Ca and PO4 homeostasis Flashcards
1
Q
Regulation of bone turnover 1
A
- Osteocytes (mechanoreceptors) survey bone strength and when there is a weak area they activate osteoblasts by stopping the release of sclerostin
- Sclerostin normally inhibits blasts, so the blasts get activated when cytes stop releasing sclerostin
- Osteoblasts are also activated by PTH
- Osteoblasts release RANKL which stimulate osteoclasts to increase their breakdown of bone
- Activated osteoclasts release IGF1 and TGFb, which stimulate the blasts to proliferate and rebuild the bone that the clasts just resorbed
2
Q
Regulation of bone turnover 2
A
- Osteoblasts also release OPG, which consumes the RANKL and thus reduces osteoclast activity
- Bone resorption is controlled thru the OPG/RANKL balance; more RANKL = increased resorption and more OPG = increased formation
- Osteoblast activation is controlled by PTH activation, and inhibition from sclerostin
- Estrogen deficiency and inflammatory cytokines (TNFa) results in relative increase in RANKL over OPG and thus favor bone loss
3
Q
Vitamin D synthesis
A
- Vitamin D (cholcalciferol) is absorbed from the diet or made in the skin via sunlight
- It is stored in adipose tissue (reservoir) and to be activated it first must go to the liver and be hydroxylated to 25OHD
- To complete the activation process it must be hydroxylated once more to 1,25OHD which occurs in the kidneys
- The kidneys can also hydroxylate it to 24,25OHD which is an inactive form
4
Q
Vit D deficiency testing
A
- If suspect the pt is vitamin D deficient, want to measure levels of 25OHD and not 1,25OHD since the body will convert all of the 25OHD to 1,25OHD to maintain homeostasis so the 1,25OHD level may be normal but the 25OHD levels are low
- These pts usually won’t have Ca absorption problems, but PTH will be high and may have excessive bone resorption
- If the deficiency is severe enough the 1,25OHD will be low and there will be inadequate absorption of Ca
5
Q
Regulation of Vit D activation
A
- The 1 and 24 hydroxylases are heavily regulated (not 25) to maintain a normal level of active 1,25OHD
- Fall in plasma PO4 levels will directly activate 1 hydroxylase and increase 1,25OHD levels
- Increased PTH levels (which rise due to a fall in serum Ca) will directly activate 1 hydroxylase and increase 1,25OHD levels
- Estrogen and prolactin directly increase 1 hydroxylase and thus increase 1,25OHD levels (consistent w/ the need for Ca uptake needed during pregnancy and lactation)
- High levels of 1,25OHD will negatively feedback on the 1 hydroxylase nz and decreased the levels of 1,25OHD
- High levels of PO4 will inhibit 1,25OHD formation
- Anytime 1 hydroxylase activity falls the 24 hydroxylase activity increases
6
Q
Effects of 1,25OHD 1
A
- It promotes the uptake of Ca (and PO4) from the gut, and promotes bone resorption and thus release of bone Ca
- In the gut 1,25OHD binds to its cytoplasm receptor, the complex then moves to the nucleus to activate TFs and increase Ca transporters
- 1,25OHD also causes kidneys to increase reabsorption of PO4, but not Ca
- 1,25OHD also boots the effects of PTH
- The effects on the gut are more long-term, where as the effects on bone resorption, PO4 reabsorption, and increasing PTH effects are acute
7
Q
Effects of 1,25OHD 2
A
- Also: TLR and cytokes (IFNg) promote synthesis of 1,25OHD in macs, since 1,25OHD helps immune cells clear out pathogens
- Overall, on its own (not PTH), 1,25OHD primarily regulates PO4 levels (increases them), since it increases PO4 absorption from gut, bone resorption, and reabsorption of PO4 from kidneys
- It does not change Ca levels much b/c the increase in Ca will be offset by the increased renal excretion of Ca
8
Q
Vit D deficiency
A
- Children that lack vit D develop rickets (insufficient bone formation and bowing of the legs)
- In adults vit D deficiency results in osteomalacia
