(endo) regulation of calcium and phosphate Flashcards
what is the recommended daily intake of calcium?
approx 1000mg/day
where is the majority of calcium found in the body?
skeleton & teeth
in what form is calcium mainly found in the body?
calcium hydroxyapatite crystals
what percentage of total body calcium is intracellular and what is extracellular?
intracellular = 1% extracellular = 0.1%
where is extracellular calcium found?
mainly plasma
approx 2.5 mmol/L
what are the two forms of extracellular calcium?
1) ionised Ca2+ (biologically active)
2) bound Ca2+
which form of extracellular calcium is the biologically active form?
(unbound) ionised calcium
what is bound calcium usually bound to?
1) plasma proteins (45%)
2) anions (e.g. bicarbonates, phosphate, lactate)
which anions is extracellular Ca2+ usually bound to in its inactive state?
bicarbonates, phosphates, lactate
how is total body calcium usually distributed?
1) skeleton (99%)
2) intracellular (1%)
3) extracellular (0.1%)
which two susbtances increase serum calcium levels?
1) parathyroid hormone
2) vitamin D
from where is PTH secreted?
parathyroid glands
where is vitamin D produced?
1) synthesised in the skin
2) ingestion via diet
where do the main regulators of calcium & phsophate act?
1) kidney
2) bone
3) gut
which substance acts to decrease serum calcium levels?
calcitonin
from where is calcitonin secreted?
thyroid parafollicular cells
what impact does calcitonin have on serum calcium levels?
can acutely reduce serum calcium levels
what is the impact of a thyroidectomy on serum calcium levels?
1) thyroid parafollicular cells removed = no calcitoni secretion BUT no significant negative effect
2) parathyroid glands removed = hypocalcaemia
what are the two sources of vitamin D?
1) diet
2) synthesis in the skin
which form of vitamin D is taken in via the diet?
ergocalciferol (vitamin D2)
which form of vitamin D is synthesised in the skin?
cholecalciferol (vitamin D3)
explain how vitamin D is metabolised in the skin
in the skin =
7-dehydrocholesterol to pre-vitamin D3 to vitamin D3
in the liver =
25-hydroxylase converts vitamin D3 into 25-OH cholecalciferol
in the kidneys =
1-alpha hydroxylase converts 25-OH cholecalciferol into 1,25(OH)2-cholecalciferol
explain how vitamin D ingested via the diet is metabolised
ingested in the diet =
vitamin D3
in the liver =
25-hydroxylase converts vitamin D3 into 25-OH cholecalciferol
in the kidneys =
1-alpha hydroxylase converts 25-OH cholecalciferol unto 1,25(OH)2-cholecalciferol
which enzyme is involved in vitamin D metabolism in the liver?
25-hydroxylase
which enzyme is involved in vitamin D metabolism in the kidney?
1-alpha hydroxylase
what is the active form of vitamin D alternatively known as?
calcitriol
vitamin D levels are not directly measured in the body
what is a good indicator of vitamin D levels in the body?
measure serum 25-OH cholecalciferol levels
how is calcitriol synthesis regulated?
calcitriol regulates its own synthesis by reducing 1-alpha hydroxylase transcription (and therefore function) in the kidney
what are the three primary sites of action of calcitriol?
1) bone
2) gut
3) kidney
how does calcitriol act on bone?
stimulates osteoclast activity to increase bone resorption
= increases serum Ca2+
how does calcitriol act on the gut?
1) stimulates increased calcium absorption
2) stimulates increased phosphate absorption
how does calcitriol act on the kidney?
1) stimulates calcium reabsorption from the tubular filtrate
2) stimulates phosphate reabsorption from the tubular filtrate
where are the parathyroid glands found?
embedded in the posterior region of the thyroid glands
four glands = one up & down on each side
which cells make up the parathyroid gland?
chief cells
how is PTH secreted?
secreted as a precursor molecule, pre-pro-PTH then cleaved to PTH
what is the precursor molecule of PTH?
pre-pro-PTH
which receptors on chief cells detect serum calcium levels?
G-protein coupled calcium sensing receptor
what is the relationship between PTH secretion and serum calcium?
