7) Thyroid Gland Flashcards
What are the three structures that produce hormones as part of the thyroid gland?
- Thyroid gland
- Parathyroid gland
- C-cells
Where is the thyroid gland located?
Below the larynx
What are the functional units of the thyroid gland?
Thyroid follicles
What is the structure of thyroid follicles?
Single layer of epithelial cells surrounding a lumen that contains colloid
Are thyroid hormones stored or secreted immediately following synthesis? Why is this particular?
Thyroid hormones are lipophilic, but they are capable of being stored within the colloid of the thyroid follicles (7-8 weeks)
What controls blood flow to the pituitary gland?
Postganglionic sympathetic nerves
What regulates T4 and T3 release?
Blood flow by affecting the delivery of TSH, iodine, and nutrients
How do thyroid follicles differ in the underactive and overactive state?
- Underactive: expansion of the colloid
- Overactive: expansion of the follicles, decrease in colloid
Where are C-cells contained?
Within the walls of the follicle
What are the two biologically active forms of thyroid hormone?
- T4
- T3
What are the two inactive forms of thyroid hormone? How are they produced?
- reverse-T3 (deiodination of T4)
- T2 (deiodination of T3)
What are the six steps required for the synthesis of T3 and T4? (6)
1) Active transport of iodine into the thyroid cell
2) Oxidation of iodide and iodination of thyroglobulin
3) Linking pairs of iodotyrosines in thyroglobulin to form T3 and T4
4) Proteolysis of thyroglobulin to release T3 and T4
5) Deiodination of iodotyrosines in thyroid cell and recycling of iodine
6) Intrathyroidal 5-deiodination of T4 to T3
What is the active transport of iodine into the thyroid cell referred as?
Trapping
What is oxidation of iodide and iodination of thyroglobulin referred as?
Organification
What is iodinated in thyroglobulin?
Tyrosyl residues
What is linking pairs of iodotyrosines in thyroglobulin to form T3 and T4 referred as?
Coupling
How is T4 converted to T3 within the thyroid?
5’-deiodination
What three components must be present for thyroid hormone synthesis?
1) Na+/I- symporter
2) Thyroglobulin
3) Thyroid peroxidase
What are the two major effects of TSH binding to its cognate receptor?
- Growth of the cell
- Synthesis of thyroid hormones
Which GPCRs do TSH-receptors contain?
- Gs
- Gq
How is iodide transported into the thyroid follicle cell from the extracellular fluid?
- Na+/I- symporter
- Na+ is brought back to the extracellular fluid with an ATPase
What are the two functions of thyroid peroxidase?
1) Iodination reaction
2) Couple MIT and DIT on the thyroglobulin molecule itself
What is the function of lysozyme in the synthesis of thyroid hormones?
Proteolytic breakdown of thyroglobulin, releasing compounds for recycling, and T3/T4
Which negative anions in the extracellular fluid block the active transport of iodine?
- ClO4-
- SCN-
- Bromide
- Nitrite
Transport of iodine into the follicular thyroid cell occurs against what type of concentration gradient?
- Steep concentration gradient
- Iodine concentration in the blood plasma is extremely low (30 to 40-fold difference)
What is used to block hyperthyroidism, while acting as an environmental inhibitor of the thyroid gland?
Perchlorate
What may be used to destroy thyroid tissue, in the case of cancer or hyperthyroidism?
Radioactive iodine (I-131)
What are competitive inhibitors of iodine uptake that are present in the diet?
- Bromide
- Nitrite
What may prevent the bioconcentration of radioactive iodine?
- Non-radioactive iodine
- Iodine itself is an inhibitor of the Na+/I- symport
- If an excess of iodine is ingested, paradoxically, hypothyroidism occurs as you inhibit more uptake of iodine
How are TPO and thyroglobulin synthesized?
- TSH stimulates their transcription and translation
- They are co-packaged into vesicles, and exocytosed into the lumen of the follicle
_____ is extensively glycosylated in the Golgi and is 10% carbohydrate by weight.
Thyroglobulin
What carries out the iodination of thyroglobulin (organification)?
Thyroperoxidase (TPO)
How is TPO activated?
At the apical membrane by cofactors
What does TPO require to function?
Hydrogen peroxide
What is the target for many drugs to reduce thyroid hormone production?
TPO
What are inhibiting compounds for TPO that are found in food?
- Goitrogens
- Present in milk from cows fed certain plants, and brassicae
What are the effects of the blockage of iodination by the inhibition of TPO?
