REB 5. Thyroid Hormone: Synthesis, Transport and Cellular Mechanisms Flashcards
When does the thyroid gland first start to develop in the body?
24th day of gestation
Where does the thyroid gland originate from?
it originates as proliferation of endodermal epithelial cells on median surface of developing pharyngeal floor
Which pharyngeal arch does the thyroid gland arise from?
1st pharyngeal arch
Which duct does the thyroid precursor develop from?
thyroid precursor develops from the Thyroglossal Duct, a diverticulum
the thyroid precursor descends in the neck as an initially hollow structure which later solidifies and become bilobed connected by an isthmus
After initial descent, the thyroid gland is still connected to the tongue by the thyroglossal duct, when is the thyroglossal duct fully obliterated?
7 to 10 weeks
*note: remnant of duct may persist
After the thyroid gland descends, it forms its mature shape by which week?
7 to 8 weeks of gestation
What is the final position of the thyroid gland?
anterior to trachea
What is Thyroid Dysgenesis?
it is disorders of the thyroid gland development
What are disorders of the thyroid gland development called?
Thyroid Dysgenesis
What are the 2 main categories of disorders of the thyroid gland development (Thyroid Dysgenesis)?
[1] Ectopic Thyroid Gland
(a) Failure to Descend
(b) Incomplete Descent
[2] Thyroglossal Duct Cyst
What is an ectopic thyroid gland and what are the 2 ways it can occur?
Ectopic Thyroid Gland: thyroid tissue is not located in its usual position and it is associated with congenital hypothyroidism (screened for at birth)
Causes:
(a) Failure to Descend - a lingual thyroid, is the most common at base of tongue
(b) Incomplete Descent - if duct does not atrophy, remnant manifests clinically as thyroglossal duct cyst
- 50% present as midline cystic masses just below level of hyoid bone
What are the 2 main associated endocrine glands or cells with the thyroid gland?
[1] Parathyroid Glands
[2] Parafollicular or C-Cells
*note: they are both involved with altering calcium levels
Where are the parathyroid glands located and what do they synthesize and secrete?
- they are 2 pairs of small glands on the posterior surface of thyroid gland
- synthesize and secrete Parathyroid Hormone (PTH)
- PTH increases blood calcium levels
What is the function of Parathyroid Hormone?
it increases blood calcium levels
Where are the parafollicular cells/C cells located and what do they synthesize and secrete?
- they are single cells in epithelial lining of follicle or in groups of connective tissue between follicles
- they secrete Calcitonin
- Calcitonin lowers blood calcium levels
What is the function of Calcitonin?
it lowers blood calcium levels
The thyroid gland is divided into… or…
Clusters or Follicles by connective tissue
What does a follicle in the thyroid gland consist of?
- thin layer of epithelial cells, responsible for synthesis of thyroid hormones
- colloid, proteinaceous material, thyroglobulin source
Where are the thyroid hormones synthesized?
thyroid hormones are epithelial cells and secreted into the lumen of follicle
What is required in the synthesis of thyroid hormones?
[1] Thyroglobulin (Protein)
[2] Iodine
note: thyroid hormones are the only constituents in the body that contain bound iodine
What are the 2 types of thyroid hormones?
[1] Triiodothyronine (T3) - 3 iodines present
[2] Thyroxine (T4) - 4 iodines present
What is thyroglobulin? What stimulates the synthesis of thyroglobulin?
- it is a precursor for thyroid hormone
- it is a large dimeric glycoprotein
- Thyroid Stimulating Hormone (TSH) stimulates the synthesis of thyroglobulin
Where is thyroglobulin synthesized?
epithelial cells surrounding the follicle
What is the process in which thyroglobulin is synthesized to thyroid hormone?
[1] thyroglobulin synthesis is stimulated by TSH
[2] thyroglobulin synthesized in epithelial surrounding the follicle
[3] thyroglobulin is released into the colloid space
[4] the tyrosine residues of the thyroglobulin are iodinated
- 8 to 10 of the tyrosines are processed into active hormone (out of around 40)
How to form T3 and T4? What is an important enzyme involved with the formation of T3 and T4?
[1] DIT + MIT = T3
[2] DIT + DIT = T4
enzyme: thyroperoxidase
What is thyroperoxidase? And what are the 2 reactions it is involved in?
