Lecture 22: Calcium and Magnesium, physiology and disorder Flashcards
What are the crucial functions of calcium?
- essential co-factor in enzymatic processes such as coagulation and mitosis
- Intracellular second messenger
- Skeletal support
- used for muscular contraction and tone
What is the distribution of calcium in the body?
99% of body calcium is in the skeleton
1% is in the ECF
Of the 99% in skeleton, only 1% of that 99% is exchangeable with blood upon hormonal stimuli
ECF Ca = 1-3 mM
ICF Ca = <10^-3 mM
-thus there is a very favorable gradient for calcium to flow into the cell
Calcium inside of the cell is kept VERY LOW, and even when calcium does come into the cell due to the steep gradient, Ca is sequestered by binding proteins, the mitochondria, by SRC ATPase, etc
What is the distribution of calcium in the blood?
40% of blood calcium is bound to protein (albumin)
10% is part of circulating complexes (with phosphate, citrate, etc)
50% is in free ionized form
-this is the active fraction
The complex and free ionized (60%) are filtered in kidney, whereas those bound to protein are not
What consists of the biologically active portion of calcium? Significance?
Only the FREE ionized fraction
Significance: If you have low serum albumin, you reduce the total serum calcium, but not the ionized fraction
-thus you have low total serum calcium but is irrelevant since there is no change in free calcium in serum
Corrected serum Ca = serum calcium + 0.8 * (4 – serum albumin)
Free ionized calcium can be measured directly by ion sensitive electrode
What is the acid-base effect on free ionized and protein bound calcium?
Hydrogen ion competes with calcium for albumin binding
In acidemia, less calcium is bound to albumin and more is in free ionized fraction
Thus higher the pH, the more calcium is bound to albumin, the less calcium is freely floating, because there is less H+ to compete for albumin binding sites
What is a likely causes of hypocalcemia if patient’s total serum calcium is reduced but shows no signs of hypocalcemia?
Patients = acidotic, so less calcium bound to albumin but more calcium in serum to protect from effects of hypocalcemia
How does alkalosis lead to hypocalcemia symptoms?
Alkalosis = more calcium bound to albumin = less free ionized calcium = hypocalcium
How is calcium steady-state regulated in the body?
- Intestine
- regulated by Vit D
- Kidney
- regulated by CaSR
- Bone
- regulated by PTH
What are the hormones/factors that regulate calcium metabolism?
- Vitamin D regulates absorption of Ca from blood
- more vitamin D = more Ca absorption
- PTH regulates Ca resorption from the bone
- more PTH = more Ca in serum due to breakdown of bone
- Calcium levels in lumen of nephron regulate excretion by acting on calcium sensing receptors (CaSR)
What are the characteristics of PTH?
Binds to cell surface receptors in bone and kidney
Secretion is regulated by plasma calcium concentration
More calcium = less PTH
Negative feedback loop
Has the following function:
1. increases osteoclastic resorption
-acts directly on osteoblasts to activate osteoclasts
2. increases calcium reabsorption
3. stimulates 1,25 vit D synthesis
-thus indirectly affects GI uptake
4. decreases phosphate absorption/increases phosphate excretion
What are the characteristics of the calcium sensing receptors?
- located in parathyroid and LoH/DCT of nephron
- in the parathyroid, activation if CaSR will downregulate PTH synthesis
- in the kidney, activation of CaSR will suppress calcium transport in LoH/DCT
What is PTH related peptide (PTHrP)?
A peptide that is usually locally acting for cartilage differentiation and lactation
But if PTHrP levels are high enough, it can have similar actions to PTH
What is calcidiol?
25 OH vitamin D
Storage and plasma metabolite
What is calcitriol?
1,25 OH vitamin D
The most active form of vitamin D
What does one measure to determine vitamin D levels?
Calcidiol levels, since this is the storage unit
Vitamin D is a very ambiguous term: Can be the parent vitamin D (ergocalciferol/cholecalciferol) Calcidiol (storage of vit D) Calcitriol = active form of vit D So three forms
How is vitamin D made?
- dietary vitamin D
- UV light + 7 dehydrocholesterol in the skin
Usually is 25 hydroxyation takes place in the liver
1,25 hydroxylation occurs in the kidney
What are the actions of calcitriol?
- increases calcium and phosphate absorption
- increases activity of luminalintestinal calcium channel (TRPV6), albindin and basolateral active calcium transporters
- suppresses PTH transcription
- binds to vitamin D receptor in nucleus of parathyroid cells
- increases renal tubular calcium reabsorption
- Increases osteoblast/osteoclast activity
- potentiates PTH action
In kidney failure, most electrolytes accumulate because they cannot be secreted (example is hypernatremia with volume overload). Why then do you get HYPOcalcemia in kidney failure?
