Regulation of Calcium and Phosphate

Question 1

What is the most abundant metal in the body?

Answer 1

calcium

Question 2

How is calcium distributed in the body?

Answer 2

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

Question 3

What is extracellular calcium?

Answer 3

In plasma
- ionised Ca (45%)
- Bound Ca2+

Bound Ca2+= Plasma proteins (45%) or anions (bicarbonate, phosphate, lactate)

Question 4

What increases serum calcium and phosphate and what do they act on?

Answer 4

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

Question 5

What decreases serum calcium and phosphate?

Answer 5

Calcitonin (secreted by thyroid parafollicular cells)

• Can reduce calcium acutely, but no negative effect if parafollicular cells are removed eg thyroidectomy

Question 6

What are sources of vitamin D?

Answer 6

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)

Question 7

Describe vitamin D metabolism.

Answer 7

Question 8

What is the active form of vitamin D called?

Answer 8

calcitriol

Question 9

How does the sun make vitamin D3 (cholecalciferol)?

Answer 9

7-dehydrocholesterol
-> pre-vitamin D3
-> cholecalciferol (D3)

Question 10

How does 1,25(OH)2 cholecalciferol regulate its own synthesis?

Answer 10

by decreasing transcription of 1 alpha- hydroxylase

Question 11

What is the major role of calcitriol?

Answer 11

Increase Ca2+ and PO4(3-) reabsorption from the GUT

Question 12

What is the effect of calcitriol in 3 major parts of the body?

Answer 12

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

Question 13

What is calcitriol?

Answer 13

1,25(OH)2 cholecalciferol (active form of vitamin D)

Question 14

What secretes parathyroid hormone?

Answer 14

Chief cells in the parathyroid glands

Question 15

How is parathyroid hormone secreted?

Answer 15

Secreted as a large precursor (pre-pro-PTH) & cleaved to PTH

Question 16

What triggers parathyroid hormone secretion?

Answer 16

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)

Question 17

How do the calcium sensing receptors work?

Answer 17

Question 18

When serum calcium increases, what happens to parathyroid hormone (PTH)?

Answer 18

It decreases

Question 19

What are the actions of parathyroid hormone (PTH) on 3 parts of the body?

Answer 19

Gut bone and kidney

Overall increased plasma Ca2+

Most of the time PO4 loss is greater than absorption, so overall PO4 is lost

Question 20

How does PTh affect bone strength?

Answer 20

It decreases as Ca2+ is released

Question 21

what are osteoblasts and osteoclasts?

Answer 21

osteoblast= build bone
osteoclast= consume bome

Question 22

What is the PTH action in bone?

Answer 22

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

Question 23

What is the effect of calcitriol in bone?

Answer 23

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

Question 24

How is PTH regulated?

Answer 24

Increased plasma Ca2+ produces a negative feedback loop

Question 25

What is calcitonin?

Answer 25

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

Question 26

Where is PTH stored?

Answer 26

colloid

Question 27

What are the actions and regulations of calcitonin?

Answer 27

Question 28

What are the cells in the proximal convoluted tubule of the kidney?

Answer 28

Cuboidal epithelia

Question 29

How does PO4(3-) enter cuboidal epithelia of PCT from the filtrate?

Answer 29

Na+PO4(3-) co-transporter Na+ enters at the same time

Question 30

What inhibits Na+PO4 co-transporter?

Answer 30

FGF23 FGF23 gene provides instructions for making a protein called fibroblast growth factor 23

Question 31

How does FGF23 inhibit Na+PO4- co-transporter?

Answer 31

Inhibits calcitriol

Question 32

Where is FGF23 found?

Answer 32

In the cuboidal epithelial cells of the PCT

Question 33

Describe the regulation of serum phosphate by FGF23.

Answer 33

Question 34

What effect does calcitriol have on serum phosphate?

Answer 34

calcitriol increases PO4(3-) reabsorption Increases serum phosphate (and calcium)

Question 35

What is high serum calcium?

Answer 35

Hypercalcaemia

Question 36

What is low serum calcium?

Answer 36

Hypocalcaemia

Question 37

What does hypercalcaemia cause when it comes to action potentials?

Answer 37

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

Question 38

What does hypocalcaemia cause when it comes to action potentials?

Answer 38

enables GREATER Na+ influx, so MORE membrane excitability

Question 39

what does hypocalcaemia cause and what it the mnemonic to remember?

Answer 39

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]

Question 40

What are 2 tests for a sign of hypocalcaemia?

Answer 40

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

Question 41

What surgical process can lead to a risk of low Ca2+?

Answer 41

Parathyroid surgery

Question 42

What is low PTH levels called?

Answer 42

hypoparathyroidism

Question 43

What are the causes of hypocalcaemia?

Answer 43

Hypoparathyroidism - surgical- neck surgery - auto-immune - magnesium deficiency - congenital (agenesis, rare) Vitamin D deficiency

Question 44

What are causes of vitamin D deficiency?

Answer 44

Malabsorption or dietary insufficiency Inadequate sun exposure Liver disease Renal disease Vitamin D receptor defects (rare)

Question 45

What stimulates renal 1-alpha-hydroxylase?

Answer 45

PTH

Question 46

What are the consequences of vitamin D deficiency?

Answer 46

Lack of bone mineralisation= soft bones

Question 47

What is vitamin D deficiency lead to in children and adults?

Answer 47

children= rickets (bowing of bones) adults= osteomalacia (fractures, proximal myopathy (muscle weakness of upper/ lower limbs))

Question 48

What are the signs and symptoms of hypercalcaemia?

Answer 48

‘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)

Question 49

What are causes of hypercalcaemia?

Answer 49

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)

Question 50

What is the hormonal control of phosphate regulated by?

Answer 50

FGF23 Vitmain D PTH