Thyroperoxidase is an enzyme located on the apical (colloid-facing) membrane of epithelial cells.
It catalyzes 2 reactions:
[1] Iodination of Tyrosines (on thyroglobulin)
- adding iodines
[2] Coupling Reaction (synthesis of thyroxine or triiodothyronine from 2 iodotyrosinne molecules)
- creating T3 and T4
How does thyroid hormones move around in the blood? (aka how is it transported?)
[1] <1% of T3 and T4 remains unbound or free (hydrophobic hormones)
[2] 99% of T3 and T4 is bound to specialized transport proteins:
(a) Thyroxine-Binding Globulins (TBGs)
(b) Albumin
(c) Other Plasma Proteins
*note: this complex prevents their free diffusion into bodt cells and from excretion
What are the 3 types of transport proteins that thyroid hormones may bind to?
[1] Thyroxine-Binding Globulins (TBGs)
[2] Albumin
[3] Other Plasma Proteins
What are the half-lives of T4 and T3?
T3 = ~1.5 days T4 = ~6.5 days
What thyroid hormone does the thyroid gland secrete the most?
It secretes 90% of T4
Which thyroid hormone is more biologically active than the other?
T3 is more active than T4
What can T4 be metabolised to? [2]
[1] to biologically active T3
[2] to the biologically inactive, reverse T3
What is the average amount of iodine in the adult body? Where is most of the iodine located?
- between 20 and 50 mg of iodine
- more than 60% of iodine is located in thyroid gland
the iodine content of food and water is dependent on what?
- dependent on iodine in the soil
- glaciated, mountainous or heavy rainfall areas low in iodine
What are some sources of iodine?
- iodized salt
- seaweed
- dairy
- eggs
- tuna
What are goitrogenous substances and what is an example?
Goitrogenous Substances - are substances that disrupt the production of thyroid hormones by interfering with iodine uptake in the thyroid gland
- example: cruciferous vefetables and legumes
What are the 2 mechanisms of iodine metabolism that can happen?
[1] Iodide Excreted by Kidneys
[2] Iodine Taken Up by Thyroid Gland
Explain the steps in how iodine is excreted by the kidneys.
[1] dietary iodine is absorbed in the GI tract
[2] iodine is converted to iodide in the gut, absorbed + circulated bound to serum proteins
[3] iodide is excreted by the kidneys
Explain the steps in how iodine is taken up by the thyroid gland.
[1] dietary iodine is absorbed in the GI tract
[2] iodine is converted to iodide in the gut, absorbed + circulated bound to serum proteins
[3] iodide taken up by thyroid gland
[4] transport of iodide into follicular cells depends on the Na+/I- cotransporter
[5] iodide taken up by the thyroid gland oxidized by peroxide in the lumen of the follicleto produce iodine
[6] iodine can then be used to create T3 and T4
Explain the basis of the Sodium-Iodide Symporter (NIS)
[1] 2 Na+ and 1 I- ion from ECF enter the thyroid epithelial cells
[2] Na+ is then pumped out of the cells by Na+/K+ ATPase pump to maintain high extracellular Na+
*TSH increases activity of iodine transport and Na+/K+ ATPase
Hormone synthesis (of TSH) is dependent on…
[1] availability of iodide
[2] integrity of thyroid gland
Where is Thyrotropin-Releasing Hormone (TRH) synthesized, what is its action and what are some regulators of it?
Synthesis:
TRH is synthesized in the hypothalamus and derived from the larger prepro-molecule
Action:
stimulates TSH synthesis in thyrotropes of the anterior pituitary gland
Regulators of TRH Synthesis:
(a) intracellular T3
(b) circulating T4 levels
- inhibits synthesis of TRH
- blocks capacity of TRH to stimulate release of TSH
Where is Thyroid Stimulating Hormone (TSH) synthesized and how is it regulated?
it is produced by thyrotrope cells in the anterior pituitary gland
Regulated:
[1] suppressed by T3 (mainly beta subunit) in thyrotropes
[2] increased by TRH from hypothalamus
What is special about thyroid stimulating hormone (TSH) secretion?
- secreted in low amplitude pulses
- it is lower during day with slightly higher levels at night (circadian)
What is Thyroxine Binding Globulin (TBG) and where is it synthesized?
it is a glycoprotein synthesized in the liver
What is the affinity and capacity of Thyroxine Binding Globulin (TBG)? What does it bind more, T3 or T4?
