Regulation of Calcium and Phosphate Metabolism Flashcards
Where is calcium distributed in the body?
What is the active form of calcium?
99% in bones and teeth
more in ICF than ECF
free, ionized Ca = active
What percentage of total Ca is free ionized?
50%
What is the the normal calcium level for adults?
How does it differ in children?
in the 9s = btw 9 and 10 mg/dl
higher in teens/puberty age
What are indicators of hypocalcemia?
numbness and tingling, spontaneous twitching
chvostek sign = twitching of facial ms from tapping on facial nerve
trousseau sign = carpopedal spasm upon inflation of bp cuff
What occurs to membrane potentials in hypocalcemia?
reduces threshold for na channels –> easier APs
can get hypocalcemic tetany
What occurs to membrane potentials in hypercalcemia?
harder to get APs –> nervous sys depressed and reflex responses slowed
How does plasma protein concentration affect Ca levels?
alter total Ca concentration in same direction (more protein, more total Ca)
no change in ionized Ca
How do changes in anion concetration affect Ca concentration?
changes fraction of Ca complexed w/ anions
if Pi increases, ionized Ca decreases
How does acid base affect ionized Ca?
acidemia –> H+ take up spots on albumin –> more free calcium
alkalemia –> decreased free Ca
To maintain Ca balance, what occurs?
kidneys must excrete the same amount of Ca that is absorbed by the GI tract
What is the relationship btw Ca and phosphate?
inversely related
extracellular concentration of Pi is regulated by same hormones that regulate Ca
Where is Pi distributed?
85% in bone
84% of plasma is ionized
more in ICF than ECF
Where is PTH synthesized and secreted?
from chief cells of the parathyroid gland
main stimulus is decreased plasma Ca
What type of hormone is PTH?
How is it synthesized?
peptide hormone
preproPTH(115 aa) –> proPTH (90 aa) –> PTH in golgi –> packaged in secretory granules
What does Vit D do to PTH signaling?
down regulates PTH gene
stimulates CaSR gene –> PTH can more sensitively respond to Ca
How does increased Ca influence PTH?
inhibits PTH synthesis and secretion
How do chronic hyper and hypocalcemia affect PTH?
chronic hyper –> decreased synthesis and storage of PTH, increased breakdown and relase of inactive fragments
chronic hypo –> increased synthesis and storage, hyperplasia of parathyroid glands
How does magnesium affect PTH?
parallel to Ca, but less significant effects
severe hypomagnesemia (seen in alcoholism) –> inhibition of PTH synthesis, storage and secretion
What type of receptor does PTH work on?
Gs GPCR
What are the actions of PTH on bone, kidney, and intestine?
Bone: increases bone resorption
kidney: decreased Pi reabsorption, increased ca reabsorption, increased urinary cAMP
intestine: increased Ca absorption
What type of hormone is Vit D?
steroid hormone
25 OH cholecalciferol = inactive circulating
1, 25 OH cholecalciferol = active
24,25 OH cholecalciferol = inactive
How is Vit D activated?
via 1 alpha-hydroxylase in proximal tubule of kidney
Where are PTH receptors located in bone?
What are its short and long-term actions?
on osteoblasts
short-term = bone formation
long-term = bone resorption indirectly via cytokines from osteoblast –> osteoclasts
How does Vit D act on bone?
synergistically w/ PTH –> stim osteoclast activity and bone resorption
What two important signals act on osteoclasts to promote bone resorption?
IL-6
Rank ligand
What is M-CSF?
growth factor
induces stem cells –> differentiate into osteoclast precursors –> mononuclear osteoclasts –> mature multinucleated osteoclasts
What are RANK and RANKL?
RANK = cell surface protein on osteoclasts and osteoclasts precursors
RANKL = cell surface protein produced by osteoblasts, bone lining cells, and apoptotic ostocytes
they bind –> osteoclasts form –> bone resorption
What is OPG?
soluble protein made by osteoblasts
decoy receptor for RANKL –> inhibits RANKL/RANK and inhibits formation of osteoclasts and therefore resorption
How does PTH act on the kidney to affect Pi?
