Calcium Dysregulation

Question 1

What are the 3 main hormones that regulate calcium balance?

Answer 1

Increase:
1. Vitamin D - taken in via our skin from the sun or via our diet
2. PTH - released from the parathyroid gland (PTG)
Main regulators of calcium and phosphate

Decrease:
3. Calcitonin - secreted by thyroid parafollicular cells
irrelevant, does not need replacing after thyroidectomy

Question 2

How is Vitamin D metabolised, from UVB to active vitamin D?

What is active vitamin D called?

Answer 2

UVB shines on the skin
7-dehydrocholesterol is converted into the precursor pre-vitamin D3
This is converted into Vit D3
In the liver vit D3 is converted by 25-hydroxylase to 25(OH)cholecalciferol
Biological activation of 25-hydroxycholecalciferol = in the kidney: 2nd hyhdroxylation by 1-alpha hydroxlase to 1,25-dihydroxycholecalciferol (AKA Calcitriol)

Calcitriol

Question 3

How are Vit D levels in the blood measured?

Answer 3

Measure 25-hydroxycholecalciferol (As most people with normal kidneys can convert it to the active version)
Calcitriol (1,25 dihydroxy vitamin D) is very difficult to measure

Question 4

What does calcitriol negatively feedback to?

Answer 4

Negatively feeds back to the 1-alpha hydroxylase by decreasing transcription of 1 alpha hydroxylase to reduce / stop making calcitriol

Question 5

Calcitriol acts on which 3 areas and what are its effects?

Answer 5

Kidneys - increases reabsorption of calcium and phosphates
Bones - increases osteoblast activity
Gut - increases calcium and phosphate absorption from the gut

Question 6

PTH acts on which 3 areas and what are its effects?

How does it regulate serum Calcium levels?

Answer 6

Kidney - increases calcium reabsorption and phosphate excretion, also increases calcitriol production by stimulating 1-alpha hydroxylase
Gut - indrect effect from PTH, the increased calcitriol from the kidneys then increase calcium and phosphate reabsorption in the gut
Bone - osteoclast activity (resorption of calcium from the bone - release Ca2+)

All the mechanisms work to increase plasma Ca2+

Question 7

How is phosphate reabsorbed in the kidneys?

How does PTH affect this mechanism?

How does FGF23 affect this mechanism?

Answer 7

Na+/phosphate co-transporter allows for reabsorption of phosphate from the urine in the kidney

PTH inhibits this channel - increases phosphate excretion

FGF23 also inhibits this channel, and it also inhibits calcitriol which then reduces gut phosphate reabsorption

Question 8

What is hypocalcaemia?

How does this present clinically?

Answer 8

Low calcium

Tetany - contraction of muscle and it cannot relax
Paraesthesia - tingling around the mouth / hands / feet / lips
Convulsions - seizures
Arrhythmias - heart requires calcium
Chvostek’s sign = facial paresthesia
Trousseau’s sign = carpopedal spasm

Mneumonic = CATs go numb

Question 9

What are some causes of hypocalcaemia?

Answer 9

Low PTH levels = hypoparathyroidism due to: surgery (neck surgery), autoimmune, magnesium (required for PTH release) deficiency, congenital (v. rare)

Low vitamin D due to: deficiency (diet, IV light), malabsorption (e.g. coeliac disease), impaired production (renal failure)

Question 10

What is hypercalcaemia?

How does it present clinically?

Answer 10

High calcium

Renal effects (stones); GI effects (anorexia, nausea, dyspepsia, constipation, pancreatitis); CNS effects (fatigue, depression, impaired concentration, altered mental state, coma)
Muscles slow down in  hypercalcaemia

Mneumonic = Stones, abdominal moans and psychic groans

Question 11

What are some causes of hypercalcaemia?

Answer 11

Primary hyperparathroidism due to: PTG adenoma = benign tumour that secretes excessive PTH (negative feedback loop broken)

Malignancy (metastasis e.g. bone)

Cancers can release PTH-like peptides that work on PTH receptors

Vitamin D excess (rare)

Question 12

What happens to the PTH when calcium levels fall?

