Ca/Ph regulation Flashcards
Calcium regulation, why do we care?
Where is it stored?
what happens as we age with calcium?
what about as women get older?
critical for homeostasis tightly regulated.
bones and teeth
decreases in the amount of calcium absorbed from dietary intake of calcium —> so bone cells are reabsorbed by body faster than new bone is made –> leads to osteoporosis
decrease in estrogen –> function of protecting our bones and leading to bone function. declining in age = impact in calcium
Where is the distribution of calcium in the body?
Bones and teeth - 99%
1% ICF
Plasma and ECF, very little
What is the active form of calcium?
what are the relative groupings of the total Ca2+?
what can Ca be bound to in a “free” scenario?
what can phosphate do?
Free, ionized Ca2+
“Total Ca2+” constitutes the protein bound vs. the free.
but some of the free are complexed to other ions (Phosphate), the rest is just ionized Ca2+
phosphate can bind to the ca, so the more phosphate you have, the more you can alter calcium in the blood. (CaPO4)
Explain the amount of calcium as we age (ranges)
Calcium is kept within a narrow range throughout the life (in the 9’s)
the only time it spikes is when kids are growing (in the 10’s)
What happens when you have Hypocalcemia?
what does it mean?
symptoms?
What are different tests you can do?
low plasma calcium concentration
hyperreflexia, twitching, cramping, tingling and numbness (tetany)
Chvostek sign = twitching of the facial muscles elicited by tapping on the facial nerve
Trousseau sign: carpopedal spasm upon inflation of a blood pressure cuff.
Hypercalcemia?
what does it mean
symptoms?
Increased plasma Ca2+ concentration
pretty much opposite of hypo.
Decreased Q T interval, constipation, lack of appetite, polyuria, polydipsia, muscle weakness, hyporeflexia, lethargy, coma
What does Ca2+ do to the membrane?? Use this for the basis behind hypocalcemia and explain the process.
what is this process going to result in from our sensory neurons and motor neurons?
Plasma calcium = extracellular calcium
low extracellular Ca2+ = Hypocalcemia
reduces the activation threshold for Na+ channels and easier to evoke AP, which results in an increase in membrane excitability (spontaneous APs)
because of the increased AP, that’s the idea behind hypocalcemia tetany (spontaneous contractions due to low Extracellular Ca2+)
produces tingling and numbness (on sensory neurons) and twitches (on motoneurons and muscle)
What is the basis behind Hypercalcemia?
more calcium extracellularly lowers membrane excitability.. so the nervous system becomes depressed and reflexive responses are slowed.
What happens to calcium with regards to plasma proteins?
what’s going to be the change in total Ca?
what about just ionized Ca?
remember, calcium is going to be bound to plasma proteins (one of them is albumin), so whenever we have changes we can alter the total.
NO CHANGE IN IONIZED CA2+
the reason why we don’t see many significant changes in ionized calcium is because the changes in protein tend to be slow and chronic.. giving the system time to regulate the calcium levels.
so the total will be higher because the ionized is keeping up with what’s being taken out of the pool to be bound
What is the main response to low calcium?
parathyroid hormone
if we have changes in anion concentration, what can happen to Ca2+?
changes the fraction of Ca2+ complexed with anions…
ex) increase phosphate concentration –> lowers ionized Ca2+ concentration
Acid base abnormalities and Ca2+?
what binds to what and what is the scenario for academia and alkalemia and free ionized Ca2+
alter the levels of ionized concentration by changing the fraction of Ca2+ bound to albumin…
Albumin is a protein that tends to have negative charges so it attracts Ca2+ and hydrogen.
so in acidemia you have a lot of hydrogen ions that are competing with the binding sites of calcium, so whenever we have acidemia we are going to expect an INCREASE in ionized calcium
if it’s alkalemia, you’ll have DECREASE Ionized free ca because more spots are available on the Albumin to bind to!
What 3 organs do calcium help regulate?
what 3 hormones?
bone, kidney, intestine
PTH, Vit D, Calcitonin (not a lot of evidence of calcitonin changing calcium homeostasis)
High PTH levels stimulate and/or inhibit which of the following processes to return plasma calcium levels towards normal.
Stimulate bone resorption, leading to release of calcium into the plasma
Where in the renal tubule do you reabsorb calcium?
