Calcium is an essential intracellular signalling molecule and has additional extracellular functions – its control is vitally important.
Three hormones are primarily involved with calcium homeostasis:
- 1,25-dihydroxycholecalciferol – steroid hormone formed by vitamin D by successive hydroxylation in liver and kidneys
- Increases calcium absorption from intestine
- Parathyroid hormone – secreted by parathyroids
- Mobilises calcium from bone, and increase urinary phosphate excretion
- Calcitonin – secreted by thyroid
- Inhibits bone resorption (relatively minor)
Phosphate homeostasis is also critical, particularly given its role in ATP, and as a biologic buffer and protein modifier
Calcium
- 1100 g of calcium in young adult – 99 % in skeleton
- Plasma calcium is partly bound to protein and partly diffusible
- Free ionised calcium (Ca2+) in the body fluid that is vital second messenger necessary for coagulation, muscle contraction and nerve function
- Extent of calcium binding to plasma proteins is dependent on plasma protein levels
Calcium in bone is of two types:
- Large poor of stable calcium only slowly exchangeable
- Readily exchangeable reservoir
There are two systems which affect the calcium in bone:
- System regulating plasma Ca – from readily exchangeable pool
- Bone remodelling by interplay of bone resorption and deposition
Calcium is absorbed across brush border of intestinal epithelial cells and then transported into bloodstream – this is regulated by 1,25-dihydroxycholecalciferol
- Increased plasma Ca causes reduction in 1,25-dihydroxycholecalciferol levels
Plasma calcium is filtered by the kidneys, but 98-99 % of filtered Ca is reabsorbed (60 % in proximal tubule, remainder in ascending loop and distal tubule)
- Distal tubular reabsorption depends on the TRPV5 channel which is regulated by PTH
- PTH increases reabsorption of Ca, in response to low serum Ca levels
Phosphorous
- Total body phosphorous 500 – 800 g – 85-90% in skeleton
- 2/3 of total plasma phosphorous is in organic compounds, and the remaining third in inorganic (Pi) compounds (PO4, HPO4, H2PO4)
- Plasma Pi if filtered, and 85 – 90 % of filtered Pi is reabsorbed
- PTH inhibits reabsorption of inorganic phosphorous (thus incr. phosphate excretion)
- Pi is absorbed in the duodenum and small bowel – unclear mechanism into bloodstream, perhaps related to Ca and 1,25-dihydroxycholecalciferol
Vitamin D
Vitamin D3 (cholecalciferol) is produced in the skin by the action of sunlight. It is also ingested in the diet.
Vitamin D3 is then hydroxylated in the liver and converted to 25-hydroxycholecalciferol, and then converted further in the proximal tubules of kidneys to 1,25-dihydroxycholecalciferol (calcitriol).
- This step in the kidneys is regulated by plasma Ca and PO4 – little 1,25-dihydroxycholecalciferol is produced if the plasma Ca levels are high – the kidneys produce an inactive metabolite instead
- Conversely, when serum Ca is low, PTH secretion is increased, and more 1a-hydroxylase is produced which is the enzyme in the kidney which does the conversion to 1,25-dihydroxycholecalciferol
- Low serum PO4 also stimulates increased production of 1,25-dihydroxycholecalciferol
This increases calcium absorption in the intestine, and also facilitates Ca reabsorption in the kidney as well as increasing synthetic activity of osteoblasts.
Parathyroid hormone
PTH is synthesised and secreted by chief cells in the parathyroids.
Half life of PTH is about 10 minutes, and it is rapidly cleaved by Kupffer cells in the liver to inactive fragments, and these are cleared by the kidneys.
Actions of PTH:
- Act directly on bone to increase bone resorption mobilising calcium
- Increases phosphate excretion in the urine, reducing serum phosphate
- Increases reabsorption of Ca in distal tubules; but there is often still hypercalciuria in hyperparathyroidism because the serum load of calcium is so high from bone resorption
- Increases formation of 1,25-dihydroxycholecalciferol in kidneys, increasing Ca gut absorption
- Hyperfunctioning parathyroid adenomas characterised by hypercalcaemia and hypophosphatemia
- Secondary hyperparathyroidism may occur in CKD, where the serum calcium is chronically low with associated chronically excessive PTH secretion leading to parathyroid hypertrophy
- Low Ca in CKD because the kidneys lose the ability to make 1,25-dihydroxycholecalciferol
When plasma Ca is high, PTH is inhibited, and Ca is deposited into the bones.
Magnesium is required to maintain normal PTH secretion – therefore hypocalcaemia can occasionally occur with magnesium deficiency.
Calcitonin
- Calcium lowering hormone release from thyroid
- Released in hypercalcaemia
- Also, may be released in response to gastrin, cholecystokinin, glucagon, secretin, beta agonists, dopamine and oestrogen
- Gastrin most potent – high calcitonin in Zollinger Ellison syndrome
- Calcitonin receptors found in bones and kidneys
- Inhibits bone resorption, which reduces serum calcium. It also increases urinary Ca excretion.
- Exact physiological role in uncertain – no Ca change after thyroidectomy as long as parathyroids remain – and no role in phosphate regulation
Hypercalcaemia of malignancy is a common metabolic complication of cancer
- 20 % of this is due to bone metastases produce bone erosion and increased serum calcium (bone erosion produced by prostaglandins from the tumour)
- The other 80 % is due to elevated circulating levels of PTH related protein (PTHrP) – often seen in RCC
Causes of hypercalcaemia:
- Hyperparathyroidism
- Malignancy
- Vitamin D intoxication
- Granulomatous disease (sarcoidosis, TB, IBD)
- Phaeochromocytoma
- Acute and chronic renal failure, renal transplant
Emergency management of hypercalcaemia:
- Aggressive IV rehydration
- Frusemide
- Bisphosphonates (zoledronic acid)
- Calcitonin
In summary:
- PTH increases serum calcium by mobilising it from bone and increasing reabsorption in the kidney. It also increases production of 1,25-dihydroxycholecalciferol in the kidney from vitamin D.
- 1,25-dihydroxycholecalciferol increases calcium absorption from the intestine and increases reabsorption in the kidney.
- Calcitonin inhibits bone resorption and increases urinary excretion of calcium, lowering serum Ca levels.