4. calcium phosphate magnesium

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Calcium, Phosphate and Magnesium

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  1. 1. Summary of review: Calcium, phosphate and magnesium have important intracellular and extracellular functions with their metabolism often linked through common hormonal signals. A predominant portion of total body calcium is unionised within bone and serves an important structural function. Intracellular and extracellular ionised calcium changes are often linked and have important secretory and excitatory roles. The extracellular ionised calcium is carefully regulated by parathyroid hormone and vitamin D, whereas calcitonin is secreted largely in response to hypercalcaemia.
  2. 2. Phosphorous is needed for bone structure although it also has an important role in cell wall structure, energy storage as ATP, oxygen transport and acid-base balance. Ionised calcium, in as far as it controls PTH secretion, indirectly controls urinary phosphate excretion. When plasma phosphate increases, tubular reabsorption also increases up to a maximum, thereafter phosphate is excreted. The minimum oral requirement for phosphate is about 20 mmol/day
  3. 3. Magnesium is a predominantly intracellular ion that acts as a metallo-coenzyme in more than 300 phosphate transfer reactions and thus has a critical role in the transfer, storage and utilisation of energy within the body. Extracellular magnesium concentrations are largely controlled by the kidneys with the renal tubular maximum reabsorption controlling the plasma magnesium concentration
  4. 4. INTRODUCTION: Calcium is the most abundant mineral in the human body. The average adult body contains approximately 25 000 mmol (1 kg), of which 99% is bound in the skeleton. The total calcium content of the extracellular fluid (ECF) is only 22.5 mmol, of which about 9 mmol is in the plasma.
  5. 5. BONE Bone consists of osteoid, a collagenous organic matrix, on which is deposited complex inorganic hydrated calcium salts known as hydroxyapatites. These have the general formula: Ca10(PO4)6(OH)2 Even when growth has ceased, bone remains biologically active. Continuous turnover ('remodelling') occurs with bone resorption (mediated by osteoclasts) being followed by new bone formation (mediated by osteoblasts).
  6. 6. At any one time, about 5% of bone mass in adults is subject to remodelling. This process is controlled and coordinated by hormones, growth factors and cytokines. Bone formation requires osteoid synthesis and adequate calcium and phosphate for the laying down of hydroxyapatite.
  7. 7. Alkaline phosphatase, secreted by osteoblasts, is essential to the process, probably acting by releasing phosphate from pyrophosphate. Bone provides an important reservoir of calcium, phosphate and, to a lesser extent, magnesium and sodium.
  8. 8. PLASMA CALCIUM In the plasma, calcium is present in three forms: bound to protein (mainly albumin), complexed with citrate and phosphate, and free ions. Only the latter form is physiologically active and it is the concentration of ionized calcium that is maintained by homoeostatic mechanisms.
  9. 9. In alkalosis, hydrogen ions dissociate from albumin, and calcium binding to albumin increases. There is also an increase in calcium complex formation. As a result, the concentration of ionized calcium falls, and this may be sufficient to produce clinical symptoms and signs of hypocalcaemia although total plasma calcium concentration is unchanged. In an acute acidosis, the reverse effect is observed, that is, the ionized calcium concentration is increased.
  10. 10. The most frequently used methods for determining plasma calcium concentration measure total calcium, although ionized calcium can be measured using an ion-selective electrode. Fortunately, measurements of total calcium are satisfactory for most clinical purposes. Changes in plasma albumin concentration will affect total calcium concentration independently of the ionized calcium concentration, leading to possible misinterpretation of results in both hypoproteinaemic and hyperproteinaemic states.
  11. 11. Various formulae have been devised to indicate the total calcium concentration to be expected if the albumin concentration were normal. Although globulins bind calcium to a lesser extent than albumin, the increase in - globulin in patients with myeloma can also increase the total plasma calcium concentration.
  12. 12. CALCIUM-REGULATING HORMONES Calcium concentration in the ECF is normally maintained within narrow limits by a control system involving two hormones: parathyroid hormone (PTH) and calcitriol (vit D) (1,25- dihydroxycholecalciferol). These hormones also control the inorganic phosphate concentration of the ECF. Calcitonin probably has only a minor role in calcium homoeostasis.
  13. 13. Parathyroid hormone This hormone is a single-chain polypeptide, comprising 84 amino acids; as with many peptide hormones, it is synthesized as a larger precursor, pre-pro-PTH (115 amino acids). Prior to secretion, two amino acid sequences are lost; the removal of a 25 amino acid chain produces pro-PTH, a further six amino acids being removed to form PTH itself.
  14. 14. PTH is secreted by the parathyroid glands in response to a fall in plasma (ionized) calcium concentration and secretion is inhibited by hypercalcaemia. These effects are mediated by the calcium- sensing receptor (CaSR). Calcitriol (see below) inhibits PTH synthesis. PTH acts on bone and the kidneys, tending to increase the plasma concentration of calcium and reduce that of phosphate.
  15. 15. PTH mobilizes calcium from bone: this action is biphasic, a rapid phase involving existing cells (probably osteocytes) and a longer-term response dependent on the proliferation of osteoclasts. In the kidneys, PTH increases the fraction of the filtered load that is reabsorbed. However, because increased resorption of bone increases the amount of calcium that is filtered, there is hypercalciuria despite the increased reabsorption.
  16. 16. Also in the kidneys, PTH promotes phosphaturia by decreasing the reabsorption of filtered phosphate and stimulates the formation of calcitriol, the calcium-regulating hormone derived from vitamin D.
  17. 17. Despite the importance of PTH in the control of phosphate excretion, changes in phosphate concentration do not directly affect secretion of the hormone. Mild hypomagnesaemia stimulates PTH secretion, but more severe hypomagnesaemia reduces it, as the secretion of PTH is magnesium dependent.
