SM 198 Flashcards
Is calcium widely or narrowly distributed in the body?
Calcium is widely distributed in the body
What type of serum calcium is relevant and regulated?
Ionized Calcium is regulated because it is biologically active
What is the largest reservoir of Calcium in the body?
Bone
Where is dietary calcium primarily absorbed?
The Duodenum and Jejunum of the Small Intestine via active and passive processes, dependent on gastric acid
Is dietary calcium absorption a passive or active process?
Both, and it’s gastric acid dependent
How might Omeprazole effect Calcium absorption?
Omeprazole is a PPI, which lowers acid secretion into the stomach, and therefore lowers Calcium absorption due to the loss of stomach acid
Does Vitamin D increase or decrease intestinal phosphorus absorption?
Vitamin D increases intestinal phosphorus absorption
Where and how does Calcium reabsorption occur in the Kidneys?
In the Kidneys, Calcium is reabsorbed passively in the PCT and actively in the TALH and DCT
What factors enhance renal reabsorption of Calcium?
PTH and Vit D increase reabsorption of Calcium
How does Calcium regulate PTH production?
The Calcium Sensing Receptor binds excess serum Calcium when Calcium levels are high, and reduces GI absorption of Calcium as well as renal reabsorption of Calcium, while also reducing PTH production
What is the largest reservoir of Calcium?
Bone
How and when is Calcium extracted from bones?
Calcium is resorped from bone when Calcium levels are low through the action of PTH
What is the largest reservoir of Phosphate?
Bone (also biggest reservoir of Calcium)
Where is the major source of Phosphorous reabsorption?
The Jejunum of the Small Intestine
What channel in the GI tract is involved in Phosphorous transport?
The NaPi 2b channel, which actively transporters Phosphorus in a Sodium dependent manner
How does Vit D effect GI absorption of phosphorus?
Vit D enhances GI absorption of Phosphorus
Where is most phosphorus reabsorbed in the Kidney?
Most phosphorus is reabsorbed in the PCT
What channels mediate phosphorus reabsorption int he PCT?
The NaPi 2a and 2c channels mediate active reabsorption of phosphorus
What decreases renal reabsorption of Phosphorus?
PTH and FGF23
What produces FGF23?
Bone
What are the effects of PTH on reneal reabsorption of Phosphorus?
PTH decreases renal reabsorption of Phosphorus
What are the effects of FGF23 on renal reabsorption of Phosphorus?
FGF23 decreases renal reabsorption of Phosphorus
“FGF is a FosFate inhibitor”
What hormone is measured to broadly classify the types of hypercalcemia?
PTH - in theory, PTH should be low in the setting of high Calcium, but Hypercalcemia can result in the setting of both high and low PTH
Does high or low PTH cause hypercalcemia?
Both - Hypercalcemia can broadly be categorized as high or low PTH Hypercalcemia
What test should be done if Hypercalcemia is found in the setting of high PTH?
Measure the Urine Calcium/Creatinine;
If low, Familial Hypocalcuric Hypercalcemia
If high, Primary Hyperparathyroidism
What should be done if Hypercalcemia is found in the setting of low PTH?
Measure PTHrP and Vitamin D levels
What is PTHrP?
An analog of PTH often secreted by tumors that mimics the effects of PTH and causes hypercalcemia
What does a high PTHrP suggest?
Cancer
What can cause high levels of Vitamin D and Hypercalcemia?
Sarcoid (proliferation of monocytes which can activate Vit D via 1-hydroxylase)
Granulomatous disorders
What should be done if elevated Vitamin D precursors are found in the setting of Hypercalcemia?
Suggests too much dietary intake of Vitamin D, so restrict Vitamin D consumption
What can cause hypocalcemia?
Loop diuretics and Hypomagnesemia
What serum level indicates hyperphosphatemia?
Serum phosphate > 4.5 mg/dL
What could cause true hyperphosphatemia in the setting of normal kidney function?
Hypoparathyroidism (elevated PTH)
FGF23 deficiency
Bisphosphonates
What could cause false hyperphosphatemia in the setting of normal kidney function?
Paraproteinemia
Hyperlipidemia
Amphotericin B
What could cause hyperphosphatemia in the setting of decreased kidney function?
Excessive phosphate intake, rhabdomyolysis, hemolysis
What are bisphosphonates?
Bisphosphonates are a class of drugs that prevent the breakdown of bone and increase phosphate levels, potentially causing hyerphosphatemia
What could cause hypophosphatemia?
Shifts into cells, decreased intake, and renal loses
What factors regulate Calcium and Phosphate homeostasis?
