Calcium dysregulation

Question 1

How to increase serum calcium

Answer 1

Vitamin D
Synthesised in skin or intake via diet

Parathyroid hormone (PTH) (secreted by parathyroid glands)

Main regulators of calcium (& phosphate) homeostasis via actions on kidney, bone and gut

Question 2

What decreases serum calcium

Answer 2

Calcitonin (secreted by thyroid parafollicular cells)
Can reduce calcium acutely, but no negative effect if parafollicular cells are removed eg thyroidectomy

Question 3

Explain the metabolism of vitamin D

Answer 3

Synthesis from UV exposure
Or from diet

7-dehydrocholesterol –> vitamin D3 —> In the liver, 25-hydroxylase —> 25 (OH) cholecalciferol —> 1 alpha hydroxylase in kidney –> 1,25 OH cholecalciferol

Question 4

What do we measure in blood to show vitamin D status

Answer 4

25 OH cholecalciferol

Question 5

How is vitamin D (calcitriol) regulated?

Answer 5

Via decreasing transcription of 1 alpha hydroxylase

Question 6

What are the effects of calcitriol?

Answer 6

Increase osteoblast activity in bones
Increase in Ca2+ and PO43- reabsorption in kidney
Increase in Ca2+ and PO43- reabsorption in gut

Question 7

What are the actions of parathyroid hormone?

Answer 7

Ca2+ resorption from bone
Increase in Ca2+ and PO43- excretion and 1 alpha hydroxylase activity (leads to more calcitriol) in kidney
—This leads to increase in Ca2+ and PO43- reabsorption in gut

Net result of PTH and Vitamin D is increase in plasma calcium

Question 8

How does PTH result in excretion of PO43- from kidney?

Answer 8

Phosphate reabsorption occurs via the gut and the kidneys. Phosphate is reabsorbed via sodium phosphate transporter cells. In the kidney, shown here, reabsorption of phosphate via these transporters results in less sodium excretion in the urine.
Increased phosphate loss in the urine would lower serum phosphate levels.
PTH inhibits renal phosphate reabsorption by inhibiting these transporters – so in primary hyperparathyroidism, serum phosphate is low due to increased urine phoshate excretion.
FGF23 – derived from bone – also inhibits phosphate reabsorption in the kidneys by inhibiting these transporters and also inhibits synthesis of calcitriol, causing less phosphate absorption from the gut.

Question 9

What are signs of hypocalcaemia?

Answer 9

Sensitises excitable tissues; muscle cramps, tetany, tingling

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

Sensitises excitable tissues; muscle cramps, tetany, tingling
Signs & symptoms
Paraesthesia (hands, mouth, feet , lips)
Convulsions
Arrhythmias
Tetany
Mnemonic - [CATs go numb

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

Question 10

What are the causes of hypocalcaemia in terms of hypoparathyroidism?

Answer 10

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

Question 11

What are the causes of hypocalcaemia in terms of low vitamin D levels?

Answer 11

Deficiency – poor diet/malabsorption, lack of UV light, impaired production (renal failure)

Question 12

What are the signs and symptoms of hypercalcaemia?

Answer 12

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 13

What are the causes of hypercalcaemia?

Answer 13

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 14

What happens when calcium is high?

Answer 14

Negative feedback - decrease in PTH

Question 15

What does a parathyroid adenoma do?

Answer 15

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

Question 16

What is the biochemistry of primary hyperparathyroidism

Answer 16

High calcium
Low phosphate – increased renal phosphate excretion (inhibition of Na+/PO43- transporter in kidney)
High PTH (not suppressed by hypercalcaemia)

Question 17

What is the treatment for primary hyperparathyroidism?

Answer 17

Parathyroidectomy is treatment of choice for primary hyperparathyroidism

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 happens in secondary hyperparathyroidism

Answer 19

Secondary hyperparathyroidism is a normal physiological response to hypocalcaemia

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 20

What is the cause of secondary hyperparathyroidism?

Answer 20

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 21

What is the treatment for secondary hyperparathyroidism?

Answer 21

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, so can’t activate 25 hydroxy vitamin D preparations
Give Alfacalcidol - 1a hydroxycholecalciferol

Question 22

What is tertiary hyperparathyroidism?

Answer 22

Caused by chronic renal failure as you can’t make calcitriol so vitamin D deficiency, therefore reduction in calcium
PTH therefore goes up drastically and the parathyroid glands have hypertrophy
Then an increase in calcium reabsorption

Tertiary hyperparathyroidism = rare
Occurs in chronic renal failure
Can’t make calcitriol
PTH increases (hyperparathyroidism)
Parathyroid glands enlarge (hyperplasia)
Autonomous PTH secretion causes hypercalcaemia
Treatment is parathyroidectomy

Question 23

What to do when a patient has high calcium

What does normal PTH response show

What does raised PTH show

Answer 23

When looking at a patient with hypercalcaemia, always look at the PTH!

Normal PTH response to hypercalcaemia is for PTH to fall
Hypercalcaemia due to malignancy
High calcium (hypercalcaemia)
Low/suppressed PTH

If patient with hypercalcaemia has raised PTH, the diagnosis is hyperparathyroidism
Primary hyperparathyroidism if renal function is normal (eg parathyroid adenoma)
Tertiary hyperparathyroidism (all 4 glands enlarged – hyperplastic) if chronic renal failure

Question 24

What is the diagnostic approach to vitamin D deficiency?

Answer 24

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
Calcitriol (1,25 dihydroxy vitamin D) is very difficult to measure