PTH secretion is inversely proportional to serum calcium
what is the impact of high serum Ca2+ levels on PTH secretion?
more Ca2+ binds to the calcium-sensing receptor
increased inhibition of PTH secretion from chief cells of the parathyroid gland
what is the impact of low serum Ca2+ levels on PTH secretion?
less Ca2+ binds to the calcium-sensing receptor
reduced inhibition of PTH secretion from chief cells of the parathyroid gland
what are the three primary sites of action of PTH?
1) bone
2) gut
3) kidney
what is the effect of PTH on bone?
effects dependent on both levels of PTH and duration of exposure
1) low levels = stimulate osteoblasts & bone formation
2) prolonged high levels = stimulate osteoclasts & bone resorption
what is the effect of PTH on the kidney?
1) stimulates Ca2+ reabsoprtion
2) stimulates phosphate excretion
3) increases 1-alpha hydroxylase acitivity (to increase calcitriol synthesis)
what is the effect of PTH on the gut?
no direct effect
only indirect effects due to PTH increasing 1-alpha hydroxylase activity in the kidney
= increases calcitriol synthesis
= acts ont he gut to increase Ca2+ and phosphate absorption
what is the effect of PTH on the gut?
no direct effect
only indirect effects due to PTH increasing 1-alpha hydroxylase activity in the kidney
= increases calcitriol synthesis
= acts on the gut to increase Ca2+ and phosphate absorption
the activity of which enzyme is increased as a result of PTH?
1-alpha hydroxylase
which bone cells have the PTH receptor?
osteoblasts and osteocytes
how does PTH act to stimulate osteoclast activity when they do lack the PTH receptor?
1) PTH binds to PTH receptor on osteoblasts
2) stimulates osteoclast activating factors (e.g. RANKL)
3) OAFs stimulate osteoclast activity
4) increased bone resorption
how does calcitriol act to stimulate osteoclast activity when they do lack the calcitriol receptor?
1) calcitriol binds to calcitriol receptor on osteoblasts
2) stimulates osteoclast activating factors (e.g. RANKL)
3) OAFs stimulate osteoclast activity
4) increased bone resorption
what do calcitriol effects on bone depend on?
serum calcium levels
how do serum calcium levels affect how calcitriol affects bones?
low serum calcium = calcitriol increases calcium resorption (osteoclasts > osteoblasts)
normal serum calcium = calcitriol increases bone formation (osteoblasts > osteoclasts)
how does calcitriol act on bone when serum calcium levels are low?
calcitriol increases calcium resorption (osteoclasts > osteoblasts)
how does calcitriol act on bone when serum calcium levels are normal?
calcitriol increases bone formation (osteoblasts > osteoclasts)
explain the three paths of the negative feedback system that regulates PTH levels
1) increased PTH increases serum calcium which feeds back negatively to reduce PTH secretion
2) increased PTH increase calcitriol synthesis which binds to the calcitriol receptor on chief cells and inhibits PTH synthesis
3) increased PTH increases calcitriol which increases serum calcium which feeds back negatively to reduce PTH secretion
what is the function of calcitonin?
reduces serum calcium levels
where are the parafollicular cells of the thyroid gland found?
in between the follicular cells of the thyroid gland
what triggers calcitonin release?
elevated plasma Ca2+ levels detected by the parafollicular cells of the thyroid gland
what are the two main sites of action of calcitonin?
1) bone
2) kidney
how does calcitonin act on bone?
reduces osteoclast activity
how does calcitonin act on the kidney?
increases Ca2+ excretion
where does phosphate reabsorption occur?
kidney
gut
explain how phsophate is reabsorbed in the kidney
phosphate is transported from the tubular filtrate into the proximal tubule cells via the apical Na+-PO43- co-transporter
this phosphate is then transported into the bloodstream
which transporter in the kidney is responsible for phosphate reabsorption?
Na+-PO43- co-transporter
apical
what are the wider implication of increased phosphate reabsorption?
with increased phosphate reabsorption via the sodium phosphate transporter, more sodium is also reabsorbed and less is excreted
= can lead to hypernatraemia
what is the effect of PTH on phosphate reabsorption in the kidney?
PTH inhibits the sodium-phosphate transporter
= inhibits phosphate reabsorption
in primary hyperparathyroidism, what are the expected serum phosphate levels?
low serum phosphate levels due to increased urinary phosphate excretion
what is FGF23 and where does it come from?
fibroblast growth factor 23
= bone-derived
what is the effect of FGF23 on phosphate reabsorption in the kidney?
