🧪Endocrinology🧪 - Calcium Dysregulation

Question 1

What are the main regulatory hormones of calcium homeostasis?

Answer 1

Vitamin D and parathyroid hormone (PTH)

Question 2

What acts to increase calcium levels?

Answer 2

Vitamin D and PTH

Question 3

What acts to decrease calcium levels?

Answer 3

Calcitonin

Question 4

Outline calcitonin

Answer 4

Secreted by thyroid parafollicular cells (note not parathyroid cells)
Can reduce calcium acutely, not physiologically important as thyroidectomy shows no negative impact on calcium levels

Question 5

Outline Vitamin D3 production

Answer 5

Occurs in skin - 7-dehydrocholesterol interacts with UVB light to make pre-vitamin D3, which is then converted into vitamin D3

Question 6

Outline vitamin D production

Answer 6

Vitamin D3 from skin and D2 from diet enters the liver through the bloodstream
25-hydroxylase catalyses conversion into 25(OH)cholecalciferol in the liver
25(OH)cholecalciferol converted to 1,25(OH)2cholecalciferol (calcitriol) in the kidney, catalysed by 1 alpha-hydroxylase

Question 7

How is serum vitamin D measured?

Answer 7

Calcitriol never measured itself
25-OH much more stable in blood and easy to measure - gives good indicator of vitamin D status

Question 8

What are the actions of calcitriol?

Answer 8

Overall effect is increase in serum calcium and phosphate
Increases calcium and phosphate reabsorption in kidney
Increases calcium and phosphate absorption in the gut

Question 9

What are the actions of PTH?

Answer 9

Net effects is increased calcium and decreased phosphate
Increases calcium resorption from bone (increases osteoclast activity)
Increases calcium reabsorption in the kidney
Increases phosphate excretion/decreases phosphate reabsorption
Increase 1 alpha-hydroxylase activity (therefore increases calcitriol synthesis)
Indirectly increases gut absorption of calcium and phosphate(overall net decrease in phosphate due to increased excretion)

Question 10

How does PTH increase renal phosphate excretion?

Answer 10

Inhibits sodium phosphate co-transporter in the kidney - responsible for reabsorption of phosphate
Inhibits this transporter along with FGF23

Question 11

What is the overall role of FGF23?

Answer 11

Increases phosphate excretion by preventing phosphate reabsorption, and also decreases phosphate absorption in the gut

Question 12

What is the mechanism of FGF23?

Answer 12

FGF23 prevents renal phosphate reabsorption by inhibiting the sodium/phosphate co-transporter from transporting sodium and phosphate out of the renal filtrate (note sodium is affected here, not calcium)
FGF23 also reduces 1 alpha-hydroxylase activity and promotes calcitriol degradation, lowering calcitriol levels and reduces phosphate absorption in the gut

Question 13

What are the signs and symptoms of hypocalcaemia?

Answer 13

Sensitises excitable tissue; muscles, neurons etc…
Paresthesia (hands, mouth, feet, lips)
Convulsions
Arrythmias
Tetany (muscle contracts and cannot relax)
Chvostek’s sign - tapping of zygomatic arch causes facial twitch
Trousseau’s sign - carpopedal spasm induced by inflating of blood pressure cuff

Question 14

What are the 2 main overarching causes of hypocalcaemia?

Answer 14

Low PTH levels - hypoparathyroidism
Low vitamin D levels - vitamin D deficiency
(can have low calcium in diet, but generally looking at the 2 above causes)

Question 15

How can hypoparathyroidism arise?

Answer 15

Surgery - neck surgery, classic example is a thyroidectomy
Autoimmune damage
Congenital (i.e. agenesis - rare, would present as a neonate)

Question 16

How can vitamin D deficiency arise?

Answer 16

Poor diet/malabsorption
Lack of UV light, sunlight exposure
Impaired production (renal failure)

Question 17

What are the signs and symptoms of hypercalcaemia?

Answer 17

“Stones, abdominal moans, psychic groans”
Reduced excitability of tissue - lack of 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)
Overall: kidney stones, slowing of GI tract, slowing of CNS

Question 18

What are the causes of hypercalcaemia?

