Thyroid physiology Flashcards
What are the 3 steps for making thyroid hormone?
(1) Iodide transport: into the cell via active transport, against the concentrated gradient
(2) Oxidation, organic binding & coupling: Iodide is oxidized & bound to tyrosine molecules, which are attached to thyroglobulin (stored in follicular lumen as colloid in 10:1 ratio T4: T3)
• Thyroperoxidase is the enzyme that does this
(3) Proteolysis, release & dehalogenation: TH is taken back up into thyrocytes & is cleaved/released into the circulation at 10:1 ratio; some of it has the iodide removed, which is recycled or excreted
What three major classes of disease can you get related to the thyroid hormone receptor (THr)?
Somatic mutation: toxic thyroid adenomas
Germline: autosomal dominant hereditary hyperthyroidism; sporadic congenital thyrotoxicosis
Immunologic: Graves disease
Where does your circulating T3 and T4 come from?
100% of circulating T4 comes from the thyroid
20% of circulating T3 comes directly from the thyroid; the rest is derived from peripheral monodiodonation i.e. in liver, kidney
What binds thyroid hormone in circulation?
TBG: thyroid binding globulin
TTR: transthyrotin
Alubmin
What’s the principal pathway of TH metabolism? Which enzymes do this reaction?
Monodiodonation (removal of an iodine)
Deiodonases do this
Type 1: thyroid, liver, kidney - makes plasma T3
Type 2: makes intracellular T3 in CNS, pituitary, brown adipose tissue
Type 3: inactivates T4 and T3; universally distributed
What is low T3 syndrome/euthyroid T3 syndrome?
Due to reduced peripheral conversion of T4 to T3 (so you have normal T4 but low T3)
Can be due to:
o Physiologic stress: fetus & early neonate, elderly
o Pathologic stress: starvation (carb restriction), major systemic illness (acute & chronic), and post-op
o Pharmacologic: propylthiouracil, glucocorticoids, propranolol, radiologic contrast agents, amiodarone
Why is it true that as T3 levels fall, reverse T3 levels rise?
Because the same enzyme (5’ monodeiodinase) converts T4 to T3 and converts reverse T3 to T2
So reverse T3 is high i.e. in newborn, acute febrile illness, chronic hepatitic cirrhosis, chronic renal failure; it’s reversible when you correct the underlying problem
Note that reverse T3 is inactive
Which is the most potent form of thyroid hormone?
T3: 4x as potent as T4
Faster onset of action, shorter action of duration
Where does thyroid hormone bind the cell?
Membrane receptors –> enters cell via energy requiring process
Loose association with cytosolic binding proteins which act as sponges to soak up extra TH, might be involved in its degradation
Mitochondrial membrane receptors –> lots of O2 consumption!
Nuclear= major receptor –> transcription, protein synthesis
- binds hormone response elements near start point as homodimer or heterodimer with retinoid receptor –> dissociation with corepressor –> recruitment of coactivator –> translation & new mRNA synthesis
What’s responsible for the temp/sweating changes associated with TH?
Na/K ATPases are thyroid responsive –> heat production
in hyperthyorid = increased temp, sweating
in hypothyroid = decreased temp
What’s the pathway from hypothalamus to thyroid hormone synthesis?
Hypothalamus makes TRH –> secreted into hypothalmic pituitary portal system –> stimulates anterior pituitary thyrotrophs to make TSH –> binds follicular cells of thyroid glands –> T3 and T4 production
T3 is a neg inhibitior at pituitary to shut down TSH production
HCG has a similar structure to TSH –> during preg you get more TH production
What are the 2 potential causes of changes in thyroid hormone levels?
Abnormal thyroid gland secretion
Changes in levels of binding proteins
What can cause total T4 elevation?
Hyperthryoidism: increased total and free T4
Elevatd thyroid binding globulins –> increased total T4 and normal free T4
- congenital: X-linked
- prengnancy
- liver dz
- drugs: estrogens, tamoxifen, raloxifene
What can cause total T4 depression?
Hypothyroidism: decreased total and free T4
Decreased TBP –> decreaed total and normal free T4
- Congenital: X-linked
- Acromegaly
- Nephrotic syndrome (pee out lots of proteins)
- chronic liver dz
- Drugs
Inhibition of thyroidal T4 release without hypothyroidism = due to exogenous T3 administration
Acute medical illness: free T4 is variable
Why is the T3 resin uptake used as a measure of the free T4 index?
Free T4 index= total T4 x THBR (thyroid hormone binding ratio).
In the resin uptake test, you put radioactive T3 into the pt’s serum + a resin. The radioactive T3 preferentially binds the free THG’s, then the extra is soaked up into the resin, which is a “sponge’ for the extra T3. Because you know how much radioactive T3 you put in, you can measure how much unbound THG’s the patient’s blood had based on how much was left in the resin. The amount of free/unbound THG’s (that soaked up the radioactive T3) is proportional to the free T4 in the serum. This is the major assumption behind this test and is why T3 RU is used as a test for free T4!
Chart of hyper/hypothyroidism + TBG excess/deficiency
o If total T4 and resin move in same direction = problem with thyroid gland secretion
o If they change in opposite directions, it’s a problem with they binding proteins; note that free T4 index is normal bc when you multiply them they cancel out which corrects the problem