FGF23 inhibits the sodium-phosphate transporter
= inhibits phosphate reabsorption
what is the impact of FGF23 on calcitriol?
inhibits calcitriol synthesis
= less phosphate reabsorption in the gut and kidney
what is the term used to describe high serum calcium?
hypercalcaemia
what is the term used to describe low serum calcium?
hypocalcaemia
what is required for action potential generation in nerves and skeletal muscle?
requires Na+ influx across a cell membrane
what is the impact of hypercalcaemia on membrane excitability?
increased Ca2+ blocks Na+ influx, so LESS membrane excitability
what is the impact of hypocalcaemia on membrane excitability?
less Ca2+ so more, unopposed Na+ influx, so MORE membrane excitability
what are the signs and symptoms of hypocalcaemia?
convulsions
arrythmias
tetany
paraesthesia (hands, mouth, feet, lips)
(CATs go numb)
= also muscle cramps & tingling
which two signs are associated with hypocalcaemia?
1) Chvostek’s sign
2) Trousseau’s sign
what is Chvostek’s sign and how do you test for it?
tap facial nerve below the zygomatic arch
twitching of facial muscles = positive sign
explain why Chvostek’s sign occurs in patients with hypocalcaemia
hypocalcaemia = lack of Ca2+, unopposed Na+ influx into neurones so increased membrane excitability
= easier contraction + twitching of facial muscles (neuromuscular irritability)
what is Trousseau’s sign and how do you test for it?
inflate a BP cuff for several minutes
= should induce a carpopedal spasm in patients w hypocalcaemia
explain why Trousseau’s sign occurs in patients with hypocalcaemia
hypocalcaemia = lack of Ca2+, unopposed Na+ influx into neurones so increased membrane excitability
= carpopedal spasm cue to neuromuscular irratibility
what are the two main causes of hypocalcaemia?
1) low PTH levels (hypoparathyroidism)
2) vitamin D deficiency
in hypocalcaemia, explain how hypoparathyroidism can be the cause
1) surgical (neck, thyroidectomy)
2) auto-immune damage
3) magnesium deficiency
4) congenital
in hypocalcaemia, explain how vitamin D deficiency can be the cause
1) malabsorption/dietary insufficiency
2) inadequate sun exposure
3) liver disease
4) kidney disease
5) vit D receptor defects
what stimulates renal 1-alpha hydroxylase?
PTH
why can magnesium deficiency lead to hypocalcaemia?
PTH is required to regulate serum calcium levels
= PTH requires magnesium to work
what is the main consequence of vitamin D deficiency?
lack of bone mineralisation = ‘soft bones’
how do ‘soft bones’ present in adults compared to children?
and why?
children = rickets (bowing of bones)
adults = osteomalacia (fractures, proximal myopathy)
(only children’s bones bow as they are more plastic than adult bones due to increased density of Haversian canals)
what are the signs and symptoms of hypercalcaemia?
‘stones, abdominal moans, groans’
1) stones - renal effects
2) abdominal moans - 3) GI effects
groans - CNS effects
what are the renal effects of hypercalcaemia?
nephrocalcinosis - kidney stones + renal colic
what are the GI effects of hypercalcaemia?
dyspepsia constipation pancreatitis anorexia nausea
what are the CNS effects of hypercalcaemia?
fatigue altered mentation depression impaired concentration coma (>3mmol/L)
what are the three main causes of hypercalcaemia?
1) hyperparathyroidism
2) malignancy
3) vitamin D excess
how can hyperparathyroidism cause hypercalcaemia?
(primary) usually due to a parathyroid gland adenoma
= high PTH and subsequent high calcium (w no negative feedback)
how can malignancy cause hypercalcaemia?
1) bony mets can produce local osteoclast activating factors (OAFs) to increase bone resorption
2) certain cancers release PTH-related peptides that act at PTH receptors (e.g. squamous cell carcinomas)
explain how hypercalcaemia can cause constipation
hypercalcaemia = hyponatraemia = reduced neuronal excitability
so atonal muscles in the GI tract
= slowed peristalsis
= constipation
