(PM3B) Thyroid Axis Flashcards
What is TRH?
Thyrotropin Releasing Hormone
What is TSH?
Thyroid Stimulating Hormone
Can also be called ‘thyrotropin stimulating hormone’
Where is TRH secreted?
Parvocellular neurosecretory cells in the hypothalamus
What is the inflow of blood called in the pituitary gland?
Superior hypophyseal artery
Which organs are involved in the regulation of thyroid hormone release?
(1) Hypothalamus
(2) Anterior pituitary gland
(3) Thyroid
Which organ releases TRH?
Hypothalamus
Which organ releases TSH?
Thyroid
Which hormones provide negative feedback on the regulation of thyroid hormone?
(1) TSH
(2) T3
(3) T4
Which organ releases T3 and T4?
Thyroid
What hormone(s) does the thyroid produce?
(1) T3
(2) T4
What hormone(s) does the anterior pituitary gland produce?
TSH
What hormone(s) does the hypothalamus produce?
TRH
Which organs does the negative feedback of T3/T4 effect?
(1) Anterior pituitary gland
(2) Hypothalamus
What is the cascade of events in thyroid hormone regulation?
(1) Hypothalamus produces TRH
(2) TRH stimulates anterior pituitary gland
(3) Anterior pituitary gland produces TSH
(4) TSH stimulates thyroid
(5) Thyroid produces T3 and T4
(6) T3 and T4 enter bloodstream
(7) Effect of T3 and T4 on target cells
What is the mechanism of action of TSH?
TSH binds to a GPCR of a thyroid follicle epithelial cell. This triggers two pathways.
(1) Activates adenylate cyclase - leads to a cAMP/ PKA-dependent pathway
(2) Activates phospholipase C - leads to PI turnover and production of DAG and IP3 (inositol triphosphate)
What is the structure of a thyroid follicle?
Hollow sphere
Comprised of epithelial cells surrounding a lumen which is filled with a gelatinous colloid
This gelatinous colloid contains thyroglobulin
How does the structure of a thyroid follicle change when the follicle is UNDERactive?
The lumen enlarges
How does the structure of a thyroid follicle change when the follicle is OVERactive?
The lumen reduces in size
What does a ‘C-cell’ in a thyroid follicle do?
Produces calcitonin
This is involved in calcium balance
Where is thyroglobulin made?
Synthesised in the thyroid follicular cells
What does thyroglobulin contain large concentrations of?
Tyrosine
Where can tyrosine be found in large concentrations?
Thyroglobulin
How does iodide (I-) enter the lumen?
Blood -> Follicular cells
via active transport
Then is transported to lumen
What converts iodide to ‘free iodine’?
Thyroid Peroxidase
Where does thyroid peroxidase convert iodide to free iodine?
In the lumen of thyroid follicular cells
What type of iodine is included in the tyrosine residues?
Free iodine
What atom is included in the tyrosine residues?
Free iodine
Where are tyrosine residues found?
Thyroglobulin molecules
What is MIT?
Mono-iodotyrosine (MIT)
Has 1 iodine per tyrosine (T1)
What is DIT?
Di-iodotyrosine (DIT)
Has 2 iodines per tyrosine (T2)
DIT + DIT = ?
T4
Thyroxine
MIT + DIT = ?
T3
Triodothyronine
MIT + MIT = ?
Nothing, they do not couple.
T2 (DIT) cannot be synthesised this way.
What is the first stage of thyroid hormone synthesis?
(1)
Iodide (I-) trapping.
Actively transported into follicles from blood.
What is the second stage of thyroid hormone synthesis?
(2)
Synthesis of TBG
TBG = Thyroxine-Binding Globulin
What is the third stage of thyroid hormone synthesis?
(3)
Oxidation of iodide to iodine (I2)
It is initiated by thyroid peroxidase
What is the fourth stage of thyroid hormone synthesis?
(4)
Iodination of tyrosine
Iodine (I2) is incorporated into tyrosine residues
What is the fifth stage of thyroid hormone synthesis?
(5)
Coupling of MIT and DIT molecules to form T3 and T4
What is the sixth stage of thyroid hormone synthesis?
(6)
Pinocytosis and digestion of colloid.
Lysosomal enzymes digest iodinated thyroglobulin
What is the seventh stage of thyroid hormone synthesis?
(7)
Secretion of thyroid hormones
T3 and T4 diffuse through plasma membrane into blood
What is the eighth stage of thyroid hormone synthesis?
(8)
T3 and T4 (thyroid hormones) are transported through the blood to target cells
How many stages are there in thyroid hormone synthesis?
8 stages
What is TBG?
Thyroid-binding globulin
What does TBG do? Why?
(1) Allows for T3/ T4 binding - prevents urinary excretion*
(2) Buffers against acute changes of thyroid function
*T3 and T4 have poor solubility in water (blood)
What percentages of overall secreted thyroid hormone do T3 and T4 comprise?
T3 = 10% T4 = 90%
Which thyroid hormone is more potent? Why?
T3 is about 4x more potent
T3 binds to the intracellular thyroid hormone receptor with greater affinity
What happens to most T4 in the target tissue?
Most is converted to T3 by removing one iodine
Which organs are particularly important for activating the conversion of T4 to T3?
Liver and kidneys
Where do T3 and T4 bind?
Intracellular thyroid hormone receptor
Are thyroid hormones hydro/ lipophilic?
