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Magnesium and phosphorus
ELECTROLYTE QUINTET
Electrolyte quintet
Magnesium and phosphorus
José R Weisinger, Ezequiel Bellorín-Font A summary of new findings regarding alterations of magnesium (Mg2+) and phosphorus (P) metabolism are reviewed for the clinician caring for patients in general wards. Alterations in serum concentrations of Mg2+ and P are frequently observed in acute or very ill patients in emergency rooms or intensive-care areas. A significant proportion of these alterations are iatrogenic. Most of the symptoms related are non-specific, and usually they are associated with changes in concentration of other ions. The need to measure Mg2+ and P routinely and to define better the real abnormal values is stressed. Correction of the abnormalities must be early in the course of the alterations. stores in bone or muscle and the extracellular fluid Magnesium is the fourth most abundant cation in the (ECF). TBMg depends mainly on gastrointestinal body, behind sodium, potassium, and calcium, and the absorption and renal excretion. second most prevalent intracellular cation. The normal The average daily dietary intake fluctuates between 300 body magnesium content is around 1000 mmol or 22·66 and 350 Mg, and intestinal absorption is inversely g, of which 50–60% is in bone. Extracellular magnesium proportional to the amount ingested. Mg2+ absorption accounts for only 1% or so of total body magnesium occurs by a saturable transport system and passive (TBMg). The normal serum magnesium concentration or diffusion. [Mg2+] ranges between 0·75 and 0·95 The kidney is the principal organ mmol/L (1·7–2·2 Mg/dL, 1·5–1·9 involved in magnesium regulation. meq/L). About 100 mg is excreted daily into Mg2+ is essential for the function of the urine. Tubular reabsorption of important enzymes, including those Mg2+ is different from that for other related to the transfer of phosphate ions because the proximal tubule has a groups, all reactions that require limited role and 60–70% of the ATP, and every step related to the reabsorption of Mg2+ takes place within replication and transcription of DNA the thick ascending loop of Henle.1 and the translation of mRNA. This Nevertheless the distal tubule, despite cation is also required for cellular normally reabsorbing only 10% of energy metabolism and has an imfiltered Mg2+, is the major site of portant role in membrane magnesium regulation. Many factors, stabilisation, nerve conduction, ion Figure 1: Normal range for plasma [Mg2+] both hormonal and nonhormonal (eg, transport, and calcium channel parathyroid hormone [PTH], calcitonin, glucagon, and activity. Magnesium deficiency may thus result in a vassopressin and magnesium restriction, acid-base variety of metabolic abnormalities and clinical changes, and potassium depletion) influence both loop of consequences. Henle and distal tubule reabsorption. However, the major Total body phosphorus content in normal adults is regulator of reabsorption is the plasma [Mg2+] itself. around 700 g and about 85% is present in the skeleton, Hypermagnesaemia inhibits loop transport while the remaining 15% being in the extracellular fluid and hypomagnesaemia stimulates transport whether there is soft tissues. Unlike magnesium, where the major clinical magnesium depletion or not. The mechanism appears to importance lies in the consequences of deficiency, be regulated by the Ca2+/Mg2+-sensing receptor, located phosphorus concentrations when abnormal are more on the capillary side of the thick-ascending-limb cells, likely to be the result of disease. which senses the changes in Mg2+.2 Other factors that could influence reabsorption are hypercalcaemia and the Magnesium homoeostasis rate of sodium chloride reabsorption. While the distribution of magnesium may flow between In cases of negative magnesium imbalance, the initial losses will have come from the ECF with a rapid fall in Lancet 1998; 352: 391–96 serum [Mg2+]. This leads to a reduction in urinary [Mg2+] Departments of Medicine, Universidad Central de Venezuela, and unless there is magnesium wasting for other reasons. Division of Nephrology and Renal Transplantation, Hospital Equilibration with the bone stores usually takes several Universitario de Caracas (Prof J R Weisinger MD); and Research weeks. Centre, Centro Nacional de Diálisis y Trasplante, MSAS, Caracas, Venezuela (E Bellorín-Font MD) Correspondence to: Prof José B Weisinger, Servicio de Nefrologia y Trasplante Renal, Hospital Universitario de Caracas, AP 47365, Los Chaguaramos 1041, Caracaus, Venezuela (e-mail: [email protected])
