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Block 4 > Calcium and phosphate homeostasis > Flashcards

Calcium and phosphate homeostasis Flashcards

1
Q

What is the role of the parathyroid glands in Ca2+ and PO4 homeostasis?

A
  • Detect plasma levels of Ca2+ and PO4
  • Produce and secrete parathyroid hormone
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2
Q

What is the role of the kidneys in Ca2+ and PO4 homeostasis?

A
  • Ca2+ and PO4 reabsorption from filtrate
  • Site of vitamin D activation
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3
Q

What is the role of the gut in Ca2+ and PO4 homeostasis?

A

Uptake of Ca2+ and PO4

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4
Q

What is the role of the thyroid in Ca2+ and PO4 homeostasis?

A

Calcitonin synthesis

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5
Q

What is the role of bone in Ca2+ and PO4 homeostasis?

A
  • Storage of Ca2+ and PO4
  • Produces fibroblast growth factor
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6
Q

What are the physiological roles of calcium?

A
  • Bone and teeth formation and remodelling
  • Muscle contraction
  • Nerve function
  • Enzyme co-factor
  • Intracellular second messenger
  • Stabilisation of membrane potentials
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7
Q

What are the roles of parathyroid hormone?

What stimulates its production?

A

Stimulated by low Ca2+

  • Alters 1aOHase to convert 25(OH)D to 1,25(OH)2D in the kidney
  • Stimulates increased reabsorption of Ca2+ in the kidney
  • Stimulates bone resorption and Ca2+ release from bones.
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8
Q

What are the actions of active vitamin D (1,25(OH)2D)?

A
  • Stimulates Ca2+ and PO4 reabsorption in kidneys
  • Increases Ca2+ uptake in gut
  • Stimulates bone resorption and release of Ca2+
  • Required for osteoblast and osteoclast differentiation
  • Regulates immune system
  • Increases bone remodelling by promoting resorption
  • Essential for cartilage production and bone mineralisation
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9
Q

What are the actions of calcitonin?

What is it synthesised by?

A

Synthesised by C-cells (neuroendocrine parafollicular cells) in the thyroid gland.

  • Acts via g-protein linked receptor
  • Inhibits bone resorption by preventing osteoclast activity
  • Decreases reabsorption of PO4 and Ca2+ in the kidneys
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10
Q

Which hormones regulate Ca2+ reabsorption from filtrate in the kidneys?

A

Parathyroid hormone (stimulates)

Vitamin D (stimulates)

Calcitonin (inhibits)

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11
Q

What is the role of the parathyroid glands?

A

Detect circulating Ca2+ levels

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12
Q

Where is parathyroid hormone produced?

A

Chief cells in the parathyroid glands

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13
Q

How do calcium sensing receptors in the parathyroid gland stimulate or suppress production of PTH?

A

When there is sufficient or excess calcium, it is able to bind to the calcium sensing receptor.

High Ca2+:

  • Binding to receptor causes activation of phospholipase C which suppresses PTH secretion and gene expression.
  • G-protein signalling from the receptor also inhibits adenylate cyclase which then reduces CAMP causing suppression of PTH production.

Low Ca2+:

  • Decreased binding to calcium receptor prevents the inhibition of adenylate cyclase; increased CAMP is produced which stimulates production and secretion of PTH.
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14
Q

What can bind to and activate Parathyroid hormone receptor 1 (PTHR1)?

A

Parathyroid hormone and Parathyroid Hormone Related Peptide

Both have same effect

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15
Q

What are the actions of parathyroid hormone related peptide? (PTHrP)

A
  • Paracrine and autocrine action
  • Mimics PTH, binds to PTHR1→ Increases Ca2+ in plasma
  • Regulates endochondral bone formation/mineralisation
  • Produced by some cancers: hypercalcaemia
  • Does not increase activation of vit D
  • Calcium regulation in foetus and lactation
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16
Q

How does bone buffer Ca2+ and PO4?

A

Resorption releases Ca2+ and PO4

Formation deposits Ca2+ and PO4

17
Q

How is calcium absorbed in the gut in high and low levels?

A

High levels of Ca2+:

  • Paracellular route (when vitamin D levels are low because of high calcium)

Low levels of Ca2+:

  • Low levels of Ca2+ triggers Vit D activation
  • Vitamin D activates calcium channels (TRPV6) to upregulate calcium absorption.
18
Q

What are the two routes of active reabsorption of Ca2+ in the GI tract?

A

Active uptake and extrusion:

  • Ca2+ enters activated Ca2+channels (TRPV6) on the luminal membrane of GI epithelial cells.
  • Binds to Calcium Binding Protein (CaBP) inside the cell.
  • Transported out of the basolateral membrane of the cell via CaATPase or Ca2+/Na+ exchanger

Endocytosis and Exocytosis:

  • Calcium enters the cell via TRPV6 on the luminal membrane.
  • Taken up into vesicles along with CaBP
  • Ca2+-CaBP complex Released from the basolateral membrane via exocytosis.
19
Q

How does vitamin D upregulate absorption of Ca2+ in the gut?

A
  • Increases production and translocation of TRPV6 and insertion into the luminal membrane.
  • Increases available CaBP
  • Increases transport mechanisms (basolateral ATPase, Ca2+/Na+ transporters)
20
Q

What are the 2 methods of calcium reabsorption in the kidney?

Where do they occur?

A

Passive:

  • Unregulated paracellular transport.
  • Proximal convoluted tubule (60-70%)
  • Thin ascending loop of Henle (20-25%)

Active:

  • Vit D and PTH upregulate TRPV5 channels and basolateral Ca2+ efflux transporters (Ca2+ATPase and Ca2+/Na+ exchanger
  • Distal convoluted tubule (5-10%)
  • Collecting duct (0.5-1%)
21
Q

How is Ca2+ reabsorbed in the distal convoluted tubule of the kidney?