- it has a high affinity for thyroid hormone
- low capacity (amount it can hold)
- mainly carries T4
What is the affinity and capacity of Thyroxine Binding Pre-Albumin (TBPA)/Transthyretin? What does it bind more, T3 or T4?
- it has a low affinity for thyroid hormone
- higher capacity
- mainly carries T3
What is the affinity and capacity of Albumin (ALB)? What does it bind more, T3 or T4?
- it has a low affinity for thyroid hormone
- it has a high capacity
- mainly carries T3
Is protein-bound thyroid hormone biologically active?
No, the thyroid hormone needs to dissociate from the protein to be active
Explain the genomic action of thyroid hormones?
[1] thyroid hormone receptors are nuclear receptors activated by binding of thyroid hormone
[2] lipophilic T3 binds to nuclear thyroid receptor (TR)
[3] complex binds to thyroid hormone response element (TRE) with Retinoid X Receptor (RXR) [a transcription factor]
[4] TR/DNA/coactivator complex recruits RNA polymerase that transcribes DNA
What are some actions of the thyroid hormone?
[1] influence body’s basal metabolic rate
[2] initiate the transcription of genes involved in glucose oxidation
[3] thyroid hormones are also required for protein synthesis
[4] development of the nervous system both in utero and in early childhood
[5] thyroid hormones increase the body’s sensitivity to catecholamines
[6] regulate heart rate and increases blood pressure
What is the clinical presentation of hyperthyroidism?
- CNS symptoms (nervousness, irritability, fatigue)
- heat intolerance, elevated metabolic rate, weight loss
- tachycardia: may develop congestive heart failure
- hypertension
- goitre
- muscle wasting
- proptosis (apparent bulding of eyes)
What is proptosis? What is it a clinical presentation of?
- it is the apparent bulging of the eyes
- it is a clinical presentation of hyperthyroidism
What does an early onset of hypothyroidism result in?
- it leads to a delayed or incomplete physical and mental development
- this is screened for is newborns with the heel prick test
What is another name for the adult onset of hypothyroidism?
Myxoedema
What are the symptoms of the adult onset of hypothyroidism?
- tiredness, lethargy, decreased metabolic rate
- slowing of mental function and motor activity
- cold intolerance
- weight gain
- goitre
- hair loss, dry skin
- may result in coma
What does thyroid hormone have on the metabolic rate?
[1] Low Thyroid Hormone Levels = Low Metabolic Rate
- increased protein synthesis (growth)
- increase glycogen synthesis (storage of energy)
- anabolic phase
[2] High Thyroid Hormone Levels = High Metabolic Rate
- increased protein degradation (energy)
- increased glycogen breakdown (glucose production)
- catabolic
List some of the effects of thyroid hormones on intermediary metabolism.
- increase glucose absorption from GI tract
- increase carb, lipid and protein turnover
- increased glycolysis
- increased glycogenolysis
- increased gluconeogenesis
- stimulate fat mobilization and lead to increased free fatty acid
- increases mitochondrial oxidative phosphorylation (ATP production)
overall result: increased metabolic rate + increased heat/energy production (calorigenic effect)
List some of the effects of thyroid hormones on the cardiovascular and respiratory system.
cardiovascular system:
- increase heart rate
- increase force of cardiac contractions
- increase stroke volume
- upregulate catecholamine receptors
respiratory system:
- increase resting respiratory rate
List some of the effects of thyroid hormones on growth and tissue development.
- required for GH and prolactin production and secretion
- required for GH action (growth, cell proliferation)
- increased growth and maturation of bone
- increased tooth development and eruption
- increase growth and maturation of epidermis, hair follicles and nails
- increase rate and force of skeletal muscle contraction
List some of the effects of thyroid hormones on the nervous system.
- essential for normal CNS development
- increased speed and amplitude of peripheral nerve reflexes
- enhances alertness
- enhances memory and learning capacity
List some of the effects of thyroid hormones on the reproductive system.
- normal reproductive behaviour and physiology is dependent on normal levels of thyroid hormone
- follicular development and ovulation
- maintenance of pregnancy
- normal spermatogenesis
- hypothyroidism in particular is commonly associated with infertility
