Basic sciences review The Essentials of Calcium, Magnesium and Phosphate Metabolism: Part I. Physiology S. B. BAKER, L. I. G. WORTHLEY Department of Critical Care Medicine, Flinders University of South Australia, Adelaide, SOUTH AUSTRALIA ABSTRACT Objective: To review the components of calcium, phosphate and magnesium metabolism that are relevant to the critically ill patient in a two-part presentation. Data sources: A review of articles reported on calcium, phosphate and magnesium disorders in the critically ill patient. 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. 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 (TmPO4), thereafter phosphate is excreted. The minimum oral requirement for phosphate is about 20 mmol/day. 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 (TmMg) controlling the plasma magnesium concentration. Conclusions: In the critically ill patient calcium, magnesium and phosphate metabolism, are often disturbed with an alteration in intake, increased liberation from bone and damaged tissue and reduced excretion (e.g. during renal failure), causing alterations in extracellular concentrations and subsequent disordered organ function. (Critical Care and Resuscitation 2002; 4: 301-306) Key words: Calcium, phosphate, magnesium, vitamin D, parathyroid hormone, calcitonin CALCIUM METABOLISM predominantly found in bone providing an important The extracellular fluid (ECF) ionised calcium (1 structural function to the human body, whereas the mmol/L) concentration is 104 times the concentration of ionised calcium is responsible for a variety of physiol- the intracellular fluid (ICF) ionised calcium with the ogical effects that are characteristic of the cell type (e.g. latter varying during normal function by up to 10-fold secretion, neuromuscular impulse formation, contractile (e.g. from 10-4 to 10-3 mmol/L). Nonionised calcium is functions, clotting). Correspondence to: Dr. S. B. Baker, Department of Critical Care Medicine, Flinders Medical Centre, Bedford Park, South Australia 5042 301 S. B. BAKER, ET AL Critical Care and Resuscitation 2002; 4: 301-306 The distribution of total body calcium in a 70 kg normal ventilatory response and previously man is shown in Table 1. Normal plasma calcium, which normal albumin and bicarbonate levels usually consists of protein bound, ionised and complexed has little effect on ionised calcium levels1) and calcium, ranges from 2.10 - 2.55 mmol/L. Normal 2) bicarbonate (e.g. for each 1 mmol/L decrease in plasma ionised calcium ranges from 1.15 - 1.30 mmol/L. bicarbonate, the ionised calcium increases by If the total plasma calcium is 2.45 mmol/L then the 0.004 mmol/L, due largely to a liberation of Ca2+ distribution of plasma calcium is approximately: from unionised calcium bicarbonate).2 - 1.0 mmol/L protein bound (i.e., 40% of the total Therefore in the critically ill patient, for an accurate plasma calcium; 80% of which is bound to albumin assessment of plasma ionised calcium status, direct and 20% of which is bound to globulins), measurement of the ionised calcium should be perform- - 1.15 mmol/L ionised (i.e. 47% of the total plasma ed,3,4 and is often readily available (using an ion specific calcium) and, electrode) in association with standard blood gas - 0.3 mmol/L complexed with plasma bicarbonate, estimations. lactate, citrate, phosphate and sulphate (i.e. 13% of Numerous hormones can influence calcium the total plasma calcium). metabolism (e.g. 1,25 dihydroxycholecalciferol, parath- yroid hormone, calcitonin, parathyroid hormone related Table 1. Distribution of total body calcium in a protein, oestrogen, corticosteroids, thyroxin, growth 70 Kg man hormone) although only 1,25 dihydroxycholecalciferol, mmol parathyroid hormone, calcitonin are primarily concer- ned with the regulation of calcium metabolism. Bone and teeth (nonexchangeable) 30 000 (exchangeable) 100 Daily calcium balance Extracellular fluid Of the 20 mmol of calcium ingested daily, Interstitial fluid 23 approximately 40% (i.e. 8 mmol) is absorbed in the Plasma 12 duodenum and upper jejunum, although this varies from 10 - 90% (2 - 18 mmol) depending on the circulating Total 30,135 level of 1,25 dihydroxycholecalciferol (1,25(OH)2D3). About 10% of calcium absorption