Because calcium levels are regulated at the level of the GI tract
In kidney failure, calcitriol and intestinal calcium absorption fall, therefore making the serum calcium fall as well
How is calcium handled along the nephron?
Parallels that of Na reabsorption
65% of Ca reabsorbed in PCT
25% of Ca reabsorbed in TAL
How is calcium reabsorbed in the proximal tubule?
- passive paracellular transport
- Solvent drag
- some calcium channels in the apical membrane
Calcium is basically reabsorbed with sodium
What is the significance of salt and calcium reabsorption being so closely linked?
Salt loading = calciuric (you want to excrete more salt and hence excrete more calcium)
Salt depletion = anticalciuric (because you need to reabsorb more salt and hence more Ca)
What is the only ion that is NOT primarily reabsorbed in the proximal tubule?
Magnesium
Only 15-25% of filtered magnesium is rebsorbed in prox tubule
How is calcium uptake regulated in the TAL?
Calcium will bind to CaSR and INHIBIT NKCC2 tranporters as well as ROMK transporters,
Thereby inhibiting sodium reuptake
This makes sense because if you have too much calcium in tubule, you would want to excrete more, and the only way you can secrete Ca is if you secrete Na concomitantly too
Thus calcium is natriuretic as well
Mechanism: lowers level of cAMP to decrease NKCC2 transporter
Thus CaSR and PTH have OPPOSITE effects on TAL, since CaSR downregulates cAMP and thus NKCC2 where as PTH upregulates cAMP and thus NKCC2
How is calcium reabsorbed in the TAL?
Usually the NKCC2 channel creates a positive lumen gradient that allows Ca and Mg to diffuse paracellularly into the blood
How does magnesium affect calcium transport?
Since magnesium and calcium are reabsorbed in the same way, Mg can also activate CaSR to decrease cAMP and shut down NKCC2
Thus hypermagnesemia = effects of hypercalcemia = natriuresis, calciuresis and magniuresis
Magnesium also binds the CaSR in the parathyroid as well!!
What are the characteristics of normal calcium levels?
- normal Ca serum = 8.8-10.3 mg/dL
- Serum Ca is lower in woman, so women with 10 mg/dL of Ca may have hypercalcemia
- 7-12 mg/dL fluctuation = asymptomatic
What are the three possible causes of hypercalcemia?
- increased absorption from intestine
- Increased resorption from bone
- Decreased excretion by the kidney
Normally these processes are balanced
Usually are multiple mechanisms for hypercalcemia (individual kidney excretion defect for example doesn’t usually cause hypercalcemia because of gut regulation)
-kidney only plays a maintenance role in hypercalcemia in order to maintain steady state
What are the clinical manifestations of hypercalcemia?
- Asymptomatic (80% of cases, usually during screening)
- Non-specific symptoms (typically calcium over 12 mg/dL)
- Neuropsychiatric
- fatigue, vomiting, depression, altered mental status
- Renal
- cardiac
- short QT, sensitivity to digitalis intoxication, Ventricular fibrillation
What are the renal manifestations of hypercalcemia?
- Polyuria (nephrogenic diabetes insipidus)
- Natriuresis
- Nephrolithiasis
- Renal insufficiency
i. acute and reversible = ECF volume contraction and glomerular vasoconstriction
ii. Chronic and irreversible = nephrocalcinosis
What does hypercalcemia do to the collecting duct?
Inhibits ADH action on collecting duct, and thus downregulates aquaporin activity
Thus you get polyuria
This is important in order to protect against kidney stones, so you want to get more calcium out of body through increasing urine output
How does hypercalcemia lead to acute renal failure?
Due to volume contraction (remember natriuresis is taking place as well)
Also due to calcium-mediated mesangial contraction in glomeruli as well, which reduces GFR
If hypercalcemia persists, calcium deposits in renal parenchyma can cause irreversible kidney damage
-nephrocalcinosis
What is nephrocalcinosis?
Calcium deposits in renal parenchyma
Can cause irreversible kidney damage
Different from nephrolithiasis, because kidney stones are in the renal collecting system rather than in the parenchyma itself
Nephrolithiasis does not cause renal failure, just pain
IRREVERSIBLE DAMAGE
What are the causes of hypercalcemia?
- Primary hyperparathyroidism
- Malignancy
- Vitamin D
- Milk-alkali syndrome (Calcium-alkali syndrome as Goldfarb calls it)
- Thiazides
- Immobilization
What are the key characteristics of primary hyperparathyroidism?
