SM 198a - Calcium and Phosphate Flashcards
FGF-23 will ___________ production of 1,25-OH2 Vitamin D3 (active) by [stimulating/inhibiting] __________________.
FGF-23 will decrease production of 1,25-OH2 Vitamin D3 (active) by inhibiting 25 alpha hydroxylase .
FGF-23 is secreted in response to too much serum phosphorous
What belongs in box E?
1,25-OH2-D3
The active form of vitamin D3
PTH upregulates 1 alpha hydroxylase activity -> more 1,25-OH2-D3 -> works to increase serum Ca2+
FGF23 inhibits 1 alpha hydroxylase activity -> less 1,25-OH2-D3 -> works to decrease serum Ca2+
Which enzyme belongs in box B?
Where does it act?
25 alpha-hydroxylase
Acts in the liver to covert cholecalciferol to 25-hydroxy-D3
What is claudin 16?
What deos it do?
Claudin 16 is a protein between the epithelial cells of the thick ascending limb of the loop of Henle
It allows for paracellular reabsorption of Ca2+ down its concentration and electrical gradient
(The lumen in thick ascending loop is positively charged due to the action of ROMK)
Which 3 enzymes are important for the synthesis of active vitamin D?
- 25 alpha hydroxylase (liver)
- Cholecalciferol -> 25-OH-D3
- 24 alpha hydroxylase (renal PCT cell)
- 25-OH-D3 -> inactive 24,25-OH2-D3
- 25 alpha hydroxylase (renal PCT cell)
- 25-OH-D3 -> active 1,25-OH2-D3
Also: UV light to convert 7-dehydrocholesterol to cholecalciferol
What belongs in box A?
7-dehydrocholesterol
This is the starting material for active vitamin D synthesis
Which enzyme belongs in box C?
24 alpha-hydroxelase
Converts 25-OH-D3 to the inactive 24,25-hydroxy-D3
This enzyme is upregulated when serum calcium levels are too high
What is the effect of PTH on Ca2+ reabsorption in the intsetine?
PTH has no direct effect on Ca2+ reabsorption in the intestine
Vitamin D (1,25 Hydroxy-D3) is the primary regulator of Ca2+ reabsorption in the intestine
However, PTH secreted in response to low Ca2+ increases activation of vitamin D in the kidney, thus indirectly increaseing Ca2+ reabsorption in the intestine
When you are re-feeding a patient with starvation, why would you need to give phosphorus as well?
Feeding -> increased metabolism -> increased PO4 demand
This uses up the phosphorous that is available in the blood
How does FGF-23 affect phosphorous homeostasis?
FGF-23 promotes the excretion of phosphorous to lower serum phosphorous levels
What factors regulate PTH secretion from the chief cells of the parathryroid gland?
- Promote PTH synthesis and release
- Low Ca2+ levels
- Inhibit PTH synthesis and release
- High Ca2+ levels
- High vitamin D
- FGF-23
- Phosphorous
What belongs in box B?
Cholecalciferol
Created when UV light acts on 7-dehydrocholesterol in the skin
Dietary sources of vitamin D can also enter the vitamin D synthesis pathway here
What is the effect of gastric acid on Ca2+ reabsorption?
Gastric acid enhances Ca2+ absorption
Low PTH is a physiological response to ____________
Low PTH is a physiological response to high Ca2+
Describe Ca2+ reabsorption in the thick ascending limb of the loop of Henle
- K+/Na+/2Cl- cotransporter (NKCC2) in the apical membrane gets these ions from the lumen to the epithelial cell
- Na+/K+ ATPase on the basolateral membrane moves Na+ into the interstitium and K+ into the epithelial cell – electrically neutral
- Chloride channels on the basolateral membrane transport Cl- ions are into the insterstitium
- ROMK on the apical membrane pumps K+ back into the lumen -> positive charge in the lumen
- This positive charge drives paracellular Ca2+ reabsorption through claudin 16
Which enzyme belongs in box A?
No enzymes!
UV light hits the skin and converts 7-dehydrocholesterol to colecalciferol (pre-vitamin D)
Which enzyme blelongs in box D?
