Calcium and Phosphate Regulation Flashcards
1,25 (OH)2 Vitamin D3 - other names
Calcitriol
What is the effect of PTH?
Increases serum Ca2+
How does PTH increase serum Ca2+?
- Bone: binds to PTHRs on osteoblasts which release OAFs (incl RANKL) that activate osteoclasts to break down bone and release Ca2+ and PO43- into the bloodstream.
- Kidneys: Binding of PTH causes increased reabsorption of Ca2+ and increased excretion of PO43-
Also: increases the production of 1-alpha-hydroxylase which increases calcitriol concentration and causes increased absorption of phosphate and calcium in the small intestine.
In what form is calcium found in bones?
hydroxyapatite crystals (containing calcium and phosphate)
How is phosphate regulated?
- in the gut and in the kidneys
- FGF23 -> inhibits the Na+/PO43- cotransporter in cells of proximal convoluted tubule -> reduces reabsorption, increases excretion in urine
- FGF-23 also has a negative effect on calcitriol and there is less phosphate absorption in the kidney
FGF-23 reduces the levels of phosphate in the blood.
How is phosphate reabsorbed?
- in the proximal convoluted tubule cells in the kidney
- via a sodium phosphate cotransporter which is inhibited by FGF23 and PTH
Where is FGF 23 derived from?
Bone (from osteocytes)
What are the serum phosphate levels in primary hyperparathyroidism?
- low because there is a lot of phosphate excretion via urine
- PTH inhibits sodium phosphate cotransporter
How are parathyroid cells regulated?
- high serum calcium -> binding of Ca2+ to calcium receptors inhibits PTH release
- low serum calcium, less binding -> less inhibition -> more PTH release
What are the effects of calcitriol?
- increased Ca absorption in the gut
- Ca2+ maintenance in bone
- negative feedback on PTH
What are the 2 sources of vitamin D?
- ergocalciferol (Vitamin D2) from the diet
- 7-dehydrocholesterol is turned into VitaminD3 (cholecalciferol) via UVB light
What are the 5 main causes of Vitamin D deficiency?
- Malabsorption or dietary insufficiency (e.g. coealiac disease, IBD)
- Lack of access to UVB light / lack of sunlight
- Liver disease / liver failure
- Renal disease / renal failure
- Receptor defects (very rare, autosomal recessive, resistant to vitamin D treatment)
What is the role of the liver with regards to vitamin D?
- stores inactive precursor
HOW DO CHANGES IN EC CALCIUM AFFECT NERVE AND SKELETAL MUSCLE EXCITABILITY?
- To generate an AP in nerves/skeletal muscle requires Na+ influx across cell membrane
- HIGH ec calcium (HYPERcalcaemia) = Ca2+ blocks Na+ influx, so LESS membrane excitability
- LOW ec calcium (HYPOcalcaemia) = enables GREATER Na+ influx, so MORE membrane excitability
What are the signs and symptoms of HYPOcalcameia?
- Ca2+ below normal range (2.2 - 2.6 mmol/L)
- sensitises excitable tissues (muscle cramps/ tetany, tingling)
- parasthesia (= pins and needles, hands, mouth, feet, lips)
- convulsions & seizures if it drops very fast
- arrythmias
- tetany
-> CATs go numb
What is chvosteks sign? What does it indicate?
- Tap facial nerve just below zygomatic arch
- Positive response = twitching of facial muscles
- Indicates neuromuscular irritability due to hypocalcaemia
What is trousseaus sign?
Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia
What are some causes of hypocalcaemia?
- Vitamin D deficiency
- Low PTH levels = hypoparathyroidism
Surgical – neck surgery
Auto-immune (AI destruction of PT glands is possible)
Magnesium deficiency - PTH resistance eg pseudohypoparathyroidism
- Renal failure
Impaired 1a hydroxylation
decreased production of 1,25(OH)2D3
What are the signs and symptoms of hypercalcaemia?
- moans, bones, stones and groans
- reduced neuronal excitability; atonal muscles.
- stones = renal effects (polyuria and thirst (not known why) nephrocalcinosis, renal cholic, chronic renal failure
- abdominal moans = GI effects (anorexia, nausea, dyspepsia, constipation, pancreatitis) -> gut has slowed down
- psychic groans = CNS effects (fatigue, depression, impaired concentration, altered mentation, Coma (usually >3mmol/L)
What are the signs and symptoms of hypercalcaemia?
- moans, bones, stones and groans
- reduced neuronal excitability; atonal muscles.
- stones = renal effects (polyuria and thirst (not known why) nephrocalcinosis, renal cholic, chronic renal failure
- abdominal moans = GI effects (anorexia, nausea, dyspepsia, constipation, pancreatitis) -> gut has slowed down
- psychic groans = CNS effects (fatigue, depression, impaired concentration, altered mentation, Coma (usually >3mmol/L)
What are some causes of hypercalcaemia?
- Parathyroid adenoma
- some tumors secrete a PTH-like peptide
(these first 2 are the cause of hypercalcaemia 90% of the time) - conditions with high bone turnover (hyperthyroidism, Paget’s disease of bone - immobilised patient)
- vitamin D excess (rare) -> would be e.g. if someone is taking tablets containing calcium
What happens in primary hyperparathyroidism?
- there is an adenoma of the PTG that produces PTH inappropriately and increases serum calcium.
- there is NO negative feedback: Autonomous PTH secretion DESPITE hypercalcaemia
Blood biochemistry in primary hyperparathyroidism
- Raised calcium
- Low phosphate
- Raised (unsuppressed) PTH
Hypercalcaemia of malignancy
- raised calcium
- suppressed PTH
(in HC of malignancy there are two reasons why Ca2+ might be increased”
- tumor secretes a PTH like peptide.
- in bony metastases: cancer spreads to bone and causes calcium release
(treat with bisphosphonates)
What does vitamin D deficiency cause?
- Definition: lack of mineralisation in bone
- Results in “softening” of bone, bone deformities, bone pain; severe proximal myopathy.
- Rickets in children
- osteomalacia in adults
Treatment of primary hyperparathyroidism?
Surgery - parathyroidectomy
Secondary Hyperparathyroidism
- PTH increases appropriately to try and increase serum calcium levels
- e.g. vitamin D deficiency causing hypocalcaemia
What are the biochemical findings in vitamin D deficiency?
- low 25-hydroxy-vitamin D3
- plasma Ca2+ low (may be normal if secondary hypreparathyroidism has developed)
- low PO43- in plasma
- high PTH in secondary hyperparathyroidism
How is vitamin D measured in the blood?
- generally measure 25-hydroxy Vitamin D
- calcitriol is very difficult to measure because you would have to have special tubes and with special foil etc.
How do you treat vitamin D deficiency?
In patients with normal renal function: - Give 25 hydroxy vitamin D (25 (OH) D) Patient converts this to 1,25 dihydroxy vitamin D (1,25 (OH)2 D) via 1a hydroxylase Ergocalciferol 25 hydroxy vitamin D2 Cholecalciferol 25 hydroxy vitamin D3 Gives as tablets.
In patients with renal failure
- inadequate 1a hydroxylation, so can’t activate 25 hydroxyl vitamin D preparations
Give Alfacalcidol - 1a hydroxycholecalciferol
Excess vitamin D
- intoxication
- Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium
- Can occur as a result of:
- excessive treatment with active metabolites of vitamin D eg Alfacalcidol
- granulomatous diseases such as sarcoidosis, leprosy and tuberculosis (macrophages in the granuloma produce 1a hydroxylase to convert 25(OH) D to the active metabolite 1,25 (OH)2 D
