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Year 1 Locomotion > Calcium & Phosphate homeostasis > Flashcards

Calcium & Phosphate homeostasis Flashcards

1
Q

Name the 5 tissues involved in regulating calcium and phosphate homeostasis

A
  1. Parathyroid glands
  2. Kidney
  3. Gut
  4. Thyroid
  5. Bone
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2
Q

Which tissue detects levels of plasma Ca2+ and PO4 levels?

A

Parathyroid gland

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3
Q

Where is Calcitonin synthesised?

A

Thyroid

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4
Q

What makes FGF-23?

A

bone

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5
Q

Name the 6 important physiological roles of calcium

A
  1. Bone formation (growth and remodelling)
  2. Muscle contraction (initiates attraction between actin/myosin –> remember calcium channel blockers & hypertension)
  3. Nerve function
  4. Enzyme co-factor (EDTA chelates chelates calcium, often added to blood tubes)
  5. Intracellular second messenger
  6. Stabilisation of membrane potentials
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6
Q

Why is it so important for calcium levels to be tightly regulated?

A

Calcium is involved in important mechanisms such as stabilisation of membrane potentials in cardiac contraction, if levels are too high/low this can lead to arrythmias

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7
Q

Outline the distribution of total body calcium

A
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8
Q

Explain what is meant by adjusted calcium in regards to plasma levels

A

The higher the albumin the higher the total calcium, but free calcium is unaffected by albumin (and visa versa), so adjusted calcium allows for the level of circulating calcium, so that the total calcium reflects the free calcium.

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9
Q

Calcium Homeostasis

Explain what happens when calcium levels are low

A

Low calcium causes PTH secretion

PTH:

  1. Increases bone resorption and release of calcium
  2. Increases calcium reabsorption in the kidneys
  3. Increases 1-a-hydroxylase activity to product more active vitamin D

Active vitamin D:

  • further Increases calcium reabsorption in the kidneys
  • increases release of calcium from bone
  • increases absorption in the GI tract

(PTH does not directly alter GI absorption but does indirectly via altering levels of active vitamin D)

There is a negative feedback loop - calcium levels switch off PTH and so does vitamin D

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10
Q

Calcium Homeostasis

What happens when calcium levels are too high?

A

High calcium causes the thyroid to produce CALCITONIN

This inhibits bone resorption and inhibits calcium reabsorption in the kidneys to decrease serum calcium

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11
Q

How many parathyroid glands do we have?

A

4

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12
Q

What cells synthesise and secrete parathyroid hormone (PTH)?

A

Chief cells

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13
Q

What sort of hormone is PTH?

What is its half life?

A

Peptide hormone, half life is minutes

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14
Q

What receptor type does PTH act on?

What else acts on thesame receptor as PTH?

A

via G-protein coupled receptor PTHR1

PTH-related peptide (PTHrP) also works here

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15
Q

If calcium levels are low, explain the effect on CaSR signalling and the resulting effect on PTH levels

A
  • Decreased binding of Ca2+ leads to decreased CaSR signalling so inhibition is removed.
  • Increase cAMP
  • Increased production and secretion of PTH
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16
Q

If calcium levels are high, explain the effect on CaSR signalling and the resulting effect on PTH levels

A
  • Ca2+ ans CaSR activates PLC
  • leads to suppression of PTH secretion and gene expression
  • Activation of GPCR signalling inhibits AC and decreases cAMP
  • Leads to suppression of PTH production
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17
Q

How is the action of PTHrP classified?

A

Paracrine and Autocrine - only acts locally and not systemic

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18
Q

What are some important functions of PTHrP?

A
  • mimics PTH elevating plasma Ca2+ by binding to PTHR1
  • regulation of endochondral bone formation/mineralisation - important for chondrocytes and cartilage
  • Calcium regulation in foetus and lactation
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19
Q

what effect does PTHrP have on vitamin D?

A

Does not cause increased levels like PTH does

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20
Q

How does PTHrP relate to cancer?

A
  • PTHrP is produced by some cancers, it can cause hypercalcaemia
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21
Q

Why is bone remodelling important in calcium and phosphate metabolism?

A

Acts as a buffer to tweak levels

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22
Q

What effect does bone resorption and formation have on calcium and phosphate?