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Hypomagnesaemia Causes of magnesium deficiency Hypomagnesaemia (figure 1) is often found in inpatients (eg, 65% of those intensive care and up to 12% of these 391
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Panel 1: Differential diagnosis of magnesium deficiency Gastrointestinal losses Prolonged nasogastric suction Acute and chronic diarrhoea Malabsorption syndromes Steatorrhoea Extensive bowel resection Primary intestinal hypomagnesaemia Acute pancreatitis Severe malnutrition Intestinal fistulae Renal losses Chronic parenteral fluid therapy Volume expanded states Hypercalcaemia and hypercalciuria Osmotic diuresis (diabetes, urea, mannitol) Drugs Diuretics [thiazide or loop], alcohol, aminoglycoside antibiotics, cisplatin, amphotericin B, cyclosporine, foscarnet, pentamidine Phosphate depletion Hungry-bone syndrome Correction of chronic systemic acidosis Postobstructive nephropathy Renal transplantation Diuretic phase of acute renal failure Primary renal tubular magnesium wasting
on general wards).3 The usual reason is loss of magnesium from the gastrointestinal tract or the kidney (panel 1). Depletion by gastrointestinal causes occurs during acute or chronic diarrhoea, in the presence of malabsorption steatorrhoea, and after extensive bowel resection. There is also a rare inborn error of metabolism (primary intestinal hypomagnesaemia) characterised by a selective defect in magnesium adsorption, and hypomagnesaemia can also be observed in acute pancreatitis. Urinary Mg2+ loss is often the basis for magnesium depletion either because of sodium reabsorption in the same tubular segments (magnesium transport passively follows that of sodium) or because of a primary defect in renal tubular magnesium reabsorption. Thiazide and loop diuretics inhibit Mg2+ reabsorption but here, any hypomagnesaemia is usually mild because of increased proximal tubular reabsorption of Mg2+ induced by the volume depletion. Renal Mg2+ reabsorption is related to urine flow so long-term parenteral fluid therapy and volume expansion could result in magnesium deficiency. Hypercalcaemia and hypercalciuria decrease renal Mg2+ reabsorption so magnesium wasting may be observed in hypercalcaemic states such as hyperparathyroidism or malignancy. Diabetes mellitus is the most common cause of hypomagnesaemia, probably secondary to glycosuria and osmotic diuresis. Of the drugs implicated in hypomagnesaemia alcohol is very common, hypomagnesaemia being found in 30% of alcoholic patients admitted to hospital.4 Other nephrotoxic drugs include aminoglycoside antibiotics, cisplatin, amphotericin B, cyclosporin, foscarnet, and pentamidine. They hypomagnesaemia can persist for a long time after the acute tubular damage has been reversed. Two conditions are associated with a primary renal tubular Mg2+ wasting. One is characterised by hypercalciuria, nephrocalcinosis, and a tubular 392
Glossary of abbreviations [Mg2+] Ca ⫻ P product >70 abnormal Magnesium concentration; 1 mmol/L=2 meq/L=2·43 mg/dL [P] Phosphorus concentration, measured as phosphate; 1 mmol/L=3·125 mg/dL PTH Parathyroid hormones TBMg Total body magnesium TBP Total body phosphorus
acidification defect; the other, Gitelman’s syndrome, is associated with hypocalciuria and a defect in the gene encoding for the thiazide-sensitive Na+/Cl– cotransporter. Hypomagnesaemia may also accompany other disorders, including phosphate depletion, hungry-bone syndrome after parathyroidectomy, correction of chronic systemic acidosis, postobstructive nephropathy, renal transplantation, and the diuretic phase of acute tubular necrosis.