Most common cause of hypercalcemia
Presents on incidental discovery usually
Cause of kidney stones, osteoporosis and kidney injury
Patient demographic: 45+ yo and female
What are the characteristics of hypercalcemia due to malignancy?
- prevalence = 10-20% of patients with cancer
- Most common cancers include
i. breast
ii. lung
iii. multiple myeloma - Hypercalcemia tends to be severe and short duration
- Osteolytic metastases or humorally mediated
Bad prognostic sign
What are the humoral mediators of hypercalcemia of malignancy?
- PTH related peptide
- can be produced in carcinomas/lymphomas
- 80%-90% of patients
- Lymphotoxin
- found in multiple myeloma
- mediates bone resorption
- Calcitriol (which can be produced by hodgkins/non-Hodgkin’s lymphomas)
- too much absorption leads to hypercalcemia
What are the characteristics of vitamin D mediated hypercalcemia?
Vitamin D intoxication, usually iatrogenic
-used to treat renal failure or hypoparathyroidism
Granulomatous disease
i. unregulated production of calcitriol by macrophages
ii. Sarcoidosis, berylliosis, fungal diseases, TB
iii. Lymphoma
All of which increases calcitriol production
What is milk alkali syndrome?
Occurs in patients who take large amounts of calcium to treat osteoporosis
-can be exacerbated by concurrent administration of thiazides
Alkali diminishes renal calcium excretion by increasing TRPV5 activity in distal tubule
Goldfarb article said calcium and alkali (because patients now take calcium supplements)
What is the TRPV5?
Transient Receptor Potential Cation Channel subfamily 5
How do thiazides increase calcium reabsorption, especially since we learned that calcium and sodium reabsorption occurred together?
By blocking the Na/Cl symporter in DCT, sodium concentration within epithelial cells are decreased
Thus, since epithelial cells are decreased, Na/Ca antiporter on the basolateral membrane of distal tubule will pump more Na into the cell and more Ca back into the blood!
-very interesting
-this lowers intracellular Ca concentration so that more Ca can diffuse into the blood via TRPV5, Ca-selective channels
How does immobilization lead to hypercalcemia?
More bone resorption occurs in immobilized patient
Mechanism not discussed
What is the DDx of hypercalcemia?
Asymptomatic or minimally symptomatic
PTH assay = mainstay of diagnosis
Short duration, significant symptoms = malignancy
Low phosphate levels are expected since increased PTH/PTHrP is usually the primary cause
How do you know hypercalcemia is due to malignancy?
Low PTH serum
Usually PTH is increased
How do you know hypercalcemia is due to primary hyperparathyroidism?
Because PTH serum is normal or high
Normal PTH serum in hypercalcemia is ABNORMAL because calcium usually downregulates PTH levels, so you would expect PTH levels to be low
How does one treat hypercalcemia?
- Enhance renal Ca excretion
- Suppress osteoclastic bone resorption
- Remove Ca from blood
- hemodialysis
How does one enhance renal Ca excretion?
- isotonic saline with loop diuretic
2. correct volume contraction, suppress proximal tubule calcium transport
What type of diuretic do you not want to give to a hypercalcemic patient?
THIAZIDES!
Because of the mechanism described above
How does one suppress osteoclastic bone resorption?
- Bisphosphonates
2. Calcitonin
What is the most common cause of hypocalcemia? Significance?
Low albumin (but not true ionized hypocalcemia) Thus, always correct serum calcium for hypoalbuminemia or measure ionized calcium content
What are the mechanisms of true hypocalcemia?
- Impaired mobilization of Ca from bone
- implies a defect in PTH-vitamin D axis
- Tissue or intravascular complexation of Ca (binding to Ca inappropriately)
What are signs and symptoms of acute hypocalcemia?
- usually total calcium < 0.8 mmol/L
- Circumoral and acral paresthesias
- Tetany
- carpopedal spasm
- Chvostek’s sign (tap on facial nerve and you see twitch of lip)
- Trousseau’s signs (claw hand when you inflate blood pressure)
- seizures
- muscle stiffness and spasms
- Depression, altered mental status
- Prolonged QT interval on ECG
What are carpopedal spasms?
Spasms of hand and feet
What is tetany defined as?
When you get multiple responses to a single stimulus
What are circumoral and acral parathesias mean?
Circumoral = around mouth Acral = affecting limb or extremity (fingers, limbs or ears)
What is Chvostek’s sign?
When you tap on facial nerve and you see twitch of lip
What is Trousseau’s signs?
Claw hand when you inflate blood pressure cuff
Mechanism of claw hand is unknown
What are the causes of true hypocalcemia (not hypoalbuminemia)?