Distal convoluted tubule and ascending loop of Henle
What is the overall goal of calcium homeostasis?
maintain an ECF concentration of 10mg/dL
what is the most active form of vitamin D?
where is it acting mostly?
1,25-dihydroxycholecalciferol
also called 1,25-vitamin D
intestine (only one acting on the intestine for Ca absorption)
Bone resorption
vitamin D is increasing ca/p uptake in the kidney
Ingestion of 1000mg of Ca, what happens through the intestine?
a portion is going to be absorbed through Vitamin D!
So PTH is increasing the absorption of calcium through Vitamin D
there is also a bit secreted back into the intestine too!
With regards to the bone, what happens for remodeling for Ca2+?
PTH and Vitamin D are going to increase bone resorption (breakdown)
Calcitonin inhibits bone resorption and favors deposition.
What happens on the kidney?
know the differences!!
SUPER IMPORTANT
PTH are going to be causing reabsorption of Ca2+ and the secretion of Phosphate!
Vitamin D is going to be causing the increase of absorption of phosphate and calcium
Phosphate:
how is it related to Ca?
Phosphate, how is it regulated?
where is phosphate stored?
Phosphate –> the Extracellular concentration of Phosphate is inversely related to free ionized calcium (because if you elevate phosphate you decrease the level of free ionized because it binds to it)
same hormones are involved, but it’s regulated at less of an impact
mostly in bone, but whatever is in plasma: 85% is ionized, 10% protein bound, 6% complexed to cations.
Where is PTH secreted? (include cell type)
how many parathyroid glands do we have?
by chief cells in the parathyroid gland.
4 or 5
What is PTH hormone wise?
how does it become PTH?
what’s different between this and insulin?
how big is PTH?
what’s the biologically active part?
peptide hormone similar to insulin.. there’s a cleavage of a preprohormone to pro hormone, its cleaved again to PTH.
Insulin is cleaved and insulin and polypeptide C is released with it… PTH is cleaved into PTH.
85 AA long, but only 1-34 of them are active and they’re located at the N terminal
what stimulates PTH secretion?
what does PTH do?
low plasma Ca2+
increase it
how do the chief cells of the parathyroid gland sensing high levels of calcium? where are they also found?
what happens when there’s high levels of calcium?
what about 1,25 Vitamin D?why is the active form repressing PTH?
what is PTH doing for Vitamin D?
the CaSR (Calcium sensor receptor) –> in the kidney!
this is going to monitor the ECF Ca.. when we have high calcium levels, there will be a repression on the expression and secretion of PTH (inhibits PTH gene) (this is going to happen through Gi or inhibition of Gq)
Vitamin D is going to be inhibiting PTH Gene and it’s going to be promoting the synthesis and expression of CaSR.
PTH is needed for the generation of the active form of vitamin D… so if there’s active form of Vitamin D around, that means there’s a negative feedback.
PTH is up regulating 1-alpha-hydroxylase, which is found in the kidney.. which will allow the vitamin D to be made into the most active form of vitamin D.
If we have chronic hypercalcemia, what’s going to happen to PTH? (include synthesis, storage, breakdown, and release)
lower synthesis and lower storage of PTH, increasing breakdown of PTH and release of inactive PTH fragment into the circulation.
Chronic Hypocalcemia, what’s going to happen to PTH (include synth, storage, and clinical manifestations)
increased synthesis, increased storage, and hyperplasia of parathyroid glands
this is also called secondary hyperparathyroidism
Magnesium and PTH?
exception??
Mg is next to calcium on the periodic table to gives off the same effect
high magnesium = low PTH secretion
low magnesium = high PTH secretion
very very low mg inhibits PTH release we need Mg for normal CaSR functioning–> alcoholics
alcoholics = low magnesium
PTH on G protein linked receptor? where is it found?
where is it not found and why?
increased cAMP levels in a patient, where is that coming from?
binding of PTH to the PTH-receptor is dependent on a Gs that will lead to the activation of adenyl cyclase –> more cAMP
PLACES THAT ARE DIRECTLY MODIFIED BY PTH… this happens in bone, and the kidney tubule
not on the intestine because that’s being modulated by vitamin D, which is being acted on by PTH
coming from the binding of PTH to the receptor
Other than PTH, what other element can activate the PTH receptor?
