Disorders of calcium and phosphate metabolism

Question 1

What network are osteocytes encased in?

Answer 1

Osteocytes encased in canaliculi network

Question 2

What does a decrease in serum calcium result in?

Answer 2

• 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

Question 3

What is FGF-23 secreted by and what does it act on?

Answer 3

FGF-23 is secreted by osteocytesand acts on distant structures like kidneys

Question 4

What does FGF-23 increase excretion of?

Answer 4

○ Increases excretion of phosphate from kidney – promotes phosphate loss

Question 5

What does FGF-23 inhibit the conversion of?

Answer 5

○ Inhibits the conversion/activation of vitamin D by inhibiting 1α hydroxylase enzyme

Question 6

Where is vitamin D(calcitriol) synthesised and in response to what?

Answer 6

• Synthesised in skin in response to exposure to UV

Question 7

What are the 2 steps in the activating vitamin D?

Answer 7

○ 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

Question 8

What is an accurate measure for the total vitamin D status and why?

Answer 8

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

Question 9

What defines vitamin D deficiency?

Answer 9

○ Low to low normal Ca
○ Low phosphate
○ Low 25OH D3

Question 10

Why is the vitamin D precursor levels measured instead of vitamin D itself?

Answer 10

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

Question 11

What is simple vitamin D deficiency the most common cause of?

Answer 11

Simple vitamin D deficiency is the most common cause of osteomalacia and hypercalcaemia

Question 12

What is vitamin D dependent rickets type 1?

Answer 12

• 1α hydroxylase mutation so the enzyme is inactivated

Question 13

What are the levels of Ca, phosphate, 25-OH D3 and calcitriol in vitamin D dependent rickets type 1?

Answer 13

○ Low Ca
○ Low phosphate
○ Low 25OH D3
○ Very low calcitriol

Question 14

What is vitamin D dependent rickets type 2?

Answer 14

Vitamin D receptor mutation

Question 15

What are the levels of Ca, phosphate, 25-OH D3 and calcitriol in vitamin D dependent rickets type 2?

Answer 15

○ Hypocalcaemia and hypophosphatemia
○ Normal 25OH D3
○ High calcitriol

Question 16

What could the high calcitriol in vitamin D dependent rickets type 2 be a result of?

Answer 16

§ Could be because of the result of feedback control

Question 17

Why is high levels of calcitriol i vitamin D dependent rickets type 2 ineffective?

Answer 17

§ High calcitriol but receptor not working so no effect of vitamin D

Question 18

What are the PTH levels in both vitamin dependent rickets and what can we treat this as a form of?

Answer 18

• PTH levels in all abnormalities is high to very high

-Can treat this as a form of secondary hyperparathyroidism

Question 19

Why is high PTH levels an appropriate response in both types of vitamin D dependent rickets?

Answer 19

§ Appropriate response to low Ca so PTH increases

Question 20

What disease can arise from vitamin D dependent rickets and what function deteriorates?

Answer 20

• Renal disease

Kidney function deteriorates

Question 21

What is the function of the kidney involving vitamin D?

Answer 21

one function of the kidney is production of 1α hydroxylase which converts/activates 25OH D3

Question 22

What are the levels of Ca, phosphate, 25-OH D3, calcitriol, PTH and FGF23 in hypophosphataemic rickets/ostamalacia?

Answer 22

• Ca will be low/low normal 
• Phosphate low
• 25 OH D3 normal
• Calcitriol low/normal
• PTH high/normal
• FGF-23 high

Question 23

What does a lack of vitamin D cause and counteract?

Answer 23

Lack of vitamin D = low Ca = stimulates PTH = counteracts effects of FGF-23 by stimulating calcitriol production 

Question 24

How does high FGF-23 result in phosphate wasting?

Answer 24

FGf-23 increases renal excretion of phosphate so high FGF-23 accounts for low phosphate 
-Results in phosphate wasting  

Question 25

Why is there less levels of calcitriol when FGF-23 levels are high?

Answer 25

Inhibits 1α hydroxylase so less levels of active form - calcitriol 

Question 26

What is an oncogenic osteomalacia and what does it secrete?

Answer 26

Oncogenic osteomalacia – benign tumour in bone which secretes FGF-23

Question 27

What do FGF-23 exert there phosphate wasting actions mainly on and by opposing what?

Answer 27

FGF-23 exerts its phosphate wasting actions mainly on PCT by opposing sodium-phosphate co-transporter -Opposes reabsorption of phosphate 

Question 28

What are the 2 transporters targeted by FGF-23?

Answer 28

type 2a and type 2c that are targeted by FGF-23

Question 29

Where are both type 2a and type 2c transporters found?

Answer 29

Both in the brush border of the luminal side 

Question 30

How do both type 2a and type 2c bring in phosphate?

Answer 30

Use a Na gradient to bring in phosphate by secondary active transport 

Question 31

What do both type 2a and type 2c transporter require association with?

Answer 31

Transporter requires association with Na-H exchanger regulatory factor (NHERF) to be activate in the membrane

Question 32

Why is the NHERF cofactor necessary?

Answer 32

This cofactor is necessary for expression of the transporter in the brush border membrane 

Question 33

What does FGF-23 do to the NHERF cofactor?

Answer 33

FGF phosphorylates this protein causing it to detach and therefore internalises the transporter  -Reduces phosphate reabsorption and increasing phosphate lost in urine

Question 34

What co-receptor is needed when FGF binds to its receptors?

Answer 34

When FGF binds to its receptor, it needs KLOTHO as a co-receptor 

Question 35

What happens if something impairs FGF-23?

Answer 35

more reabsorption of phosphate = hyperphosphataemia 

Question 36

What upregulates FGF-23?

Answer 36

Phosphate itself upregulates FGF-23

Question 37

What sense a rise in extracellular phosphate and what does this lead to an increased production of?

Answer 37

Osteocytes – encased in their canaliculi network  - sense a rise in extracellular phosphate and so increase production of FGF-23

Question 38

What do FGF-23 inhibit activation of?

Answer 38

FGF-23 inhibits activation of vit D 

Question 39

What does FGF-23 inhibit production of?

Answer 39

Inhibitory effect on production of PTH 

Question 40

What does calcitriol cause a negative feedback on and by stimulating what?

Answer 40

Calcitriol causes negative feedback on itself by stimulating FGF-23 which then causes decreased production of 1, 25OH D3 

Question 41

What are the levels of Ca and phosphate in renal disease?

Answer 41

Low Ca | High phosphate

Question 42

What is the high phosphate in renal disease due to?

Answer 42

•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 

Question 43

Why is there impaired formation of calcitriol in renal disease?

Answer 43

Due to renal function decline

Question 44

What does the low Ca cause in renal disease?

Answer 44

Secondary hyperparathyroidism

Question 45

Why are there high PTH levels and what does this cause and what does this mean to the negative feedback loop?

Answer 45

* 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

Question 46

What is renal failure associated with and what does this exacerbate?

Answer 46

•Renal failure is also associated with metabolic acidosis because of impaired proton excretion  -Acidosis exacerbates bone erosion