Clinical manifestations Most of the symptoms of moderate to severe hypomagnesaemia (panel 2) are non-specific and symptomatic magnesium depletion is usually associated with additional ion abnormalities such as hypocalcaemia, hypokalaemia, and metabolic alkalosis.5 Hypocalcaemia is typical in severe hypomagnesaemia, and its degree seems to be related to the severity of the magnesium depletion, usually appearing at a serum [Mg2+] below 0·49 mmol/L. Patients may present evidence of neuromuscular hyperexcitability, with positive Chvostek and Trousseau signs or spontaneous carpopedal spasm. Most hypocalcaemic/hypomagnesaemic patients have a low or normal (PTH) concentration, suggesting impaired synthesis or secretion of PTH. Magnesium supplementation leads to a rapid rise in plasma PTH. Many observations are compatible with a primary role for PTH resistance, where severe hypomagnesaemia may alter signal transduction from the PTH receptor to catalytic adenylate cyclase.6 Hypokalaemia is also a frequent feature of magnesium deficiency (40–60% of cases). In magnesium deficiency potassium secretion in the loop of Henle and the cortical collecting tubule increases. The hypokalaemia here does not respond to potassium replacement, and the magnesium deficit itself has to be corrected.7 Magnesium is vital to carbohydrate metabolism and the generation of both anaerobic and aerobic energy, and it influences glucose catabolism and insulin sensitivity. Thus metabolic alterations secondary to deficiency could increase the risk of atherosclerosis, since experimental magnesium deficiency has resulted in hypertriglyceridaemia and hypercholesterolaemia. Panel 2: Clinical manifestations of magnesium depletion Neuromuscular Trousseau and Chvostek signs Carpopedal spasm Seizures Vertigo and ataxia Muscular weakness Depression, psychosis
Cardiovascular Widening of QRS complex, prologation of PR interval, inversion of T wave, U waves Severe ventricular arrhythmias Sensitivity to cardiac glycosides
Metabolic Carbohydrate intolerance Hyperinsulinism Atherosclerosis
Bone Osteoporosis and osteomalacia
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Magnesium depletion may produce acute electrocardiographic changes such as widening of the QRS complex and the appearance of peak T waves. In severe depletion the PR interval is prolonged, with progressive widening of the QRS, T-wave inversion, and the appearance of U waves. Hypomagnesaemia has been implicated in severe ventricular arrhythmias, especially during myocardial ischaemia and cardiopulmonary bypass procedures. There is also an association between hypomagnesaemia and sensitivity to cardiac glycosides. Persistent magnesium deficiency has been implicated as a risk factor for osteoporosis and osteomalacia, especially in patients with chronic alcoholism, diabetes mellitus, and malabsorption syndromes.8
Diagnosis There is no consensus on what is an abnormally low plasma [Mg2+]. However, a concentration below 0·75 mmol/L usually indicates some degree of magnesium depletion. If gastrointestinal or renal losses cannot be distinguished, measurement of 24 h Mg2+ excretion or the fractional excretion should help. In some patients a magnesium-tolerance test (measuring urinary Mg2+ excretion over 24 h after an intravenous magnesium load9,10) can be useful.
Hypermagnesaemia Hypermagnesaemia (a plasma [Mg2+] above 0·95 mmol/L would be considered abnormal) is rare and usually iatrogenic—eg, after intravenous magnesium or when magnesium-containing cathartics or antacids have been given. Those most at risk are the elderly and patients with bowel disorders or renal insufficiency.13 A new syndrome of hypokalaemic metabolic alkalosis with hypomagnesuric hypermagnesaemia and severe hypocalciuria has been recently described.14 Clinical manifestations of hypermagnesaemia include hypotension, bradycardia, respiratory depression, depressed mental status, and ECG abnormalities. Treatment should include discontinuation of magnesium in whatever form and haemodialysis may be necessary in severe cases.
Phosphorus homoeostasis
The average diet provides 800–1400 mg phosphorus daily. 60–80% will be absorbed in the gut, mainly by passive transport but there is also active transport stimulated by 1,25dihydroxyvitamin D3 (1,25[OH]2 D3). Normal plasma phosphorus, usually expressed as phosphate-ranges between 0·89 and 1·44 mmol/L (2·8–4·5 mg/dL). Concentrations are higher in children, decreasing to adult values in late adolescence.15,16 Treatment Phosphorus is freely filtered in the The choice of route of magnesium glomerulus. More than 80% of the repletion varies with the severity of the filtered load is reabsorbed in the proximal clinical findings. An acute infusion of tubule and a small amount in the distal magnesium could decreased magnesium tubule. Proximal reabsorption occurs by reabsorption in the loop of Henle, most passive transport coupled to sodium (Naof the infused magnesium ending up in P cotransport). Two different Na-P the urine. For this reason, oral Figure 2: Normal range for plasma transporters have been identified in replacement is preferred, especially in the phosphate rabbit, mouse, and human kidney.17 symptom-free patients. Commercial Cotransport is regulated mainly by preparations, contain magnesium chloride or lactate and phosphorus intake and PTH.18 Phosphorus restriction provide 2·5–3·5 mmol per tablet. In severe increases reabsorption and intake decreases it.19 Acute hypomagnesaemia 15–20 mmol in divided doses could be adaptation to a low or high phosphorus diet involves the indicated, while 5–15 mmol may be enough for mild insertion or retrieval of Na-P transporters from the brushasymptomatic cases. border membrane. Chronic adaptation to a lowSymptomatic moderate-to-severe magnesium phosphate diet involves synthesis of new transport deficiency should be treated by parenteral administration. proteins.17 The mechanisms which initiate phosphate Patients with tetany or severe ventricular arrhythmia transport adaptation may include changes in ATP or should receive 25 mmol magnesium intravenously over calcium concentration within the cells. 