A

Bone resorption = releases Ca2+ and PO4

Bone formation deposits Ca2+ and PO4

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23
Q

Where is dietary calcium absorbed?

A

Mostly th eduodenum and upper jejunum of the intestine

Uptake is facilitated by vitamin D

High serum Ca = paracellular route

Low serum Ca = vit.D activation is triggered - TRPV6 + !,25D

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24
Q

Describe how calcium enters and exits cells in the intestine.

What effect does vitamin D have on these mechanisms?

A
  • Enters via TRPV6 calcium channels
  • Travels through the cell via CBP (calcium binding protein)
  • Exits the cell via Ca2+/Na+ exchanger pr Calcium ATPase pump on the basolateral membrane
  • Can also exit via exocytosis of Ca2+/CaBP complex

Vitamin D upregulates luminal Ca2+ channels, CaBP and basolateral Ca2+ efflux transporters

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25
Q

Where is calcitonin produced?

(Gland and cell type)

A

Thyroid

C cells - parafollicular cells

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26
Q

What actions does calcitonin (CT) have on bone?

A
  • Acts via GPCR
  • Inhibits bone resorption by preventing osteoclast action - Decr. Ca2+ and PO4 release
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27
Q

What actions does calcitonin (CT) have on the kidney?

A

•decreases reabsorption of PO4 and Ca2+

28
Q

What is Calcitonin (CT) regulated by?

A

Circulating Ca2+ (CaSR)

Incr Ca2+ = incr CT

Decr Ca2+ = decr CT

(opposite of PTH)

29
Q

What are the kidneys 3 roles in calcium and phosphate homeostasis?

A
  • Calcium reabsorption from filtrate
  • Phosphate reabsorption from filtrate
  • Makes 1,25(OH)2D (calcitriol)
30
Q

What inhibits/stimulates phosphate reabsorption from filtrate in the kidney?

A

–inhibited by PTH, FGF23, calcitonin,

  • stimulated by vitamin D
31
Q

Where is calcium primarily reabsorbed in the kidney ?

A
  • DCT = 5-10%, via active transport
  • Proximal Tubule = 60-70%, mostly passive transport
  • TALH = 20-25%, passively
32
Q

How does calcium enter the cells of the distal tubule from the lumen?

How doe cells exit the cells of the distal tubule into the renal interstitial fluid?

What upregulates these channels?

A

Enter via luminal Calcium channels (TRPV5)

Exit via basolateral Ca2+ efflux transporters - Ca2+ ATPase and Na+/Ca2+ exchanger

both are upregulated by PTH and Vitamin D

33
Q

What sort of hormone is Vitamin D?

what is its half life?

A

Steroid hormone that binds to a nuclear receptor

Half life = hours

Has cell membrane and intracellular transport proteins to facilitate uptake into cells

34
Q

What type of action does Vitamin D hormone act out?

A

Paracrine and endocrine

35
Q

What are the functions of vitamin D?

A
  • Facilitates Ca2+ uptake from the gut
  • Facilitates Ca2+ and PO4 reabsorption in the kidney
  • Cartilage production and bone mineralisation
  • Required from osteoblast and osteoclast differentiation
  • Increases bone remodelling (by promoting bone resotption)
  • Regulates the immune system (infection & inflammation)
36
Q

Where do we get our vitamin D from?

A
  • our diet - D2 and D3
  • Main source of vitamin D is from sunlight ~90% of requirements
37
Q

How is vitamin D synthesised in the skin?

Where is it transported to after?

A

7-dehydrocholesterol is converted into Colecalciferol D3 in the skin, under UV light

D3 and D2 are then transported to the liver

38
Q

What reaction occurs when D2 and D3 are transported to the liver?

A

Hydroxylation

Colecalciferol is converted into 25(OH)D - Calcidiol

This is what is measured in blood tests, reflects the amount of vitamin D in the blood as the conversion enzyme is regulated only by the amount of substrate available.

39
Q

What happens to Calcidiol 25(OH)D in the kidney?

What are the effects of vitamin D made in the kidney?

A
  • It is converted to 1,25(OH)2D CALCITRIOL in the kidney by 1-a-hydroxylase
  • Vitamin D made in the kidney has an endocrine function
  • Regulates bone and calcium effects
  • The bone and calcium effects depend on how much circulating active vitamin D is present.
40
Q

What happens to calcidiol 25(OH)D in non-renal tissues?