1-alpha hydroxylase
Converts 25-OH-D3 to the active 1,25-hydroxy-D3
This enzyme is upregulated when serum Ca2+ levels are low
Increased bone mineralization will result in [high/low] phosphate in the blood
Increased bone mineralization will result in low phosphate in the blood
Bone mineralization moves phosphate from serum -> bone
What is the most common cause of hypocalcemia?
Low PTH
- Usually post-surgical
- Thyroidectomy, parathyroidectomy, radial neck dissection
- Autoimmune or genetic possible
Where in the kidney tubule is the majority of phosphorous reabsorbed?
Proximal convluted tubule
Describe the clinical manifestation of hyposphosphatemia
- Neuro
- Lethergy
- Paraesthesia
- Siezure
- Cardiac
- Arrhythima
- Hypotension
- Hematologic
- Hemolysis
- Skeletal
- Bone demineralization (to increase serum phosphate)
What is the active form of vitamin D?
1,25 Hydroxy-D3
______ is the single most important factor that affects PTH secretion
Serum Ca2+ level is the single most important factor that affects PTH secretion
- High Serum Ca2+
- Ca2+ binds to CaSR on the chief cells of the parathyroid gland
- Inhibits PTH production and secretion
- Low Serum Ca2+
- Ca2+ does not bind to CaSR
- PTH is produced and released from the chief cells of the parathyroid gland
What stimulus promotes the secretion of FGF-23?
What is the effect?
FGF-23 is secreted in response to too much serum phosphorous
FGF-23 -> Decreased Vitamin D synthesis -> decreased phosphorous absorption from the intestine
In primary hyperparathyroidism, would you expect the following serum levels to be high or low?
Calcium:
Phosphorous:
1,25-OH2-D3:
- Calcium: High
- Increased renal reabsorption
- Increased active vitamin D -> increased intestinal reabsorption
- Increased resorption from bone
- Phosphorous: Low
- Decreased renal reabsorption
- 1,25-OH2-D3: Varies
- Increased vitamin D synthesis in the kidney, but some studies have shown that primary hyperparathyroidism is associated with vitamin D deficiency
What is the role of CaSR on Ca2+ reabsorption in the distal convoluted tuble?
In the DCT, CaSR is located on the apical membrane
- CaSR senses increased Ca2+ in the urine
- If Ca2+ in the urine is high, CaSR stimulates increased reabsorption of PO4 to prevent kidney stone formation
What factors affect GI absorption of calcium?
- Increase absorption
-
Vitamin D (1,25-OH2-D3)
- PTH indirectly, by increasing Vitamin D syntheisis
- Gastric acid
-
Vitamin D (1,25-OH2-D3)
- Decrease abosrption
-
Billiary and pancratic insufficiency
- Ca2+ binds to unabsorbed fat and is excreted
-
Serum hypercalcemia
- Via CaSR, which binds to Ca2+ and inhibits the effects of vitamin D
-
Billiary and pancratic insufficiency
What is a “pseudo-state” as it refers to an electrolyte?
Low total electrolyte, but no change in the level of its active form
Ex: Low albumin causes a pseudo-decrease in calcium. The amount of protein-bound Ca2+ decreases which decreases total Ca2+, but the levels of ionized (active) Ca2+ remain the same
What is the effect of biliary and pancreatic insufficiency on Ca2+ absorption in the gut?
Biliary and pancreatic insufficiency -> decreased Ca2+ absorption in the gut
- Biliary and pancreatic insufficiency -> trouble absorbing fat
- Ca2+ loves fat. If there is more fat in the intestine, Ca2+ will bind to it and be excreted.
- Therefore, Ca2+ will not be absorbed
How does tumor lysis lead to hypocalcemia?
Would you expect high or low PTH?
- Cell lysis -> PO4 release
- PO4 in the blod binds to Ca2+, creating a Ca2+/PO4 product
- This decreases the amount of ionized Ca2+ in the blood
You would expect high PTH, since the body is “seeing” low Ca2+ levels due to low ionized Ca2+
High PTH = physiological response to low Ca2+
Which forms of Ca2+ are filtered in the glomerulus?
