Calcium and Magnesium Physio and Disorders Flashcards
Where is most calcium in your body?
In bone, but most of it (99%) isn’t accessible.
Is calcium more in ECF or ICF?
ECF. Calcium is normally kept very very low in the cytosol.
Why is 40% of plasma Ca++ not ultrafilterable?
Because it’s bound to proteins.
What percentage of plasma Ca++ is in the free ionized (biologically active) form?
50%
40% is protein bound, 10% is in complexes with anions like citrate, lactate, phosphate etc.
What effect does low serum albumin have on Ca++ levels?
It reduces total serum Ca++, but the free ionized fraction is relatively unaffected (so it won’t cause hypocalcemia symptoms.
Since labs usually measure total Ca++ (unless you ask for free Ca++), how do you correct that value when albumin is low?
Corrected serum Ca++ = serum Ca + 0.8*(4 - albumin)
Normal albumin is 4, so if albumin is normal, corrected value won’t be different.
How does acid-base balance affect free Ca++ levels?
Acidemia liberates Ca++ from albumin -> increased free Ca++.
Alkalemia -> more Ca++ bound to albumin -> decreased free Ca++.
(Acidosis can mask total Ca++ depletion)
If you were to link intestinal absorption, bone, and kidney Ca+ handling to one most important regulatory molecule each, what would you pick?
GI absorption: Vitamin D.
Bone: PTH
Renal Ca++ handling: CaSR
PTH’s effect on calcium?
Ca++’s effect on PTH?
PTH raises plasma Ca++.
High Ca++ suppresses PTH.
2 important locations of calcium sensing receptor (CaSR)?
Parathyroids: mediates PTH suppression.
Renal tubules.
What effect does Ca++ binding CaSR in the renal tubules?
Ca++ binding CaSR inhibits Ca++ reabsorption in the loop of Henle.
3 activities of PTH on Ca++? (2 target organs)
Bone -> Ca++ reabsorption via osteoclasts.
Kidney -> Ca++ reabsorption, Vit D activation
In what form in Vit D stored in the body?
25-OH-D, aka. calcidiol
What is the active form of Vit D?
1,25-(OH)2-D, aka calcitriol.
2 stimuli for activation of 25-OH-D to 1,25-(OH)2-D?
High PTH.
Low phosphate.
4 sites of action of calcitriol (1,25-(OH)2-D)?
Intestine -> increase Ca++ absorption.
Parathyroids -> PTH suppression.
Kidney -> increased Ca++ reabsorption.
Bone -> increased bone resorption, potentiates PTH.
Most electrolytes (Na, K, PO4, H+) accumulate in kidney failure, but not so for Ca++. Why?
Kidney failure -> impaired activation of calcidiol to calcitriol.
When calcitriol is deficient, intestinal absorption is impaired enough to cause hypocalcemia.
What cation’s reabsorption locations in the nephron does that of Ca++ resemble?
Na+
Most reabsorption occurs in the proximal tubule, but fine tuning is done distally.
Most important way Ca++ is reabsorbed in the proximal tubule?
Paracellular passive transport via solvent drag and diffusion.
How does volume / total Na+ affect Ca++ reabsorption?
Low volume / Na+ -> increased Ca++ reabsorption.
High volume / Na+ -> increased Ca++ excretion (calciuria).
What drives Ca++ reabsorption in the thick ascending limb? What generates this gradient?
Positive charge in the lumen generated by the activity of NKCC2 and ROMK.
How is Ca++ reabsorption in the thick ascending limb regulated?
High Ca++ binds CaSR -> inhibition of NKCC2 and ROMK (like a loop diuretic) -> reduced Ca++ absorption.
How is Mg++ reabsorption in the think ascending limb regulated?
Exactly like Ca++. Mg++ binds CaSR -> inhibition of NKCC2 and ROMK -> loss of + charge in lumen -> reduced Ca++, Mg++, K+, etc. reabsorption.
Normal serum Ca++?
8.8 - 10.3 mg/dL
not necessary to memorize for the exam… but good to know…
Of our 3 Ca+ regulating organs (intestine, bone, kidney), which is least likely to be the primary cause of hypercalcemia?
Kidney. Kidney failure would cause impaired Ca++ excretion, but impaired Vit D activation would have the greater effect.
Effects of hypercalcemia?
Often asymptomatic.
Sometimes vague symptoms like constipation, nausea fatigue.
When more severe: neuro, renal, and cardiac problems.
Cardiac manifestations of hypercalemia?
Shortened Q-T interval.
When more extreme -> V fib.
4 renal manifestations of hypercalcemia?
Polyuria (nephrogenic diabetes insipidus).
Natriuresis (NKCC2 inhibition).
Nephrolithiasis.
Renal insufficiency (acute or chronic)
2 reasons why hypercalcemia causes polyuria?
High Ca++ acts like a loop diuretic via CaSR.
High Ca++ inhibits the insertion of Aquaporin-2 in the collection duct membrane, blocking ADH activity.
How can hypercalcemia cause acute renal insufficiency?
Diuretic effects of hypercalcemia -> volume contraction.
How can hypercalcemia cause chronic renal insufficiency?
Nephrocalcinosis. (Ca deposits in renal parenchyma)
3 main causes of hypercalcemia?
Primary hyperPTH.
Malignancy
Vit D intoxication
2 mechanisms by which malignancy can cause hyperPTH?
Osteolytic metastases.
Humorally mediated.
3 humoral mediators of hypercalcemia of malignancy?
PTH-related peptide (PTH-rP).
Lymphotoxin (multiple factors).
Calcitriol.
2 ways people can get Vit D levels so high that it causes hypercalcemia?
