Calcium dysregulation

Question 1

What increases 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 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

How do we replenish vitamin D?

Answer 3

UVB light shines on our skin, cholesterol precursor, Vit D3 precursor taken to liver and first hydroxylation step takes place via 25-hydroxylase, making inactive vitD (25(OH)cholecalciferol). Second hydroxylation gives active form of Vit D (1,25(OH)2 cholecalciferol) via 1 alpha-hydroxylase.

Question 4

What is the active form of Vitamin D known as?

Answer 4

Calcitriol

Question 5

How is Calcitriol regulated?

Answer 5

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

Question 6

What enzyme catalyses the first step of Vitamin D3 metabolism?

Answer 6

25-hydroxylase

Question 7

What enzyme catalyses the second step of Vitamin D3 metabolism?

Answer 7

1 alpha-hydroxylase

Question 8

What are the effects of Calcitriol?

Answer 8

Increased reabsorption of Calcium and phosphate from the kidney and gut. Increased osteoblast activity.

Question 9

What are the effects of PTH?

Answer 9

Negative effects on bone, bone resorption due to increased osteoclast activity, increased plasma Calcium. Increases Calcium reabsorption in the kidney and Phosphate secretion. Stimulates 1-alphahydroxylase activity, so you have increased calcitriol synthesis, increase in calcium and phosphate absorption in the gut. Phosphate balances out.
Very high PTH can block the Na+/PO43- co-transporter.

Question 10

How does FGF23 regulate serum Phosphate?

Answer 10

Phosphate usually reabsorbed in the PCT cells via Na+/PO43- co-transporter. FGF23 inhibits co-transporter.
It also inhibits Calcitriol Formation, so less Phosphate absorption from the gut.

Question 11

What are the signs and symptoms of Hypocalcaemia?

Answer 11

Sensitises excitable tissues; muscle cramps, tetany tingling. CAT
Convulsions
Arrhythmias
Tetany

Question 12

What is Trousseu’s sign

Answer 12

carpopedal spasm

Question 13

What is Chvosteks’ sign?

Answer 13

facial paraesthesia

Question 14

What are the causes of Hypocalcaemia?

Answer 14

Low PTH levels = hypoparathyroidism
 - Surgical – neck surgery
 - Auto-immune
 - Magnesium deficiency
 - Congenital (agenesis, rare)
Low vitamin D levels
 - Deficiency – diet, UV light, malabsorption, impaired 
   production (renal failure

Question 15

What are the signs and symptoms of Hypercalcaemia?

Answer 15

SAP
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 16

What are the causes of hypercalcaemia?

Answer 16

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 17

What is the relationship between PTH and calcium?

Answer 17

Negative feedback

Question 18

What happens in Primary Hyperparathyroidism?

Answer 18

Parathyroid adenoma producing too much PTH

Calcium increases, but no negative feedback to PTH due to autonomous PTH secretion from parathyroid adenoma

Question 19

What is the biochemistry for Primary hyperparathyroidism?

Answer 19

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

Question 20

What is the treatment for Primary Hyperparathyroidism?

Answer 20

Parathyroidectomy is treatment of choice for primary hyperparathyroidism

Question 21

What are the risks associated with untreated hyperparathyroidism?

Answer 21

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

Question 22

What happens in Secondary hyperparathyroidism?

Answer 22

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 23

What are the causes of secondary hyperparathyroidism?

Answer 23

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 24

What is the treatment for secondary hyperparathyoirdism?

Answer 24

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 preparation
Give Alfacalcidol - 1a hydroxycholecalciferol

Question 25

What happens in Tertiary hyperparathyroidism?

Answer 25

RARE
Occurs in patients with impaired renal function.
Occurs in chronic renal failure
Can’t make calcitriol
PTH increases (hyperparathyroidism)
Parathyroid glands enlarge (hyperplasia)
Autonomous PTH secretion causes hypercalcaemia Initially calcium falls and PTH rises (secondary hyperparathyroidism), but over a long period high PTH drive by enlarged parathyroid glands increases calcium

Question 26

What is the treatment for Tertiary hyperparathyroidism?

Answer 26

Parathyroidectomy

Question 27

What should you do if you have a patient with hypercalcaemia?

Answer 27

Look at PTH level, Normal response to hypercalcaemia is for PTH to fall. Hypercalcaemia due to malignancy PTH is switched off.

Question 28

What would happen in Vitamin D deficiency?

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