Ionized Ca2+ only
Describe the management of hypercalcemia
-
Improve excretion
- Saline fluids
- Loop diuretics
- Dialysis (last resort)
-
Decrease production
- Give calcitonin and bisphosphates
- Treat the underlying cause
What is the effect of PTH on reabsorption of Ca2+ in the kidney?
PTH is secreted when Ca2+ is low, and workds to increase reabsorption of Ca2+ in the thick ascending limb of the loop of Henle
- PTH increases Claudin 16 production
- Ca2+ must pass through Claudin 16 in order to be reabsobed paracellularly in the thick ascending limb
Describe the process of intestinal absorption of phosphorous
Transcellular transport:
-
NaPi-IIb: Lumen -> intestinal cell
Absorbs HPO4- with 2 Na+ - Unknown channel: Intestinal cell -> interstitium
There is also a paracellular pathway
How does immobilization affect Ca2+ homeostasis?
Immobilization impairs bone formation
- Physical, mechanical load is required to promote bone formation
- Immobilization can result in hypercalcemia
- Less Ca2+ moving into bone = more remains in the serum
A 50 year old male with chronic kidney disease stage 5, DM type 2, and hypertension presents for routine follow-up with his nephrologist. Labs reveal markedly elevated serum phosphorous. All of the following interventions would help treat his hyperphosphatemia except:
- Low phosphorous diet
- Low sodium diet
- Vitamin D supplementation
- Dietary phosphorous binders
c. Vitamin D supplementation
What substance regulates Calcium absoprtion in the intestine?
1,25 Hydroxy-D3 (The active form of vitamin D)
- If Ca2+ levels are high, Ca2+ binds to the Ca2+ sensing receptor (CaSR)
- CaSR downregulates 1,25 Hydroxy-D3 synthesis
- Decreased 1,25 Hydroxy-D3 -> decreased Ca2+ absorption
- If Ca2+ levels are low, CaSR does not downregulate 1,25 Hydroxy-D3 synthesis
- The presence of 1,25 Hydroxy-D3 -> Ca2+ absorption
How do antacids affect Ca2+ absorption?
Gastric acid enhances Ca2+ absorption
Antacids decrease gastric acid, and therefore decrease Ca2+ absorption
Which form of Ca2+ is biologically active?
Ionized Ca2+
What belongs in box D?
24,25-OH2-D3
This is a waste product, created when the body does not need more active vitamin D3 (ex: when calcium levels are normal or high)
What is the effect of CaSR activation on the epithelial cells of the thick ascending loop?
CaSR binds to Ca2+ when serum Ca2+ levels are elevated
Binding of Ca2+ to CaSR downregulates Ca2+ reabsorption:
- Decreased ROMK activity
- -> Decreased liminal positivity
- -> Decreased driving force for Ca2+ reabsorption
- Decreased Claudin 16 production
- -> Fewer channels for paracellular Ca2+ reabsorption in the thick ascending limb of the loop of Henle
Describe the clinical manifestation of hyperphosphatemia
- Symptoms of hypocalcemia
- Phosphorous binds to Ca2+, thus reducing the amount of ionized Ca2+
- Bone fractures, stomach cramps, dysrhythmia, irritability, anxiety, carpopedal spasm, siezure
- Itching
- Metastatic calcifications
Describe the management of hypophosphatemia
Eat high-phosphate foods!
- Replete phosphorous
- Eat high-phosphate foods
- IV if severe or patient cannot eat
- Treat underlying cause
What are the expected levels for a patient with hyperparathyroidism?
Calcium:
Phosphorous:
Calcium: high
Phosphorous: low
PTH = increased renal Ca2+ reabsorption and phosphorous excretion
What is Milk alkali syndrome?
Milk consumption -> loss of regulation of GI Ca2+ absorption -> hypercalcemia
Describe the process of phosphorous reabsorption in the renal tubules
- NaPi-IIa and NaPi-IIc: Lumen -> Tubular epithelial cell
- Unknown channel: Tubular epithelial cell -> interstitium
Which diuretics are known for causing hypercalcemia?
