calcium and phosphate regulation Flashcards
calcium homeostasis
is a complex process involving the following 4 components
- serum calcium
- serum phosphate
- parathyroid hormone
- 1,25-dihydroxyvitamin D3 (calcitriol)
more than
99% of total body calcium is stored in bone predominantly as hydroxyapatite, only a very small portion of calcium is available for exchange in the serum
parathyroid hormone is
released by the parathyroid glands in response to low levels of calcium
PTH end organ targets are
- kidneys
- bone
- skeletal system
- GI tract
in the Kidneys PTH
increases renal calcium resorption and phosphate excretion, it does so by blocking the reabsorption of phosphate in the proximal tubular and promotes reabsorption of calcium in the ascending loop of henle, distal tubule and collecting tubule
In the bone
PTH promotes absorption of calcium from the bone in 2 ways; rapid and slow phase
rapid phase
- the rapid phase brings about a rise in serum calcium within minutes and occurs at the levels of osteoblasts and osteocytes, although it seems counter-intuitive that cells that promote deposition of bone are involved in resorption, these cells form an interconnected network known as the osteolytic membrane overlying the bone matrix, but with a small layer of interposed fluid called bone fluid when PTH binds to receptors on these cells, the osteolytic membrane pumps calcium ions from the bone fluid into the extra-cellular fluid
slow phase
bone resorption which takes several days, osteoclasts are activated to resorb bone and then the osteoclasts proliferate
PTH also
converts 25-hydroxyvitamin D to its more active metabolite 1,25-dihydroxyvitamin D3 (calcitriol) by activation of enzyme 1-hydroxylase in the proximal tubules of the kidney
vitamin D3 otherwise known as
cholecalciferol
cholecalciferol is formed
in the skin when a cholesterol precursor (7-dehydroxycholesterol) is exposed to UV light, activation of cholecalciferol then occurs when the substance undergoes 25-hydroxylation in the liver and 1-hydroxylation in the kidney to form calcitriol
primary action of calcitriol
promotes gut absorption of calcium by stimulating formation of calcium binding protein within the interstitial epithelial cells and it also promotes the intestinal absorption of phosphate
calcium in the serum
is normally bound to albumin and only free calcium is biologically active, therefore if a patient has low albumin levels (i.e. liver of renal failure), calcium levels may be measured as low but the patient does not have hypocalcaemia (i.e. there calcium levels are normally or even high) so you have to work out there corrected calcium level
corrected calcium
Ca+ 0.8x(4-albumin)
calciums affect on neuronal membranes
calcium stabilises and discharges neuronal membranes therefore, significant disturbances in serum calcium levels will always cause neurological disturbances
overall net affect of PTH is to
increase calcium and decrease phosphate
calcitonin
is released by the parafollicualr C cells of the thyroid gland in response to hypercalcemia and has the opposite affect to PTH
affect of calcitonin
- inhibits the activation of osteoclasts
- reduces reabsorption of calcium and phosphorous in the GI tract
- reduces reabsorption of calcium in the kidneys
causes of hypercalcaemia
- primary hyperparathyroidism is the most common cause
- malignancy= bone demineralisation caused by metastases to bone or PTHrP
- Drugs
- familial hypocalciuric hypercalcaemia
- sarcoidosis
PTHrP
squamous cell lung cancer can release parathyroid hormone resembling peptide which mimics PTH
drugs causing hypercalcaemia
Vitamin D toxicity, Thiazide diuretics, lithium
why do thiazide diuretics cause hypercalcaemia
they promote potassium and magnesium excretion but inhibit calcium excretion
familial hypocalciuric hypercalcaemia
- autosomally dominant inherited condition caused by mutations in the CASR gene
- Biologically characterised by moderate hypercalcaemia but inappropriate levels of PTH and urinary calcium
- PTH levels are normal and calcium in the urine is low
- rarey ever causes any symptoms and is usually an incidental finding and requires no treatment
sarcoidosis
causes hypercalcemia due to the uncontrollable synthesis of 1,25- dihydroxyvitamin D3 (CALCITRIOL) by macrophages
saying for remembering the symptoms of hypercalcaemia
stones, groans, bones and psychiatric overtones
symptoms of hypercalcaemia
ACUTE= thirst, dehydration, confusion, polyuria CHRONIC= Myopathy, nephrolithiasis, osteoporosis, abdominal pain, pancreatitis, nephrogenic diabetes insidious
why does hypercalcaemia cause nephrogenic diabetes insipidus
because Calcium is a competitive inhibitor of ADH
primary hyperparathyroidism
overactivity of the parathyroid gland causing the excessive production of PTH, high PTH and High Calcium (BUT PTH CAN BE INNAPROPRIATLEY NORMAL)
causes of primary hyperparathyroidism
- most commonly caused by a benign adenoma
- more rarely caused by parathyroid hyperplasia associated with MEN 1 and MEN2A Syndromes
- even more rarely caused by a parathyroid carcinoma