A
  • Paracellular by osmosis
  • PTH and Vit D upregulate TRPV5 channels on the luminal membrane and basolateral Ca2+ transporters
  • Enters the cell via TRPV5, binds to CaBP and exits the cell via Ca2+ATPase and Ca2+/Na+ exchanger
22
Q

What roles does the kidney play in calcium and phosphate homeostasis?

A
  • Reabsorption of calcium from filtrate:
    • Passive
    • Active (regulated by PTH, vitamin D and calcitonin)
  • Reabsorption of phosphate from filtrate:
    • Inhibited by PTH, FGF23 and calcitonin
    • Stimulated by vitamin D
  • Makes 1,25(OH)2D (calcitriol- active vitamin D)
23
Q

How is vitamin D synthesised and activated?

A

UV light converts 7-dehydroxycholesterol to colecalciferol in the skin.

In the liver, colecalciferol is converted to 25(OH)D (calcidiol, inactive vit D)

1aOHase in the kidneys converts 25(OH)D into 1,25(OH)2D (calcitriol- active vitamin D)

Excess 1,25(OH)2D is inactivated by 24hydroxylase and excreted in urine.

24
Q

What are the physiological roles of phosphate?

A
  • Intracellular metabolism (e.g. ATP synthesis)
  • Phosphorylation (e.g. enzyme activation)
  • Phospholipids in membranes
25
Q

How are phosphate levels regulated?

A

Low PO4:

  • Stimulates activation of 1aOHase which then activates vitamin D
  • Stimulates release of klotho which is also activated by 1aOHase

Active vitamin D increases reabsorption of PO4 in kidneys and gut, as well as PO4 (and Ca2+) release from bone through resorption.

Also causes production of FGF-23 (fibroblastic growth factor 23) in bone.

Negative Feedback:

  • High PO4 causes FGF-23 and klotho to bind as a complex:
    • Inhibits 1aOHase to prevent Vit D activation
    • Increases 24hydroxylase to inactivate active Vit D
    • Inhibits PO4 reabsorption in the kidneys by inhibiting NPT2a and NPT2c phosphate transporters.
26
Q

How is phosphate absorbed in the kidney?

How is this stimulated and inhibited?

A

Through NPTC2a and NPTC2c transporters

  • Stimulated by active vitamin D
  • Inhibited by FGF-23-klotho complex and PTH
27
Q

How is phosphate absorbed in the gut?

How is this stimulated and inhibited?

A

Through NPT2b

  • Stimulated by low levels of PO4 and active vitamin D
  • Inhibited by high levels of dietary PO4
28
Q

What are the common causes of hypercalcaemia?

A

Primary hyperparathyroidism:

  • Increased PTH secretion by parathyroid glands causes increased Ca2+
  • Usually caused by benign tumour of parathyroids

Malignancy:

  • E.g. breast or lung cancer; tumours produce PTHrP which mimics PTH.
29
Q

What are the symptoms of hypercalcaemia?

A
  • Polyuria/polydipsia
  • Tiredness/confusion
  • Headaches
  • Depression
  • Nausea and vomiting
  • Constipation
  • Muscle weakness
  • Abdo pain
  • Cardiac arrhythmias: decreased QT interval (severe cases)
  • Chronic= bone loss, kidney stones, ectopic calcification
30
Q

How is hypercalcaemia treated?

A
  • IV fluids + loop diuretic
  • Calcitonin
  • Bisphosphonates
  • Oral phosphate
  • Parathyroid surgery (if long term)
31
Q

What are the common causes of hypocalcaemia?

A

Hypoparathyroidism (low PTH)

Calcium deficiency

  • Usually caused by vitamin D deficiency
  • Low dietary calcium intake
32
Q

How is hypocalcaemia treated?

A

Acute (neuromuscular symptoms): IV calcium gluconate

Hypoparathyroidism:

  • Limited options: lifelong vitamin D supplements, high Ca2+ diet, Ca2+ supplementation

Calcium deficiency:

  • Vitamin D deficiency: supplements (colecalciferol-inactive form)
    • Active form causes hypercalcaemia: can only be given to renal failure pts.
  • Low dietary intake: high Ca2+ diet, supplements
33
Q

What are the symptoms of hypocalcaemia?

A
  • Paraesthesia (fingers, toes and around mouth usually)
  • Tetany
  • Carpopedal spasm
  • Seizures
  • Increased QT interval +/- heartblock/VF (severe cases)
34
Q

What is secondary hyperparathyroidism?

A

Caused by hypocalcaemia

Usually caused by kidney disease:

  • Kidneys can’t respond to PTH so can’t produce vit D
  • Can’t increase absorption of Ca2+ or PO4 from kidneys or gut
  • Can’t increase PO4 excretion
  • =Gland enlarges and produces unregulated amounts of PTH causing hypercalcaemia
35
Q

How is secondary hyperparathyroidism caused by kidney disease treated?

A
  • Increase Ca2+ levels
  • Calcimimetics
  • Parathyroid surgery
36
Q

What would the following blood results indicate:

Low Ca2+ and high PTH

Low Ca2+ and low/normal PTH

High Ca2+ and high PTH

High Ca2+ and low PTH

Normal Ca2+ and high PTH

A

Low Ca2+ and High PTH =

  • PT responding correctly, hypocalcaemia

Low Ca2+ and low/normal PTH =

  • Probable hypoparathyroidism

High Ca2+ ​and high PTH =

  • Hyperparathyroidism (imaging to ?cause)

High Ca2+ and low PTH =

  • PT responding correctly, ?cause of high Ca2+

Normal Ca2+ and high PTH =

  • Mild hyperparathyroidism

Block 4 (20 decks)

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