PTH related Peptide
low plasma calcium
1) first responder
2) what happens on the bone (1 thing)
3) what happens on the kidney (3 things)
4) what happens on the intestine
5) overall what is the result
1) PTH secretion up
2) increased bone resorption
3) lower phosphate reabsorption (shoving into urine), increased ca2+ reabsorption, increased urinary cAMP
4) increased ca2+ absorption via Vitamin D
5) Plasma calcium raised to normal
why will PTH increase urinary cAMP on the kidney?
Binding of PTH to the urinary kidney is going to create more cAMP levels to do it’s job, but it’ll go into the urine too.
What is the term for lowering phosphate reabsorption (into the urine)?
Phosphaturia
PTH creates vitamin D how? where?
increases the expression of 1-a-hydroxylase in the kidney!… that is the enzyme that increases the conversion to the active form of vitamin D
What does vitamin D do?
what do these do things that it increases do in turn?
even though vitamin d is acting to do this, what’s opposing it and what’s the net effect?
where does it act?
increases both Ca2+ and Phosphate plasma concentration
if you increase Ca and Pi combined is a net bone creation
PTH! it’s going against it to bone resorption and that’s the overall net effect
intestine, kidneys, bone
How is vitamin D activated?
how is this activation process regulated?
it needs to be hydroxylated (2 times) to an active metabolite via 1-a-hydroxylase –> this is regulated by negative feedback mechanisms
What kind of hormone is vitamin D?
how does vitamin D bind to its receptor? what is this receptor composed of?
what binds to this receptor?
What happens once the vitamin D is bound?
lipid soluble, steroid hormone.
VDR is a dimer with retinoid Vitamin D receptor (RXR).. binds similarly like thyroid hormone, but since its a steroid hormone it goes into the nucleus to have this done!
25-vitamin d, or 1,25vitamin D but the most active and the one that binds most preferably is 1,25..
it finds the segment that it needs to go on for synthesis/suppression and does either depending on the end goal.
7 dehydrocholesterol is the starter for vitamin D synthesis.. explain the rest of the pathway
include the enzymes
what part can we get from the diet?
what is the main circulating form. what kind of activity does it have?
where is the conversion to the active form happening?
7-dehydrocholesterol + UV light on the skin –>
Cholecalciferol (which can also come from the diet) –>
in the liver it is hydroxylated to 25-hydroxyl-cholecalciferol –> this circulates in the body until it gets to the kidney (super low activity!!)
the kidney then changes it to either the active form or the inactive form
the active form = 1,25-dihydroxycholecalciferol (created by 1a-hydroxylase in the renal proximal tubule)
or the inactive form 24,25 dihydroxycholecalciferol (by 24-hydroxylase)
What up regulates 1a-hydroxylase activity? (3 things)
Low calcium, high PTH, low phosphate concentrations
more Vitamin D active form will bring higher concentrations of Phosphate in, higher calcium in, and high PTH is a trigger for it too saying we need help
of all the vitamin d molecules, what is the highest circulating molecule?
25-hydroxycholecalciferol (even though its low activity)
What creates the active form of vitamin D (region of the body)
What up regulates the production of 1a-hydroxylase?
what inhibits this gene?
what about 1,25 dihydroxy vitamin D? it upregulates one thing and down regulates one thing
at the Proximal tubule of the kidney
we have PTH acting a Gs pathway to increase cAMP which will up regulate CYP1a gene (gene encodes 1a-hydroxylase
high levels of calcium is going to stimulate the CaSR which represses the expression of this gene
we have enough vitamin D generated, this is the active form, so it’ll come into the cell and shut down the cyp1a-gene (creating 1a-hydroxylase).. it’s going to UPREGULATE 24 hydroxylase, which will help create the INACTIVE form of vitamin D.
Where are PTH receptors located on the bone? why is this weird?
short term action of PTH?
