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Molecular Endocrinology > Thyroid (10-11) > Flashcards

Thyroid (10-11) Flashcards

1
Q

What are the 2 types of cells that make up the thyroid gland?

A

Follicle cells → absorb iodide from blood and produce thyroxine (T4) and triiodothyronine (T3)

C-Cells → produce calcitonin (calcium homeostasis) - involved in parathyroid not thyroid

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2
Q

What are the 6 stages of T3 and T4 synthesis?

A
  1. Thyroglobulin synthesis
  2. Uptake and concentration of iodide
  3. Oxidation of iodide to iodine
  4. Iodination of thyroglobulin → add iodine to tyrosine residues
  5. Coupling of 2 iodinated tyrosine molecules to make T3/T4
  6. Secretion
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3
Q

What is the main role of T3/T4?

A

Basic metabolic rate regulation
→ increase ATP and ability to produce more energy

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4
Q

How is monoiodotryosine (MIT) made from thyroglobulin?

A

Iodine is adde to C3 on the tyrosine aa in thyroglobulin

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5
Q

How is diiodotyrosine (DIT) made from monoiodotyrosine?

A

A 2nd iodine is added to C5 on the tyrosine aa in thyroglobulin

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6
Q

What makes up T3?

A

A monoiodotryosine (MIT) and a diiodotrysone (DIT)

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7
Q

What makes up T4?

A

2 diiodotyrosines (DIT)
→ ends up with 4 iodines - ‘T4’

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8
Q

How is T3/T4 made in follicular cells?

A
  1. Protein synthesis → thyroglobulin gene transcribed and modified
  2. Exocytosis into colloid space around the follicular cells
  3. Tyrosine residues on thyroglobulin undergo iodination then coupling → forming MIT and DIT
  4. The thyroglobulin with T4 (+T3) is pinocytosed
  5. Thyroglobulin digested by lysosomal proteases → to form T3/T4
  6. T3/T4 is excreted out of the follicular cell
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9
Q

What controls the synthesis of T3/T4?

A

Hypothalamus-pituitary thyroid axis

Hypothalamus → thyrotrophin-releasing hormone
Pituitary → thyroid-stimulating hormones
Thyroid → T3/T4

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10
Q

What is thyrotrophin-releasing hormone (TRH)?

A

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

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11
Q

What is the function of thyrotrophin-releasing hormone?

A

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

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12
Q

How does TSH signal to stimulate thyroglobulin transcription?

A

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

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13
Q

How are thyroid hormones found in circulation?

A

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

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14
Q

Which of the thyroid hormones is active?

A

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

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15
Q

How are thyroid hormones released from their carrier proteins?

A

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

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16
Q

How is T4 converted into T3?

A

T4 (inactive form) is converted into T3 (active form) by deiodinase

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17
Q

What are type 1 deiodinases (ID1)?

A

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

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18
Q

What are type 2 deiodinases (ID2)?

A

Found in cytoplasm (intracellular)
→ if T4 enters cytoplasm, can only be converted to T3
→ doesn’t produce rT3

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19
Q

What are type 3 deiodinases (ID3)?

A

Main deactivation deioninase
→ converts T4 to rT3
→ converts T3 to T2

inhibitory enzyme

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20
Q

What are the physiological actions of T3?

A
  1. Increases polymerase I and II → increased transcription (ATP pump and receptors)
  2. Increases production of NA/K ATPase pumps → increases uptake of glucose, increases speed of neuronal repolarisation - fire APs quicker
  3. 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

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21
Q

What is cretinism?

A

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

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22
Q

What is hyperthyroidism?

A

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)

23
Q

What is Graves’s disease?

A

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

24
Q

What is hypothyroidism?

A

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

25
Q

What is Hasimotos thyroiditis?

A

Autoimmine attack on the thyroid leading to hypothyroidism
→ auto-reactive antibody that kills target cel
→ causes immune response that recognised thyroid cells

26
Q

What is goitre?

A

Enlarged thyroid gland - not fluid retention, not temporary
→ caused by low or high T4 expression

  1. iodine deficiency (low levels of T4) → induces TSH secretion, negative feedback loop - mistakenly make more follicle cells
  2. 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
  3. Tumours (benign or cancer) → constant replication of follicular cells due to mutation
27
Q

How do both low and high T4 induce goitre?

A

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

28
Q

What are the treatments for thyroid disease?

A
  1. Drugs → inhibit production/replace hormone
  2. Radioactive iodine (131I) → destroys gland
  3. Surgery → general surgery issues, local cord damage, bleeding, parathyroid gland damage
29
Q

What is the physiological role of calcium?

A

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

30
Q

Where is calcium distributed?

A

99% in skeleton (bone)
1% intracellular - Er
0.1% extracellular - plasma → 55% bound to proteins, 45% ionised

31
Q

What parts of the body regulate calcium levels?

A

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

32
Q

What are the 2 types of cells found in the parathyroid?

A

Chief cells → production/release of parathyroid hormone
Oxyphil cells → believed to be deactivated chief cells (no physiological role)

33
Q

How is parathyroid hormone (PTH) synthesised?

A

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

34
Q

What are the effects of parathyroid hormone (PTH)?

A

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

35
Q

What is the role of vitamin D?

A

Ca2+ uptake from gut
Cartilage production
Required for osteoblast and osteoclast differentiation
Increase osteoclast action via osteoblasts

36
Q

Is the vitamin D you absorb active?

A

No → the vitamin D you absorb is not active
→ needs to be modified twice (hydroxylated)

37
Q

How does PTH effect calcitriol expression?

A

Vitamin D3 → calcidiol (by 25-hydroxylase)

Calcidiol → caclitriol (by 1α-hydroxylase)

PTH drives expression of 1α-hydroxylase

38
Q

What occurs when low Ca2+ is detected?

A

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

39
Q

How is prolonged loss of PO4 counteracted?

A

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

40
Q

Why is phosphate important?

A

Important in intracellular metabolism
Needed for phosphylation to occur (kinases)
Phospholipids in membranes
Levels vary widely throughout the day

41
Q

What is involved in phosphate homeostasis?

A

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

42
Q

What is fibroblast growth factor (FGF)-23?

A

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

43
Q

What are the actions of fibroblasts growth factor (FGF)-23?

A

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

44
Q

Where does our calcium intake come from?

A

The intestine
→ uptake regulated by vitamin D

from the luminal surface of the GIT, to the basolateral surface into the blood

45
Q

What is TRPV6 in Ca reabsorption?

A

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

46
Q

What are the 3 ways in which Ca can be absorbed from the gut?

A

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

47
Q

What is calcitonin?

A

Made by C cells in thyroid gland
→ parathyroid hormone (PTH) inhibitor
→ Ca2+ too high - thyroid gland makes calcitonin

48
Q

What are the action of calcitonin?

A

Bone → prevents osteoclast action, inhibits bone reabsorption
Kidney → decreases absorption of PO4 and CA2+ in the proximal tubules
Inhibits 1α-hydroxylase

49
Q

What happens when calcium homeostasis goes wrong?

A

Hypercalcaemia
Hypocalcaemia
Hyperparathyroidism
Bone problems
Ectopic calcification

50
Q

What is hypocalcaemia?

A

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

51
Q

What is hypercalcaemia?

A

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

52
Q

What is primary hyperparathyroidism?

A

Increased PTH secretion by parathyroids
→ normally a benign tumour
→ individual cells respond normally to Ca, but increased numbers more PTH produced

53
Q

What is secondary hyperparathyroidism?

A

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

54
Q
A

Molecular Endocrinology (7 decks)

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