Thyroid Gland Flashcards
Where is the thyroid gland?
in anterior neck, on trachea just inferior and lateral to thyroid cartilage of larynx
Does the thyroid gland receive higher or lower blood flow per unit weight than kidneys?
higher
How many lobes does the thyroid gland have?
2 – left and right
What are the lobes of the thyroid gland connected by?
isthmus (median tissue mass)
What are thyroid glands composed if?
20 million thyroid follicles (spherical functional units)
What are the walls of follicles formed by?
follicular cells (cuboidal epithelial cells)
What do follicular cells produce?
thyroglobulin (TGB)
What is thyroglobulin (TGB)?
glycoprotein containing about 130 tyrosine amino acids
What does the lumen of each follicle do?
stores gelatinous colloid made primarily of TGB
What do C (parafollicular) cells do?
responsible for secretion of calcitonin
What is calcitonin?
hormone involved in calcium homeostasis
What are thyroid hormones?
iodinated thyronines and are called:
- tetraiodothyronine (thyroxin or T4)
- triiodothyronine (T3)
What is the structure of T4?
two tyrosine amino acids linked together + 4 iodines
What is the structure of T3?
two tyrosine amino acids linked together + 3 iodines
Describe the amount of T4 vs. T3.
- more than 90% of TH released from thyroid gland is T4
- but almost all of it is eventually converted to T3 in target tissues
What are the functions of plasma membranes of epithelial cells?
different functions depending on location:
- exposed to lumen – apical surface
- exposed to interstitial space – basolateral surface
What are the general steps of thyroid hormone synthesis?
- formation and storage of TGB
- iodide trapping and oxidation to iodine
- iodination
- coupling
- colloid pinocytosis
- proteolysis
- secretion and recycling
What are the general steps of thyroid hormone synthesis?
- formation and storage of TGB
- iodide trapping and oxidation to iodine
- iodination
- coupling
- colloid pinocytosis
- proteolysis
- secretion and recycling
Thyroid Hormone Secretion – 1. formation and storage of TGB
Where is TGB gene?
long arm of chromosome 8
Thyroid Hormone Secretion – 1. formation and storage of TGB
What happens in this step?
- translation of TGB mRNA in RER of follicular cells – nucleus
- protein is glycosylated in Golgi apparatus, packaged into vesicles and released by exocytosis into lumen of follicle to become a major component of the colloid
Thyroid Hormone Secretion – 2. iodide trapping and oxidation to iodine
What happens in this step?
- follicular cells accumulate iodide (or iodine ions) from blood
- uptake of I- into cell is Na+ K+ ATPase-dependent
- SECONDARY ACTIVE TRANSPORT: uptake of I- into cell by Na+/I- symporter (NIS or iodide trap) – co-transports 1 I- with 2 Na+ across basolateral membrane into cell
- iodide diffuses across follicular cell
- FACILITATED DIFFUSION: transported across apical membrane into colloid by pendrin (chloride-iodide ion counter-transporter)
- iodide is also oxidized to iodine by thyroid peroxidase (TPO)
result: iodide in colloid
Thyroid Hormone Secretion – 3. iodination
What happens in this step?
- within the colloid, TPO catalyzes immediate binding of iodine with 10-12 tyrosine amino acids on each TGB
- each tyrosine can interact with either: one iodine to form monoiodotyrosine (MIT) OR two iodines to form diiodotyrosine (DIT)
What is monoiodotyrosine (MIT)?
tyrosine + one iodine
What is diiodotyrosine (DIT)
tyrosine + two iodines
Thyroid Hormone Secretion – 4. coupling
What happens in this step?
internal rearrangement within TGB links MITs and DITs in a highly specific fashion:
- coupling of two DITs results in T4
- coupling of MIT and DIT produces T3
- coupling can occur within a single molecule, or between different molecules of TGB
Thyroid Hormone Secretion – 4. coupling
Coupling of what results in T4?
two DITs
Thyroid Hormone Secretion – 4. coupling
Coupling of what produces T3?
MIT and DIT
Thyroid Hormone Secretion – 4. coupling
Why is T4 the main product?
because coupling of two DITs is more frequent
Thyroid Hormone Secretion – 4. coupling
Note: At this point, both thyroid hormones are still attached to…..
TGB molecules, and stored in colloid
Thyroid Hormone Secretion – 5. colloid pinocytosis
What happens in this step?
small droplets of colloid (endosomes) containing iodinated thyroglobulins enter follicle cells by endocytosis, and combine with lysosomes to form endolysosomes
Thyroid Hormone Secretion – 6. proteolysis
What happens in this step?
lysosomal enzymes within endolysosomes release T3 and T4, and MITs and DITs, from thyroglobulin molecules
Thyroid Hormone Secretion – 7. secretion and recycling
What happens in this step?
