Regulation Of Calcium And Phosphate Metabolism Flashcards
How is Ca compartmentalized?
ECF: 0.1%
Plasma: 0.5%
ICF: 1%
Bones and teeth: 99%
Ca exists in ionized form, bound to plasma proteins or in nonionized form
Protein-bound: 40%
Ultrafilterable: 60% -> complexed non-ionized form 10%, ionized 50%
Describe how total and ionized Ca is altered in the plasma?
Total Ca is altered by changing the plasma protein concentration to alter the total Ca concentration in the same direction as protein conc
Ionized Ca is altered by changing the fraction of Ca complexed with anions:
Increasing plasma Pi, increases the fraction of complexed Ca and decreases ionized Ca
Albumin binds Ca and H; in academia (high H+) albumin binds more H+, increasing ionized Ca In alkalemia (low H+) albumin binds more Ca, decreasing ionized Ca)
How do Ca levels influence membrane excitability?
What regulates this?
Hypocalcemia: increases neuromuscular excitability -> hypocalcemic tetany/spasticity (lowers RMP, so easier to reach threshold)
Hypercalcemia: depresses neuromuscular excitability (raises RMP, so harder to reach threshold)
PTH, calcitonin, calcitriol
What diseases are associated with elevated Ca?
Low Ca?
Primary hyperparathyroidism, malignancy
Hypoparathyroidism, renal disease, vitamin D deficiency
Ca homeostasis is tightly regulated and involves the actions of what organs?
What hormones?
Bone, kidney, intestines
PTH, calcitriol, calcitonin
Where is phosphate stored?
How is it stored in serum?
85% bone
14% cells
< 1% serum -> 84% ionized, 10% protein-bound, 6% complexed to cations
Extracellular concentration of Pi is inversely correlated to that of Ca. Extracellular concentration of Pi is regulated by same hormones that regulate Ca concentration
(High Pi, low Ca and vice versa)
Fine-tuning circulating Pi is under the control of ____.
Renal excretion
Na/Pi cotransporters in the apical membrane
Four regulators of phosphate metabolism
Dietary: Pi intake and absorption
Calcitriol: increase phosphorus resorption from bone and absorption from intestine; increases Pi reabsorption in kidneys
PTH: Pi resorption directly from bone; indirectly activates intestinal absorption through stimulation of calcitriol production
Renal tubular: reabsorption of Pi, stimulated by tubular filtered load of Pi and inhibited by PTH
What are fibroblast growth factors?
Promote to growth of fibroblasts
Role in growth, development, cell survival, endocrine signaling
Bind to FGF-receptors (FGFRs)
Mutation in FGFR3 causes achondroplasia
FGF-23 is an endocrine growth factor and uses Klotho as a cofactors
What is FGF-23 and where is it from?
What regulates it?
What are its three renal effects?
Derived from bone
Phosphate and vitamin D levels regulate expression of FGF-23 and therefore regulate phosphate homeostasis
- Directly downregulates NaPi transporters in the kidney
- Stimulates PTH to downregulates NaPi transporters in the kidney
- Decreases calcitriol production in the kidney
Used in hyperphosphetemia because it decreases Pi
What does PTH do?
What secretes it?
Regulator of Pi and Ca homeostasis
Synthesized and secreted from chief cells of parathyroid gland
Cleavage of PTH
Chief cells store PTH in vesicles
Can regulate Ca levels minute by minute
How does low plasma Ca simulate PTH secretion?
Mutation in CaSR causes what?
Though Ca-sensing receptor (CaSR): uses G protein to activate PTH genes
Increased ECF Ca inhibits PTH secretion
Low Ca will stimulate PTH secretion
Hypocalciuric hypercalcemia (FHH)
Chronic hypercalcemia
Chronic hypocalcemia
Decreases synthesis/storage of PTH and breaks down any stored PTH
Increases synthesis/storage of PTH resulting in hyperplasia of parathyroid glands
Magnesium effects on PTH
Similar to Ca
Severe hypomagnesemia inhibits PTH synthesis, storage, and secretion
PTH signals through a ____.