What effects does vitamin D produced here have?

A
  • Almost every tissue can produce active vitamin D as most tissues contain 1-a-hydroxylase
  • No effect on calcium homeostasis but does regulate the immune system and response to infection
  • Acts in an Autocrine/Paracrine fashion - does not enter the blood and acts within a tissue or in adjactent tissue
  • Independent of serum 1,25(OH)2D
  • Even if there is a lot of circulating vitamin D, if a tissue cannot produce vitamin D it will not respond to vitamin D in an inflammatory response
41
Q

Which enxyme inactivates vitamin D and how is it excreted?

A

24-hydroxylase

excreted in the urine

42
Q

Explain step-by-step how UV light is utilised to produce active vitamin D in the body

A
  • 7-dehyrdocholesterol is converted to colecalciferol D3 in the skin by UV light
  • D2 and D3 (dietary and sunlight vit.D) are transported to the liver where they undergo hydroxylation to become 25(OH)D Calcidiol
  • Calcidiol then travels to the kidney where it is converted into 1,25(OH)2D - active vitamin D - by 1a-hydroxylase
  • Calcidiol can also travel to non-renal tissues containing the 1a-hydroxylase enzyme where it is also converted into active vitamin D
43
Q

When we measure vitamin D levels in the blood, what are we actually measuring?

A

25(OH)D Calcidiol

This reflects the amount of vitamin D as the conversion enzyme in the liver is regulated only by the amount of substrate available.

44
Q

The balance of phosphate homeostasis depends on what?

A
  • Diet and uptake of the gut
  • Intracellular:extracellular movement
  • Urinary excretion- actively reabsorbed by PCT, excretion only occurs in the kidney
  • 84% ionised (compared with 45% calcium
45
Q

Which of calcium or phosphate is more dependent on vitamin D to enable absorption in the gut?

A

Calcium is more dependent on vitamin D for absorption

Phosphate is 70-90% efficient whereas calcium is only 20% efficient

46
Q

Where is phosphate reabsorbed in the kidney?

A

Actively reabsorbed in the PCT

47
Q

Name some physiological roles of phosphate

A
  • Intracellular metabolism (e.g. ATP synthesis)
  • Phosphorylation (e.g. enzyme activation)
  • Phospholipids in membranes
48
Q

Phosphate Homeostasis

Explain what happens when phosphate levels are LOW

A
  • Low phosphate stimulates vitamin D synthesis by activating 1-a-hydroxylase
  • Low phosphate causes an increase in serum phosphate levels by increasing phosphate reabsorbtion in the kidney and increasing phosphate absorption in the gut

Negative feedback loop

Active vitamin D causes production of KLOTHO protein and causes bone to release FGF23

Klotho and FGF23 work as a heterodimer to

  1. Inhibit 1-a-hydroxylase (stop active vit.D formation)
  2. Increase 24-hydroxylase to inactivate vit.D
  3. Inhibit phosphate reabsorption from the kidney
49
Q

Explain the negative feedback loop which occurs after phosphate levels have been increased?

A

Active vitamin D causes production of KLOTHO protein and causes bone to release FGF23

Klotho and FGF23 work as a heterodimer to

  1. Inhibit 1-a-hydroxylase (stop active vit.D formation)
  2. Increase 24-hydroxylase to inactivate vit.D
  3. Inhibit phosphate reabsorption from the kidney

This brings phosphate levels back down to normal

50
Q

Phosphate Homeostasis

What happens when phosphate levels are too high?

A
  • Phosphate directly increases FGF23 levels to

Klotho protein and FGF23 work as a heterodimer to

  1. Inhibit 1-a-hydroxylase (stop active vit.D formation)
  2. Increase 24-hydroxylase to inactivate vit.D
  3. Inhibit phosphate reabsorption from the kidney

To bring phosphate levels back down to normal

51
Q

How does FGF23 counteract the actions of Vitamin D induced phosphate changes?

A
  • Prevents vitamin D mediated hyperphosphataemia
  • Inhibits type II sodium-phosphate co- transporters (NaPi-2a, 2c) in PCT
  • Inhibits 1a-hydroxylase (prevents vitamin D activation)
  • Stimulates 24-hydroylase (inactivates vitamin D)
  • Inhibits PTH
52
Q

How is phosphate absorbed in the PCT of the kidney?