Describe the mechanism
Thiazides
- Decrease Na+ reabsorption in the distal convoluted tubule (Inhibit Na+/Cl- cotransporter)
- -> Decreased intracellular Na+
- -> Increased Na+/Ca2+ antiporter activity on the basolateral membrane; Na+ into the cell, Ca2+ into the interstitium
- -> Decreased intracellular Ca2+ promotes reabosrption of Ca2+ from the lumen via TRPV5
What factors regulate phosphorous reabsorption in the renal tubules?
-
FGF-23
- Acts on FGFR-1 and Klotho to promote the excretion of phosphorous
-
PTH
- Promotes the excretion of phosphorous by preventing reabsorption
What is the effect of vitamin D on PTH in the parathyroid cell?
When Vitamin D reaches a threshold level in the serum, it binds to VDR in the chief cell and inhibits production of PTH.
-> decreased GI absorption, renal reabsorption of Vitamin D
How would low albumin affect the calcium homeostasis in the blood
Low albumin would decrease the protein-bound calcium, thus lowering total calcium levels in the body
However, there would be no change in ionized Ca2+, and therefore no difference in biological funciton
This means you have to determine low serum Ca2+ levels in the context of albumin
What is Calbindin? What does it do?
Calbindin is a protein produced in intestinal epithelial cells
Within the cell, it moves Ca2+ from the luminal side to the serum side
FGF-23 plays a very important role in the regulation of vitamin D and PTH.
How?
FGF-23 is the key negative feedback mechanism -
basically FGF-23 is yelling
“CALM DOWN WE HAVE ENOUGH SERUM CA2+”
-
Vitamin D
- Increases FGF-23 expression in bone
- -> FGF-23 acts on the kidney to decease vitamin D synthesis
-
PTH
- Increases FGF-23 express
- -> FGF-23 acts on teh parathyroid to decrease PTH
What factors affect HPO4- absorption in the intestine?
Vitamin D (1,25 Hydroxy-D3) increases abosrption of HPO4- in the intestine
How does vitamin D affect Ca2+ homeostasis?
Increased levels of active vitamin D (1,25 Hydroxy-D3) increase Ca2+ absorption in the intestinal epithelium
- 1,25 Hydroxy-D3 binds to the Vitamin D Receptor (VDR)
-
VDR acts on the nucleus to increase production of TRPV6, Calbindin, Ca2+ ATPase or Na+/Ca2+
- All of these proteins are required for Ca2+ reabsorption in the intestine
Describe the management of hyperphosphatemia
- Low phosphorous diet (this is hard)
- Give Phosphorous binders
- Bind to and excrete dietary phosphorous
- Common for ESRD and dialysis patients
- Hemodialysis
- Treat underlying cause
Why is it important to take Ca2+ supplements with food?
Gastric acid enhances Ca2+ absorption in the gut
Food increases gastric acid secretion, which increases Ca2+ absorption
What are the clinical manifestations of hypocalcemia?
- Neuro
- Anxiety, irritability, tetany, twitching, carpopedal spasm, seizure
- Bone
- Fractures
- GI
- Cramps
- Cardiac
- Prolonged QT, dysrhythmia
- Blood
- Hypercoagulable state
What is the biggest Ca2+ reservoir in the body?
Bone
What is the effect of calcitonin on serum Ca2+?
Calcitonin lowers serum Ca2+
- Increases renal excretion
- Decreases bond resorption
What is the effect of estrogen on Ca2+ homeostasis
Estrogen decreases bond resorption
It decreases the movement of Ca2+ from bone to serum
What is the DDx for hypercalcemia with low PTH?
Low PTH is a normal response to high Ca2+ - the CaSR system is working to suppress PTH secretion
So, what could be causing persistent high Ca2+ in the setting of low PTH?
- If PTHrP is elevated, malignancy is likely
- If 1,25-OH2-D3 is elevated, tumor or granulomatous disorder
- Produces 25 alpha hydroxylase that activates vitamin D
- If 25-OH-D3 is elevated, vitamin D intake is too high
- If Vitamin D and PTHrP are normal, consider myeloma, Vitamin A, or thyrotropin
Where in the intestine is Ca2+ absorbed?