GPCR
Actions of PTH on bone, kidney, and intestine
Low Ca -> increase PTH ->
Bone: increase bone resorption; increase Ca and Pi in blood
Kidney: decrease Pi reabsorption; increase Ca absorption; increase urinary cAMP (biomarker of PTH secretion)
Intestine: increase Ca absorption
Actions of vitamin D
Promotes mineralization of new bone through Ca/Pi
Opposing effects on Pi levels
Increase Ca/Pi products to promote mineralization of new bone
Names for biologically active forms of vitamin D
1,25-dihydroxycholecalciferol
1,25 hydroxy vitamin D
1,25(OH)2D3
Calcitriol
Synthesis of vitamin D
?????
1alpha-hydroxyase
Regulation of 1alpha-hydroxylase is tightly regulated
Feedback loop dihyroxyvitamin D inhibits 1alpha-hydroxylase
High Ca inhibits the enzyme
Trrty
Utyu
PTH receptors are located on ___.
Short-term actions?
Long-term actions?
What acts synergistically with PTH to simulate osteoclast activity?
Osteoblasts
Direct effect on osteoblasts bone formation
Indirect effect on osteoclast bone resorption
Vitamin D
Agents involved in bone formation and resorption
M-CSF: simulates stem cells to become osteoclast precursors
RANKL: cell surface protein produced by osteoblasts; primary mediator of osteoclast formation
RANK: cell surface protein on osteoclasts and osteoblasts precursors
OPG: soluble protein produced by osteoblasts; decoy receptor for RANKL; inhibits RANKL/RANK interaction
PTH inhibits ____ on the apical membrane of the kidney.
What does this cause?
PTH also stimulates reabsorption of ____ in the distal tubule.
PTH stimulates what enzyme to make vitamin D?
Na/Pi absorption (NPT)
Phosphaturia
Ca
1alpha-hydroxylase
Action of vitamin D on the intestines
Kolkka
Function of calcitonin
Released from thyroid gland
Lowers Ca and Pi levels by inhibits bone resorption
Parafollicular C cells of the thyroid express CaSR -> senses elevated extracellular Ca -> synthesis and secretion of calcitonin
Decreases activity of osteoclasts
Promotes renal excretion of Ca/Pi
Primary hyperparathyroidism
Hypersecretion of PTH
Results in hypercalcemia and hypophosphatemia due to bone demineralization, increased GI and renal Ca reabsorption
Stones
Secondary hyperparathyroidism
What can cause low blood Ca?
Increased PTH secondary to low blood Ca
Renal failure, vitamins D deficiency
Hypoparathyroidism
Symptoms?
Caused by thyroid/ parathyroid surgery
From low Ca: muscle cramps, increased neuromuscular excitability
Pseudohypothyroidism type I (Albright hereditary osteodystrophy, AHO)
Phenotype
Tissues are PTH resistant because problem with PTH receptor
Defective cAMP signal transduction
Increases PTH secretion, low Ca levels
Short neck
Humoral hypercalcemia of malignancy
Treatment?
High PTH-related peptide which is produced by tumors
Decrease bone formation, PTH, vitamin D
Furosemide
Problems due to vitamin D
Treatment?
Impaired vitamin D metabolism: vitamin D resistant
Rickets: low Ca/Pi, growth failure
Osteomalacia: new bone fails to mineralize
Vitamin D
Peudovitamin D deficiency
Rickets
Osteoporosis
Depends on age, sex
Decrease bone mass
What directly or indirectly controls Pi activities?
What increases renal Pi reabsorption?
What decreases renal Pi reabsorption?
PTH, vitamin D, FGF-23
PTH reduces Na/Pi activity leading to Na excretion
Insulin, GH, TH
Calcitonin, glucocorticoids, ANP
