15. Regulation of Calcium and Phosphate Metabolism Flashcards
Ca2+ distribution in the body
40% is bound to protein.
60% is “ultrafilterable”, with 10% being attached to anions and 50% being free Ca2+
Sx of hypocalcemia
Hyporeflexia, twithcing. tingling, numbness.
+ Chvostek sign (facial twitching via facial n.)
+ Trousseau sign (carpopedal spasm upon inflation of BP cuff).
Sx of hypercalcemia
Lowered QT int., constipation, decreased appetite, polyuria, weakness, hyporeflexia.
How does low Ca2+ lead to numbness, tingling and twitching?
Low Ca2+ lowers the threshold for Na+ channels making it easier to fire an AP –> increased excitability –> spontaneous APs –> tetany.
How does increased Ca2+ affect membrane excitability?
Increases threshold for Na+ channels –> decreased excitability.
What does acidemia mean for free Ca2+ levels?
More H+ is bound to albumin, so more Ca2+ is free.
Increases plasma [Ca2+].
What does alkalemia mean for free Ca2+ levels?
Less H+ is bound to albumin, so less Ca2+ is free.
Decreases plasma [Ca2+].
How does bone remodeling change Ca2+ levels?
It doesn’t.
Amt of Ca2+ resorbed = Amt of Ca+ deposited
What must occur at the kidneys and GI tract to maintain Ca2+ balance?
Kidneys must excrete the same amt of Ca2+ as is absorbed by the GI.
How are Ca2+ levels and PO4- levels related?
Inversely
What secretes and produces PTH?
Chief cells of the PTG.
How does PTH become secreted by the PTG?
PreproPTH (115 aa) –> proPTH (90 aa) –> PTH (84 aa) –> Golgi secretes PTH via granules.
What happens in chronic hypercalcemia?
What is another name for it?
A decrease in synthesis/storage of PTH.
Increased breakdown of stored PTH and it releases fragmented PTH into circulation.
Secondary hypoparathyroidism.
What happens in chronic hypocalcemia?
What is another name for it?
An increase in synthesis/storage of PTH.
Hyperplasia of the PTG.
Secondary hyperparathyroidism.
What is the “general” effect of Mg2+ on PTH secretion?
Usually follows PTH rules.
Low Mg2+ triggers an increase in PTH.
What is the exception of Mg2+ and PTH secretion?
Severe hypomagnesemia (alcoholism). Inhibits PTH synthesis/storage.
PTH effects on bone, kidneys, GI tract:
Bone: + bone resorption.
Kidneys: + Ca2+ reabsorption, - Pi reabsorption, increase urinary cAMP.
GI: indirectly + Ca2+ absorption by activating Vit D.
What is the goal of Vit D?
To increase Ca2+, Pi.
What kind of hormone is Vit D?
Steroid.
What is the main circulating form of Vit D, which is inactive?
25-OH-cholecalciferol
What is the Vit D we get from diet?
Cholecalciferol.
What enzyme activates Vit D?
1a-hydroxylase
AKA CYP1a
What is the stimuli for 1a-hydroxylase activity? (3)
Low Ca2+
Low Pi
High PTH
Where is 1a-hydroxylase regulated? What level is it regulated at?
Kidneys at the transcriptional level.
Where is the PTR R located?
On osteoblasts.
S-T actions of PTH on bone:
What can PTH be used as a therapy for, then?
Bone formation.
Osteoporosis.
L-T actions of PTH on bone:
Increased bone resorption by indirect action on osteocytes by cytokines from osteoblasts.
What is the function of M-CSF?
Activates stem cells to differentiate into osteoclasts.
What is the function of RANKL and RANK?
Primary mediators of osteoclast formation.
RANKL is a protein produced by bone cells to + remodeling. RANK is the R on osteoclasts.
What is the function of OPG?
What produces it?
To inhibit RANKL/RANK.
Produced by osteoblasts.
Osteoclast formation can be approximated by:
RANKL/OPG
What effects does PTH have on RANKL and OPG?
PTH: + M-CSF, increases RANKL, decreases OPG.
How does PTH inhibit Pi reabsorption in the PT?
PTH binds and triggers GPCR. cAMP activates a protein kinase that inhibits the NPT2a channel (symport w/ Na+ and Pi) on the luminal membrane.
How does PTH increase urinary cAMP?
cAMP in the PT is excreted in the urine –> increase urinary cAMP.
Besides the PT, where else can PTH act along the nephron to increase Ca2+? Why?
DT/TAL to complement the increase in [Ca2+] from bone resorption and phosphaturia.
What protein is upregulated in the GI by Vit D to increase Ca2+ and Pi absorption?