Duodenum and jejunum
What percentage of filtered Ca2+ is reabsorbed by the kidney tubule?
In which segments of the kidney tubule?
95-99% of filtered Ca2+ is reabsorbed
- Proximal convoluted tubule: Most (50-60%) Ca2+ is reabsorbed (Ca2+ follows Na+)
- Thick ascending limb: 20-25%
- Distal convoluted tuble: 5-10%
- Collecting tubule = fine tuning
This is not super different from general reabsorption in the kidney tubules
What belongs in box C?
25-OH-D3
Created when 25 alpha hydroxylase acts on cholecalciferol in the liver
25-OH-D3 binds to D-binding protein, is exported to the blood and absorbed by a proximal tubular cell (via megalin mediated endocytosis), where it is either activated to 1,25-OH2-D3 or turned into the waste product 24,25-OH2-D3, depending on the needs of the body
What is the most common cause of hyperphosphatemia?
Decreased kidney function resulting in impaired phosphorous excretion
Exacerbated by…
- Excess intake
- Cellular breakdown (cells contain a lot of phosphorous)
What factors regulate Ca2+ reabsorption in the DCT?
- Vitamin D (1,25 Hydroxy-D3)
- Increases Ca2+ reabsorption
- PTH
- Increases Ca2+ reabsorption
- CaSR on the luminal epithelium
- Senses increased Ca2+ in the filtrate
- If Ca2+ is high, CaSR will derease reabsorption of PO4
- This will protect against stone formation
How does hypoerphosphatemia lead to hypocalcemia?
Hyperphosphatemia
- -> Increased FGF-23 + Reduced 1,25-OH2-D3
- Increased FGF-23 further reduces 1,25-OH2-D3 synthesis
- Low active vitamin D -> Hypocalcemia
Decreased bone mineralization will result in [high/low] phosphate in the blood
Decreased bone mineralization will result in high phosphate in the blood
Bone mineralization moves phosphate from serum -> bone
What are the major causes of hypercalcemia?
- Parathyroid mediated (too much PTH)
-
Non-parathyroid mediated
- Malignancy
- Vitamin D intoxication
- Chronic granulomatous disease
-
Medications
- Thiazides
- Lithium
- Misc
- Hyperthyroid
- Immobilization
- Milk alkali syndrome
What is the effect of androgens (testosterone) on Ca2+ homeostasis?
Testosterone = increased bone formation
Promotes the movement of Ca2+ from the serum to the bone
What is secondary hypothyroidism?
What are the most common causes?
Secondary hypothyroidism = hypocalcemia in the setting of high PTH
(PTH is not doing its job increasing serum Ca2+ - think of this like reduced effect of PTH, rather than low PTH)
Causes:
- Vitamin D deficiency
- Loss of Ca2+ from the circulation
- Ca2+ is being used up by something else
- Drugs or medications that affect Ca2+ binding
- Disorders of Mg2+ metabolism: Low Mg2+ leads to low Ca2+
- Mg2+ is preferentially reabsorbed, resulting in decreased Ca2+ reabsorption
Describe the clinical presentation of hypercalcemia
-
Painful bones
- Weakness, bone pain, osteopenia
-
Renal stones
- Polyuria, nephrolithiasis, AKI
-
Abdominal groans
- Nausea, vomiting, constipation, pancreatitis
-
Psychic moans
- Confusion, fatigue
- Heart
- Bradycardia, short QT
Describe the management of hypocalcemia
- Ca2+ supplementation
- Thiazide diuretics
- Increase Ca2+ reabsorption
- Treat the underlying cause
- Replenish Mg2+ or vitamin D if necessary
- Stop drugs that are binding Ca2+
Is the lumen in thick ascending limb of the loop of Henle positively charged or negatively charged?
Why?
Positively charged
- The K+/Na+/2Cl- cotransporter (NKCC2) in the apical membrane gets these ions from the lumen to the epithelial cell is electrically neutral, but ROMK in the apical membrane pumps K+ into the lumen to recycle it
- This creates a positively charged lumen
- Creates an electrical gradient that pushes Ca2+ through claudin 16 into the interstitium (Drives Ca2+ reabsorption)
How do bisphosphates treat hypercalcemia?
