Calcium and phosphate regulation

Question 1

Where is PTH (parathyroid hormone) secreted from?

Answer 1

From the parathyroid glands

Question 2

Where are the parathryoid glands located and how many are there?

Answer 2

• Behind the thyroid gland
• 4 of them

Question 3

1) What is the ultimate function of PTH?
2) What are the 3 mechanisms by which PTH carries out this function?

Answer 3

1) To increase [serum calcium]

2)

1. PTH causes the kidneys to absorb more calcium (so less is excreted)
2. PTH promotes calcium (and phosphate) release from the bones
3. PTH regulates the conversion of 25-hydroxy-vitamin D to calcitriol (it stimulates renal 1α-hydroxylase to convert 25-hydroxyl-vitamin D₃ into 1,25-hydroxyl-vitamin D₃ -i.e. calcitriol) which itself promotes calcium reabsorption at the bones and the gut

Question 4

In phosphate regulation, how is phosphate excreted?

Answer 4

• Excreted at the kidneys

Question 5

In phosphate regulation, how does phosphate reabsorption at the kidneys occur?

Answer 5

• Sodium and phosphate enter the cells of the PCT via Na⁺/PO₄^3- cotransporters (symporters) i.e. from the tubule lumen into the cells of the PCT
• Here at the PCT, you can get reabsorption into the blood

Question 6

1) In phosphate regulation, what role does PTH play and by what mechanism?
2) In phosphate regulation, what would happen in primary hyperparathyroidism?

Answer 6

1)

• PTH inhibits the Na⁺/PO₄^3- symporter at the PCT
• So there is less PO₄^3- entering the cells at the PCT so there is less reabsorption of phosphate at the kidneys - so it promotes phosphate excretion

2)

• It overstimulates phosphate excretion by inhibiting phosphate reabsorption at the PCT by inhibiting the Na⁺/PO₄^3- symporters

Question 7

1) In phosphate regulation, what overall effect does FGF23 have on serum phosphate levels?
2) By what 2 mechanisms does FGF23 have this effect?
3) Where is FGF23 secreted from?

Answer 7

1)

• Decreases serum phosphate levels

2)

1. FGF23 inhibits the Na⁺/PO₄^3- symporters at the PCT so it inhibits phosphate reabsorption at the PCT of the kidneys - thereby increasing phosphate excretion
2. FGF23 inhibits calcitriol release from the kidneys which would otherwise go on to increase phosphate (and calcium) reabsorption at the gut and bones

3)

• Osteocyte

Question 8

How is PTH secretion regulated in response to serum calcium levels to give a homeostatic effect on serum calcium levels?

1) To decrease PTH secretion?
2) To increase PTH secretion?

Answer 8

1)

• Calcium binds calcium sensing receptors on parathyroid cells
• Increased activation of these receptors (given higher [serum calcium]) inhibits PTH secretion
• So less PTH so this lowers serum calcium again

2)

• Less calcium binding calcium sensing receptors on parathyroid cells due to low [serum calcium]
• So lowered activation of these receptors
• So less inhibition of PTH secretion - i.e. increased PTH secretion
• Increased PTH secretion works to increase [serum calcium] again

Question 9

What role does vitamin D play in regulating serum calcium levels and what form of vitamin D does this - note vitamin D has opposing effects?

Answer 9

• Active vitamin D (calcitriol)
• Increases calcium and phosphate absorption from the gut
• Increases renal Ca²⁺ reabsorption
• Ca²⁺ maintenance in bones
• Produces negative feedback effect on PTH via calcitriol receptors on PT cells

Question 10

Outline the pathways by which you derive vitamin D precursors and the conversions to form the active vitamin D (calcitriol)

Answer 10

1. 7-dehydrocholesterol in the skin is converted into cholecalciferol upon exposure to UVB light
2. OR you directly receive ergocalciferol from the diet
3. In the liver, cholecalciferol and ergocalciferol is converted into 25-hydroxy-vitamin D (25-OH-D₃)
4. 25-hydroxy-vitamin D (25-OH-D₃) is converted into 1,25-OH-D₃ (calcitriol) using the enzyme renal 1α-hydroxylase in the kidneys

Question 11

Answer 11

Question 12

What are 6 means by which you can be deficient / resistant to the effects of vitamin D?

Answer 12

1. Poor exposure to (UVB) light - i.e. lack of sunlight
2. Insufficient dietary intake of ergocalciferol
3. GI malabsorption of ergocalciferol from diet - e.g. due to coeliac’s disease and inflammatory bowel disease
4. Renal failure (so lack of renal 1α-hydroxylase so poor conversion from 25-hydroxy-vitamin D into 1,25-hydroxy-vitamin D)
5. Liver failure (so lack of conversion of cholecalciferol / ergocalciferol into 25-hydroxy vitamin D)
6. Vitamin D resistant rickets - receptor resistance to vitamin D

Question 13

Describe how changes in EC calcium affect nerve and skeletal muscle excitability

Answer 13

• High EC calcium (Hypercalcaemia) - Ca²⁺ blocks Na⁺ influx, so less membrane excitability
• Low EC calcium (Hypocalcaemia) - enables greater Na⁺ influx so MORE membrane excitability

Question 14

What is the normal range for serum calcium?