occurs by passive While the plasma ionised calcium can be directly diffusion. The bone liberates and reabsorbs approx- measured, the total plasma calcium is commonly imately 500 mmol of calcium per day from an measured, which varies with the variation in plasma exchangeable pool of 100 mmol. The minimum daily requirement of calcium for an healthy adult is about 5 protein levels. A correction factor of 0.02 mmol/L added 5 to the measured calcium level for every 1 g/L increase in mmol. plasma albumin (up to a value of 40 g/L), may be used About 250 mmol of ionised calcium is filtered by the to calculate the effect of plasma albumin on total plasma kidneys daily. About 65% (i.e. 170 mmol) of the filtered calcium (e.g. if the measured total plasma calcium is load is passively reabsorbed with sodium in the 1.83 mmol/L and plasma albumin is 25 g/L, the proximal tubule, 20% (i.e. 50 mmol) is reabsorbed in the corrected plasma calcium is, 1.83 + (40 - 25) x 0.02 thick ascending loop of Henle and 10% (i.e. 25 mmol) is mmol/L = 2.13 mmol/L). The correction factor for absorbed in the distal nephron. Parathyroid hormone globulin is 0.004 mmol/L for each 1 g/L rise in globulin. (PTH) increases calcium absorption in the thick However, in critically ill patients, there are large ascending loop of Henle as well as in the distal variations in ionised calcium due to: convoluted tubule. PTH has no effect on calcium reabsorption in the proximal tubule. The urinary excretion of calcium is 2.5 - 7.5 mmol per day and a) pH alterations in calcium binding by albumin (e.g. 5 for every 0.1 unit reduction in plasma pH, the represents about 3 - 5% of the filtered calcium. albumin bound calcium decreases by 0.07 mmol/L Approximately 60% (i.e. 12 mmol) of the oral daily and ionised calcium increases by 0.07 mmol/L) and intake is excreted with the faeces. b) alterations in calcium complexed with: Regulation of ionised calcium in the extracellular 1) lactate (e.g. for each 1 mmol/L increase in lactate fluid the ionised calcium decreases by 0.006 mmol/L, In health, the plasma ionised calcium does not vary due largely to an increase in unionised calcium by more than 5% and is maintained largely by the lactate, although lactic acidosis in patients with a actions of PTH and vitamin D. Calcitonin does not 302 Critical Care and Resuscitation 2002; 4: 301-306 S. B. BAKER, ET AL normally regulate plasma calcium levels and is only recommended intake is 400 IU/day (1 mg of vitamin D3 secreted when hypercalcaemia exists. = 40 000 IU). Parathyroid hormone Metabolism. Vitamin D3 is converted to 25 (OH)D3 Parathyroid hormone (PTH) is an 84 amino acid in the liver, and transported in the blood bound to an polypeptide that has a molecular weight of 9500, a alpha-2-macroglobulin (vitamin D-binding protein). plasma half-life of 10 min (PTH is cleaved by hepatic This metabolic step is not tightly regulated and the Kupffer cells and the fragments are excreted by the circulating 25(OH)D3 functions mainly as a vitamin D3 kidneys) and a plasma level that varies between 1.0 and store. The plasma half-life of 25(OH)D3 is 15 days. It is 6.5 pmol/L. It is synthesised as part of a larger molecule converted to either 1,25 (OH) 2D3, by a 1α -hydroxylase containing 115 amino acid residues (preproPTH) which in the renal tubular cells of the distal part of the is modified to form proPTH by the removal of 25 amino proximal convoluted and straight tubule, or to the poorly 8,12 acids. Finally PTH is formed by the removal of 6 amino active metabolite, 24,25 (OH)2D3. The latter is an acid residues and is packed in secretory granules. The escape route for 25(OH)D3 metabolism when no further main factor controlling the secretion of PTH is plasma 1,25 (OH)2D3 is required. The biological activity of 1,25 ionised calcium, stimulating the calcium-sensing (OH)2D3 is 500-1000 times greater than its precursor receptor on the cell membrane of the parathyroid chief 25(OH)D3, and has a half-life of 15 hr. Extrarenal 1,25 cell to inhibit secretion of PTH with hypercalcaemia and (OH)2D3 production can also occur in the macrophage in promote secretion of PTH with hypocalcaemia.6,7 The granulomatous diseases (e.g. in sarcoidosis when the 8 8 production of PTH is inhibited by 1,25 (OH)2D3.