  18. 18. Actions of the Hormones Involved in Calcium Homeostasis Hormone Effect on bones Effect on GI Effect on kidneys PTHCa++ , PO4 levels in blood Supports osteoclast resorption Indirect effects via calcitriol from 1- hydroxylation Supports Ca++ resorption and PO4 excretion, activates 1-hydroxylation Vitamin D Ca++ , PO4 levels in blood No direct effects Supports osteoblasts Ca++ and PO4 absorption No direct effects Calcitonin Ca++ , PO4 levels in blood when hypercalcemia present Inhibits osteoclast resorption No direct effects Promotes Ca++ and PO4 excretion
  19. 19. Calcitriol This hormone is derived from vitamin D by successive hydroxylation in the liver (25- hydroxylation) and kidneys (1- hydroxylation). In the gut, it stimulates absorption of dietary calcium and phosphate; this process involves the synthesis of a calcium-binding protein (calbindin D) in enterocytes.
  20. 20. Calcitriol is derived from a metabolite of cholesterol, 7-dehydro- cholesterol formed in the liver. Non-ezymatic breakage of the B-ring by ultraviolet light exposure in the skin form cholecalciferol (vitamin D3) which may also be obtained in the diet, e.g., in vitamin D fortified milk. Liver hydroxylates chole- calciferol on the sidechain to form 25- hydroxycholecalciferol which is carried by the vitamin D carrier protein in serum to the kidney. In the kidney the molecule can be hydroxylated once or twice more to form the active hormone calcitriol or the inactive metabolites 24,25-dihydroxycholecalciferol or 1, 24, 25- trihydroxycholecalciferol. PTH promotes 1 hydroxylation & activation, CT promotes 24 hydroxylation & inactivation.
  21. 21. Vitamin D 25(OH)D 1,25(OH)D 26 + cells throughout the body 7-dehydrocholesterol UVB photons
  22. 22. In bone, calcitriol promotes mineralization largely indirectly, through its role in the maintenance of ECF calcium and phosphate concentrations. The binding of calcitriol to osteoblasts increases the production of alkaline phosphatase and of a calcium-binding protein, osteocalcin, the exact function of which is uncertain.
  23. 23. At high concentrations, calcitriol stimulates osteoclastic bone resorption, which releases calcium and phosphate into the ECF. In the kidneys, calcitriol inhibits its own synthesis. It may have a small stimulatory effect on calcium reabsorption, acting permissively with PTH.
  24. 24. Calcitonin This polypeptide hormone, produced by the C-cells of the thyroid, is secreted when plasma calcium concentration rises and also in response to certain gut hormones. It can be shown experimentally to inhibit osteoclast activity, and thus bone resorption, but its physiological role is uncertain. Subjects who have had a total thyroidectomy do not develop a clinical syndrome that can be ascribed to calcitonin deficiency.
  25. 25. Plasma calcitonin concentration is elevated during pregnancy and lactation. So, too, is calcitriol concentration, and calcitonin may block the action of calcitriol on bone and permit increased calcium uptake from the gut to take place to satisfy increased requirements without loss of mineral from bone.
  26. 26. CALCIUM AND PHOSPHATE HOMOEOSTASIS Hypocalcaemia stimulates the secretion of PTH and, through this, increases the production of calcitriol. There is an increase in the uptake of both calcium and phosphate from the gut and in their release from bone.
  27. 27. PTH is phosphaturic, so the excess phosphate is excreted but the fractional reabsorption of calcium by the kidney is increased, some of the mobilized calcium is retained and the plasma calcium concentration tends to rise towards normal.
  28. 28. In hypophosphataemia, calcitriol secretion is increased but PTH is not. Indeed, any tendency for calcitriol to increase the plasma calcium concentration should inhibit PTH secretion. Calcium and phosphate absorption from the gut are stimulated.
  29. 29. Calcitriol has a much smaller effect on renal calcium reabsorption than PTH with the result that, in the absence of PTH, the excess calcium absorbed from the gut is excreted in the urine. The net outcome is the restoration of the phosphate concentration towards normal, independently of that of calcium.
  30. 30. DISORDERS OF CALCIUM, PHOSPHATE AND MAGNESIUM METABOLISM Hypercalcaemia Two conditions account for up to 90% of cases: primary hyperparathyroidism and malignancy. Hypercalcaemia may be discovered during the investigation of an illness of which it is known to be a potential complication or during the investigation of clinical features suggestive of hypercalcaemia. However, hypercalcaemia is often clinically silent and discovered incidentally when calcium is measured as part of a biochemical profile.
  31. 31. Malignant disease This is a very common cause of hypercalcaemia. Patients with hypercalcaemia and malignant disease are usually symptomatic, owing to the malignancy, the hypercalcaemia or both. With most solid tumours, it is due to the secretion by the tumour of PTH-related peptide (PTHrP).
  32. 32. This is a peptide having some N-terminal amino acid sequence homology with PTH. In patients with metastases in bone, there is often no relationship between the extent of metastasis and the severity of the hypercalcaemia, suggesting that humoral factors may be involved. Other humoral factors that have been implicated include transforming growth factors, prostaglandins and, particularly in haematological malignancies, osteoclast- activating cytokines.
  33. 33. Primary hyperparathyroidism The prevalence of this condition is of the order of one case per 1000 persons. It is usually due to a parathyroid adenoma, less often to diffuse hyperplasia of the glands, and only rarely to parathyroid carcinoma.
  34. 34. The definitive treatment for hyperparathyroidism is surgery. Patients with mild (