Answer 18

(Primary/secondary/tertiary) hyperparathyroidism
Malignancy - certain cancers secrete PTH-related peptide that acts at PTH receptors
Vitamin D excess (rare)

Question 19

What is primary hyperparathyroidism?

Answer 19

Parathyroid adenoma - produces too much PTH
Calcium increases - no negative feedback due to autonomous secretion of PTH from adenoma

Question 20

What is the biochemistry of primary hyperparathyroidism?

Answer 20

High calcium
Low phosphate - increased renal phosphate excretion
High PTH (not suppressed by hypercalcaemia)

Question 21

What is the normal treatment for primary hyperparathyroidism?

Answer 21

Parathyroidectomy

Question 22

What are the risks of untreated hyperparathyroidism?

Answer 22

Osteoporosis
Renal calculi (stones)
Psychological impact - mental function, mood

Question 23

What is secondary hyperparathyroidism?

Answer 23

Increased PTH due to hypocalcaemia, normal physiological response
Problem lies with root cause of hypocalcaemia, not PTH
PTH Is unable to raise calcium levels for whatever reason

Question 24

What is the main difference between primary and secondary hyperparathyroidism?

Answer 24

Primary has abnormal parathyroid gland, secondary is normal
Primary has hypercalcaemia, secondary has hypocalcaemia

Question 25

What are the causes of secondary hyperparathyroidism?

Answer 25

Most common is vitamin D deficiency
common - diet, reduced sunlight
less common, but important - renal failure, inability to make calcitriol
Absence of calcitriol makes elevating calcium almost impossible

Question 26

What is the treatment of secondary hyperparathyroidism?

Answer 26

Vitamin D replacement
Normal renal function - 25(OH) vitamin D - patient’s kidneys will convert to calcitriol
Impaired renal function/renal failure - give alfacalcidol (active vitamin D replacement)

Question 27

What can untreated secondary hyperparathyroidism lead to?

Answer 27

Tertiary hyperparathyroidism

Question 28

What is tertiary hyperparathyroidism?

Answer 28

Chronic hypocalcaemia (chronic vit-D deficiency or chronic renal failure)
Chronic elevated PTH production - leads to eventual hyperplasia of parathyroid glands
Parathyroid glands start to** autonomously secrete PTH**

Question 29

Outline tertiary hyperparathyroidism

Answer 29

Tertiary hyperparathyroidism is rare
Occurs usually in chronic renal failure - inability to make calcitriol
PTH increases (hyperparathyroidism)
Parathyroid glands enlarge (hyperplasia)
Autonomous PTH secretion eventually leads to hypercalcaemia
Notice secondary hyperparathyroidism features hypocalcaemia, leading to tertiary which is hypercalcaemic

Question 30

What is the treatment for tertiary hyperparathyroidism?

Answer 30

Parathyroidectomy
Can also give bisphosphonates, prevents osteoclast activation

Question 31

What is the diagnostic approach with hypercalcaemia?

Answer 31

First thing to look at should be the PTH

Question 32

What might cause high calcium with low PTH?

Answer 32

Malignancies (secretion of PTH-related peptide)
Malignancy always needs to be ruled out first

Question 33

What is the diagnosis for raised calcium and PTH?

Answer 33

Hyperparathyroidism
Primary if renal function is normal
Tertiary if abnormal renal function

Question 34

What can you expect to see with Vitamin D deficiency?

Answer 34

Calcium will be low (also can be lower end of normal), PTH will be high
Vitamin D is measured as 25(OH) vitamin D, calcitriol itself very difficult to measure

Question 35

How does PTH cause bone resorption?

Answer 35

Binds to PTH receptor on osteoblast, which combined with osteoclast binding factors produces an osteoclast, which resorbs bone

Question 36

What can be used to counteract chronically raised PTH levels?

Answer 36

Bisphosphonates

Question 37

What is the mechanism of action for bisphosphonates?

Answer 37

Inhibits osteoclast activation and activity

Question 38

What are some risk factors for vitamin D deficiency?

Answer 38

Pigmented skin (South asian, african, carribean, south american ancestry etc…)
Living in low sunlight country (e.g. the UK)
Low calcium in diet (poor diet, vegan diets - no dairy and so potentially low calcium)