1B calcium dysregulation Flashcards
Describe the hormonal control in the increase of serum calcium
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Vitamin D
- Synthesised in skin or intake via diet
- Parathyroid Hormone (PTH) (secreted by parathyroid glands)
- Main regulators of calcium (and phosphate) homeostasis via actions on kidney, bone and gut
Describe the hormonal control in the decrease of serum calcium
- Calcitonin (secreted by thyroid colloid)
Can reduce calcium acutely, but no negative effect if parafollicular cells are removed eg thyroidectomy
What are the 2 types and sources of Vitamin D?
- Vitamin D2 (ergocalciferol) from diet e.g. oily fish
- Vitamin D3 (cholecalciferol) synthesised in skin when exposed to sunlight
How is vitamin D3 made and both D2 and D3 metabolised?
Vitamin D becomes activated after undergoing both hydroxylation steps
1,25(OH)2 cholecalciferol is aka calcitriol - the active form of vitamin D
What is serum 25-OH cholecalciferol a good indicator of?
Body vitamin D status, as calcitriol is difficult to measure in blood
How does calcitriol regulate its own synthesis?
It decreases transcription of 1 alpha hydroxylase - negative feedback
What are the effects of calcitriol on the bone?
Increases Ca2+ reabsorption by binding to calcitriol receptors on osteoblasts which release OAFs → Osteoclasts > osteoblasts (ONLY AT LOW SERUM CALCIUM)
- in normal serum calcium, calcitriol works to increase bone formation → osteoblasts > osteoclasts
- n.b. Increase of reabsorption of Ca2+ from the bones itself INTO the blood stream
What are the effects of calcitriol on the kidney?
Increases Ca2+ and phosphate reabsorption into blood by kidney from urine
What are the effects of calcitriol on the gut?
Increases Ca2+ and phosphate absorption from food into blood
What are the effects of PTH on the bone?
Increases reabsorption of calcium from bone
What are the effects of PTH on the kidney?
- Increases calcium reabsorption from kidney from urine
- Increases phosphate excretion
- Increases 1-alpha-hydroxylase activity → Increases calcitriol synthesis
What are the effects of PTH on the gut?
Through increase in 1-alpha-hydroxylase activity and through increased calcitriol synthesis, there is increase in Ca2+ and phosphate absorption from gut.
So PTH doesn’t directly affect gut
What is the overall affect of PTH on plasma calcium levels?
Overall increase
What is the overall affect of PTH on plasma phosphate levels?
Net loss → the phosphate loss from the kidney tends to outweigh the phosphate reabsorption from the gut.
What specifically happens when PTH interacts with bone?
- PTH binds to PTH receptor on osteoblasts (cells that build bone)
- Stimulates osteoblasts to make osteoclast activating factors (OAFs) e.g. RANKL (receptor activator of nuclear factor kappa-B ligand)
- Osteoclasts (cells that consume bone) are switched on and dissolve bone, releasing calcium into the blood stream
How does phosphate reabsorption in kidneys happen?
- Phosphate is reabsorbed via sodium-phosphate co-transporter - this also results in less sodium excretion in urine
- Increased phosphate loss in urine would lower serum phosphate levels
How does PTH work in phosphate reabsorption?
- PTH inhibits renal phosphate reabsorption by inhibiting these transporters
- In primary hyperparathyroidism, serum phosphate is low due to increased urine phosphate excretion
What is FGF23 and what does it do?
- Fibroblast Growth Factor 23 (hormone) is derived from bone
- Also inhibits phosphate reabsorption in kidneys by inhibiting Na+/PO43- co-transporters
- Also inhibits calcitriol synthesis causing less phosphate absorption from gut from food
What is hypocalcaemia?
Low serum calcium
How does hypocalcaemia affect action potential generation?
- There’s low extracellular calcium so this enables greater Na+ influx as there’s less competition for Na+ to move across membrane
- Means MORE membrane excitability
What are clinical symptoms of hypocalcaemia?
- It sensitises excitable tissues
- Paraesthesia (tingling) of hands, mouth, feet, lips
- Convulsions- fits
- Arrhythmias- unusual heart rhythms
- Tetany- contract muscles but can’t relax again
- Mnemonic- CATs go numb
What is Chvostek’s sign?
- You tap facial nerve just below zygomatic arch (cheekbone)
- Since there’s more membrane excitability, you get a positive response of twitching of facial muscles
- Indicates neuromuscular irritability due to hypocalcaemia
What is Trousseau’s sign?