Calbindin
How does Vit D stimulate Pi reabsorption in the kidneys? What kind of effect does it have on Ca2+ reabsorption?
+ NPT2a
MInimally affects Ca2+ in the kidney.
How does Vit D affect the PTG?
+ CaSR expression, which increases Ca2+ secretion.
Where does calcitonin act?
Bone and kidney.
What is the goal of calcitonin and how does it do that?
To lower Ca2+ and Pi.
Inhibits bone resorption (binds its R on osteoclasts) and reabsorption at the kidney.
What kind of role does calcitonin play in chronic regulation of plasma Ca2+?
It does NOT play a role.
What happens to calcitonin levels post thyroidectomy?
Lowers calcitonin but does not change Ca2+ metabolism.
What happens to calcitonin levels w/ a thyroid tumor?
Increases calcitonin but does not change Ca2+ metabolism.
What is the effect of Estradiol-17B on Ca2+ regulation?
+ GI to absorb Ca2+ and kidneys to reabsorb.
Promotes survival of osteoblasts (favors bone formation > resorption).
What is the effect of glucocorticoids (cortisol) on Ca2+ regulation?
Promotes bone resorption, + renal Ca2+ wasting, and inhibits Ca2+ absorption in the GI.
Pt can develop osteoporosis.
What do patients excrete in high quantities with Primary HyperPTHism? (3)
What are symptoms?
What is the treatment?
What effect does it have on PTH, Ca2+, Pi and VitD levels?
Increased excretion of Pi, cAMP, Ca2+.
Ca2+ stones, constipation.
PT-ectomy.
+PTH, +Ca2+, -Pi, +VitD.
What happens in Secondary HyperPTHism?
What are the causes? (2)
Increase in PTH is secondary to decrease [Ca2+].
Renal failure, Vit D deficiency.
Effects on PTH, Ca2+, Pi, Vit D in a patient with:
RF
Vit D deficiency
RF: +PTH, -Ca2+, +Pi, -Vit D
Vit D deficiency: +PTH, -Ca2+, -Pi, -Vit D
Causes of hypoPTHism:
Sx of hypoPTHism:
TTM of hypoPTHism:
HypoPThism effects on PTH, Ca2+, Pi, Vit D
Thyroid or Pt surgeries. Rarely autoimmune/genetic dz.
Same as those associated with low Ca2+.
TTM is oral Ca2+.
-PTH, -Ca2+, +Pi, -Vit D
Albright hereditary osteodystrophy (AKA Pseudohypoparathyroidism type 1a) effects PTH levels how?
What do patients develop?
The Gs for PTH is ineffective in bone and kidneys.
Pts develop HYPOcalcemia and HYPERphosphaturia.
How do patients develop hyperphosphaturia in Pseudohypoparathyroidsm?
PTH cannot activate the Gs to activate cAMP/AC to inhibit NPT2a, so the reabsorption of Pi is accelerated.
What is the phenotype of a pt w/ Pseudohypoparathyroidism?
What is its effects on PTH, Ca2+, Pi, Vit D?
Short stature, obese, shortened hands/feet.
+ PTH, -Ca2+, +Pi, -Vit D
What happens in Humoral Hypercalcemia of Malignancy physiologically?
What is its effect on PTH, Ca2+, Pi, Vit D?
What is the TTM?
PTHrP is produced by tumor cells and binds and activates PTH R.
Causes inhibition of PTH.-
-PTH, +Ca2+, -Pi, -Vit D
Lasix or Etidronate to inhibit Ca2+ absorption/reabsorption/resorption).
What happens in Familial Hypocalciuric Hypercalcemia?
How does it effect serum and urinary Ca2+ levels?
Mutations arise that inhibit CaSR in the PTG.
There is an increase serum Ca2+ and a decrease in urinary Ca2+
What are 2 causes of Rickets?
Dietary deficiency in Vit D.
Vit D resistance by inhibition of 1a-hydroxylase or mutations in the Vit D R.
Main problem in Rickets:
Osteomalacia:
Rickets - not enough Ca2+ or Pi to mineralize bone.
Osteomalacia - new bone cannot mineralize.
What causes Vit D-dependent Rickets type I?
What causes Vit D-dependent Rickets type II?
I: Low activity of 1a-hydroxylase.
II: Problems w/ Vit D R
What happens to levels of PTH, Ca2+, urinary Pi, urinary cAMP and Vit D in a patient w/ Rickets?
+PTH (secondarily), -Ca2+, +urinary Pi, +urinary cAMP, -Vit D.
TTM for Osteoporosis includes:
Anabolic therapy (1):
Anti resorptive therapy (5):
Anabolic therapy: PTH
Anti resorptive therapy: biophosphonates, estrogen, SERMs, calcitonin, RANKL inhibitors.