Long term?
on the osteoblasts!! (not osteoclasts).. which is weird
weird due to it’s short term effect which is for osteoblast formation.
short term = bone formation (via DIRECT action on the osteoblast)
bone resorption! (indirect action on osteoclasts mediated by cytokines RELEASED FROM THE OSTEOBLAST)
what does Vitamin D do synergistically with PTH on bones?
stimulate osteoclast activity and bone resorption
Explain the long term action of PTH on osteoblasts
what are the indirect actions of the osteoblast (3 things it makes)
what is the main thing that osteoblasts make and what does it do?
you have osteoblast with receptor of PTH
PTH leads to the generation of Monocyte Colony Stimulating Factor (M-CSF), RANK ligand, and IL-6
MCSF is important because it leads to the differentiation of osteoclast stem cells –> differentiates into mononuclear osteoclasts!
mononuclear osteoclasts which have ONE NUCLEUS (proosteoclasts) will then become Osteoclasts.. which are MULTINUCLEATED, which resorb bone.
what does RANK ligand do?
what competes with it when we want to stop resorption? where does this molecule come from?
it’s leads to bone resorption.
it’s the primary mediator of osteoclast formation –> to continue differentiation into multinucleated osteoclasts (final form)
when we want to stop bone resorption, we have this mimic called OPG (it’s a decoy receptor) that’s competing with the RANK receptor for the RANK ligand. when RANK ligand binds to OPG it’ll shut down the resorption signal.
it is produced by osteoblasts as a decoy for RANKL
What is the action of PTH and Vitamin D on RANKL and OPG?
PTH –> increases bone resorption so increases RANKL, downregulates OPG
Vitamin D increases RANKL as well.
mechanism of action on PTH on the kidney:
1) where is this happening?
2) main goal of PTH on the kidney again?
what’s so different about the kidney with regards to its signaling?
what does end up doing?
Proximal Tubule
PTH is going to increase the absorption of calcium and lead to the secretion of phosphate.
PTH binds to Receptor (on the blood side), and through Gs increases cAMP, which IN THIS CASE is going to depress phosphorylation and inactivation of the Na/Phosphate Transporter (on the ureter side)
PTH is inhibiting the Na/Phosphate Transporter which causes Phosphate to not go into the blood.
How does the vitamin D work on the kidney?
increases Ca2+ and Pi reabsorption
What’s happening with vitamin D in the intestine?
What’s being synthesized to help move ca? what does this do? (2 functions)
how does calcium come into the intestinal cell?
what two ways does it go out into the blood?
we’re going to have that whenever we have low Calcium levels, we activate vitamin D, which leads to the protein synthesis transporter, leading to the absorption of calcium through calbindin creation and other stuff.V
itamin D is going to go into the cell and modulate transcription.
Calbindin forms kind of a shuttle to bring calcium from the luminal to the intracellular and to the basolateral side. It also is associated with keeping the intracellular calcium in check (buffering)
It comes into the intracellular compartment through TRPV6!
Na/Ca transporter that uses the electrochemical gradient of sodium to shove out Ca to the blood
Ca/H+ ATPase –> Calcium is coming to the blood again (reabsorption)
What are the actions of Calcitonin?
what does it do to osteoclasts?
where are the receptors expressed on?
what role does it have on chronic regulation of plasma ca?
lowers blood calcium and phosphate concentrations by inhibiting bone resorption
lowers the activity and number of osteoclasts
osteoclasts
no role in chronic regulation of plasma
What happens if you have a thyroidectomy and the levels of calcitonin and calcium levels?
what about a thyroid tumor?
lower calcitonin but no effect in Ca2+ metabolism
increase calcitonin but no effect on Ca2+ metabolism
What is Primary Hyperparathyroidism?
what do patients excrete tons of?
what happens on bone? kidneys? Intestines?
it’s coming from a parathyroid adenoma!
it’s secreting high levels of PTH!
Pi, cAMP, Ca2+
increasing resorption of Ca and Pi released into the blood… increasing Ca2+ reabsorption, increasing Pi excretion in urine, increasing Ca2+ absorption in the intestine through higher levels of Vitamin D
What is a Ca2+-Oxalate stone?
what do patients present with?
patients get this with primary hyperparathyroidism
Stone, Bones, and Groans
stone from excessive calcium
bones from resorption problems
groans from constipation (high Ca = constipation)
Primary hyperparathyroidism:
PTH
Ca2+
Pi
Vitamin D
High
High
Low
High
What is secondary hyperparathyroidism?
what can cause this? (2 things)
elevated PTH is secondary to low [Ca2+] in the blood.
kidney disease –> no formation of Vitamin D, not good excretion or absorption
vitamin D deficiency –> can’t uptake calcium then, so you’re deficient.
