calcium Flashcards
what % of body calcium is in the bones?
99%
what % of bone calcium is exchangeable with the ECF?
1%
what % of blood calcium is protein bound?
50%
what does blood calcium bind to?
(40% albumin, 10% globulin)
what binds the same biding sites on albumin molecules?
hydrogen
what happens to ionised calcium in acidosis?
increases
what happens to ionised calcium levels in alkalosis?
decreases
why does alkalosis cause tingling of the lips and fingers?
hyperventilation causes respiratory alkalosis bc you’re blowing off excess CO2. Tinging of the lips and fingers occurs in hyperventilation fall in ionised calcium
• More calcium outside the cell than inside the cell
what are the 5 phases of cardiac APs and what happens during them?
- 4 – resting membrane, -ve potential maintained by Na/K exchanger – 3 Na for 2 K
- 0- Opening of fast Na+ channels – stabilised by extracellular calcium
- 1 – Early repolarisation as fast sodium channels close
- 2 - plateau phase: Na-Ca exchanger: Na in and calcium out, maintains positive potential
- Repolarisation – sodium and calcium channels close
how does calcium cause tetany and tachyarrhythmias?
• Ca2+ can sit in the Na+ membrane and block it
• Drop in extracellular Ca2+ means less Na+ channels are blocked. Na+ can enter the cell freely and uncontrolled depolarisations happen tetany and tachyarrhythmias
o Hypocalcaemia reduces the threshold for APs to fire
what effect does hypercalcaemia have on nerve firing? what effect does this have on the body?
• Hypercalcaemia slows nerve firing
o Slows muscle contraction
o Slows nerve firing in the brain depression and inability to concentrate
o Slows nerve firing in the smooth muscle of the gut slows peristalsis constipation
how much of body phosphate is mineralised in bone?
85%
how much of serum phosphate is ionised?
almost all
what is extracellular calcium needed for?
o Bone mineral
o Blood coagulation
o Membrane excitability
what is intracellular calcium needed for?
signalling
what is extracellular phosphate needed for?
bone mineral
what is intracellular phosphate needed for?
o Structural
o High energy bonds
o Phosphorylation
what effect does calcium have on PTH?
high levels of calcium inhibits PTH
what does PTH act on?
o Get calcium from bone
o Stop losing calcium from the kidneys
o Absorb more calcium from the gut
what are the 2 cell types in the parathyroid gland? what do they do?
oxyphilic cells - nothing important lol
chief cells - secrete PTH
what cells secrete PTH?
chief cells of the parathyroid gland
when are oxyphilic cells useful?
useful when imaging for if someone has an overactive gland. It takes up technetium-sestambi which helps identify which gland is overactive
how is PTH processed?
- PreproPTH is cleaved by the RER to proPTH
- ProPTH is cleaved by the Golgi to PTH
- PTH is secreted in vesicles
what type of receptor is the calcium sensing receptor?
GPCR
what does the calcium sensing receptor do?
- Reduces PTH secretion
- Increases breakdown of stored PTH
- Suppresses transcription of PTH gene
- Inactivating mutations lead to FHH
what is FHH?
(familial hypocalciuric hypercalcaemia) – calcium levels are higher than normal without any clinical consequences
what is activated vitamin D?
Calcitriol - 1,25-dihydroxycholecalciferol
what stimulates and suppressed PTH gene transcription?
- activated vitamin D suppresses PTH gene transcription
- phosphate stimulated PTH gene transcription
what activates CASR and reduces calcium levels?
cinacalcet
what does CASR activation restrain?
parathyroid proliferation
what organs does PTH act on and what effect does this have?
- Kidney: decreases calcium excretion and increases phosphate excretion
- Bone: increases calcium and phosphate resorption
- Intestine: increases absorption of calcium and phosphate; some evidence for direct effects but mainly indirectly through calcitriol
how is calcium handled in the PCT?
how much is reabsorbed? how? what drives it? and is PTH involved?
- 65% reabsorption
- Paracellular
- PTH-independent
- Driven by voltage gradient
how much calcium is reabsorbed in the LoH?
20%
how does calcium pass into the LoH?
para/transcellular
what is the effect of CASR on the LoH and how?
• CASR downregulates NaK2Cl
o Calcium sensing receptor on the PTH cells is the same one of the LoH cells
what inhibits calcium reabsorption in the LoH and how?
• Inhibited by loop diuretics
o Loop diuretics inhibit NaK2Cl cells
o Furosemide inhibits Na+, K+, Cl- reabsorption, which reduces the gradient for calcium reabsorption
o Serum calcium will fall and urine calcium will increase
how much calcium is reabsorbed in the distal tubule?
10%
what does PTH upregulate in the distal tubule?
o TRPV calcium channels
o Calcium ATPase
o Na/Ca exchanger
what diuretic acts on the distal tubule and what effect does it have?
• Thiazide diuretics target Na+/Cl-channels
o Have opposite effects to loop diuretics
o Na+ levels fall in the cell increases gradient across opposite cell membrane
o Na+ can therefore enter down the conc gradient while calcium passes out the other way
o Thiazide diuretics increase serum calcium
what other effects does PTH have on the kidney?
