Calcium and phosphate homeostasis

Question 1

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

Answer 1

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

Question 2

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

Answer 2

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

Question 3

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

Answer 3

Uptake of Ca²⁺ and PO₄

Question 4

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

Answer 4

Calcitonin synthesis

Question 5

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

Answer 5

• Storage of Ca²⁺ and PO₄
• Produces fibroblast growth factor

Question 6

What are the physiological roles of calcium?

Answer 6

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

Question 7

What are the roles of parathyroid hormone?

What stimulates its production?

Answer 7

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.

Question 8

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

Answer 8

• 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

Question 9

What are the actions of calcitonin?

What is it synthesised by?

Answer 9

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

Question 10

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

Answer 10

Parathyroid hormone (stimulates)

Vitamin D (stimulates)

Calcitonin (inhibits)

Question 11

What is the role of the parathyroid glands?

Answer 11

Detect circulating Ca²⁺ levels

Question 12

Where is parathyroid hormone produced?

Answer 12

Chief cells in the parathyroid glands

Question 13

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

Answer 13

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.

Question 14

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

Answer 14

Parathyroid hormone and Parathyroid Hormone Related Peptide

Both have same effect

Question 15

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

Answer 15

• 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

Question 16

How does bone buffer Ca²⁺ and PO₄?

Answer 16

Resorption releases Ca²⁺ and PO₄

Formation deposits Ca²⁺ and PO₄

Question 17

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

Answer 17

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.

Question 18

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

Answer 18

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.

Question 19

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

Answer 19

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

Question 20

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

Where do they occur?

Answer 20

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%)

Question 21

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

Answer 21

• 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

Question 22

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

Answer 22

• 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)

Question 23

How is vitamin D synthesised and activated?

Answer 23

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.

Question 24

What are the physiological roles of phosphate?

Answer 24

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

Question 25

How are phosphate levels regulated?

Answer 25

**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.

Question 26

How is phosphate absorbed in the kidney? How is this stimulated and inhibited?

Answer 26

Through NPTC2a and NPTC2c transporters * Stimulated by active vitamin D * Inhibited by FGF-23-klotho complex and PTH

Question 27

How is phosphate absorbed in the gut? How is this stimulated and inhibited?

Answer 27

Through NPT2b * Stimulated by low levels of PO₄ and active vitamin D * Inhibited by high levels of dietary PO₄

Question 28

What are the common causes of hypercalcaemia?

Answer 28

**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.

Question 29

What are the symptoms of hypercalcaemia?

Answer 29

* 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

Question 30

How is hypercalcaemia treated?

Answer 30

* IV fluids + loop diuretic * Calcitonin * Bisphosphonates * Oral phosphate * Parathyroid surgery (if long term)

Question 31

What are the common causes of hypocalcaemia?

Answer 31

Hypoparathyroidism (low PTH) Calcium deficiency * Usually caused by vitamin D deficiency * Low dietary calcium intake

Question 32

How is hypocalcaemia treated?

Answer 32

**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

Question 33

What are the symptoms of hypocalcaemia?

Answer 33

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

Question 34

What is secondary hyperparathyroidism?

Answer 34

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

Question 35

How is secondary hyperparathyroidism caused by kidney disease treated?

Answer 35

* Increase Ca²⁺ levels * Calcimimetics * Parathyroid surgery

Question 36

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

Answer 36

**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