Iatrogenic (Vit D given for renal failure or hypoPTH). Granulomatous disease (activated macrophages release calcitriol).
Clinically, how are hypercalcemia caused by hyperPTH and hypercalcemia of malignancy easy to distinguish?
HyperPTH is often asymptomatic to mild and slowly progressing (years).
People with hypercalcemia of malignancy are very sick, and it develops relatively quickly.
How would you definitively distinguish hyperPTH from hypercalcemia of malignancy?
Measure PTH.
If PTH is high or inappropriately normal in hypercalcemia, it’s primary hyperPTH.
3 goals of teatment of hypercalcemia?
How is each achieved?
Enhance renal Ca++ excretion - Give istonic saline +/- loop diuretic (depending on volume status).
Suppress bone resorption - bisphosphonates, calcitonin.
Remove Ca++ from blood - hemodialysis.
Most common cause of hypocalcemia?
Hypoalbuminemia (but this doesn’t reflect a real deficit in ionized Ca++).
2 mechanisms of true hypocalcemia?
Impaired mobilization from bone (something wrong with PTH/ Vit D).
Tissue or intravascular complexation of Ca.
(Note that impaired GI absorption / renal loss are absent here. Ostensibly, reabsorption from bone should be able to compensate for those and prevent hypocalemia unless an above problem is present.)
What musculoskeletal signs can alert you to danger hypercalcemia?
Tetany
(can be elicited with Trousseau’s sign: ischemia causes carpopedal spasm)
(also Chvosktek’s sign: tapping on facial nerve -> spasm)
What does hypocalcemia look like on ECG?
Prolonged QT interval.
Neuro effects of hypocalcemia?
Depression, altered mental status.
5 causes of hypoPTH?
Hypomagnesemia. Post-surgical. Autoimmune. Infiltrative (e.g. hemochromatosis). Congenital (eg. DiGeorge's)
Why does hypomagnesemia cause hypocalcemia refractory to Ca++ repletion?
Mild hypoMg++ stimulates PTH release, but severe hypoMg++ actually impairs PTH release.
What’s the mechanism of hypocalcemia in autoimmune polyglandular syndrome type I?
Activating autoantibodies to CaSR.
causes a variety of problems, including pernicious anemia and predisposition to mucocutaneuous candidiasis
What do you measure to determine if someone is Vit D deficient (in terms of intake /production)?
25-OH-D, aka calcidiol
The storage form.
Intestinal malabsorption can be cause of Vit D deficiency.
That makes sense.
3 features of Vit D deficiency other that hypocalemia?
Osteomalacia, secondary (appropriate) hyperPTH, hypophosphatemia.
4 ways to cause hypocalcemia with complexation?
Hyperphosphatemia.
Hungry bone syndrome (recall: reduction in PTH post parathyroidectomy),
Citrated blood products.
Acute pancreatitis.
4 things to check first when you see hypocalcemia?
Make sure it’s real (check albumin, ionized Ca++).
Serum Mg++.
Serum PO4.
BUN and creatinine.
Treatment of acute hypocalcemia?
IV Ca++
IV Mg++
Correct alkalosis if present (will free Ca++ from albumin).
Oral calcium and Vit D can be given for chronic hypocalcemia.
If a patient has renal disease, how do you give Vit D?
Calcitriol, as they won’t be able to activate calcidiol.
Does bone Mg buffer serum Mg?
Nope.
What’s unique about where in the neprhon most Mg++ is reabsorbed?
Only 10-15% is absorbed proximally.
60-70% is in loop of Henle.
Specific protein involved in Mg diffusion paracellularly?
Claudin 16 (encoded by paracellin-1)
Again, what does Mg++ absorption in the thick ascending limb depend upon?
Positive lumen potential generated by NKCC2 and ROMK.
Recall Mg regulates own absorption via CaSR -> inhibition of NKCC2 and ROMK.
Significance of hyperMg?
It’s not rare, but rarely significant.
Severe hyperMg is induced in the treatment of eclampsia.
What condition predisposes to hyperMg?
renal insufficiency
If hyperMg is severe, what can happen?
Neuromuscular problems: loss of reflexes, paralysis, stupor/coma.
Bradycardia/hypotension.
Hypocalcemia (due to inhibited PTH).
Heart block / cardiac arrest.
Treatment for hyperMg?
Stop giving Mg.
Saline and loop diuretic.
IV Ca++ (for neuro and cardiac effects).
Dialysis (for pts. with kidney failure)
There are lots of reasons for GI and renal loss of Mg.
True. Some things like proton pump inhibitors, acute pancreatitis are harder to remember.
But things like loop diuretics, diarrhea, hypercalemia, etc. make a lot of sense.
Some drugs cause renal Mg wasting.
It’s true. Look out for it.
If someone has hypoMg, what other electrolytes might be low?
K+ and Ca++
HypoMg tends to get less attention, but can it cause dangerous arrhthmias?
Yes, including long QT and Torsade de pointes.
What do neuromuscular symptoms of hypoMg resemble?
HypoCa++… including tetany / Chovstek’s and Trousseau’s signs.
If you’re not sure what’s causing hypoMg, what should you assess?
Fractional excretion.
I’m not going to memorize this formula… it’s on slide 76 if you need it.
Can serum Mg look normal… but there’s still Mg depletion?
Sure thing. Seen in diarrhea and alcohol-related hypoMg…. and it might be contributing to hypocalcemia.
Treatment of severe hypoMg?
IV Mg (but it’s inefficient due to CaSR stimulation)
Treatment for mild hypoMg?
Oral slowly absorbed substances (MgCl2, Mg-lactate).
Treat underlying disease (eg. amelioride for renal loss)