12–24 hours. In cases of seizure or acute arrhythmia 4–8 PTH induces phosphaturia by inhibition of Na-P mmol should be administered as an intravenous load in cotransport. The effect is exerted mainly in the proximal 5–10 minutes, followed by 25 mmol per day. The aim tubule. The hormone binds to specific receptors in the should be to keep the plasma [Mg2+] above 0·4 mmol/L. basolateral membrane, resulting in activation of two If the patient is also hypocalcaemic magnesium treatment pathways—the adenylate-cyclase/cyclic AMP/proteinshould be maintained for 3–5 days. kinase-A and the phospholipase-C/calcium/proteinMagnesium has also been used as a therapeutic agent kinase-C systems, both of which are involved in the (ie, in the absence of hypomagnesaemia) in patients with inhibition of Na-P cotransport.20 One of the most pre-eclampsia, ischaemic heart disease, cardiac interesting renal effects of phosphate deficiency is arhythmias, urolithiasis, and bronchial asthma.11 In one resistance to the phosphaturic action of PTH. The recent placebo-controlled study, magnesium prevented cellular mechanisms involved in the adaptive response of the increase in action potential duration and the phosphate transport during phosphate deprivation are not prolongation of membrane repolarisation that occur in clearly defined. Studies from our laboratory have the ischaemic myocardium.12 Nevertheless, clinical trials demonstrated resistance of adenylate cyclase to PTH in acute myocardial infarction have proved controversial activation, probably due to an alteration in signal and this theapy should only be considered in high-risk transduction from the receptor to catalytic adenylate coronary patients, especially those who are not candidates cyclase.18,20 Other studies have demonstrated an for reperfusion. association with low intracellular ATP levels.21 THE LANCET • Vol 352 • August 1, 1998
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Panel 3: Causes of hypophosphataemia Internal redistribution Respiratory alkalosis (pain, anxiety, salicylate poisoning, sepsis, heatstroke) Recovery from malnutrition Recovery from diabetic ketoacidosis Hormonal and other agents (insulin, glucagon, epinephrine, cortisol, glucose, fructose, lacatate) Sepsis Hungry bone syndrome Increased urinary excretion Hyperparathyroidism Disorders of vitamin-D metabolism (D deficiency, D-dependent rickets, X-linked hypophosphataemic rickets) Kidney transplantation Volume expansion Malabsorption Renal tubular defects Alcohol abuse Carbonic anhydrase inhibition Metabolic or respiratory acidosis Decreased intestinal absorption Severe dietary phosphorus restriction Antacid abuse Vitamin D deficiency Chronic diarrhoea Steatorrhoea
Hypophosphataemia Hypophosphataemia (figure 2), defined as a plasma phosphate below 0·97 mmol/L is observed in 0·25–2·15% of general admissions to hospitals,22,23 but the frequency has been as high as 25% in selected series.24
Causes Pathophysiological and mechanisms include internal redistribution, increased urinary excretion, and decreased intestinal absorption (panel 3). Combinations of these abnormalities are also common. Internal redistribution is the most frequent cause of hypophosphataemia.16 The associated clinical conditions are acute respiratory alkalosis, increased insulin during glucose administration, recovery from diabetic ketoacidosis, and refeeding of malnourished patients. These conditions stimulate glycolysis, leading to the formation of phosphorylated glucose compounds and a intracellular shift of phosphorus.25 In the hungry-bone syndrome, after parathyroidectomy for correction of hyperparathyroidism, massive deposition of phosphorus and calcium in the bone results in hypocalcaemia and hypophosphataemia. Hypophosphataemia due to respiratory alkalosis is common in states associated with severe hyperventilation such as pain, anxiety, and sepsis. Serum phosphorus may decrease below 0·32 mmol/L but the patient usually has no symptoms and the phosphorus concentration rapidly returns to normal after the cause has been removed. Hyperventilation is a frequent precipitating cause of symptomatic hypophosphataemia in patients with severe phosphorus depletion, such as alcoholic and malnourished patients. Increased urinary excretion of phosphorus: hypophosphataemia as a consequence of renal losses is usually seen in primary hyperparathyroidism. These patients present hypercalcaemia and moderate hypophosphataemia and decreased renal tubular reabsorption. 394
Decreased vitamin-D synthesis or vitamin-D resistance cause hypocalcaemia and secondary hyperparathyroidism. The hypophosphataemia resulting from the PTH increase is aggravated by a decrease in intestinal absorption of phosphorus. Vitamin-D deficiency may occur as a consequence of poor sun exposure and inadequate intake. Also, in hepatic insufficiency 25-hydroxylation of vitamin D in the liver is impaired, decreasing the substrate for 1␣-hydroxylase in the kidney and leading to reduced synthesis of 1,25(OH)2 D3. Familial disorders of vitamin D metabolism associated with hypophosphataemia include vitamin-D-resistant rickets and X-linked vitamin-D-resistant rickets.16 Hypophosphataemia due to urinary losses is observed in up to 30% of patients with malignant neoplasms,26 after osmotic diuresis, inhibition of carbonic anhydrase with acetazolamide, acute volume expansion, and renal transplantation (panel 3). In Fanconi’s syndrome there is a general dysfunction of the proximal tubule that results in increase phosphaturia, glysosuria, hypouricaemia, aminoaciduria, and type-2 renal tubular acidosis.27 Modest dietary restriction of phosphorus does not lead to hypophosphataemia and phosphate depletion. However, if phosphorus restriction is severe and prolonged, or if intestinal absorption is reduced by the chronic use of phosphate binders, the constant intestinal secretion of phosphorus may induce phosphate depletion. Chronic diarrhoea and steatorrhoea may also reduce intestinal absorption. In these cases the concomitant decrease in vitamin-D absorption enhances phosphaturia, and negative phosphorus balance.