PTH
Vitamin D
FGF23
Calcitonin
How does PTH effect bones and Calcium levels?
PTH promotes bone resorption, ie moving Calcium from bone to serum
How does PTH effect renal handling of Calcium?
PTH promotes renal reabsorption of Calcium
How does PTH effect bones and Phosphate levels?
PTH promotes bone resorption, ie moving Phosphate from bone to serum
How does PTH effect renal handling of Phosphate?
PTH inhibits renal reabsorption of Calcium
In what organ does PTH have the same effect on Phosphate and Calcium?
PTH promotes Phosphate and Calcium resorption in bone, raising serum levels of both
In what organ does PTH have opposing effects on Phosphate and Calcium?
PTH promotes Calcium reabsorption in the Kidneys to raise serum Calcium levels
PTH inhibits Phosphate reabsorption in the Kidneys to lower serum Phosphate levels
What is Calcitriol?
The man made active form of Vitamin D
What hormone promotes Ca and Phosphate reabsorption from the GI tract?
Calcitriol/Vitamin D
What effect does Vitamin D have on renal handling of Calcium?
Vitamin D promotes reabsorption of Calcium, raising serum levels
What effect does Vitamin D have on renal handling of Phosphate?
Vitamin D promotes reabsorption of Phosphate, raising serum levels
What effect does Calcitonin have on bone, Calcium, and Phosphate?
Calcitonin inhibits reabsorption of Calcium and Phosphate from bone, lowering serum Ca and Phosphate
What organ produces Calcitonin?
Calcitonin is produced by the Thyroid gland
What are common functions of Calcium?
Forms bones and teeth
Neurotransmission
Muscle contractility
Signaling
Normal calcium homeostasis involves absorbing 300mg/day from the GI tract and excreting 150mg/day - why?
Allows for fine tuning of Ca intake
What are the 3 forms of Calcium in blood?
Ionized Ca (biologically active)
Protein bound Ca
Ca complexed with Citrate/Bicarb/Phosphate
How does Alkalemia effect serum Calcium levels?
Alkalemia increases protein binding of Calcium, decreasing the ionized Calcium fraction, without altering total Calcium
Symptoms of Hypocalcemia occur because ionized Calcium decreases
How does changes in Albumin change the bound fraction of Calcium?
Increasing Albumin levels results in more Ca bound to Albumin, but does not change the ionized Calcium
Symptoms of Hypocalcemia do not occur
Why do nephrotic syndromes not change the serum Calcium?
Nephrotic syndromes lose the charge barrier at the Glomerulus and therefore lose Albumin + bound Ca, but the serum Ca remains unchanged
Symptoms of Hypocalcemia do not occur
How does Vitamin D regulate Calcium absorption in the Intestine?
In the Intestine:
Vitamin D binds the Vitamin D Receptor on the basolateral membrane and forms a complex
Complex translocates to Nucleus
Expression of Na/Ca exchanger and Ca ATPase on Apical side facing blood is increased
How does the Ca sensing receptor effect Vitamin D signaling in the intestine?
Ca Sensing Receptor detects hypercalcemia and inhibits Vitamin D signaling
How does Calcium get absorbed in the intestine?
Calcium from the diet binds the TRPV6 receptor on the Apical membrane
Calcium binds the Calbindin protein and gets moved from the Apical membrane to the Basolateral membrane
Calcium is then exported out of the intestinal cell via the Na/Ca exchanger and the Ca ATPase
How does Calcium get exported out of the intestine?
Calcium is released into the blood via the Na/Ca exchanger and Ca ATPase on the Apical membrane
Why does it take ATP to move Calcium out of the intestine and into the blood?
Calcium concentrations are higher in the blood than the intestinal cell, so it takes ATP to pump it out
Does paracellular absorption play a role in Calcium uptake in the intestine?
Yes, but a very small role (5%)
Why does Calcium intake saturate in the intestine?
The Ca Sensing Protein detects hypercalcemia and inhibits Vit D as well as further Ca absorption
Where in the intestine does Calcium get absorbed?
Duodenum and Jejunum
How does pancreatic insufficiency effect Calcium absorption?
Pancreatic insufficiency leads to Fat in the blood which binds Calcium and lowers serum Calcium
How do Androgens and Estrogens effect Bone?
Androgens and Estrogens have the same effect on bone but with different mechanisms, ultimately lowering serum Ca
How do Androgens and Estrogens differ on Bone?
Androgens promote Bone formation, Estrogens inhibit Bone Resorption
Both lower Serum Ca
How does immobilization effect bones?
Immobilization decreases bone formation and raises serum Ca
How much Calcium is excreted?
