Thyroid (10-11) Flashcards
What are the 2 types of cells that make up the thyroid gland?
Follicle cells → absorb iodide from blood and produce thyroxine (T4) and triiodothyronine (T3)
C-Cells → produce calcitonin (calcium homeostasis) - involved in parathyroid not thyroid
What are the 6 stages of T3 and T4 synthesis?
- Thyroglobulin synthesis
- Uptake and concentration of iodide
- Oxidation of iodide to iodine
- Iodination of thyroglobulin → add iodine to tyrosine residues
- Coupling of 2 iodinated tyrosine molecules to make T3/T4
- Secretion
What is the main role of T3/T4?
Basic metabolic rate regulation
→ increase ATP and ability to produce more energy
How is monoiodotryosine (MIT) made from thyroglobulin?
Iodine is adde to C3 on the tyrosine aa in thyroglobulin
How is diiodotyrosine (DIT) made from monoiodotyrosine?
A 2nd iodine is added to C5 on the tyrosine aa in thyroglobulin
What makes up T3?
A monoiodotryosine (MIT) and a diiodotrysone (DIT)
What makes up T4?
2 diiodotyrosines (DIT)
→ ends up with 4 iodines - ‘T4’
How is T3/T4 made in follicular cells?
- Protein synthesis → thyroglobulin gene transcribed and modified
- Exocytosis into colloid space around the follicular cells
- Tyrosine residues on thyroglobulin undergo iodination then coupling → forming MIT and DIT
- The thyroglobulin with T4 (+T3) is pinocytosed
- Thyroglobulin digested by lysosomal proteases → to form T3/T4
- T3/T4 is excreted out of the follicular cell
What controls the synthesis of T3/T4?
Hypothalamus-pituitary thyroid axis
Hypothalamus → thyrotrophin-releasing hormone
Pituitary → thyroid-stimulating hormones
Thyroid → T3/T4
What is thyrotrophin-releasing hormone (TRH)?
Polypeptide hormone produced in the hypothalamus
→ medial neurons of the paraventricular nucleus
→ 242-aa precursor containing 6 copies of inactive TRH flanked by Arg-dipeptides
→ glutamine is pyronated and glycine is removed forming active TRH - 6 from one precursor
What is the function of thyrotrophin-releasing hormone?
Stimulates thyrotrophic cells of the anterior pituitary to produce thyroid stimulating hormone (TSH)
TSH → stimulated production of T3/T4 in the follicle cells of the thyroid
How does TSH signal to stimulate thyroglobulin transcription?
TSH binds TSH receptors on follicular cells → eventually leads to CREB phosphorylation
→ creates nuclear localisation signal - close to promoters can drive transcription
However, thyroglobulin only expressed if MAPK pathway also activated by growth factor binding
→ leads to ERK phosphorylation
→ CREB-P and ERK-P form transcription factor that drives expression of thyroglobulin
→ TSH won’t activate quiescent cells in G0
How are thyroid hormones found in circulation?
T3 and T4 are both lipophilic - insoluble in blood/sera
→ both are transported with a carrier protein
→ 30% bound to albumin, 70% bound to thyroxin binding globulin (TBG)
→ TGB has a higher affinity for T4 - due to extra iodine
Which of the thyroid hormones is active?
T3 is the active form of the hormone
→ 10x more active than T4
but T4 is 7x more stable → can be converted to T3 at the target site - less offsite effects
How are thyroid hormones released from their carrier proteins?
Change in physiological environment at the target site e.g. different conc. of ions or pH than sera causes release of T3/T4 from carrier protein
→ only free T3/T4 can enter cell - free hormones are physiologically active
How is T4 converted into T3?
T4 (inactive form) is converted into T3 (active form) by deiodinase
What are type 1 deiodinases (ID1)?
Found on the cell surface, will do one of 2 things
→ in low [T3] it specifically converts T4 into T3
→ in higher [T3] in a -ve feedback loop ID1 is phosphorylated - high levels of metabolic activity driven by T3 modify ID1 - won’t convert T4 into T3 instead rT3
What are type 2 deiodinases (ID2)?
Found in cytoplasm (intracellular)
→ if T4 enters cytoplasm, can only be converted to T3
→ doesn’t produce rT3
What are type 3 deiodinases (ID3)?
Main deactivation deioninase
→ converts T4 to rT3
→ converts T3 to T2
inhibitory enzyme
What are the physiological actions of T3?
