Regulation Of Calcium And Phosphate Flashcards
What is calcium and how much is recommended adult intake?
Most abundant metal in body
Recommended adult intake is 1000 mg/day
Calcium distribution in body
- 99% in skeleton and teeth as calcium hydroxyapatite crystals
- 1% intracellular
- 0.1% extracellular which is tightly regulated
- 2.5 mmol/L in plasma, where 45% is biologically active unbound ionised Ca2+ and 55% is bound Ca2+ (45% bound to plasma proteins like albumin and 55% to anions like bicarbonate, phosphate, lactate)
What 3 hormones are responsible for regulating serum calcium and phosphate?
- Parathyroid hormone (PTH) secreted by parathyroid glands
- Metabolite of Vitamin D3 (Calcitriol)
- Calcitonin secreted by thyroid parafollicular cells → can reduce calcium conc acutely but no -ve effect if parafollicular cells removed e.g. in thyroidectomy - so isn’t a main player in calcium regulation
What are 2 types and sources of Vitamin D?
- Vitamin D2 (ergocalciferol) from diet e.g. oily fish
- Vitamin D3 (cholecalciferol) synthesised in skin when exposed to sunlight
How is vitamin D3 made and both D2 and D3 metabolised?
In skin when exposed to sunlight, 7-dehydrocholesterol → pre-vitamin D3 → vitamin D
Vitamin D becomes activated after undergoing both hydroxylation steps (1st hydroxylation by 25-hydroxylase in the liver, 2nd hydroxylation by 1-alpha-hydroxylase in the kidney)
1,25(OH)2 cholecalciferol is aka calcitriol - the active form of vitamin D, produced by the 2nd hydroxylation
What does the 1st hydroxylation step produce
25-OH cholecalciferol
What is serum 25-OH cholecalciferol a good indicator of?
Body vitamin D status, as calcitriol is difficult to measure in blood
25-OH cholecalciferol is biologically inactive
How does calcitriol regulate its own synthesis?
It decreases transcription of 1-alpha-hydroxylase - negative feedback
What are the(3) effects of calcitriol?
- Bone- increases Ca2+ reabsorption from bone, by binding to calcitriol receptors on osteoblasts which release Osteoclast activating factors (OAFs) which switch on osteoclasts. (for VSAQ purposes: increases osteoclast activity)
- Kidney- increases Ca2+ and phosphate reabsorption by kidney from urine
- Increases calcium and phosphate reabsorption from gut
How does calcitriol action on bone depend on serum calcium?
Low serum calcium - Calcitriol increase reabsorption from bone (osteoclasts > osteoblasts)
Normal serum calcium - Calcitriol works to increase bone formation (osteoblast > osteoclast)
What is the rate limiting step for active Vitamin D synthesis?
1-alpha-hydroxylase converting 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol
What secretes PTH?
- Chief cells in parathyroid glands
- Secreted as a large precursor (pre-pro-PTH) & cleaved into PTH
What detects the changes in circulating calcium concentration?
G-protein coupled calcium sensing receptors on chief cells
How is PTH secretion related to calcium levels?
If serum calcium conc. high, PTH secretion inhibited
If serum calcium is low, more PTH secreted
- High ECF Ca2+ conc means more Ca2+ binds to receptors on parathyroid cells so PTH secretion inhibited
- Low ECF Ca2+ conc means less Ca2+ binding to receptors on parathyroid cells so PTH secreted
What are the (3) effects of PTH on the kidney?
- Increase Ca2+ reabsorption from kidney from urine
- increases expression of 1-alpha-hydroxylase → this increases calcitriol synthesis
- decreases renal phosphate reabsorption (Overall the effects on phosphate is neutral- it causes loss through kidney and gain through gut)
Explain the affect of PTH on bone and how it does this.
- Increases reabsorption of calcium from bone (for VSAQ purposes: increases osteoclast activity)
- PTH binds to PTH receptor on osteoblasts (cells that build bone)
- Stimulates osteoblasts to make osteoclast activating factors (OAFs) e.g. RANKL (receptor activator of nuclear factor kappa-B ligand)
- Osteoclasts (cells that consume bone) are switched on and dissolve bone, releasing calcium
What are the effects of PTH on the gut
Gut- through increase in calcitriol synthesis, there is increase in Ca2+ and phosphate absorption from gut (so PTH doesn’t directly affect gut)
How is PTH regulated (2 ways)?
- PTH causes increase in plasma Ca2+ which has negative feedback as it binds to Ca2+ receptors on the chief cells and decreases PTH secretion
- PTH also increases calcitriol synthesis by increasing action of 1-alpha-hydroxylase → chief cells also have calcitriol receptors and there’s negative feedback again as high calcitriol levels cause decrease in PTH secretion
Which cells secrete calcitonin?
Parafollicular cells of the thyroid gland
- What effect does calcitonin have on serum calcium?
Reduces serum calcium
Outline the actions of calcitonin on the bone and kidney
Reduces osteoclast activity
Increases Ca2+ excretion through urine (by preventing renal reabsorption of calcium)
Overall affect → Reduced calcium levels
How does phosphate reabsorption in kidneys happen?
- Phosphate reabsorbed via sodium-phosphate transporter (symporter) cells- this also therefore results in less sodium excretion in urine
- Increased phosphate loss in urine would lower serum phosphate levels
How does PTH work here affect phosphate
- PTH inhibits renal phosphate reabsorption by inhibiting these transporters
- In primary hyperparathyroidism, serum phosphate is low due to increased urine phosphate excretion
What factor regulates serum phosphate?
FGF23
- Fibroblast Growth Factor 23 is derived from bone
- Also inhibits phosphate reabsorption in kidneys by inhibiting Na-PO4 transporters
- Also inhibits calcitriol synthesis causing less phosphate absorption from gut from food