Very little (3%)
How does Hypocalcemia effect the TALH?
Hypocalcemia stimulates PTH
PTH stimulates Claudin permeability
Ca and Mg paracellular reabsorption through Claudin increases
Hypocalemia is then corrected
What does PTH do in the TALH?
PTH stimulates Claudin and increases paracellular transport of Ca and Mg
How does the CaSR mediate the TALH?
CaSR binds Calcium under Hypercalcemia
CaSR inhibits Claudin and ROMK
Loss of K leak through ROMK = no positive lumen to drive Ca/Mg paracellular transport
CaSR makes Claudin less permeable = inhibit Ca/MG paracellular transport
CaSR results in decreased paracellular transport of Ca and Mg
Is the NKCC channel electrogenic?
No, 2 positive charges from Na and K are cancelled out by 2 negative charges from Cl
What effect does PTH have on the GI Tract?
None, PTH only effects the Kidney and Bones
How does PTH regulate the DCT?
PTH binds to it’s receptor and increases Calbindin activity and Calcium uptake
How does the CaSR effect the DCT?
The CaSR binds Calcium and activates the Np2a phosphate transporter to promote Phosphate reabsorption
How does FGF23 regulate phosphate reabsorption in the kidney?
FGF23 binds the FGF Receptor on the apical membrane
FGF23 bound to FGFR interacts with Klotho on the membrane
FGF + FGFR + Klotho inhibits NaPi-mediated absorption of phosphate
Describe the pathway for Vitamin D activation?
7-dehydrocholesterol from the body is converted to pre-vitamin D3 by UV light
Pre-vitamin D3 is converted into 25 OH Vit D3 in the liver by 25 alpha hydroxylase
25 OH Vit D3 is bound to the D-binding protein and crosses the Glomerulus
PCT cells take up DBP + 25 Vit D3 via Absorptive Endocytosis
25 Vit D3 is either activated by 1 alpha Hydroxylase or inactivated by 24 alpha Hydroxylase
How does Vit D3 cross the glomerular membrane?
Vit D3 bound to D binding protein crosses the Glomerulus and is taken up by PCT cells via absorptive endocytosis
Which PCT enzyme activates Vit D3?
1 alpha Hydroxylase
Which PCT enzyme inactivates Vit D3?
24 alpha Hydroxylase
What effect does PTH have on the PCT?
PTH activates 1 alpha Hydroxylase to promote Vit D activation
What effect does FGF23 have on PCT?
FGF23 inhibits 1 alpha Hydroxylase to inhibit Vit D activation
What is the major negative regulator of PTH?
Calcium, due to signaling via the CaSR on the Parathyroid Chief Cell
Why does Vitamin D negatively regulate PTH?
PTH activates Vitamin D so Vitamin D negatively regulates PTH in a form of negative feedback
What class of medication can cause hypercalcemia?
Thiazides
How does hypercalcemia present?
Bones, Stones, Groans, Thrones, Moans
Which class of diuretics should be used to treat hypercalcemia?
Loop diuretics, which promote calcium loss
Which type of fluid should be used to treat hypercalcemia?
Sodium containing IV fluids
How can a lack of sunglight lead to hypocalcemia?
Vitamin D deficiency, due to lack of UV light to activate 7-dehydrocholesterol
How does tumor lysis syndrome cause hypocalcemia?
Dying tumor cells release phosphate which sequesters calcium in the serum and causes hypocalcemia
What are clinical manifestations of hypocalcemia?
Tetany, twitches, bone fractures, hypocoagulable state
What is chvosteks sign?
Tapping the facial nerve results in a contraction of the facial muscle
How should hypocalcemia be treated?
Supplement calcium and thiazide diuretics?
How can urine sedimentation reveal whether or not elevated protein is causing false hyperphosphatemia?
Spinning down the urine will show a larger protein band, suggesting that hyperphosphatemia is due to more protein and not true hyperphosphatemia
What ionic changes accompany CKD?
Increased phosphate
Increased PTH
Increased FGF23
Decreased Ca
What disorders can cause metastatic calcifications?
Hypercalcemia
Hyperphosphatemia
What are symptoms of hyperphosphatemia?
Itching and metastatic calcifications
How should hyperphosphatemia be managed?
Phosphorous binders like Sevelamer
Low phosphorous diet
Why does refeeding after a period of malnutrition lead to hypophosphatemia?
Food intake results in ATP production which uses up the phosphate in the blood, causing hypophosphatemia
What are the clinical manifestations of hypophosphatemia?
Arrhythmias, lethargy, bone demineralization
How should hypophosphatemia be treated?
IV phosphate or food, treat underlying cause