- hypoparathyroidism
- Vitamin D deficiency
- Magnesium deficiency
- Renal failure
- Calcium complexation
- Alkalosis (due to albumin binding competition with H and Ca)
- drugs like foscarnet, pentamidine
What are the causes of hypoparathyroidism?
- Hypomagnesemia
- Post-surgical (due to inadvertent parathyroidectomy from primary thyroidectomy)
- Autoimmune
- Infiltrative (hemochromatosis)
- Congenital/inherited (DiGeorge’s syndrome)
What are the characteristics of hypomagnesemia? Significance? What’s tricky about this?
Severe hypomagnesemia: Mg < 1 mg/dL
Mechanisms: impairs PTH release and PTH action on bone
Since hypomagnesemia, impairs PTH action, patient will be hypocalcemic if you don’t correct magnesium deficiency
Significance: must give magnesium with calcium in order to treat hypocalcemia
Tricky part: MILD hypomagnesemia actually STIMULATES PTH secretion
-only severe hypomagnesemia inhibits PTH secretion
What are the characteristics of autoimmune polyglandular syndrome type 1?
Familial triad of
1. Hypoparathyoridism
2. Adrenal insufficiency
3. Mucocutaneous candidiasis
Associated with gastric achlorhydria and pernicious anemia
There are autoantibodies that bind to CaSR, which will decrease level of PTH (since binding to CaSR activation is responsible for downregulating PTH)
Also increases Ca excretion
How does magnesium influence PTH activity?
- Hypermagnesemia leads to decreased PTH activity
- Mild Hypomagnesemia leads to increased PTH activity
- Severe Hypomagnesemia leads to decreased PTH activity
What is the definition of vitamin D deficiency?
High prevalence of deficiency 800 U = minimum 1. celiac disease 2. gastric bypass surgery 3. Crohn’s 4. Cystic fibrosis 5. Chronic pancreatitis Less absorption of vitamin D, a fat soluble vitamin
What are the features of hypocalcemia, vit D deficient patients?
- osteomalacia
- secondary hyperparathyroidism
- Hypophosphatemia
What are potential reasons for impaired vitamin D activation or action (production of calcitriol)?
- Renal failure
- caused by inhibition of 1-hydroxylase by phosphate
- due to reduced renal mass
- increased FGF-23
- hypoparathyroidism
- absence of PTH to convert calcidiol to calcitriol
What is VDDR?
Vitamin D dependent rickets
Two types:
Type 1 VDDR = 1-hydroxylase mutation so calcidiol can’t be converted to calcitriol
-can be treated with calcitriol supplements
Type 2 VDDR = mutation in vitamin D receptor so patients don’t respond to vitamin D
-cannot be treated with calcitriol supplements
How does calcium complexation contribute to hypocalcemia?
- Hyperophosphatemia
- phosphate binds calcium in the intestine
- suppresses activation of vitamin D
- stimulates osteoblast differentiation and bone formation in blood vessels!
- suppressses bone resorption
- can bind calcium to form Ca-PO4 deposits in soft tissue
- Hungry bone syndrome
- Citrated blood products
- large amounts of citrate will bind to calcium
- citrate is a preservative used in blood
- Acute pancreatitis
- leads to fat necrosis, which has calcium formed on top of it
What are the action of phosphate on calcium?
- stimulates osteoblast differentiation and bone formation in blood vessels!
- phosphate binds calcium in the intestine
- suppresses activation of vitamin D
- suppressses bone resorption
- can bind calcium to form Ca-PO4 deposits in soft tissue
What are potential causes of hyperphosphatemia?
- Chronic renal failure
- rhabdomyolysis, tumor lysis
- bowel prep for colonoscopy
How does one diagnose hypocalcemia?
- confirm true hypocalcemia by checking serum albumin
- check serum magnesium (if it’s low then hypocalcemia)
- serum phosphate
i. high in renal failure and hypoparathyroidism
ii. low in vitamin D deficiency - BUN and creatinine would be high in renal failure
- PTH levels
i. high in renal failure, vitamin D deficiency and pseudoparathyroidism (the guy never saw a case so we didn’t talk about it)
ii. Low in hypoparathyroidism - calcidiol and calcitriol levels
i. low calcidiol in vitamin D deficiency
ii. Low calcitriol in renal failure and hypoparathyroidism
How does one treat hypocalcemia?
- Tetany is a medical emergency
- Intravenous Ca/Mg
- correct alkalosis
- Chronic treatment = oral calcium and vitamin D
What are the physiological properties of magnesium?z
It is an “orphan” electrolyte because there is no hormone system to regulate it
Large Mg stores in bone, but bone Mg is not exchangeable and does not buffer changes in serum Mg
Intestinal absorption of Mg is not regulated so serum Mg tends to rise, not fall in renal failure
How is magnesium handled along the nephron?