Clinical manifestations Symptomatic hypophosphataemia is usually observed when plasma phosphorus falls below 0·32 mmol/L, particularly with concurrent phosphate depletion. The most frequent risk factors or causes are alcoholism and alcohol withdrawal, recovery from diabetic ketoacidosis, total parenteral nutrition without phosphate supplementation, and chronic ingestion of phosphatebinding antacids. Hyperventilation is frequently a precipitating factor. The clinical manifestations of hypophosphataemia are diverse and include altered bone and mineral metabolism and disorders of the skeletal muscle, cardiac, respiratory, haematological, and central nervous systems. The most prominent renal alterations of mineral metabolism are hypercalciuria and increased urinary magnesium excretion. Tubular phosphate reabsorption is enhanced by mechanisms that include an increase in NaP cotransport and resistance to PTH.20,28 Proximal myopathy, dysphagia and ileus are common alterations of skeletal and smooth muscle. Rhabdomyolysis may complicate severe cases.29 If it is massive, hypophosphataemia may be masked by the release of phosphate from damaged muscle. Alcoholic patients with phosphate depletion are at high risk of rhabdomyolysis. Respiratory failure due to weakness of respiratory muscles is another consequence of phosphate depletion that may complicate and delay recovery of patients under mechanical ventilation. In addition, there may be important impairment of cardiac contractility; this has been attributed to a decrease in ATP concentration in myocardial cells.30 Haemolysis, thrombocytopenia, and impaired phagocytosis and granulocyte chemotaxis are related to
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decreased intracellular ATP. Erythrocyte concentrations of 2,2-diphosphoglycerate decrease, enhancing the affinity of haemoglobin for oxygen and reducing oxygen release from tissues. Metabolic encephalopathy probably due to tissue ischaemia has also been described in severe hypophosphataemia. Symptoms may progress from irritability to confusion and coma.
Treatment When serum [P] is between 0·48 and 0·72 mmol/L with no clinical evidence of phosphate deficit there is no need for phosphorus administration. However, if risk factors for phosphate depletion are present, or if serum phosphorus falls below 0·32 mmol/L, replacement is advised. The safest mode of therapy is oral. 1000 mg phosphorus per day will usually correct phosphate depletion. Cow’s milk contains about 1 mg of phosphorus per mL. Oral phosphate can also be administered in tablets of sodium or potassium phosphate in doses of 2–3 g daily. Intravenous replacement of phosphorus carries a high risk of severe hypocalcaemia and this route should be reserved for patients with severe symptomatic hypophosphataemia and phosphate depletion. The administration must be by infusion in normal saline (2·5 mg/kg body weight over 6 h). Serum phosphate should be measured every 6 hours and, once it has recorded, replacement should be continued orally.16
Hyperphosphataemia Causes Hyperphosphataemia (figure 2) can occur as a consequence of increased exogenous phosphorus load or absorption in the gastrointestinal tract, increased endogenous load, decreased urinary excretion and pseudohyperphosphataemia (panel 4). Panel 4: Causes of hyperphosphataemia Increased exogenous load Intravenous infusion Oral supplementation Cow’s-milk feeding to premature babies Vitamin D intoxication Phosphate-containing enemas Acute phosphorus poisoning Increased endogenous load Tumour-lysis syndrome Rhabdomyolysis Bowel infarction Malignant hyperthermia Haemolysis Acid-base disorders (lactic acidosis, diabetic ketoacidosis, respiratory acidosis) Reduced urinary excretion Renal failure Hypoparathyroidism Acromegaly Tumoral calcinosis Vitamin D intoxication Bisphosphonate therapy Magnesium deficiency Pseudohyperphosphataemia Multiple myeloma Haemolysis in vitro Hypertriglyceridaemia