Answer 14

2.2-2.6 mmol/L

Question 15

1) Why do the symptoms and signs of hypocalcaemia occur and list the signs and symptoms
2) Apart from the classic signs and symptoms, how else can we assess hypocalcaemia?

Answer 15

1)

• Increased excitability due to increased sensitisation of excitable tissues
• PCAT (Cats go numb or pussy cat)
• Parasthaesia (of hands, mouth, feet and lips)
• Convulsions
• Arrythmia
• Tetany

2)

• Chvostek’s sign
• Trousseau’s sign

Question 16

What is Chvostek’s sign and what does it indicate?

Answer 16

• Tap the facial nerve just below the zygomatic arch
• A positive response will involve twitching of the facial muscles
• This indicates neuromuscular irritability due to hypocalcaemia

Question 17

What is Trousseau’s sign and what is it indicative of?

Answer 17

• Inflating a cuff for several minutes will induce a carpopedal spasm
• This is indicative of neuromuscular irritability due to hypocalcaemia

Question 18

Give 4 causes of hypocalcaemia

Answer 18

1. Vitamin D deficiency
2. Low PTH levels - parahypothyroidism
3. PTH resistance - in pseudohypoparathyroidism
4. Renal failure - impaired 1α-hydroxylation so decreased production of 1,25-(OH)₂-D₃

Question 19

What are the groupings for the types of signs that come with hypercalcaemia, and what are the signs within these groupings?

Answer 19

Reduced neuronal excitability

Stones, bones, groans, abdominal moans

Stones - renal effects

• Polyuria and thirst
• Nephrocalcinosis
• Renal colic
• Chronic renal failure

Abdominal moans - GI effects

• Anorexia
• Nausea
• Dyspepsia
• Constipation
• Pancreatitis

Psychic groans - CNS effects

• Fatigue
• Depression
• Impaired concentration
• Altered mentation
• Coma (if .>3mmol/L)

Question 20

4 causes of hypercalcaemia?

Answer 20

1. Primary hyperparathyroidism
2. Malignancy - tumours / metastases often secrete a PTH-like peptide
3. Conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone - immobilised patient)
4. Vitamin D excess (rare)

Question 21

1) What happens in primary hyperparathyroidism?
2) How to treat?
3) How does it differ to hypercalcaemia of malignancy?

Answer 21

1)

• Tumour in the parathyroid causes a large increase in PTH secretion
• Autonomous PTH secretion - resistant to negative feedback from high serum calcium
• So causes high PTH and calcium and low phosphate

2)

• Parathyroidectomy

3)

• There is still the negative feedback occuring in hypercalcaemia of malignancy so there’ll be hypercalcaemia but low PTH

Question 22

What problems can occur in the bones in vitamin D deficiency?

Answer 22

• Lack of mineralisation in bone
• Softening in bone
• Bone deformities
• Bone pain
• Severe proximal myopathy
• In children - RICKETS
• In adults - OSTEOMALACIA

Question 23

What occurs in secondary hyperparathyroidism?

Answer 23

• Usually due to vitamin D deficiency → low calcium
• Renal failure - so low calcitriol due to insufficient 1α-hydroxylase
• Renal failure - loss of calcium in urine
• Increased PTH to try and compensate serum calcium levels

Question 24

What occurs in tertiary hyperparathyroidism?

Answer 24

• Initial low chronic serum calcium
• Eventually the parathyroid becomes autonomous by no longer responding to negative feedback from the calcium
• So loads of PTH secreted and hypercalcaemia occurs

Question 25

Which 2 types of hyperparathyroidism are associated with hypercalcaemia and which are associated with hypocalcaemia?

Answer 25

• Primary and tertiary hyperparathyroidism are associated with hypercalcaemia
• Secondary hyperparathyroidism is associated with hypocalcaemia - it’s not causing the hypocalcaemia, it’s actually trying to correct the hypocalcaemia

Question 26

What are the biochemical findings in someone with vit D deficiency?

Answer 26

• Plasma [25(OH)D3] usually low (we don’t measure 1,25 (OH)2 D to assess body vitamin D stores
• Plasma [Ca²+] will be low (may be normal if secondary hyperparathyroidism has developed)
• Plasma [PO₄^2-] will be low (due to reduced gut absorption)
• [PTH] high (secondary hyperparathyroidism)

Question 27

How does PTH interact with 1α-hydroxylase?

Answer 27

Stimulates it

Question 28

How do you treat vit D deficiency in people with:

1) In patients with normal renal function
2) In patients with renal failure

Answer 28

1)

• Give 25 hydroxy-vitamin D₃ (25 (OH) D₃)

* Patient converts this to 1,25 dihydroxy-vitamin D₃ (1,25 (OH)2 D₃) via 1-alpha hydroxylase

* Can be given as ergocalciferol 25 hydroxy vitamin D₃ or cholecalciferol 25 hydroxy vitamin D₃

2)

• Inadequate 1-alpha hydroxylation (can’t activate 25-hydroxyl vitamin D preparations)
• Give Alfacalcidol – 1-alpha-hydroxycholecalciferol – you give them active vitamin D

Question 29

Give 2 ways you might get excess Vit D

Answer 29

1. Excessive treatment with active metabolites of vitamin D e.g. Alfacalcidol (e.g. wrong dose)
2. Granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1a hydroxylase to convert 25(OH) D₃ to the active metabolite 1,25 (OH)2 D₃ – VERY RARE