What happens to the PTH when calcium levels rise?

Answer 12

Calcium sensing receptors on the PTG detect fall in Ca2+
Triggers increase in PTH release
PTH then interacts with bone, gut and kidneys to help increase Ca2+

Calcium sensing receptors on the PTG detect rise in Ca2+
Triggers decrease in PTH release - less calcium released from bone / absorbed from the gut

Question 13

What is a parathyroid adenoma?

What are the effects of this adenoma?

Is a parathyroid adenoma a primary or secondary hyperparathyroidism?

Answer 13

Benign tumour of one of the PTGs
Results in excessive PTH release

PTH increases osteoclast activity, 1-alphahydroxlase activity, and calcium absorption in the gut = increase in serum calcium levels
Calcium’s negative feedback does not affect the adenoma as it is autonomous, so PTH is consistently being released

Primary - issue with the PTG itself

Question 14

What is seen in the blood in primary hyperparathyroidism?

Answer 14

High calcium 
Low phosphate - as PTH inhibits the Na+/phosphate co-transporter in the kidneys =  lots of phosphate lost in the kidneys via the urine 
High PTH (not suppressed by the hypercalcaemia)

Question 15

How is primary hyperparathyroidism treated?

Answer 15

Remove the parathyroid adenoma - parathyroidectomy

Question 16

What are the risks of untreated primary hyperparathyroidism?

Answer 16

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

Question 17

What is secondary hyperparathyroidism?

What is seen in the blood in secondary hyperparathyroidism?

Answer 17

Nothing wrong with the PTG itself
Low calcium results in increase in PTH release

Low calcium, high PTH (secondary to low calcium)

Question 18

What are the causes of secondary hyperparathyroidism?

Answer 18

Lack of Vit D - not enough taken in via diet / sunlight (UVB)

Renal failure - 1-alpha hydroxylase cannot make calcitriol

Question 19

How is secondary hyperparathyroidism treated?

Answer 19

Vit D replacement:

Patients with normal kidney function = give the inactive form (25-hydroxycholecalciferol) - this is converted by the patient’s kidneys

For renal failure patients = give Alfacalcidol (1-alpha hydroxycholecalciferol) - active synthetic form of vit D

Question 20

What is tertiary hyperparathyroidism?

What causes tertiary hyperparathyroidism?

Answer 20

All PTGs have grown / increased in size (hyperplasia)

Seen in prolonged kidney disease patients or chronic vit D deficiency = chronic low Ca2+
PTH goes up to try restore the Ca2+ to normal

Overtime, the PTGs grow and become autonomous as the PTGs are continuously stimulated by the low Ca2+, until eventually even when Ca2+ levels are normal, the PTGs act autonomously (unregulated)

Question 21

What is the treatment for tertiary hyperparathyroidism?

Answer 21

Surgery - parathyroidectomy

Question 22

What is the diagnostic approach to hypercalcaemia? i.e. What is seen in the bloods to decide what the cause / which type of hyperparathyroidism it is?

Answer 22

High Ca2+, high PTH, low phosphate = primary hyperparathyroidism
High Ca2+, low PTH = secondary hyperparathyroidism OR cancer / malignancy
High PTH, high Ca2+ and chronic renal failure / prolonged calcitriol deficiency = tertiary hyperparathyroidism

Question 23

What is the most common reason for hypercalcaemia when PTH levels are low?

Answer 23

Cancer - malignancy
(As PTH production has been switched off due to negative feedback so something else is driving hypercalcaemia)
Or secondary hyperparathyroidism (low vit D / renal failure)

Question 24

If a patient has hypercalcaemia and elevated PTH levels, what type of hyperparathyroidism is it?

Answer 24

If patient has normal renal function - primary

If patient has chronic renal failure and/or all 4 glands are englarged - tertiary