Control of Mineral Metabolism

Question 1

Roles of calcium

Answer 1

1. structural (mineral matrix of bone; reservoir for plasma calcium)
2. biochemical (excitation contraction coupling, stimulus-secretion coupling, blood clotting, memb excitability, cellular permeability)

Hypocalcemia: seizures and tetany (increase excitability)
-increased Ca: sluggishness, muscles dont work well

Question 2

Plasma Calcium and phosphate range

Answer 2

Ca: 8-10 mg/dL
Phosphate: 3-4 mg/dL

-There is a fast exchange of 20g/d b/t ECF and labile bone mediated by osteocytes

Question 3

3 compartments of calcium

Answer 3

1. bone (99% in form of hydroxyapatite)
2. intracellular compartment: 10g. Cytosolic Ca maintained by intracell mobile Ca buffers, compartmentalization into ER Ca stores, ATP linked Ca pump and Na/Ca antiporter
3. Extracellular fluid includes blood and interstitial spaces in equilibrium; 2.5 mM, 1/2 free and filtered by kidney, remainder bound to albumin

Kidney filters 10g Ca/d
98% reabsorbed

Question 4

Phosphate roles

Answer 4

• structural role (mineral matrix of bone)
• intracellular buffer
• phosphorylation reactions
• energy currency
• DNA, RNA
• Regulation

85% in ionized active form (HPO4 2- and H2PO4 2-)

Question 5

Ca forms

Answer 5

50% Albumin bound

10% HCO3-, PO43- (salt forms)

Question 6

Bone formation

Answer 6

• surface osteoblasts
• canals filled with canalicular fluid
• osteocytes
• osteoclasts (phagocytic cells): degradation of matrix
• canalicular:blood 0.6 (normally drive Ca into canalicular fluid down gradient through surface osteoblasts; taken up by surface osteocytes, then back into blood)
• So: net exchange of 10g of Ca per day (“osteocytic process”)
• phosphate is NOT part of daily exchange

Osteoclastic process exchanges both Ca, Phosphate

Question 7

Phosphate equilib

Answer 7

• exchange through kidneys
• 7g of phosphate/d filtered thru kidneys and 6.1 taken back up
• Blood range: 3-4 mg/d

Question 8

Parathyroid hormone

Answer 8

-produced in parathyroid gland
-from Chief cells
-synth as larger pre-prohormone
PTH leads to increased plasma Ca via:
1. bone:
Rapid: increased efflux of labile bone Ca (not phos)
Slow: increased bone remodeling releases Ca and phosphate

2. Kidney:
   increased Ca reabsorption in distal tubule
   decreased phosphate reabsorp
   increased 1,25 (OH)2 Vit D
3. GI tract:
   indirect via Vit D, which enhances Ca absorp

Consequence: increase serum Ca and decrease serum phosphate

But how does a low serum Ca lead to Ca dependent release (increased cytosolic Ca) of PTH?
Chief cells have Ca receptors:
-when bound with Ca: inactive; when you lower serum Ca, GPCR triggered (Gq) (ER releases Ca via IP3 and increases intracell Ca and PTH is released)

PTH receptors: GPCR

Question 9

Calcitonin

Answer 9

• Produced by parafollicular or C cells of thyroid
• secreted when Ca is high
• acts on bone to decrease efflux of labile bone Ca

Question 10

Vitamin D Synthesis and secretion

Answer 10

• 7dehydrocholesterol + sunlight leads to Vit D3 (inactive)
• In liver, on hydroxyl group added and second hydroxyl group added in kidney (1 hydroxylase)
• 1,25 OH2 Vit transported bound to transcalciferin
  (note: 24, 25 (OH)2 Vit D3 is inactive)

Question 11

Actions of Vit D

Answer 11

-GI tract: interacts with nuclear receptor, increases synthesis of mRNAs/prot. 1 of these is Calcium binding protein: promotes absorption of Ca from gut into blood

1,25 OH2 Vit D mobilizes bone similar to PTH

Question 12

Hyperparathyroidism

Answer 12

• tumors of parathyroid
• other tumors

-Ca will exceed set point (high Ca): sluggish, low mental and muscle response

Question 13

Pseudohypoparathyroidism

Answer 13

-receptors don’t function normally, but hormones are normal or even elevated

Question 14

Regulation of 1, 25 (OH)2 Vit D synthesis

Answer 14

• 1,25 Vit D acts on renal hydroxylase to decrease its action (negative feedback)
• In kidney, increased PTH positively and negatively affect the activities of 1 hydroxylase and 24 hydroxylase respectively.
• high PTH leads to increased levels of 1, 25 (OH)2 Vit D– acts on GI to increase Ca absorp
• decreased levels of phosphate pos and neg affect activities of 1 hydroxylase and 24 hydroxylase respectively
• so if plasma phosphate falls, 1,25 OH2 Vit D synth is increased, and will act on GI to promote phosphate absorp

Question 15

Minute to minute regulation of blood calcium

Answer 15

• PTH acting to mobilize Ca into plasma

- Calcitonin: help increase rate of storage for acute Ca load

Question 16

Long term regulation of ca balance

Answer 16

-Vit D: regulates intestinal aborp of Ca and phosphate

Question 17

Hyperparathyroidism

Answer 17

-primary: increased PTH increases Ca levels in plasma and urine– renal stones.
Hypercalcemia:
muscle weakness, depression, GI disorders; severe: bone pain/fractures

Secondary:
any disorder where plasma Ca is low: Rickets, renal failure

Question 18

Hypoparathyroidism

Answer 18

-low PTH leading to low Ca
Sx: neuromuscular excitability, muscle cramps, seizures, mental changes
-Chvostek’s sign (facial n.)
-PTH dependent decrease in calcitriol levels, causing decreased serum Ca due to less absorp from intestine/reabs from kidney
-increased phosphate

Tx: Vit D, Ca supp

Question 19

Vit D deficiency

Answer 19

• Kids: Rickets

- Adults: osteomalacia

Question 20

Vit D excess

Answer 20

• large ingestion of Vit D
• can cause hypercalcemia
• can lead ot pathological calcification of soft tissues