9
Q
PTH regulation 1
A
- PTH is released by parathyroid glands and regulates bone resorption, kidney function, and 1,25OHD production
- PTH release is mostly regulated by plasma Ca levels: as Ca falls PTH release is increased (more frequent rate of change-> larger PTH response)
- In the parathyroid, ionic Ca binds to Ca sensing receptors (CaSR), which activates a GPCR and causes inhibition of PTH release (when Ca is low this process stops and PTH release increases)
- The concentration of Ca producing half-maximal PTH release is called the “set point”
- Prolonged hypocalcemia leads to hyperplasia of the gland and shifts the set point to the left
10
Q
PTH regulation 2
A
- A shift of the set point to the left means sensitization of the CaSR: the receptors think there is more Ca than there is, and thus PTH will not be released as easily
- Requires a lower Ca level to reach the 50% max PTH release
- This is what’s seen in secondary hyperthyroidism (due to vit D deficiency), since 2o hyperthyroidism leads to Ca deficiency (no vit D = no absorption of Ca from gut) and prolonged Ca deficiency/high PTH leads to bone loss
- So the set point shifts to the left to reduce PTH release given the same Ca level
- PO4 levels have little effect on PTH release, unless the levels are so high that the PO4 starts complexing w/ Ca enough to where the Ca levels fall, then PTH is released
- Mg deficiency impairs PTH release, thus Mg deficiency can lead to hypoCa secondary to low PTH
11
Q
Effects of PTH
A
- PTH acts directly on osteoblasts and stimulates them to release RANKL, thus indirectly activating osteoclasts and increasing bone resorption
- In the kidney PTH increases Ca reabsorption and decreases PO4 reabsorption
- Therefore, PTH has a phosphaturic effects in that it increases PO4 excretion (opposite effect on Ca: decreases Ca excretion)
- PTH increases the activity of 1 hydroxylase in the kidney, therefore increasing the levels of 1,25OHD
- This means that PTH indirectly increases gut absorption of Ca and PO4 (thru 1,25OHD)
12
Q
Hyperparathyroidism 1
A
- Primary hyperpara can result from PTH-secreting tumors, it leads to hypercalcemia, hypophosphatemia, demineralization of bone, hypercalcuria, and kidney stones
- Secondary hyperpara is due to deficiency of 1,25OHD, usually due to renal failure and kidneys that cannot activate 25OHD
- Lack of 1,25OHD leads to inability to absorb Ca from gut which leads to hypoCa and thus increased PTH release
13
Q
Hyperparathyroidism 2
A
- Calcimimetics, like 2o hypopara or any other etiology of hypoCa, cause a shift to the left of the PTH/Ca set point (receptors become more sensitive to Ca-> lower Ca level is required to get same PTH release)
- Calcimimetics do this by allosterically binding tot he receptors and increasing their affinity for Ca
- They can be used to decrease PTH release in hyperpara by making the normal parathyroid tissue less responsive to Ca
14
Q
Pseudohypoparathyroidism (PHP)
A
- Genetic condition resembling milkd hypopara, even though normal or elevated PTH levels
- Can Dx by giving PTH and testing for cAMP in urine
- In normal pts, PTH produces a large increase in urinary cAMP
- In PHP the pts fail to respond to PTH and the urine does not contain large amounts of cAMP
- Most of these pts have mutant resistant hormone receptors (the hormone receptors that are GPCRs and work thru cAMP)
- Therefore these pts exhibit a relative resistance to hormones that act via cAMP
15
Q
Calcilytics
A
- Replenishment of PTH in true hypopara is necessary for life
- Might be possible to give these pts calcilytics instead
- Calcilytics shift the PTH/Ca curve to the right (less sensitive to Ca)
- This means a higher Ca level is sufficient to reach 50% PTH release (the gland thinks the Ca level is lower than it really is b/c of decreased Ca affinity)
- Important to give PTH/calcilytics in a pulsatile manner