In the Proximal tubule
PTH –> Gs receptor –> AC –> cAMP –> pKA –> inhibits Na-Pi symporter
Pi cannot be reabsorbed –> complements Ca increase from bone resorption
How does Vit D Act on the intestines?
acts to stimulate calbindin synthesis –> helps Ca get reabsorbed
How does PTH affect the kidney in general?
stimulates 1alpha-hydroxylase activity –> activates Vit D
stim Ca reabsorption by TAL and distal tubule
inhibits Pi reabsorption by proximal nephrons (represses NPT2a)
How does PTH affect the small intestine?
no direct action
(indirectly increases Ca absorption via activating Vit D)
How does Vit D act on the kidney?
stimulates NPT2a expression –> promotes Pi reabsorption by proximal nephrons
minimal actions of Ca
How does Vit D act on bone?
sensitizes osteoblasts to PTH
regulates osteoid production and calcification
What does calcitonin do?
receptors on osteoclasts –> decreases activity and number of osteoclasts –> decreases blood Ca and Pi (inihibits resorption)
reduces Ca uptake in kidneys
no role in min to min regulation of plasma Ca
How does estrogen affect intestines and kidneys?
estradiol 17beta –> stimulates intestinal Ca absorption and renal tubular Ca reabsorption
How does estrogen affect the bones?
estradiol 17-beta promotes survival of osteoblasts and death of osteoclasts = favors bone formation
women after menopause –> bone loss
How do glucocorticoids affect Ca?
promote bone resorption (favor RANKL over OPG)
renal Ca wasting
inhibit intestinal Ca absorption
What do you see in the urine of ppl w/ primary hyperpara?
excessive Pi, cAMP, and Ca
What are the main symptoms of primary hyperpara?
stones, bones, and groans
hypercalcuria - stones
increase bone resorption
constipation
(increased PTH, Ca, and Vit D, low Pi)
What occurs in secondary hyperparathyroidism?
low Ca –> increase in PTH secondary to this
caused by renal failure or Vit D deficiency
What are the labs you would see in secondary hyperparathyroidism from renal failure or Vit D deficiency?
in both: high PTH, low Ca and Vit D
in renal failure: high Pi bc can’t excrete it
in Vit D def: low Pi
What are common symptoms of hypopara?
most associated w/ low ca: muscle spasm or cramping, numbness and tingling
What labs do you see in hypoparathyroidism?
low: pth, ca, vit d
high: Pi
What is Albright hereditary osteodystrophy?
pseudohypopara type 1a
inherited AD
Gs for PTH in bone and kidney is defective –> low calcium and high Pi; increased PTH
What are the labs and physical features you would see in Albright hereditary osteodystrophy?
high PTH and Pi
low Ca and Vit D
short stature, neck, obese, subcutaneous calcification, shortened metatarsals and metacarpals
admin of PTH –> no phosphaturia or increase in urinary cAMP
What occurs in humoral hypercalcemia of malignancy?
tumors create PTHrP –> acts like PTH and stimulates the receptor
in urine: high Ca, Pi, and cAMP
in blood: high Ca, low blood Pi
low PTH and vit D (in cancer Vit D levels are normally suppressed)
What is Familial hypocalciuric hypercalcemia?
AD disorder
inactive CaSR in parathyroid glands and ascending LOH –> decreased urinary Ca excretion and increased serum Ca
basically body can’t tell when your calcium is raised
normal to high PTH
What are the congenital forms of rickets?
pseudoVit D-deficient rickets or Vit D dependent type I = decreased 1alpha-hydroxylase
type II = decreased Vit D receptor
either can’t make active Vit D or cells can’t use it
What labs do you see in Vit D deficiency?
high: PTH, urine Pi and cAMP, bone resorption
low: Ca, Pi, and Vit D
What can RANKL inhibitors be used to treat?
osteoporosis
What is the cyp1a gene?
How is it regulated?
The gene for 1alpha-hydroxylase that activates Vit D in the kidney
PTH promotes scrip via Gs
Ca inhibits via Gi
