Phosphate Physio and Disorders

Question 1

Normal plasma phosphate?

Answer 1

2.5 - 4.5 mg/dL

Question 2

It’s really hard to have a low-phosphate diet, but how might a person develop hypophosphatemia from low intake?

Answer 2

Starvation will cause hypophosphatemia (because it will still be lost via feces).

Question 3

Main 2 ways the body gets rid of phosphate?

Answer 3

Urine and feces.

But renal excretion is the part that gets turned up when extra phosphate is present.

Question 4

Effects of phosphate levels on bone?

Answer 4

High levels suppress bone resorption.

Low levels stimulate bone resorption.

Question 5

2 renal things that phosphate levels affect?

Answer 5

Vit D activation: High phosphate suppresses it, low levels stimulate it.
Calcium excretion: Low phosphate increases Ca++ excretion.

Question 6

Phosphate absorption in the proximal tubule is very similar to the absorption of what? How so?

Answer 6

Very similar to glucose, in that if the filtered load is beneath the maximum transport rate, it will be completely reabsorbed.
If the phosphate filtered load exceeds transport capacity, phosphate will start to appear in the urine. The excess is not absorbed at all.
(and like glucose, it’s cotransported with Na+)

Question 7

What are 3 major factors that regulate phosphate transport?

Answer 7

Dietary PO4 intake
PTH
FGF23

Question 8

What’s the transporter for phosphate reabsorption?

Answer 8

Na-PO3 cotransporter.

Question 9

How does PTH affect phosphate?

How does phosphate affect PTH release?

Answer 9

PTH decreases phosphate absorption (lowers the maximum transport rate), causing phosphaturia amd reduced serum PO4.

High plasma phosphate stimulates PTH release

Question 10

But wait, doesn’t PTH cause PO4 to be liberated from bone? Why does PTH lower PO4?

Answer 10

You’re right, PTH does PO4 liberation from bone. But the decreased absorption produces net decreased serum phosphate.

Question 11

If hypophosphatemia is caused by low intake, how will urine phosphate levels be?

Answer 11

They’ll be really low.

If they’re not, the kidney is participating in phosphate wasting.

Question 12

How will decreased PO4 intake promote its own intake?

Answer 12

Low PO4 promotes Vitamin D activation, which will lead to increased intestinal and renal reabsorption.

Question 13

Other than PTH, what’s a particularly important hormone that promotes PO4 excretion (i.e. inhibits renal PO4 absorption)?

Answer 13

FGF23

Question 14

What’s the receptor (or cofactor?) for FGF23?

Answer 14

Klotho

Trivia: Klotho knockout -> premature aging

Question 15

What affect does a carbohydrate load (e.g. glucose infusion) have on serum PO4? Is this a problem?

Answer 15

Serum PO4 will fall, but intracellular stores will buffer this drop unless phosphate is severely depleted.

Question 16

5 effects of chronic low phosphate on hormones / ions, etc.? (they’ve all been mentioned already, and make sense)

Answer 16

Reduced PTH and FGF23.
Reduced urine phosphate.
Increased Vit D activation.
Increased bone resorption.
Increased Ca++ excrettion.

(chronic high phosphate does the exact opposite)

Question 17

6 systems affected by chronic severe hypophosphatemia?

Answer 17

Musculoskeletal (muscle problems, osteomalacia).
Cardiovascular (myopathy, arrhythmia).
Pulmonary (resp. failure, can’t wean from vent.).
Neurological.
Hemotologic (impair O2 release, hemolysis).
Metabolic (metabolic acidosis, glucose intolerance).

Question 18

Why does prolonged severe hypophosphatemia cause metabolic acidosis?

Answer 18

Lack of the buffering done by PO4.

Question 19

Why does prolonged severe hypophosphatemia cause glucose intolerance?

Answer 19

Without PO4 to add to glucose (by hexokinase), glucose can’t be trapped within cells.

Question 20

How does prolonged severe hypophosphatemia impair O2 release?

Answer 20

RBCs need PO4 to synthesize 2,3-bisphosphoglycerate (2,3-BPG), which is important for O2 release from hemoglobin.

Question 21

Not being able to make ATP is really bad.

Answer 21

Yep.

Question 22

3 broad causes of hypophosphatemeia (3 different locations)?

Answer 22

Intracellular shift.
Decreased absorption in GI.
Increased renal excretion.

Question 23

4 things that can drive hypophosphatemia due to intracellular shifts?

Answer 23

Carbohydrate infusions.
Hormones (catecholamines and insulin… just like K+).
Respiratory alkalosis.
Rapid cellular proliferation.

Question 24

2 examples of rapid cellular proliferation that can drive hypophosphatemia?

Answer 24

Leukemic blast crisis.

Hungry bone syndrome (post-parathyroidectomy sudden reduction from hyperPTH causes bone to rapidly take up PO4)

Question 25

Malabsorption and Vitamin D deficiency do reduce phosphate absorption in the GI tract, but what’s the more important reason why they cause hypophosphatemia?

Answer 25

Low Ca++ will stimulate PTH.

PTH will cause PO4 to be excreted renally.

Question 26

What OTC drug can cause impaired GI phosphate absorption?

Answer 26

Antacids containing aluminum.

It’s not common, but if one really goes at it, the aluminum can chelate away the phosphate.

Question 27

How was FGF23 discovered to be important?

Answer 27

Tumors secreting FGF23 -> osteomalacia.

Genetic defects in breakdown of FGF23 -> Rickets.

Question 28

What enzyme breaks down FGF23?

Answer 28

PHEX.

If it’s defective, too much FGF23 -> PO4 wasting.

Question 29

How does hyperPTH cause CHF?

Answer 29

Decreased phosphate -> decreased 2,3-BPG -> decreased O2 delivery to cardiac muscle -> CHF

Question 30

What are 3 factors that often act in concert to produce hypophosphatemia in alcoholics?

Answer 30

Glucose infusions. (common in hospitalization)
Ethanol directly lowers serum PO4.
Poor intake.

This can be so severe that it leads to rhabdomyolysis.

Question 31

3 types of causes of hyperphosphatemia?

Answer 31

Massive PO4 load.
Renal failure.
Increased tubular reabsorption.

Question 32

4 examples of things that dump a large amount of PO4 into the blood?

Answer 32

Tumor lysis syndrome (from within the cells).
Rhabdomyolysis (similar to tumor lysis).
Exogenous phosphate delivery.
Phosphate-containing laxatives (bowel preps).

Question 33

What are 2 etiologies of excess PO4 reabsorption?

these make sense, given what hormones you know affect renal PO4 handling

Answer 33

HypoPTH.

Insufficient active FGF23 (tumoral calcinosis).

Question 34

What causes Familial Tumoral Calcinosis?

Answer 34

Defect in GALNT3, which activates FGF23.
Too much PO4 in blood -> CaPO4 deposition in tissue. (and increased CV, renal disease risk)
(more important to know about FGF23… I wouldn’t worry about GALNT3..)

Question 35

Can tumoral calcinosis be caused by something that’s not a genetic mutation?

Answer 35

Yes, renal failure -> PO4 accumulation -> CaPO4 deposits.