What affects the absorption?

A
  • Transported via sodium/phosphate co transporters NPTa and NPTc
  • PTH and FGF23 inhibit these cotransporters
  • This stops phosphate being reabsorbed back into the blood from the kidney and increases excretion in urine

Also PIT 1/2 but this is uniquitously expressed and not regulated

53
Q

How is phosphate absorbed in the gut and what affects this absorption?

A
  • Absorbed via sodium/phosphate cotransporter NPTb.
  • Vitamin D and low dietary phosphate increases NTPb
  • inhibited by high dietary phosphate

Also PIT 1/2 but this is uniquitously expressed and not regulated

54
Q

What can go wrong in calcium/phosphate metabolism?

A
55
Q

Name signs and symptoms of Hypercalcaemia

A
  • polyuria/polydipsia
  • tiredness, confusion, depression, headaches
  • nausea/vomiting/constipation/anorexia
  • muscle weakness
  • abdominal pain
  • shortened QT interval (severe cases)
  • Long standing ®loss of bone, kidney stones, ectopic calcification

“BONES, STONES AND MOANS”

56
Q

Name some common causes of hypercalcaemia

A

Primary hyperparathyroidism

  • Increased PTH secretion by parathyroid glands.
  • Normally a benign tumour. Individual cells respond normally to Ca, but increased numbers just mean that on balance there is more PTH produced.
  • 3rd most common endocrine disorder (after diabetes and hyperthyroidism)
  • sustained high levels PTH cause bone loss

Malignancy

  • e.g. breast or lung cancer or multiple myeloma.
  • usually bone loss or PTHrP production
57
Q

What is the aim of hypercalcaemia management

Outline hypercalcaemia management

A

Hypercalcaemia (>3.40 mmol/l severe - urgent)

  • fluids (normal saline)
  • loop diuretic (furosemide)
  • calcitonin
  • bisphosphonates
  • oral phosphate
  • long term ? parathyroid gland surgery
58
Q

Name some signs and symptoms of hypocalcaemia

A
  • Paraesthesia (usually fingers, toes and around mouth)
  • Tetany (as the extracellular [Ca2+] falls the peripheral nerve fibres discharge spontaneously, leading to muscle contractions)
  • Carpopedal spasm (wrist flexion and fingers drawn together).
  • Muscle cramps
  • Seizures
  • Prolonged QT interval (®VF or heart block)
59
Q

Name some causes of hypocalcaemia and the consequences of these

A
  • Hypoparathyroidism (low PTH)
  • Calcium deficiency (low dietary uptake/vit D deficiency)

Consequences: Rickets/osteomalacia, secondary hyperparathyroidism

60
Q

Outline secondary hyperparathyroidism

A

low serum Ca2+ stimulates PTH production & secretion, usually associated with kidney disease:

In kidney disease:

  • kidneys can’t respond to PTH
  • can’t make active vitamin D
  • can’t increase absorption of Ca2+ from gut or kidney
  • can’t increase PO4 excretion
  • only place Ca2+ can come from is bone
  • renal bone mineral disease

Generally, plasma Ca2+ decreases, plasma PO4 increases

  • Gland enlarges & produces unregulated amounts of PTH
  • Serum Ca2+ begins to rise – Tertiary hyperparathyroidism
61
Q

Outline management of acute and chronic hypocalcaemia

A

•acute (neuromuscular symptoms) - IV calcium gluconate

•chronic

–oral calcium (often + vitamin D)

–vitamin D (form will depend on where the defect is)

62
Q

What is the most common nutritional deficiency worldwide?

A

Vitamin D deficiency

63
Q

Name some causes of vitamin D deficiency

A
  • Lack of sunlight exposure
  • Liver disease
  • Kidney disease
  • Dietary contribution generally low
64
Q

Name vitamin D treatments

A

For lack of sunlight - Colecalciferol D3

For liver disease - Calcidiol 25(OH)D

Dietary intake - increase dietary intake

65
Q

What levels of PTH, Calcium and Phosphate would you see in primary, secondary and tertiary hyperparathyroidism?

A

Year 1 Locomotion (18 decks)

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