Where is the thyroid gland located?
ventral surface of trachea with two lobes which are connected by bridge of tissue. Very vascularized and one of the highest rates of blood per gram of tissue and secretes two types of hormones (T3 and T4). also secretes calcitonin. The parts that secrete T3 and T4 are different from those that secrete calcitonin and work in different ways.
Stimulation and inhibition of thyroid hormone secretion
- Stimulation of TH secretion:
- cold (infants) → a function of TH is to stimulate basal metabolic rate and stimulate thermogenesis (intrinsic generation of heat by body).
- Inhibition of TH secretion:
- stress
- warmth
Pathway for TH stimulation
The microscopic structure of thyroid gland
The follicle
- made up of the colloid and follicular cells
What does the colloid contain?
- Thyroglobulin = protein
- Precursor for thyroid hormones
- Contains tyrosine residues
- Located in colloid
- Enzymes
- Iodine
Where do the colloid substances come from?
- Thyroglobulin and the enzymes are made in the follicular cells and secreted into the colloid.
- Iodide is actively transported by follicular cells from the blood into the colloid.
- Enzymes then convert iodide to iodine.
Synthesis of thyroid hormone
- Iodide is actively transported from blood into follicular cells.
- Iodide diffuses through follicular cells and is transported into the colloid.
- Iodide is oxidized to iodine via enzyme, thyroid peroxidase, and added to tyrosine rings of thyroglobulin (TG) → when one iodine molecule attaches to a tyrosine ring that structure is called myoiodine tyrosine (MIT) when the addition of a second iodine to same tyrosine residue forms diodotyrosine (DIT)
- when the iodinated ring is added to another → DIT + DIT form T4 and represents 4 iodine molecules joined to TG. MIT + DIT form T3 and represent 3 iodine molecules joining to TG.
- TG structure containing the immature T3 and T4 is brought back into the follicular cell via endocytosis.
- lysosomes merge with the cargo to free T3 and T4 from TG backbone and render them active with enzymes that cleave T3 and T4 from TG
- then secreted by diffusing out of the follicular cell and into circulation
Structure of thyroid hormones
- Thyroxine (T4) → DIT + DIT
- Triiodothyronine (T3) → DIT + MIT
How is T3 and T4 released into circulation?
- TSH in circulation is released to interact with it receptor on the follicle cell membrane to stimulate the release of T3 and T4. TSH uses a G protein-linked receptor, which is a hydrophilic and uses cAMP as a second messenger system.
What makes up the bulk of TH stored in the colloid?
DIT and T4 make up the bulk each comprising about ⅓ (total ⅔) of iodinated compound within colloid, MIT about ¼ and T3 less than 10%
How long might DIT/T4 and MIT/T3 be stored in the colloid?
up to 3 months until they are released
Stages of TH secretion
Once TH (T3 and T4) are synthesized and stored in colloid
- Circulating TSH binds to its G-protein coupled receptor and and phosphorylates follicular cell protein necessary for endocytosis of THs from colloid into follicular cell prior to release (4)
- Precursor TH undergoes endocytosis by follicular cell (5)
- Endozome containing precursor TH fuses with lysosome and upon merging the lysosome enzymes (proteases) cleave the TG from the T3 and T4 and release them into the follicular cell (6)
- T3 and T4 are hydrophobic so they can free diffuse across the membrane into circulation (7)
- T3 and T4 need the help of carrier proteins in the blood to be transported (7)
When are T3 and T4 active?
Once they are cleaved from the TG in the follicular cell (via protease enzymes in the lysosome)
- They are inactive when attached to the TG
What proteins carry the TH hormones in the blood?
Thyroxine-bonding globulin (TBG) & albumin
- TBG has a high binding ability but low capacity so bind tightly but cannot bind very many before becoming saturated and albumin is the opposite so it can bind a lot before becoming saturated but not very tightly. Hence they work together to transport TH to target tissue in circulation
What are the thyroid hormones?
- T4
- Most abundant form produced → about 50% greater in concentration to T3 and has a longer half life
- Converted to T3 in tissues
- Via deiodinases (e.g. D1, D2)
- T3
- More active and potent at target tissue than T4
- RT3
- Inactive thyroid hormone
- T4 becomes RT3 via D3
Where are the deiodinase enzymes found?
- D1 (T4 to T3) → liver, kidneys, thyroid pituitary gland
- D2 (T4 to T3) → parts of brain, pituitary, brown fat
- D3 (T4 to RT3) → brain and reproductive tissues
Actions of T3 and T4
- Regulate basal metabolic rate (BMR: Rate of energy expenditure of a person at rest)
- Supports all basic processes necessary for survival that occur involuntarily
- Necessary for normal growth
- Essential for normal brain development and normal brain functioning in adults
- Promote increased energy mobilization when in excess
- can stimulate oxygen consumption by cells and regulate lipid and carb matabolism
- Increase numbers of beta-adrenergic receptors
- can promote and inhibit the expression of genes
- could increase HR and contraction of heart muscle
Hyperthyroidism
Thyroid hormone excess → forward protrusion of eyes and inflamed throat
Causes:
- tumours
- thyroid-stimulating immunoglobulins (Graves’ disease)
Symptoms: nervousness, insomnia, high heart rate, eye disease, weight loss and anxiety, excessive heat production.
Graves disease
- Autoimmune disease: Abnormal antibodies against the TSH receptor are produced
- negative feedback is not achieved because there is still release from the autoimmune response
- Cause unknown
- Most common cause of hyperthyroidism in the world
- Most common cause of general thyroid enlargement in developed countries
- symptoms can be reversible → surgery, active iodine
Hypothyroidism:
Thyroid hormone deficiency
Causes:
- lack of iodine in diet
- under active thyroid
Symptoms: lethargy, fatigue, cold-intolerance, weakness, hair loss and weight gain.
How does hypothyroidism differ depending in age?
- During development: cretinism → dwarfism and under mental development
- Adulthood: myxedema → thickness and puffiness of skin because the protein complexes accumulate and promote water retention
How can hypothyrodism be mitigated?
administrative does of TH can restore normal function and appearance
Iodine deficiency
- Goiter may be present
- Iodine deficiency leaves the thyroid gland unable to produce T4 and T3
- Lack of negative feedback leads to excess TSH secretion
- TSH stimulates growth of the thyroid gland by enhancing follicular cell division
- Uncommon in the developed world because of use of iodized salt
- Still the leading cause of preventable intellectual disability