diagnosis of primary hyperparathyroidism
- Raised PTH, Raised Calcium, increased urinary calcium excretion
- Sestimibi scan to plan for surgery
treatment of acute hypercalcaemia
- 0.9% NaCl 4-6 litres over 24 hours to treat the dehydration
- Loop diuretics (which diurese calcium) but only after rehydration
- Bisphosphonates= but work over 2-3 days so not useful acutely
- In life-threatening scenarios IV calcitonin but this has to be used with extreme caution as it can cause deadly hypocalcaemia
definitive management for primary hyperparathyroidism
Parathyoidectomy (but only if indicated)
indications for surgery
end organ damage caused by hypercalcaemia, very high serum calcium (greater than 2.85mmol/l), under age 50, EGFR less than 60ml/min
end organ damage caused by hypercalcaemia
- osteitis fibosa et cystica= skeletal disorder resulting in loss of bone mass and the weakening of bones caused by peri-trabecular fibrosis
- gastric ulcers
- renal stones
- osteoporosis
- salt and pepper sign of skull= tiny well-defined lucencies in the skull vault caused by the resorption of trabecular bone
hypercalcaemia caused by malignancy
RAISED CALCIUM AND ALP BUT LOW PTH BECAUSE OF NEGATIVE FEEDBACK
investigations for hyperclacaemia caused by malignancy
X-rays, CT, MRI, isotope bone scan
secondary hyperparathyroidism
is not a disease it is the normal physiological increase in the secretion of PTH in response to low levels of calcium (most commonly caused by renal failure which causes renal diuresis) but chronic secondary hyperparathyroidism can cause tertiary hyperparathyroidism
tertiary hyperparathyroidism
persistent hyperparathyroidism despite treating the underlying cause of the secondary hyperparathyroidism
biochemistry of primary hyperparathyroidism
- HIGH PTH
- HIGH CA
- LOW PHOSPHATE
- HIGH CALCITRIOL
biochemistry of secondary hyperparathyroidism
- HIGH PTH
- LOW CA
- HIGH PHOSPHATE
- LOW CALCITRIOL
biochemistry of tertiary hyperparathyroidsim
- HIGH PTH
- HIGH CA
- HIGH PHOSPHATE
- LOW CALCITRIOL
kidneys are responsible for
excreting phosphate and converting cholecalciferol to calcitriol which is why phosphate is high and calcitriol is low in secondary hyperparathyroidism because the kidneys cannot function properly, despite the increase in PTH, calcium cannot rise in response because calcitriol isn’t made so it can’t be absorbed through the gut
treatments of secondary hyperparathyroidism
- treat the underlying chronic kidney disease, calcitriol, restrict dietary intake of phosphate
treatment of tertiary hyperparathyroidism
calcitriol, and restrict dietary intake of phosphate, if refractory to medical management parathyroidecotmy could be considered
hypocalcaemia is most commonly caused by
hypoparathyroidism (particularly post-thyroidecomty)
hyocalcaemia can also be caused by
- vitamin D deficiency (malnutrition, malabsorption)
- chronic renal failure
- pancreatitis
- hyperventilation
- rhabdomyolysis
- loop diuretics and bisphosphonates
- congenital absence (digeourge syndrome)
- hypoamgnaesaemia
symptoms of hypocalcaemia
- neuronal hyperactivity- parasethesia, hyperactive reflexes, muscles spasms, seizures, prolongation of the QT interval, tetany, muscle weakness
signs seen in hypocalcaemia
- chovsteks sign= percussion of the facial nerve causes twitching of the facial muscles
- trousseau sign= carpopedal spasm when the upper arms is compressed by a blog pressure cuff
management of hypoparathyroidism
calcium and vitamin D supplementation
why does hypomagnasaemia cause hypoparathyroidism
calcium release from cells is dependant on magnesium, in mageniusm deficiency, intra-cellular calcium is high so PTH release is inhibited and skeletal and muscle receptors become less sensitive to PTH
management of hypomaganseamia causing hypocalcaemia
calcium and magnesium replacement
causes of hypomagnasaemia
- alcohol, drugs (thiazide diuretics and PPIS), pancreatitis, malabsorption
psuedophyoparathyroisim
generic defect caused by mutation of GNAS 1 gene
- low calcium but PTH concentrations are elevated because of PTH resistance
presentation of psudeohypoparathyroidism
- bone abnormalities (mcewan albright)
- obesity
- subcutaneous clarification
- learning disability
- brachydactyly (4th metacarpal)
pseudo-psuedohypoparathyoidism
is the exact same as pseudo-hypoparathyroidism but patients have NORMAL CALCIUM
rickets and osteomalacia
same disease except rickets is the name given when it occurs in children
what is rickets/ osteomalacia
deficiency in calcium and phosphorous causing weakened bones
people with chronic renal disease may have high
25-hydroxyvitaminD3 levels so have to check there 1,25-hydroxyviatmin D3 levels
long term consequences of vitamin D deficiency
- demineralisation/ fractures
- osteomalacia/ rickets
- malignant especially of the colon
X-linked hypophosphataemia
vitamin D resistant rickets
- PHEX or FGF23 gene mutation
- FGF 23 regulates phosphate levels in plasma and is secreted by osteocytes in response to calcitriol
- low phosphate but high vitamin D
- treat with phosphate and Vitamin D supplementation