- Increases polymerase I and II → increased transcription (ATP pump and receptors)
- Increases production of NA/K ATPase pumps → increases uptake of glucose, increases speed of neuronal repolarisation - fire APs quicker
- Increases beta-adrenergic receptors expression
→ enhances the effects of adrenaline
→ increased B1 - cardiac output, B2 - ventilation, A1 - glucose
→ increased glucose metabolism - drives cells into cell cycle
Main role → increase ATP production to help cell increase basal metabolic rate
What is cretinism?
Impaired physical and neurological development
→ caused by poor nutrition during pregnancy - not enough iodine, can’t concentrate it in follicular cells - can’t make T3/T4
→ if detected early symptoms can be reversed
→ irreversible if not treated within first 2 years of life
What is hyperthyroidism?
Too much production of thyroid hormones T3/T4
Diagnosis → serum TSH, free T3, free T4
→ increased T3/T4
→ increased TSH - fault in or above pituitary gland
→ decreased TSH - thyroid gland problem (tumour/graves)
What is Graves’s disease?
Most common cause of hyperthyroidism
→ autoimmune disorder where an auto-antibody binds to the TSH receptor, mimicking T3
→ leading to excessive hormone production
Signs → heat tolerance, sweating, weight/muscle loss, increased appetite, diarrhoea, nervous irritability, goitre
What is hypothyroidism?
When T3/T4 levels decrease enough to cause symptoms called myxoedema (polysaccharide deposition in the dermis (TSH mediated))
Signs → slow/lethargic, overweight, alopecia, goitre
Diagnosis → serum TSH, free T3, free T4
→ decreased T3/T4
→ increased TSH usually
can be caused by iodine deficiency
What is Hasimotos thyroiditis?
Autoimmine attack on the thyroid leading to hypothyroidism
→ auto-reactive antibody that kills target cel
→ causes immune response that recognised thyroid cells
What is goitre?
Enlarged thyroid gland - not fluid retention, not temporary
→ caused by low or high T4 expression
- iodine deficiency (low levels of T4) → induces TSH secretion, negative feedback loop - mistakenly make more follicle cells
- Graves disease (high levels of T4) → autoimmune disease that produces thyroid stimulating immunoglobulin - acts as TSH - increased TSH activated MAPK pathway, drives replication of follicular cells
- Tumours (benign or cancer) → constant replication of follicular cells due to mutation
How do both low and high T4 induce goitre?
Iodine deficiency → high TSH, low T4
→ pituitary recognises low T4 so increases TSH - drives cells into cell cycle
→ increased gland growth
Graves disease → low TSH, high T4
→ auto reactive antibody stimulating TSH receptor
→ negative feedback loop doesn’t work
What are the treatments for thyroid disease?
- Drugs → inhibit production/replace hormone
- Radioactive iodine (131I) → destroys gland
- Surgery → general surgery issues, local cord damage, bleeding, parathyroid gland damage
What is the physiological role of calcium?
Bone growth and re-modelling
Muscle contraction and neurotransmitter release
Enzyme co-factor
Membrane potential regulation
→ lots of important roles in the body
→ essential housekeeping ions
Where is calcium distributed?
99% in skeleton (bone)
1% intracellular - Er
0.1% extracellular - plasma → 55% bound to proteins, 45% ionised
What parts of the body regulate calcium levels?
Ca levels are regulated via the parathyroid
→ through activating kidneys, bones and GIT
→ Ca levels detected by calcium sensing receptors (CaSR) found in the parathyroid gland
Low Ca → stimulates parathyroid hormone (PTH) release
High Ca → surpasses PTH release
What are the 2 types of cells found in the parathyroid?
Chief cells → production/release of parathyroid hormone
Oxyphil cells → believed to be deactivated chief cells (no physiological role)
How is parathyroid hormone (PTH) synthesised?
Initially synthesised as a large pre-prohormone (115aa)
→ cleaved to give biologically active 84aa peptide
→ first 34aa believed to be the biologically active part
Unregulated PTH production → increase in gland size
What are the effects of parathyroid hormone (PTH)?
Primary effects:
Acts on kidney → increase Ca2+ reabsorption / promotes PO4 excretion (activates Ca2+PO4 ATPase pumps in proximal tubules)
→ increases production of active vitamin D
Acts on bine → mobilse calcium - activated osteoclasts (modified macrophages that minerals bone)
Seconday effects:
Due to increased vitamin D production → liver and kidney
PTH increases plasma Ca and decreases plasma PO4
What is the role of vitamin D?
Ca2+ uptake from gut
Cartilage production
Required for osteoblast and osteoclast differentiation
Increase osteoclast action via osteoblasts
Is the vitamin D you absorb active?
No → the vitamin D you absorb is not active
→ needs to be modified twice (hydroxylated)
How does PTH effect calcitriol expression?