Bisphosphates inhibit osteoclast-mediated bone resorption
(Prevents mobilization of Ca2+ from bone -> serum)
How do PTH and FGF-23 affect 1-alpha-hydroxylase activity?
-
PTH stimulates 1 alpha hydroxylase
- Works to create more active vitamin D3
- -> Works to increase serum Ca2+
-
FGF-23 inhibits 1 alpha hydroxylase
- Works to decrease active vitamin D3
- Increased synthesis of the waste product
24,25-OH2-D3
- Increased synthesis of the waste product
- -> Decrease serum Ca2+
*
- Works to decrease active vitamin D3
If serum phosphorous levels are high, how would you expect FGF-23 levels to change?
High serum phosphorous
- -> Increased FGF-23
- -> decreased reabsorption of phosphorous
- -> Increased excretion of phosphorous
- -> decreased reabsorption of phosphorous
What percentage of Ca2+ absorption in the intestine is through paracellular transport?
5%
Describe the process of Ca2+ reabsorption in the DCT
Very similar to Ca2+ reabsorption in the intestine
Difference = PTH has a direct effect on Ca2+ reabsorption in the kidney
- TRPV5: Lumen -> Epithelial cell
- Calbindin: Luminal side of cell -> basolateral side of cell
-
Na+/Ca2+ exchanger and Ca2+ ATPase: Basolateral side of the cell -> interstitium
- Both are active transport mechanisms
What drives Ca2+ reabsorption in the thick ascending limb?
Positive charge in the lumen
- Created by K+ secretion through ROMK
- This pushes Ca2+ reabsorption via paracellular transport
Where in the body is biologically active phosphorous in the body found?
In the blood
What is the typical picture of a chronic kidney disease patient?
- Phosphate:
- FGF23:
- Active Vitamin D:
- Calcium:
- Phosphate: high
- FGF23: high
- Active Vitamin D: low
- Calcium: low
PTH will ___________ production of 1,25-OH2 Vitamin D3 (active) by [stimulating/inhibiting] __________________.
PTH will increase production of 1,25-OH2 Vitamin D3 (active) by stimulating 25 alpha hydroxylase
What are the functions of phosphorous in the body?
- Phosphorous is a part of ATP; we need it for energy and metabolism
- It is super important for cell function
- Helps RBCs carry oxygen
- Minor role in blood buffering system for acid-base balance
- Structural component of bone and teeth when combined with Ca2+
How does 25-OH-D3 get into the proximal tubular cells of the kidney?
Megalin-mediated endocytosis
25-OH-D3 bound to D binding protein in the blood is not freely filtered through the glomerular filtration barrier
Describe the process of Calcium absorption in the intestine
- TRPV6: Lumen -> intestinal epithelial cell
-
Calbindin: Luminal side of cell -> serum side of the cell via
(still stays inside of the intestinal epithelial cell) -
Ca2+ ATPase or Na+/Ca2+ exchange:
Serum side of the cell -> serum- Both are active transpor mechanisms; Intracellular [Ca2+] is lower than extracellular [Ca2+]
What is the effect of PTH on Ca2+ homeostasis?
PTH is the major regulator of Ca2+ movement in and out of the bones
- Hypocalcemia -> PTH secretion -> increased Ca2+ resorption from the bones -> Ca2+ levels return to normal
- Hypercalcemia -> Decreased PTH secretion -> more bone formation
How does chronic kidney disease affect phosphorous homeostasis?
How does this effect Vitamin D, Calcium, PTH, and FGF23?
Chronic kidney disease ->
- Reduced renal phosphate clearance
- -> Hyperphosphatemia
- -> Increased FGF-23 + Decreased 1,25-OH2-D3 synthesis
- Increased FGF-23 further reduces 1,25-OH2-D3 synthesis
- -> Reduced renal Ca2+ reabsorption and GI absorption
- -> Hypocalcemia
- -> Increased PTH in response to hypocalcemia, but without increase in Ca2+ levels
- = secondary hyperparathyroidism