70% filtered at glomerulus
10-15% reabsorbed proximally
60-70% reabsorbed at LoH
5-10% reabsorbed in distal tubule
How is magnesium transported in LoH?
Through paracellular diffusion in TAL
Increased NKCC2 activity = more positive lumen = more Mg diffuses (like Ca) in to blood
Mg regulates its own absorption by acting on LoH CaSR
Too much Mg will lead to more Mg excretion because it activates CaSR
**changes in Mg enhance or inhibit loop CALCIUM and SODIUM transport via the calcium receptor)
What is diffusion of Mg facilitated by?
Claudin 16, a tight junction protein
What are the characteristics of hypermagnesemia?
- Mild hypermagnesemia is common but not significant
2. Severe hypermagnesemia = very rare unless on labor floor for treatment of eclampsia and preeclampsia
How does one treat eclampsia and pre-eclampsia?
By administering a fuckload of magnesium
What are the causes of hypermagnesemia?
- Magnesium infusion for eclampsia/pre-eclampsia treatment
- renal insufficiency
- Oral ingestion
i. Epsom salts (for bad breath)
ii. cathartics (medication that accelerates defecation)
iii. nonabsorbable antacids - magnesium enemas
Avoid Mg administration in renal insufficiency!
What are the signs and symptoms of hypermagnesemia?
- Neuromuscular
i. loss of deep tendon reflexes
ii. somnolence during the day
iii. muscle paralysis - Cardiac
i. bradycardia and hypotension
ii. heart block
iii. cardiac arrest - Hypocalcemia due to inhibition of PTH (since magnesium acts on CaSR)
What is curare?
A poison from south America
MoA: inhibits nicotinic acetylcholine receptors found at neuromuscular junction
Thus can lead to asphyxiation due to paralysis of the diaphragm
Effects are similar to what magnesium does
How does on treat hypermagnesemia?
- cessation of Mg administration
- Saline infusion and loop diuretic
- IV calcium (to antagonize neuromuscular effects of magnesium)
- dialysis
What are the characteristics of hypomagnesemia?
More common than hypermagnesemia
Caused by:
i. GI losses
ii. Renal losses
What are the types of GI losses that lead to hypomagnesemia?
- diarrhea
- malabsorption
- gastric bypass surgery
- acute pancreatitis
- proton pump inhibitors
What are the types of renal losses that lead to hypomagnesemia?
- diuretics/nephrotoxins
- volume expansion (primary hyperaldo)
- alcohol
- uncontrolled diabetes
- Hypercalcemia
- Gitelman’s syndrome (familial renal Mg wasting)
How does hypercalcemia lead to Mg wasting?
Because increased calcium will lead to activation of CaSR in LoH which leads to less Mg reabsorption
What are the nephrotoxins that lead to renal Mg wasting?
- aminoglycoside antibiotics
- Cisplatinum
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- Pentamidine
- Antibodies to EGF receptor (chemotherapy)
What is calcineurin?
A protein Phosphatase
Activates T cells in the immune system
What are the signs and symptoms of hypomagnesemia?
- Chovstek’s and Trousseau’s sign
- anorexia
- delirium and coma
- hypokalemia
Hypomagnesemia causes renal K wasting, and K wasting causes magnesium wasting (former mechanism is unknown) - hypocalcemia in blood because so much calcium has be excreted in hypomagnesic state
-this does not contradict the fact that hypercalcemia can cause hypomagenesia, because in this case, it is the magnesium defect that leads to calcium defect, whereas in the other scenario, calcium defect leads to magnesium defect
What are the effects of hypomagnesium on the heart?
- potentiates arrhythmias
2. exacerbates torsade de pointes
What are the three causes of tetany?
- Hypocalcemia
- Hypomagnesemia
- Alkalosis (independent of its effect on ionized serum calcium)
How do you calculate measure fractional excretion?
Fraction Excretion of Mg = (urine magnesium * PCr)/(0.7 * Pmg * Urine creatinine)
Extrarenal loss = low fractional excretion
Renal loss = high fractional excretion
Most causes of hypomagnesemia are very clear however
How does one treat severe hypomagnesemia?
- IV magneseium for symptoms of tetany
2. IV is inefficient since 50% is excreted because calcium receptor is stimulated
How does one treat asymptomatic hypomagnesemia?
Slowly absorbed oral preparations
Treat underlying disease
What does post-AKI diuretic therapy mean?
Post acute kidney injury
Can cause hypomagnesemia