Vitamin D3 → calcidiol (by 25-hydroxylase)
Calcidiol → caclitriol (by 1α-hydroxylase)
PTH drives expression of 1α-hydroxylase
What occurs when low Ca2+ is detected?
Increase in parathyroid hormone
→ increases 1α-OHase
→ increases Ca2+ reabsorption via activating pumps in kidneys
→ decreases PO4 reabsorption
→ activated osteoclasts - bone mineralisation increasing Ca2+ release
How is prolonged loss of PO4 counteracted?
Prolonged loss of PO4 has bad long term effects
→ to counteract loss of PO4 in kidney pumps due to PTH there is increased absorption in GIT
→ driven by activated via D3
Why is phosphate important?
Important in intracellular metabolism
Needed for phosphylation to occur (kinases)
Phospholipids in membranes
Levels vary widely throughout the day
What is involved in phosphate homeostasis?
Low levels of phosphate recognise in the kidney
→ activates 1α-OHase (PTH-independant)
→ increases calcitriol - increases PO4 absorption in GIT and kidneys, increases bone mineralisation (P also in bone)
→ increases phosphate in sera
Negative feedback → high PO4 down regulates 1α-OHase
What is fibroblast growth factor (FGF)-23?
Released by osteoblasts in response to excessive bone mineralisation
→ phosphate regulating hormone
→ counteracts action of vitamin D induced PO4 changes - prevents vitamin D mediated hyperphosphataemia
What are the actions of fibroblasts growth factor (FGF)-23?
Cell surface receptor on kidney
→ Klotho - essential co-receptor
Inhibits 1α-hydroxylase → prevents vitamin D activation
Inhibits type II sodium-phosphate co-transporters in DCT → prevents activation of reabsorption pumps
Where does our calcium intake come from?
The intestine
→ uptake regulated by vitamin D
from the luminal surface of the GIT, to the basolateral surface into the blood
What is TRPV6 in Ca reabsorption?
Transient Receptor Potential Cation Channel Subfamily V Member 6
Transient receptor → not normally expressed, expression depends on vitamin D3
1α-hydroxylase and PTH increase vitamin D3 → drives expression of TRPV6
Essential for Ca absorption
What are the 3 ways in which Ca can be absorbed from the gut?
Via TRPV6:
Active uptake and extrusion → taken in by TRPV6, binds to CaBP, actively pumped into blood via Na+ Ca2+ ATPase pump
Endocytosis and exocytosis → Ca2+ taken in by TRPV6, binds CaBP in endosome
Not via TRPV6:
Transcellular transport → migration between cells, associated with CaBP (not common)
CaBP - calcium binding protein
What is calcitonin?
Made by C cells in thyroid gland
→ parathyroid hormone (PTH) inhibitor
→ Ca2+ too high - thyroid gland makes calcitonin
What are the action of calcitonin?
Bone → prevents osteoclast action, inhibits bone reabsorption
Kidney → decreases absorption of PO4 and CA2+ in the proximal tubules
Inhibits 1α-hydroxylase
What happens when calcium homeostasis goes wrong?
Hypercalcaemia
Hypocalcaemia
Hyperparathyroidism
Bone problems
Ectopic calcification
What is hypocalcaemia?
Low levels of Ca2+
Symptoms:
Neuromuscular irritability
Muscle cramps/tetany
Seizures
→ can’t fire APs efficiently, low [Ca2+]. don’t get neurotransmitter release/uptake
Tetany → as the extracellular [Ca2+] falls the peripheral nerve fibres discharge spontaneously, leading to muscle contractions
→ disparage between membrane potentials - can’t relax muscles as Ca levels too low
Severe cases → prolonged QT interval on ECG
What is hypercalcaemia?
Too much Ca2+
Symptoms:
Nausea/vomiting/constipation/anorexia
Tiredness, confusion, depression, headaches
Muscle weakness
Kidney stones/ectopic calcification
Loss of bone
Polyuria/polydipsia
Severe cases → shortened QT interval
What is primary hyperparathyroidism?
Increased PTH secretion by parathyroids
→ normally a benign tumour
→ individual cells respond normally to Ca, but increased numbers more PTH produced
What is secondary hyperparathyroidism?
Low serum Ca2+ stimulated PTH secretion and production
Usually associated with kidney disease - means 1α-hydroxylase doesn’t work
→ can’t make vitamin D
→ can’t increase absorption Ca2+ from gut or kidney
→ only place Ca2+ can come from is bone - bone degradation
Gland enlarges and produces unregulated amount s of PTH
Abnormal biomarkers for kidney function → secondary hyperparathyroidism
→ dialysis to prevents full kidney failure
