Calcium Dysregulation

Question 1

What hormones act to increase serum calcium?

Answer 1

Vitamin D - synthesised in skin/diet intake
Parathyroid hormone - secreted by parathyroid glands

Question 2

What hormone acts to decrease serum calcium?

Answer 2

Calcitonin - secreted by thyroid parafollicular cells

Question 3

What would happen to serum calcium levels if parafollicular cells are removed, e.g. in a thyroidectomy?

Answer 3

Although calcitonin can reduce calcium acutely, if you remove the PF cells it’ll have no negative effect

Question 4

What substance is a good indicator of body Vitamin D levels?

Answer 4

Serum 25-hydroxycholecalciferol

Question 5

How is vitamin D synthesis regulated?

Answer 5

1,25(OH)2 vitamin D (calcitriol) regulates its own synthesis by decreasing transcription of 1 alpha hydroxylase

Question 6

Outline the production of calcitriol

Answer 6

• UVB stimulates conversion of 7-dehydrocholesterol into pre-vitamin D3 and pre -vitamin D3 into vitamin D3
• Vitamin D3/Vitamin D2 (from diet) enter the bloodstream and travel to the liver where they undergo hydroxylation reactions catalysed by 25-hydroxylase into 25(OH)cholecalciferol
• 25(OH)cholecalciferol is then hydroxylased further in the kidney to calcitriol by 1-alpha-hydroxylase

Question 7

What are the effects of calcitriol on the kidneys, gut and bones?

Answer 7

Kidney - increased calcium and phosphate reabsorption
Gut - increased calcium and phosphate absorption
Bones - increased osteoblast activity

Question 8

What are the effects of PTH on the kidneys, gut and bones?

Answer 8

Kidney - calcium reabsorption, phosphate excretion and increased 1-alpha-hydroxylase activity causing increased calcitriol synthesis
Gut - Indirect effects: increased calcium and phosphate absorption through upregulation of calcitriol synthesis
Bone - calcium resorption

Question 9

How do PTH and FGF23 regulate serum phosphate levels?

Answer 9

PTH - inhibits sodium-phosphate co-transporter - promotes phosphate excretion via urine
FGF23 - inhibits co-transporter and inhibits calcitriol synthesis

Question 10

What happens in hypocalcaemia and what are the signs and symptoms?

Answer 10

Sensitises excitable tissues causing muscle cramps, tetany, tingling

Symptoms:
Paraesthesia (hands, mouth, feet , lips)
Convulsions
Arrhythmias
Tetany
Mnemonic - [CATs go numb]

Signs:
Chvosteks’ sign – facial paresthesia
Trousseau’s sign – carpopedal spasm

Question 11

What sign is being demonstrated in this image?

Answer 11

Chvosteks’ sign - facial paresthesia

Question 12

What sign is being demonstrated in these image?

Answer 12

Trousseau’s sign – carpopedal spasm

Question 13

What are the causes of hypocalcaemia?

Answer 13

Low PTH levels = hypoparathyroidism
- Surgical – neck surgery
- Auto-immune
- Magnesium deficiency
- Congenital (agenesis, rare)

Low vitamin D levels
- Deficiency – poor diet/malabsorption, lack of UV light, impaired production (renal failure)

Question 14

What happens in hypercalcaemia and what are the signs and symptoms?

Answer 14

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 >3mmol/L)

Question 15

What are the causes of hypercalcaemia?

Answer 15

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
- Certain cancers (eg squamous cell carcinomas) secrete PTH-related peptide that acts at PTH receptors
Vitamin D excess (rare)

Question 16

Outline a cause of primary hyperparathyroidism, its effects and the biochemistry

Answer 16

Parathyroid adenoma producing too much PTH
Calcium increases, but no negative feedback to PTH due to autonomous PTH secretion from parathyroid adenoma

Biochemistry:
High calcium
Low phosphate - increased renal excretion
High PTH - no suppression

Question 17

How is primary hyperparathyroidism treated?

Answer 17

Parathyroidectomy

Question 18

What are the risks of untreated hyperparathyroidism?

Answer 18

Osteoporosis
Renal calculi (stones)
Psychological impact of hypercalcaemia – mental function, mood

Question 19

What is secondary hyperparathyroidism a response to?

Answer 19

Normal physiological response to hypocalcaemia

Question 20

What biochemistry would you observe in secondary hyperparathyroidism?

Answer 20

Calcium will be low or low/normal
PTH will be high (hyperparathyroidism) secondary to the low calcium
This is different from primary hyperparathyroidism where calcium is high

Question 21

What are the causes of secondary hyperparathyroidism?

Answer 21

Most common cause of secondary hyperparathyroidism is vitamin D deficiency
Commonly - diet, reduced sunlight
Less common, but important = renal failure – can’t make calcitriol in renal failure

Question 22

How is secondary hyperparathyroidism treated?

Answer 22

Vitamin D replacement:
In patients with normal renal function - give 25 hydroxy vitamin D
Patient converts this to 1,25 dihydroxy vitamin D via 1a hydroxylase
- Ergocalciferol 25 hydroxy vitamin D2
- Cholecalciferol 25 hydroxy vitamin D3
In patients with renal failure - inadequate 1a hydroxylation - can’t activate 25 hydroxy vitamin D preparations
- Give Alfacalcidol - 1a hydroxycholecalciferol

Question 23

What causes tertiary hyperthyroidism and what happens in this condition?

Answer 23

Rare
Occurs in chronic renal failure - can’t make calcitriol
Initially calcium falls, PTH increases (starts as secondary) but over a long period of time PTH continues to increase
Parathyroid glands enlarge (hyperplasia)
Autonomous PTH secretion causes hypercalcaemia

Question 24

What is the treatment of tertiary hyperparathyroidism?

Answer 24

Parathyroidectomy

Question 25

What is an important diagnostic tool in hypercalcaemia?

Answer 25

PTH levels

Question 26

What would you observe in hypercalcaemia due to malignancy?

Answer 26

High calcium
Low/suppressed PTH

Question 27

If a patient with hypercalcaemia has raised PTH, what is the diagnosis?

Answer 27

Hyperparathyroidism:
- Primary hyperparathyroidism if renal function is normal (eg parathyroid adenoma)
- Tertiary hyperparathyroidism (all 4 glands enlarged – hyperplastic) if chronic renal failure

Question 28

What would you observe in vitamin D deficiency? (Diagnostic approach)

Answer 28

Calcium will be low or low/normal
PTH will be high (hyperparathyroidism) secondary to the low calcium
Vitamin D is measured as 25 (OH) vitamin D as calcitriol is hard to measure