Lipophilic
Hence their need for binding to TBG in the blood
What molecule can thyroid hormones bind to in the blood to prevent urinary excretion?
(1) TBG: Thyroid-binding globulin
(2) Albumin
What are the effects of thyroid hormone?
(1) Metabolic Rate
(2) Cardiovascular system
(3) Nervous system
(4) Growth and maturation
How does thyroid hormone affect metabolic rate?
Increases basal metabolic rate
How does thyroid hormone affect the CVS?
(1) Increases heart rate
(2) Increases force of heart contraction
How does thyroid hormone affect the NS?
(1) Increases activity of sympathetic NS
(2) Increases sensitivity to catecholamines - such as adrenaline or dopamine
Name 2 examples of catecholamines
(1) Adrenaline
(2) Dopamine
How does thyroid hormone affect growth and maturation?
(1) Embyro development
(2) CNS development
(3) Linear growth - increases affect of growth hormone
How many systems/ processes does thyroid hormone affect?
Four
Growth + maturation, NS, CVS, and metabolism
What is goitre? What causes it?
Hypertrophy of thyroid gland
Over-stimulation by TSH (Thyroid-stimulating hormone)
How common is goitre?
Approximately 2% of the population
What conditions are associated with goitre?
Either hypo/ hyperthyroidism
Often autoimmune
What are the common symptoms/ features of hypothyroidism?
(1) Weight gain
(2) Intolerance of the cold
(3) Tiredness/ fatigue
(4) Goitre
(5) Hyperlipidaemia
(6) Bradycardia
(7) Dry/ thick skin
(8) Depression/ poor memory
(9) Constipation
What symptoms/ features are commonly present in children with hypothyroidism?
(1) Cretinism
(2) Obesity
(3) Stunted growth
(4) Mental retardation - irreversible foetal brain damage
How is hypothyroidism detected early in children?
Routine elevated TSH checks for neonates
High TSH indicates low T3/T4 - limited negative feedback on hypothalamus and pituitary
How is hypothyroidism treated?
Lifelong levothyroxine therapy
Dose: 150mcg/ day
How is levothyroxine administered? What advice applies?
Orally, as tablets
Take on an empty stomach - increases absorption
What does levothyroxine imitate?
Natural T4
What exception to treatment with levothyroxine is there?
Chronic dietary iodine deficiency
Treated with supplementary iodine in diet
Why is T4 (levothyroxine) chosen over T3 in the UK?
Dosing is not critical
T4 has a long half-life
When is T3 (liothyronine) recommended?
When faster-acting is required - such as myxedema coma/ preparation for ablation with radioactive iodine
What is a primary cause of hypo/ hyperthyroidism?
Failure of the thyroid gland directly
What is a secondary cause of hypo/ hyperthyroidism?
Failure of anterior pituitary gland
What is a tertiary cause of hypo/ hyperthyroidism?
Failure of the hypothalamus
What are the effects of failure of the thyroid gland in hypothyroidism?
(1) Low T3/ T4
(2) High TSH
(3) Goitre
What are the effects of anterior pituitary failure in hypothyroidism?
(1) Low T3/ T4
(2) Low TSH (and TRH)
(3) No goitre
Has the same symptoms as hypothalamic (tertiary) failure
What are the effects of hypothalamic failure in hypothyroidism?
(1) Low T3/ T4
(2) Low TSH (and TRH)
(3) No goitre
Has the same symptoms as anterior pituitary (secondary) failure
VERY RARE
What are 3 different types of primary thyroid failure in hypothyroidism?
(1) Thyroid failure
(2) Autoimmune damage to gland (Hashimoto’s thyroiditis)
(3) Chronic lack of dietary iodine
Is hyperthyroidism common?
Yes
Affects approx. 2% of women
What are common symptoms/ features of hyperthyroidism?
(1) Weight loss
(2) Nervousness
(3) Heat intolerance
(4) High cardiac output
(5) Hand tremors
(6) Eyeball protrusion - exophthalmos
(1) What is a primary cause of hyperthyroidism?
(2) What are its effects?
(1) Hypersecreting tumour
(2)
- High T3/ T4
- Low TSH
- No goitre
(1) What is a secondary cause of hyperthyroidism?
(2) What are its effects?
(1) Excess anterior pituitary/ hypothalamic secretion (2) - High TRH/ TSH - High T3 and T4 - Goitre
What are the effects of Graves’ disease?
(1) High T3/ T4
(2) Low TSH
(3) Goitre
What are the treatment options for hyperthyroidism?
Anti-thyroid drugs to interfere with thyroid hormone synthesis/ surgical resection/ thyroid ablation using iodine
What is the mechanism of action of an anti-thyroid drug?
Blocks the thyroid peroxidase enzyme
Prevents iodination of thyroglobulin
What is first line treatment for hyperthyroidism?
Carbimazole
Propylthiouracil is given if 1st line not tolerated
What are complications of hyperthyroidism treatment?
Often results in thyroid hypertrophy (goitre)
When are drugs normally used in hyperthyroidism?
Prior to surgical resection (thyroidectomy)
(1) What is a common side-effect of carbimazole?
(2) How is it treated?
(1) Rash
(2) Antihistamine + switch to propylthiouracil
What is an uncommon side-effect of carbimazole?
Suppression in bone marrow
Presents as sore throat, mouth ulcers, and fever