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An increased exogenous phosphorus load means that the amount of phosphorus that enters the intravascular compartment overwhelms renal excretory capacity. This can happen with administration of high quantities of phosphate or by vitamin D overdose. Premature babies fed cow’s milk may also develop hyperphosphataemia and this is an important factor in the pathogenesis of neonatal tetany.16 Hyperphosphataemia arising from endogenous sources may be seen in the tumour-lysis syndrome, rhabdomyolysis, bowel infarction, malignant hyperthermia, and severe haemolysis. Tumour-lysis syndrome is seen in rapidly growing malignancies (eg, leukaemia) but hyperphosphataemia is most frequently observed in association with chemotherapy,31 and serum potassium and urate are sometimes raised too. In rhabdomyolysis massive muscle-cell breakdown releases myoglobin that induces acute renal failure and aggravate the hyperphosphataemia. During recovery the serum calcium may rise due to mobilisation of abnormal softtissue calcium deposits. Acid-base disorders release phosphorus from endogenous stores. Examples are organic metabolic acidosis (increased lactic acid production, diabetic ketoacidosis), even when the TBP is low, and respiratory acidosis, when there is a shift of phosphorus from the cell interior in response to high ambient concentrations of carbon dioxide. Renal failure is the most common cause of hyperphosphataemia in clinical practice. Decreased urinary phosphate excretion follows a reduction in the filtered phosphorus load. In mild-to-moderate renal failure the retention of phosphorus is compensated by an increase in PTH, which inhibits tubular phosphate reabsorption, but in severe renal failure hyperphosphataemia is a constant finding. The mechanisms whereby phosphorus induces an increase in PTH secretion are not completely defined. One suggestion was that the excess phosphate would induce hypocalcaemia which in turn would increase PTH secretion. Also phosphorus retention decreases calcitriol synthesis,32 which induces hyperparathyroidism by lowering plasma calcium and decreasing the direct inhibitory effect of calcitriol on PTH secretion.33 However, studies in animals with severe renal insufficiency and secondary hyperparathyroidism show that a low phosphate intake results in a significant decrease in serum PTH, independent of changes in serum calcium or 1,25(OH)2 D3 levels.34 It seems more likely that phosphorus directly increases the rate of PTH secretion.35 Hypoparathyroidism, acromegaly, and thyrotoxicosis also reduce urinary phosphorus excretion. Another cause of hyperphosphataemia is tumoral calcinosis syndrome,36 with abnormal calcifications around large joints and normal PTH levels. Spurious (pseudo) hyperphosphataemia may be seen in multiple myeloma (myeloma proteins bind phosphate and interfere with the colorimetric measurement of serum phosphate), and other causes are in vitro haemolysis and extreme hypertriglyceridaemia.
Clinical manifestations Hypocalcaemia and tetany may occur with rapid increases in plasma phosphate. A rise in the serum calcium ⫻ phosphorus product above 70 results in deposition of calcium in soft tissues, decreasing circulating calcium levels. Serum calcium also falls because phosphate inhibits renal 1␣-hydroxylase so that 395
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less 1,25(OH)2 D3 is produced. Ectopic calcification is a frequent complication in patients with chronic renal failure receiving supplements of vitamin D when correction of hyperphosphataemia is inadequate.
Treatment The most effective measure to correct hyperphosphataemia is reduction of intestinal absorption by a moderate decrease in protein intake and the ingestion of phosphate-binding salts of aluminium, magnesium, or calcium. In patients with renal failure, calcium salts are preferred bcause aluminium accumulation can have dangerous consequences. Our work has been supported in part by grants S1-1223, RP-IV-C139, and G-97000808 of the Consejo Nacional de Investigaciones Cientificas y Technológicas de Venezuela (CONICIT), and Fundarenal-HUC.