- free T3 and T4 diffuse through basal membrane out of follicular cell and into vast network of capillaries surrounding the follicles
- MITs and DITs are hydrolyzed by cytoplasmic deiodinase enzyme to tyrosine amino acids and iodine ions, which are then recycled within the follicular cell
What do all steps in synthesis of thyroid hormones require?
TSH
all steps require – including expression of TGB and TPO genes, NIS action, and iodination of TGB
What does 99.5% of T3 and T4 do upon entering blood?
binds immediately with several plasma proteins (all of which are produced by liver)
- mainly thyroxine-binding globulin (TBG)
- less with transthyretin
- less with albumi
What does 0.5% of T3 and T4 do upon entering blood?
remains free (does not bind) and is responsible for biologic activity
Regulation of Biological Activity of Thyroid Hormones
What is the homeostasis of thyroid hormones (TH) regulated by? (2)
- one based on hypothalamic-pituitary-thyroid (HPT) axis
- one at intracellular level
Regulation of Biological Activity of Thyroid Hormones
Hypothalamic-Pituitary-Thyroid (HPT) Axis – Diagram
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Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
What is the main hormone produced by thyroid?
T4
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
Does T3 or T4 have higher affinity for TH receptor?
T3 possesses 100x higher affinity for TH receptor and is responsible for all biological effects
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
How does T4 bind with TH receptors?
can cross plasma membranes only through cell-specific transporters
- mutations in transporters can cause severe neurological defects in humans
- mutations in MCT8 transporter cause severe neurologic defects in humans
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
Where are TH receptors located?
in nucleus of target cells
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
Once inside the cell, the concentration of THs is controlled by what?
three deiodinase enzymes (D1, D2 and D3)
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
What does both D1 and D2 do?
generate T3 by removing 1 iodine from T
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
What does D3 do?
serves as physiological terminator of TH activity by degrading both T4 and T3 their respective inactive metabolites
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
What accounts for T3 measured in plasma?
80% – deiodinase-coordinated conversion of T4 to T3 in target tissues
20% – secreted by thyroid gland
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
What are some rapid effects by THs? (3)
(non-genomic effects)
- stimulation of sugar transport
- Ca2+ ATPase activity
- increased Na+ transport in muscle
occur within seconds or minutes
Regulation of Biological Activity of Thyroid Hormones – Intracellular Level
What are non-genomic effects mediated by?
binding to membrane receptors and activation of second messenger signaling cascades
Physiologic Functions of Thyroid Hormones
Why are THs critically important throughout pregnancy?
responsible for normal brain development in fetus
Physiologic Functions of Thyroid Hormones
What are THs important for during development and in adults?
- key regulators of basal metabolic rate (minimum level of energy required to maintain vital functions at rest) in most tissues
- critically important for normal development of nervous and skeletal systems, and maturation of reproductive system
Physiologic Functions of Thyroid Hormones
Overall, what do THs play significant role in?
almost all tissues and organs in the body
Pathology of Thyroid Hormones
Hypothyroidism – Diagram
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Pathology of Thyroid Hormones
What is the most common cause of hypothyroidism worldwide?
iodine deficiency
Pathology of Thyroid Hormones
What is the most common cause of hypothyroidism in North America?
Hashimoto’s thyroiditis
Pathology of Thyroid Hormones
What is Hashimoto’s thyroiditis?
autoimmune disorder involving anti-thyroid antibodies that block and eventually destroy thyroid function
have high levels of plasma TSH
Pathology of Thyroid Hormones
What is TH release regulated by?
hypothalamus-pituitary-thyroid axis
Pathology of Thyroid Hormones
How does the incidence of hypothyroidism change with aging?
increases
Pathology of Thyroid Hormones
What are typical symptoms of hypothyroidism? (2)
- thyroid gland enlargement (goiter)
- low metabolic rate resulting in intolerance to cold and weight gain
Pathology of Thyroid Hormones
What may result in permanent decrease in psycho-neurological function?
genetic deficiency of fetal thyroid gland or maternal factors, such as lack of iodine in diet during pregnancy
in a newborn, symptoms include profound mental retardation and short disproportionate body
Pathology of Thyroid Hormones
What is the most common form of hyperthyroidism?
Grave’s disease
Pathology of Thyroid Hormones
What is Grave’s disease?
autoimmune disorder involving production of abnormal antibodies called thyroid stimulating immunoglobulin (TSI)
TSI molecules bind to TSH receptors and permanently switch them on → continuous release of thyroid hormones
low or undetectable levels of plasma TSH
Pathology of Thyroid Hormones
What do clinical manifestations of hyperthyroidism include? (6)
- formation of goiter
- ↑ metabolic rate, resulting in intolerance to heat
- weight loss, despite adequate food intake
- rapid and irregular heartbeat
- eye and skin problems also common
- severe: exophthalmos
Pathology of Thyroid Hormones
What is exophthalmos?
bulging eyes, caused by TSI antibodies binding to muscles that move our eyeballs, and connective tissues behind the eyeballs, pushing eyeballs out
Pathology of Thyroid Hormones
Hyperthyroidism – Diagram
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