Regulation of Calcium and Phosphate Flashcards
What is the most abundant metal in the body?
calcium
How is calcium distributed in the body?
99% resides in skeleton and teeth as calcium hydroxyapatite crystals
Extracellular calcium (tiny amount of total body calcium) is tightly regulated
‘Unbound’ ionised calcium = biologically active component
What is extracellular calcium?
In plasma
- ionised Ca (45%)
- Bound Ca2+
Bound Ca2+= Plasma proteins (45%) or anions (bicarbonate, phosphate, lactate)
What increases serum calcium and phosphate and what do they act on?
Parathyroid hormone (PTH) (secreted by parathyroid glands)
Vitamin D
Synthesised in skin or intake via diet
Main regulators of calcium & phosphate homeostasis via actions on kidney, bone and gut
What decreases serum calcium and phosphate?
Calcitonin (secreted by thyroid parafollicular cells)
- Can reduce calcium acutely, but no negative effect if parafollicular cells are removed eg thyroidectomy
What are sources of vitamin D?
D2= ergocalciferol derived from UV irradiation of plants
D3= cholecalciferol derived from UV irradiation of skin (animals and humans) and certain foods (oily fish, egg yolks)
Describe vitamin D metabolism.
What is the active form of vitamin D called?
calcitriol
How does the sun make vitamin D3 (cholecalciferol)?
7-dehydrocholesterol
-> pre-vitamin D3
-> cholecalciferol (D3)
How does 1,25(OH)2 cholecalciferol regulate its own synthesis?
by decreasing transcription of 1 alpha- hydroxylase
What is the major role of calcitriol?
Increase Ca2+ and PO4(3-) reabsorption from the GUT
What is the effect of calcitriol in 3 major parts of the body?
Gut= increase Ca2+ and PO4(3-) reabsorption from the gut
kidney= increase Ca2+ and PO4 reabsorption
bone= increase Ca2+ reabsorption
Overall= Increase Ca2+ in blood
What is calcitriol?
1,25(OH)2 cholecalciferol (active form of vitamin D)
What secretes parathyroid hormone?
Chief cells in the parathyroid glands
How is parathyroid hormone secreted?
Secreted as a large precursor (pre-pro-PTH) & cleaved to PTH
What triggers parathyroid hormone secretion?
G-protein coupled calcium sensing receptor on chief cells detects change in circulating calcium concentration
PTH secretion inversely proportional to serum calcium (aka if Ca is low PTH is up)
How do the calcium sensing receptors work?
When serum calcium increases, what happens to parathyroid hormone (PTH)?
It decreases
What are the actions of parathyroid hormone (PTH) on 3 parts of the body?
Gut bone and kidney
Overall increased plasma Ca2+
Most of the time PO4 loss is greater than absorption, so overall PO4 is lost
How does PTh affect bone strength?
It decreases as Ca2+ is released
what are osteoblasts and osteoclasts?
osteoblast= build bone
osteoclast= consume bome
What is the PTH action in bone?
PTH binds to PTH receptor on osteoblast
This triggers osteoclast activating factors
- OAFs (e.g. RANKL; Receptor activator of nuclear factor kappa-B ligand)
This leads to osteoclasts consuming bone and bone reabsorption
What is the effect of calcitriol in bone?
Calcitriol effects on bone depend on serum calcium:
LOW serum calcium – calcitriol works with PTH to increase calcium reabsorption from bone
osteoclasts > osteoblasts
NORMAL serum calcium – calcitriol promotes bone formation
osteoblasts > osteoclasts
Bone RESORPTION
How is PTH regulated?
Increased plasma Ca2+ produces a negative feedback loop
What is calcitonin?
Secreted from parafollicular (C) cells of the thyroid gland
Reduces serum calcium
Physiological role in calcium homeostasis in humans unclear
Removal of thyroid gland does not affect serum calcium
Where is PTH stored?
colloid
What are the actions and regulations of calcitonin?
What are the cells in the proximal convoluted tubule of the kidney?
Cuboidal epithelia
How does PO4(3-) enter cuboidal epithelia of PCT from the filtrate?
Na+PO4(3-) co-transporter
Na+ enters at the same time
What inhibits Na+PO4 co-transporter?
FGF23
FGF23 gene provides instructions for making a protein called fibroblast growth factor 23
How does FGF23 inhibit Na+PO4- co-transporter?
Inhibits calcitriol
Where is FGF23 found?
In the cuboidal epithelial cells of the PCT
Describe the regulation of serum phosphate by FGF23.
What effect does calcitriol have on serum phosphate?
calcitriol increases PO4(3-) reabsorption
Increases serum phosphate (and calcium)
What is high serum calcium?
Hypercalcaemia
What is low serum calcium?
Hypocalcaemia
What does hypercalcaemia cause when it comes to action potentials?
Action potential generation in nerves/skeletal muscle requires Na+ influx across cell membrane
HYPERcalcaemia= high extracellular Ca=
Ca2+ blocks Na+ influx, so LESS membrane excitability
What does hypocalcaemia cause when it comes to action potentials?
enables GREATER Na+ influx, so MORE membrane excitability
what does hypocalcaemia cause and what it the mnemonic to remember?
Sensitises excitable tissues; muscle cramps, tetany, tingling
- muscle and nerve types of cells
- muscles can contract but can’t relax properly
Signs & symptoms
Paraesthesia (hands, mouth, feet , lips)
Convulsions
Arrhythmias
Tetany
Mnemonic - [CATs go numb]
What are 2 tests for a sign of hypocalcaemia?
Chvostek’s sign
Tap facial nerve just below zygomatic arch
Positive response = twitching of facial muscles
Indicates neuromuscular irritability due to hypocalcaemia
Trousseau’s sign
Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia
What surgical process can lead to a risk of low Ca2+?
Parathyroid surgery
What is low PTH levels called?
hypoparathyroidism
What are the causes of hypocalcaemia?
Hypoparathyroidism
- surgical- neck surgery
- auto-immune
- magnesium deficiency
- congenital (agenesis, rare)
Vitamin D deficiency
What are causes of vitamin D deficiency?
Malabsorption or dietary insufficiency
Inadequate sun exposure
Liver disease
Renal disease
Vitamin D receptor defects (rare)
What stimulates renal 1-alpha-hydroxylase?
PTH
What are the consequences of vitamin D deficiency?
Lack of bone mineralisation= soft bones
What is vitamin D deficiency lead to in children and adults?
children= rickets (bowing of bones)
adults= osteomalacia (fractures, proximal myopathy (muscle weakness of upper/ lower limbs))
What are the signs and symptoms of hypercalcaemia?
‘Stones, abdominal moans and psychic groans’
- Reduced neuronal excitability – atonal muscles
Stones – renal effects
Nephrocalcinosis – kidney stones, renal colic
Abdominal moans - GI effects
Anorexia, nausea, dyspepsia, constipation, pancreatitis
Psychic groans - CNS effects
Fatigue, depression, impaired concentration, altered mentation, coma (usually >3 mmol/L)
What are causes of hypercalcaemia?
Primary hyperparathyroidism:
Too much PTH
Usually due to a parathyroid gland adenoma
No negative feedback - high PTH, but high calcium
Malignancy:
Bony metastases produce local factors to activate osteoclasts, increasing calcium reabsorption from bone
Vitamin D excess (rare)
What is the hormonal control of phosphate regulated by?
FGF23
Vitmain D
PTH