- Results in an increased TSH production, as the negative feedback loop is cut-off
- Stimulation of the growth of the follicle, but lack of production of T4 and T3 given the inhibition of iodination
- Results in hyperplasia and goiter
Which residues of thyroglobulin become iodinated?
Tyrosines on the surface (about 1/3)
Which precursors of thyroid hormone are used to produce T3?
- MIT (monoiodotyrosine)
- DIT (diiodotyrosine)
Which precursors of thyroid hormone are used to produce T4?
2 x DIT (diiodotyrosine)
When does the coupling reaction occur based on the iodination reaction?
The coupling reaction occurs simultaneously with the iodination reaction, sometimes within the same molecule
What is the maximum of thyroid hormones produced from each protein molecule?
Four T3 and/or T4 hormones
Which thyroid precursor increases if there is an excess of iodine in the diet? Which thyroid hormone does it synthesize?
- Diiodothyrosine (DIT)
- T4
Which thyroid precursor increases if there is a deficiency of iodine in the diet? Which thyroid hormone does it synthesize?
- Monoiodotyrosine (MIT)
- T3
Why is the synthesis of T3 particularly important when iodine is deficient in the diet?
T3 is more bioactive than T4
Which thyroid hormone is produced when there is a deficiency in iodine? Which thyroid hormone is produced when iodine is in excess?
- Deficiency: T3
- Excess: T4
What is the effect of propylthiouracil (PTU)?
Blocks the iodination of thyroglobulin
Is iodine transported with or against its concentration gradient?
Against its concentration gradient
Which thyroid hormone is produced in a greater quantity?
T4 is produced in a greater quantity than T3
What are indicators of “sick euthyroid syndrome”?
- High levels of r-T3
- Low levels of T3
What is “sick euthyroid syndrome”?
- Thyroid is normally functioning
- Hypothyroidism due to a metabolic adaptation to some other condition (e.g. anorexia, cancer)
What synthesizes the carrier proteins for thyroid hormones?
The liver
Which thyroid hormone is more bound to a carrier protein?
- T4 is more likely to be bound to a carrier protein (less free T4)
- Free thyroid hormones are bioactive
What occurs if a drug competes with the binding to the carrier protein of thyroid hormones? What are the side effects?
- Elevation of free T3 and T4
- Hyperthyroidism
How does the half-life of T3 compare to T4?
T4 has a longer half-life
How does T3 compare to T4 in terms of bioactivity and half-life? How do they compare in terms of the quantity produced?
- T3 is more bioactive than T4 but it has a shorter half-life
- T4 is produced in greater quantities
What determines the free hormone concentration?
The level of binding proteins
Which conditions would result in a greater quantity of binding protein? What occurs?
- Pregnancy
- Oral contraceptives
- More total hormone are required to maintain a free hormone level
Which conditions would result in a lesser quantity of binding protein? What occurs?
- Starvation
- Liver disease
- Less total hormone are required to maintain free hormone level
What mechanisms may allow the body to react to an increased level of binding protein?
- Feedback control
- Tissue action
- Hormone metabolism
- Excretion
What are the effects of starvation on T3, T4, and r-T3?
- Starvation decreases binding proteins
- T3 and T4 decrease as a lesser quantity is required to maintain the free hormones
- r-T3 levels increase
What is the function of a type I deiodinase? Where does it occur?
- T4 –> T3
- Liver, kidney, muscle (peripheral conversion)
What is the function of a type II deiodinase? Where does it occur?
- T4 –> T3
- Brain, pituitary
Which deiodinase is key for the feedback on TRH and TSH?
Type II deiodinase
What is the function of a type III deiodinase?
- T4 –> rT3
- Inactivation if T3 is in excess (rT3 –> T2)
Which rare amino acid do the three deiodinases contain?
Selenocysteine (containing selenium)
What is the mechanism of action of type I and type II deiodinases?
Bioactivate the thyroid hormone by removing a single “outer-ring” iodine atom
What is the mechanism of action of type III deiodinases?
Inactivates the thyroid hormone by removing a single “inner-ring” iodine atom
Describe the basic organization of the selenodeiodinases.
- Membrane-bound proteins, containing an extracellular, transmembrane, and intracellular domain
- Exist as a dimer
What are the three physiological functions of deiodinases?
1) Permit local tissue and cell modulation of the thyroid hormone
2) Aid in the adaptation to changes, including iodine deficiency or chronic illness
3) Regulate thyroid actions during early development
How does type III deiodinase fluctuate during hyperthyroidism and hypothyroidism?
- Increases during hyperthyroidism
- Decreases during hypothyroidism