Disorders of calcium and phosphate metabolism Flashcards
What network are osteocytes encased in?
Osteocytes encased in canaliculi network
What does a decrease in serum calcium result in?
• Decrease in serum calcium = increase secretion of PTH
○ PTH increases renal absorption of calcium
○ Activates calcitriol by promoting enzymatic hydroxylation of calcitriol
§ Calcitriol acts to increase both Ca and phosphate absorption from the gut
□ Compensates for the drop in Ca that caused rise in PTH
§ At the same time, PTH will increase excretion of phosphate
□ Phosphate absorption from gut is balanced by phosphate excretion due to PTH
□ Reciprocal effect on phosphate means it can focus on maintaining serum Ca levels
What is FGF-23 secreted by and what does it act on?
FGF-23 is secreted by osteocytesand acts on distant structures like kidneys
What does FGF-23 increase excretion of?
○ Increases excretion of phosphate from kidney – promotes phosphate loss
What does FGF-23 inhibit the conversion of?
○ Inhibits the conversion/activation of vitamin D by inhibiting 1α hydroxylase enzyme
Where is vitamin D(calcitriol) synthesised and in response to what?
• Synthesised in skin in response to exposure to UV
What are the 2 steps in the activating vitamin D?
○ 25 hydroxylation in liver to form 25OH D3, major circulating metabolite
○ 1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone
What is an accurate measure for the total vitamin D status and why?
Is to measure 25-OH D3
○ More accurate measure for the total vitamin D status than active calcitriol because it is not product inhibited – the pool of 25OH D3 is a good measure of vitamin D reserves
What defines vitamin D deficiency?
○ Low to low normal Ca
○ Low phosphate
○ Low 25OH D3
Why is the vitamin D precursor levels measured instead of vitamin D itself?
Vitamin D precursor levels are measured instead of active form because although calcitriol may be normal, the precursor may not be, so need to check levels of precursor for an all-round picture
What is simple vitamin D deficiency the most common cause of?
Simple vitamin D deficiency is the most common cause of osteomalacia and hypercalcaemia
What is vitamin D dependent rickets type 1?
• 1α hydroxylase mutation so the enzyme is inactivated
What are the levels of Ca, phosphate, 25-OH D3 and calcitriol in vitamin D dependent rickets type 1?
○ Low Ca
○ Low phosphate
○ Low 25OH D3
○ Very low calcitriol
What is vitamin D dependent rickets type 2?
Vitamin D receptor mutation
What are the levels of Ca, phosphate, 25-OH D3 and calcitriol in vitamin D dependent rickets type 2?
○ Hypocalcaemia and hypophosphatemia
○ Normal 25OH D3
○ High calcitriol
What could the high calcitriol in vitamin D dependent rickets type 2 be a result of?
§ Could be because of the result of feedback control
Why is high levels of calcitriol i vitamin D dependent rickets type 2 ineffective?
§ High calcitriol but receptor not working so no effect of vitamin D
What are the PTH levels in both vitamin dependent rickets and what can we treat this as a form of?
• PTH levels in all abnormalities is high to very high
-Can treat this as a form of secondary hyperparathyroidism
Why is high PTH levels an appropriate response in both types of vitamin D dependent rickets?
§ Appropriate response to low Ca so PTH increases
What disease can arise from vitamin D dependent rickets and what function deteriorates?
• Renal disease
Kidney function deteriorates
What is the function of the kidney involving vitamin D?
one function of the kidney is production of 1α hydroxylase which converts/activates 25OH D3
What are the levels of Ca, phosphate, 25-OH D3, calcitriol, PTH and FGF23 in hypophosphataemic rickets/ostamalacia?
- Ca will be low/low normal
- Phosphate low
- 25 OH D3 normal
- Calcitriol low/normal
- PTH high/normal
- FGF-23 high
What does a lack of vitamin D cause and counteract?
Lack of vitamin D = low Ca = stimulates PTH = counteracts effects of FGF-23 by stimulating calcitriol production
How does high FGF-23 result in phosphate wasting?
FGf-23 increases renal excretion of phosphate so high FGF-23 accounts for low phosphate
-Results in phosphate wasting
Why is there less levels of calcitriol when FGF-23 levels are high?
Inhibits 1α hydroxylase so less levels of active form - calcitriol
What is an oncogenic osteomalacia and what does it secrete?
Oncogenic osteomalacia – benign tumour in bone which secretes FGF-23
What do FGF-23 exert there phosphate wasting actions mainly on and by opposing what?
FGF-23 exerts its phosphate wasting actions mainly on PCT by opposing sodium-phosphate co-transporter
-Opposes reabsorption of phosphate
What are the 2 transporters targeted by FGF-23?
type 2a and type 2c that are targeted by FGF-23
Where are both type 2a and type 2c transporters found?
Both in the brush border of the luminal side
How do both type 2a and type 2c bring in phosphate?
Use a Na gradient to bring in phosphate by secondary active transport
What do both type 2a and type 2c transporter require association with?
Transporter requires association with Na-H exchanger regulatory factor (NHERF) to be activate in the membrane
Why is the NHERF cofactor necessary?
This cofactor is necessary for expression of the transporter in the brush border membrane
What does FGF-23 do to the NHERF cofactor?
FGF phosphorylates this protein causing it to detach and therefore internalises the transporter
-Reduces phosphate reabsorption and increasing phosphate lost in urine
What co-receptor is needed when FGF binds to its receptors?
When FGF binds to its receptor, it needs KLOTHO as a co-receptor
What happens if something impairs FGF-23?
more reabsorption of phosphate = hyperphosphataemia
What upregulates FGF-23?
Phosphate itself upregulates FGF-23
What sense a rise in extracellular phosphate and what does this lead to an increased production of?
Osteocytes – encased in their canaliculi network - sense a rise in extracellular phosphate and so increase production of FGF-23
What do FGF-23 inhibit activation of?
FGF-23 inhibits activation of vit D
What does FGF-23 inhibit production of?
Inhibitory effect on production of PTH
What does calcitriol cause a negative feedback on and by stimulating what?
Calcitriol causes negative feedback on itself by stimulating FGF-23 which then causes decreased production of 1, 25OH D3
What are the levels of Ca and phosphate in renal disease?
Low Ca
High phosphate
What is the high phosphate in renal disease due to?
•High phosphate due to impairment of renal function
-One renal function is reabsorption of phosphate so if you lose that = low phosphate = more phosphate wasting
-High phosphate because there is a failure of glomerular filtration
•Net loss of phosphate loss as GFR drops because less phosphate is excreted
-Low Ca = secondary hyperparathyroidism which prevents any renal phosphate reabsorption which could be taking place
Why is there impaired formation of calcitriol in renal disease?
Due to renal function decline
What does the low Ca cause in renal disease?
Secondary hyperparathyroidism
Why are there high PTH levels and what does this cause and what does this mean to the negative feedback loop?
- High PTH levels are appropriate because the Ca is low but PTH is unable to exert its effects because it will try and get kidney to produce more calcitriol but kidney is unable to do so
- It will also try and get kidney to absorb more Ca and excrete more Phosphate but due to impaired renal function, this is also not possible
- This means the negative feedback loop is broken so PTH levels stay high
What is renal failure associated with and what does this exacerbate?
•Renal failure is also associated with metabolic acidosis because of impaired proton excretion
-Acidosis exacerbates bone erosion