- Inflate a BP cuff for several minutes around patient’s arm
- This induces carpopedal (fingers) spasm and muscles contract and can’t relax again (tetany)
- This is due to neuromuscular irritability due to hypocalcaemia
What are 2 causes of hypocalcaemia?
- Vitamin D deficiency
- Low PTH levels- hypoparathyroidism
What are causes of vitamin D deficiency?
- Malabsorption or dietary insufficiency
- Inadequate sun exposure
- Liver disease
- Renal disease
- Vit D receptor defects (rare)
What are the consequences of vitamin D deficiency?
- There is a lack of bone mineralisation causing ‘soft bones’
- In children they get rickets (bowing of bones)
- In adults, bones are more formed so they get osteomalacia (predisposed to fractures and proximal myopathy (especially thigh muscles))
What are four causes of low PTH levels?
- Surgical- neck surgery could have damaged parathyroid glands
- Auto-immune- one of the most common reasons
- Magnesium deficiency- it’s needed to make PTH
- Congenital (agenesis of parathyroid gland i.e. it doesn’t develop in embryo- rare)
What are causes of hypercalcaemia?
- Primary hyperparathyroidism (commonest)
- Malignancy
- Vitamin D excess (rare)
How does primary hyperparathyroidism cause hypercalcaemia?
- Too much PTH
- Usually due to a parathyroid gland adenoma
- No negative feedback- high PTH, but high calcium
What malignancies can be seen in hypercalcaemia?
- Bony metastases produce local factors to activate osteoclasts
- Certain cancers (e.g. squamous cell carcinomas) secrete PTH-related peptide that acts at PTH receptors
What is the relationship between PTH and calcium?
- If calcium falls, parathyroid glands sense this and release more PTH
- If we have too much calcium, there’s negative feedback and parathyroid glands don’t release PTH
What happens in primary hyperparathyroidism?
- If we get a parathyroid adenoma it produces too much PTH
- Calcium increases but there’s no negative feedback to PTH due to autonomous PTH secretion from adenoma
What is the biochemistry of primary hyperparathyroidism?
- High calcium
- High PTH (not suppressed by hypercalcaemia negative feedback)
- Low phosphate- increased renal phosphate excretion (inhibition of sodium-phosphate transporter in kidney)
What is the treatment of primary hyperparathyroidism?
Parathyroidectomy is the main treatment
What are the risks of untreated primary hyperparathyroidism?
- Osteoporosis due to osteoclasts constantly breaking down bone
- Renal calculi (stones)
- Psychological impact of hypercalcaemia- mental function, mood
What happens in secondary hyperparathyroidism?
- It’s a normal physiological response to hypocalcaemia
- Calcium will be low or normal
- PTH will be high (hyperparathyroidism) secondary to the low calcium
- This is different from primary hyperparathyroidism where calcium is high
What are the causes of secondary hyperparathyroidism?
- Most common cause is vitamin D deficiency due to diet, reduced sunlight
- Less common, due to renal failure- can’t make calcitriol in renal failure
What is the treatment for secondary hyperparathyroidism in people with and without kidney failure?
Vitamin D replacement
What vit D replacement can patients with normal renal function receive?
- 25 hydroxy vitamin D- inactive vit D
- They convert it to 1,25 dihydroxy vitamin D via 1alpha hydroxylase
- Can give ergocalciferol (25 hydroxy vitamin D2) or cholecalciferol (25 hydroxy vitamin D3)
- Can get at chemists/supermarket
What vit D replacement can patients with renal failure get?
- There’s inadequate 1alpha hydroxylation, so can’t activate 25 hydroxy vitamin D
- We give them alfacalcidol - 1alpha hydroxycholecalciferol- this is active vitamin D
- Reserved for renal failure patients so needs to be prescribed
What happens in tertiary hyperparathyroidism?
- It’s rare
- When you have chronic renal failure you can’t make calcitriol so you have chronic vit D deficiency
- Parathyroid glands start secreting more PTH to make up for drop in calcitriol so calcium doesn’t become low
- One or more of these glands enlarge (hyperplasia) to the point where they can’t be switched off
- Autonomous PTH secretion happens causing hypercalcaemia
What is the treatment for tertiary hyperparathyroidism?
Parathyroidectomy
What happens in hypercalcaemia due to malignancy?
- There is high calcium
- There is low or suppressed PTH
