, carbohydrates, and proteins, as well as the expression of the Na/K pump
70
Why is hypothyroid associated with cold intolerance?
They do not produce enough thyroid hormone to convert and utilize stored energy effectively
71
What is the effect after thyroid hormone administration?
Increase in oxygen consumption in most tissues
72
What do thyroid hormones cause in terms of ATP utilization?
An increase in ATP utilization leads to the acceleration of anabolic and catabolic pathways in macronutrient metabolism, such as lipolysis/fatty acid oxidation and increased protein turnover
73
Why is there hyperphagia in hyperthyroidism?
Hyperphagia is present even in the presence of weight loss, which is related to the direct effect of thyroid hormones on appetite stimulation
74
What is the mechanism of hyperphagia in hyperthyroidism?
In the hypothalamic nucleus arcuate, T3, produced locally by DIO2, increases the expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgPR) and decreases the anorexigenic peptide, pro-opiomelanocrtin (POMC)
75

Endocrine System (25 decks)

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