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Quamme GA. Control of magnesium transport in the thick ascending limb. Am J Physiol 1989; 256: F197–F210. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int 1997; 52: 1180–95. Wong ET, Rude RK, Singer FR, Shaw ST. A high prevalence of hypomagnesemia and hypermagnesemia in hospitalized patients. Am J Clin Pathol 1983; 79: 348–52. Elisaf M, Merkouropoulos M, Tsianos EV, Siamopoulos KC. Pathogenetic mechanisms of hypomagnesemia in alcoholic patients. J Trace Elem Med Biol 1995; 9: 210–14. Rude RJ. Magnesium metabolism and deficiency. Endocrinol Metab Clin N Am 1993; 22: 377–95. Abbott LG, Rude RK. Clinical manifestations of magnesium deficiency. Mineral Electrolyte Metab 1993; 19: 314–22. Ryan MP. Interrelationships of magnesium and potassium homeostasis. Mineral Electrolyte Metab 1993; 19: 290–95. Rude RK, Olerich M. Magnesium deficiency: possible role in osteoporosis associated with gluten-sensitive enteropathy. Osteoporos Int 1996; 6: 453–61. Al-Ghamdi SM, Cameron EC, Sutton RA. Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis 1994; 24: 737–52. Herbert P, Mehta N, Wang J, Hindmarsh T, Jones G, Cardinal P. Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med 1997; 25: 749–55. McLean RM. Magnesium and its therapeutic uses: a review. Am J Med 1994; 96: 63–33376. Redwood SR, Taggart PI, Sutton PM, et al. Effect of magnesium on the monophasic action potential during early ischemia in the in vivo human heart. J Am Coll Cardiol 1996; 28: 1765–69. Clarck BA, Brown RS. Unsuspected morbid hypermagnesemia in elderly patients. Am J Nephrol 1992; 12: 336–43. Mehrotra R, Nolph KD, Kathuria P, Dotson L. Hypokalemic metabolic alkalosis with hypomagnesuric hypermagnesemia and severe hypocalciuria: a new syndrome? Am J Kidney Dis 1997; 29: 106–14. Slatopolsky E, Rutherford R, Rosenbaum, K, Martin K, Hruska. Hyperphosphatemia. Clin Nephrol 1977; 7: 138–46. Knochel J, Agarwal R. Hypophosphatemia and hyperphosphatemia. In: Brenner BM, ed. The kidney. Philadelphia: Saunders, 1996: 1086–133.
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17 Murer H, Marcovich D, Biber J. Renal and small intestine sodiumdependent symporters of phosphate and sulphate. J Exp Biol 1994; 196: 167–81. 18 Bellorin-Font E, Milanes CL, Urbina D, Pernalete N, Paz-Marinez V. The regulation of sodium phosphate cotransport in the kidney. In: Puschett J, Greenberg A, eds. Diuretics, vol II. London: Elsevier Science, 1990: 427–33. 19 Cheng L, Liang CT, Sacktor B. Phosphate uptake by renal membrane vesicles of rabbits adapted to high and low phosphorus diet. Am J Physiol 1983; 245: F175–80. 20 Bellorin-Font E, Starosta R, Milanes CL, et al. Effect of acidosis on PTH-dependent renal adenylate cyclase in phosphorus deprivation: role of G proteins. Am J Physiol 1990; 258: F1640–49. 21 Caverzasio J, Bonjour JP. Resistance to parathyroid hormone-induced inhibition of inorganic phosphate transport in opossum kidney cells cultured in low inorganic phosphate medium. J Endocrinol 1992; 134: 361–68. 22 Betro MG, Pain RW. Hypophosphataemia and hyperphosphataemia in a hospital population. BMJ 1972; i: 273–76. 23 King AL, Sica DA, Miller G, Pierpaoli S. Severe hyophosphatemia in a general hospitalized population. South Med J 1987; 80: 831–35. 24 Stein JH, Smith WO, Ginn HE. Hyophosphatemia in acute alcoholism. Am J Med Sci 1966; 252: 78–83. 25 Brautbar N, Leibovici H, Massry SG. On the mechanism of hyophosphatemia during acute hyperventilation: evidence for an increase in muscle glycolysis. Mineral Electrolyte Metab 1983; 9: 45–49. 26 Drezner MK, Lobaugh Lyles KW. The pathogenesis and treatment of tumor-induced osteomalacia. In: Normal AW, Schaefer K, Herath D, Grigoleit HG, eds. Vitamin D: chemical, biochemical and clinical endocrinology of calcium metabolism. Berlin: Walter de Gruyter, 1982: 945–54. 27 Clark BL, Wynne AG, Wilson DM, Fitzpatrick LA. Osteomalacia associated with adult Fanconi’s syndrome: clinical and diagnostic features. Clin Endocrinol 1995; 43: 479–84. 28 Bellorin-Font E, Tamayo J, Martin KJ. Uncoupling of the parathyroid hormone receptor-adenylate cyclase system of canine kidney during dietary phosphorus deprivation. Endocrinology 1984; 115: 544–49. 29 Knochel JP. Hyophosphatemia and rhabdomyolysis. Am J Med 1992; 92: 455–59. 30 O’Connor LR, Klein KL, Bethune JE. Effect of hyophosphatemia on myocardial performance in man. N Engl J Med 1977; 297: 901. 31 Arrambide K, Toto RD. Tumor lysis syndrome. Sem Nephrol 1993; 13: 273–80. 32 Hebert LA, Lemann J, Jr, Petersen JR, Lennon EJ. Studies of the mechanisms by which phosphate infusion lowers serum calcium concentration. J Clin Invest 1966; 45: 1886–90. 33 Slatopolsky E, Weerts C, Thielen J, Horst R, Harter H, Martin MJ. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 1984; 74: 2136–43. 34 Lopez-Hilker S, Dusso A, Raap N, Martin K, Slatopolsky E. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol 1990; 259: F432–37. 35 Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents parathyroid gland growth: high phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996; 97: 2534–40. 36 Weisinger JR, Mogollon A, Lander R, et al. Massive cerebral calcifications associated with increased renal phosphate reabsorption. Arch Intern Med 1986; 146: 473–77.