- Down-regulation of NaPi transporters - Reduced phosphate reabsorption
- Vitamin D Activation - Stimulation of 25(OH) D3 1,25(OH)2 D3
- Proximal tubule gluconeogenesis
- Inhibits sodium/water/bicarbonate reabsorption via effects on Na/H exchanger and Na/K ATPase
what is bone made of mainly?
Bone = Collagen plus Hydroxyapatite
what is mineralisation made of?
calcium + phosphate + alkaline phosphatase
what are osteoblasts made from>
mesenchymal cells
what do osteoblasts do?
o Produce mineral and signal to osteoclasts to resorb bone
o When mineralisation is complete they differentiate into osteocytes
• Osteoblasts release RANKL – promotes osteoclastogenesis and osteoclast function
what are osteoclasts derived from?
myeloid origin
what stimulates RANKL production?
PTH and calcitriol
what downregulates OPG?
PTH and calcitriol
what is OPG? what does it do?
osteoprotegerin
inhibits osteoclastogenesis
what increases gut calcium absorption and how?
Calcitriol increases RANKL which increases gut calcium absorption
what effet does glucocorticoid have on bone remodelling?
reduce osteoblast numbers and mineral production; increase RANKL
what effect does oestrogen have on bone remodelling?
epiphyseal closure; reduce cytokine sensitivity and inhibits bone remodelling
what causes osteoperosis?
high levels of PTH causes breakdown of bone
what does vitamin D deficiency lead to?
osteomalacia
what does primary hyperparathyroidism present with?
- Terminal tuft erosion – breakdown of bone in the fingers
- Rugger jersey spine – breakdown of bone in the spine so it looks stripy.
- Subperiosteal erosion
- Brown tumour – focal area where there were really high levels of PTH and excess remodelling. Isn’t a tumour but can be mistaken for a malignancy
what is vitamin D produced from?
cholesterol
what is vitamin D hydroxylated into?
25-hydroxyvitamin D
in the liver, what is vitamin D converted to?
25(OH)D
what is the vitamin D receptor?
- Nuclear receptor found on DNA in a heterodimer with the retinoid acid receptor
- Also a membrane bound receptor
explain the negative feedback inhibition involving the vitamin D receptor?
In most cells there is a negative feedback inhibition: activation of the VDR inhibits the action of 1α hydroxylase, therefore reducing the amount of activated vitamin D able to bind to the VDR.
where are activated macrophages found?
TB and sarcoid granulomata
how can granulomas lead to hypercalcaemia?
• Can lead to high levels of vitamin D leaking into the circulation from the granuloma –> hypercalcaemia
what is the role of calcitrol?
increasing gut calcium and phosphate absorption
what factors determine calcium absorption?
bile salts, free fatty acids and fibre in the diet; gastric acidity
what effect do PPIs have on calcium?
PPIs reduce calcium uptake
what effect does vitamin D have on the parathyroid?
reduction in PTH transcription
what effect does vitamin D have on the bone?
reduces expression of type 1 collagen; increases levels of osteocalcin & RANKL; facilitates osteoclast differentiation
why can vitamin D deficiency lead to myopathy?
bc vitamin D is needed to increase amino acid uptake
what are the bones like in osteomalacia?
soft bones
what are the bones like in osteoperosis?
porous, brittle bones
what effect do osteoperosis and osteomalacia have on BMD?
cause a reduction in BMD
what is FGF23?
phosphatonin, hormone that reduces serum phosphate levels secreted by osteocytes
what does a mutation in FGF23 lead to?
Autosomal dominant hypophosphataemic rickets
what does paraneoplastic FGF23 lead to?
tumour induced osteomalacia
what do low levels of FGF23 lead to?
familial tumoural calcinosis
what is calcitonin a marker for?
medullary thyroid cancer
where is calcitonin released from?
thyroid c-cells
what is the role of calcitonin in humans?
role unclear
what is PTHrP important for?
important in lactation and embryological development
how may an asymptomatic patient with primary hyperparathyroidism present?
o Low BMD o Renal calculi o Renal impairment o Calcium > 3.0mmol/l o Age < 50
how do you diagnose primary hyperparathyroidism?
o Serum calcium and PTH o 24 hr urine calcium o Urine calcium creatinine excretion index o Renal ultrasound o DXA scan
how do you localise an adenoma in primary hyperparathyroidism?
o Neck USS
o MIBI scan
o CT scan
o Parathyroid Venous Sampling
what are signs and symptoms of hypocalcaemia?
convulsions, confusion, tetany, tachyarrhythmias
what causes hypocalcaemia?
Vitamin D deficiency, Chronic kidney disease, PTH resistance
how is hypoparathyroidism treated acutely?
IV or oral calcium replacement
how is hypoparathyroidism treated chronically?
alfacalcidol (1,25 vitamin D3) orally
why is there a risk of kidney stones with chronic treatment of hypoparathyroidism?
However, the lack of PTH means that calcium will continue to be lost from the kidneys at a high rate. This hypercalciuria will increase the risk of kidney stones, even if the serum calcium is low!
why cant PTH be given orally?
peptide hormone
how can PTH be given?
continuous subcutaneous infusions of PTH, given via an insulin pump
what does FHH cause and how?
- Inactivating mutations of the CaSR
- Parathyroid can’t sense high calcium
- PTH not suppressed by high calcium
- CaSR in kidney not activated
- PTH-calcium curve shifts to the right
- High serum Ca, low urine Ca, high serum Mg