Secondary Hyperparathyroidism
PTH, Ca2+, Pi, Vitamin D
for both renal failure and vitamin D deficiency
what’s the weird one?
renal failure: up, down, up, down
vitamin d: up, down, down, down
in renal failure, kidney can’t excrete phosphate so it’s higher
in Vitamin D deficiency, it won’t be able to absorb phosphate like it’s supposed to.. so you’ll have it lower
Hypoparathyroidism causes what? what happens to calcium and phosphate
causes?
low PTH,
so low levels of calcium because PTH isn’t acting
PTH usually increases Pi excretion in the kidney, but it can’t do anything now without PTH so Pi is up!… hyperphosphatemia
surgery to the parathyroid, autoimmune diseases
What’s the treatment of Hypoparathyroidism?
active form of vitamin D, oral Ca2+ supplement
hypoparathyroidism and
PTH, Ca, Pi, Vitamin D
low, low, high, low
What is Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a)
Normally PTH will bind to the PTH receptor which activates Gs and then that increases adenyl cyclase which then increases cAMP on the bone and kidney.
the deficit in this dense is the Gs –> so no cAMP and so we are not leading to the function of PTH.
What do we see in Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a)?
what symptoms?
we have a deficit in the receptor, but not in PTH.. so PTH is going to try and increase and increase and increase
but PTH isn’t working so lower Ca2+, high Pi, low Vitamin D.
short stature, short neck, short metatarsals/carpals, etc
Humoral hypercalcemia of malignancy?
what’s to note about this?
what is this similar to despite PTH and Vitamin D levels?
PTHrP (PTH related peptide) is a peptide produced by tumors with close homology in the N-terminal to PTH. so it’s competing with PTH!
it’s still stimulating reabsorption because that’s what PTHrP is doing, we just don’t see as high of PTH.
Vitamin D in this case is decreased somehow!
Primary Hyperparathyroidism
Humoral hypercalcemia of malignancy:
PTH
Ca
Pi
Vitamin D
down
up
down
down
Familial hypocalciuric hypercalcemia?
PTH? Ca? Urine Ca? P? Vitamin D?
autosomal dominant disorder
mutation in the CaSR in the parathyroid gland.. the sensor isn’t working so your system is not detecting high levels of calcium to shut down. so you have decreased sensitivity to the calcium levels.
PTH - normal or high (no information is going to PTH)
Ca - high
urine Ca - low (PTH is normal so it’s really not doing much)
P - normal
vitamin D - normal
Rickets-Osteomalacia?
what is it caused by? (3 things)
what is in kids? what do you see?
adults?
impaired Vitamin D metabolism through deficiency (diet) or a resistance
can’t synthesize active vitamin D through absence of 1a-hydroxylase or mutations affecting the vitamin D receptor
Children = rickets, epiphyseal plates haven’t been sealed so insufficient amount of Ca2+ and Phosphate can’t mineralize bones. bending of bones.
adults = osteomalacia = new bone fails to mineralize.
Rickets type 1 or 2?
1 = lower 1-alpha-hydroxylase
2= low vitamin D receptor (resistance to vitamin D)
both lead to vitamin D deficiency
What kind of parathyroidism is rickets/osteomalacia?
PTH Ca P Urine Vitamin D Bone
secondary!
higher normal or lower lower high phosphate in urine, high cAMP in urine low vitamin D increased resorption
Osteoporosis?
more common in who and why?
decrease in bone mass associated with age.
much more common decrease in females –> loss of estrogen at menopause!
estrogen has bone formation properties!
treatment of osteoporosis? (4 things)
anabolic therapy of PTH, short term, not long term that way bone growth is predominating!
Estrogen
RANKL inhibitors.. protective characteristics!
Calcitonin (kind of)
when we have hypocalcemia, PTH is secreted followed by rapid and slow responses.. what are the rapid responses?
what about the slow response?
what are the responses from these two responses?
what does that do?
increase in 1a-hydroxylase
increase in bone resorption
increase in ca absorption and pi excretion in the kidney
creating Vitamin D active from that 1a-hydroxylase.. this is a slow process that is helping out with bone resorption and increasing ca by the small intestine.
increases blood ca, resulting in negative feedback of PTH=