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Electrolyte quintet
Magnesium and phosphorus
José R Weisinger, Ezequiel Bellorín-Font A summary of new findings regarding alterations of magnesium (Mg2+) and phosphorus (P) metabolism are reviewed for the clinician caring for patients in general wards. Alterations in serum concentrations of Mg2+ and P are frequently observed in acute or very ill patients in emergency rooms or intensive-care areas. A significant proportion of these alterations are iatrogenic. Most of the symptoms related are non-specific, and usually they are associated with changes in concentration of other ions. The need to measure Mg2+ and P routinely and to define better the real abnormal values is stressed. Correction of the abnormalities must be early in the course of the alterations. stores in bone or muscle and the extracellular fluid Magnesium is the fourth most abundant cation in the (ECF). TBMg depends mainly on gastrointestinal body, behind sodium, potassium, and calcium, and the absorption and renal excretion. second most prevalent intracellular cation. The normal The average daily dietary intake fluctuates between 300 body magnesium content is around 1000 mmol or 22·66 and 350 Mg, and intestinal absorption is inversely g, of which 50–60% is in bone. Extracellular magnesium proportional to the amount ingested. Mg2+ absorption accounts for only 1% or so of total body magnesium occurs by a saturable transport system and passive (TBMg). The normal serum magnesium concentration or diffusion. [Mg2+] ranges between 0·75 and 0·95 The kidney is the principal organ mmol/L (1·7–2·2 Mg/dL, 1·5–1·9 involved in magnesium regulation. meq/L). About 100 mg is excreted daily into Mg2+ is essential for the function of the urine. Tubular reabsorption of important enzymes, including those Mg2+ is different from that for other related to the transfer of phosphate ions because the proximal tubule has a groups, all reactions that require limited role and 60–70% of the ATP, and every step related to the reabsorption of Mg2+ takes place within replication and transcription of DNA the thick ascending loop of Henle.1 and the translation of mRNA. This Nevertheless the distal tubule, despite cation is also required for cellular normally reabsorbing only 10% of energy metabolism and has an imfiltered Mg2+, is the major site of portant role in membrane magnesium regulation. Many factors, stabilisation, nerve conduction, ion Figure 1: Normal range for plasma [Mg2+] both hormonal and nonhormonal (eg, transport, and calcium channel parathyroid hormone [PTH], calcitonin, glucagon, and activity. Magnesium deficiency may thus result in a vassopressin and magnesium restriction, acid-base variety of metabolic abnormalities and clinical changes, and potassium depletion) influence both loop of consequences. Henle and distal tubule reabsorption. However, the major Total body phosphorus content in normal adults is regulator of reabsorption is the plasma [Mg2+] itself. around 700 g and about 85% is present in the skeleton, Hypermagnesaemia inhibits loop transport while the remaining 15% being in the extracellular fluid and hypomagnesaemia stimulates transport whether there is soft tissues. Unlike magnesium, where the major clinical magnesium depletion or not. The mechanism appears to importance lies in the consequences of deficiency, be regulated by the Ca2+/Mg2+-sensing receptor, located phosphorus concentrations when abnormal are more on the capillary side of the thick-ascending-limb cells, likely to be the result of disease. which senses the changes in Mg2+.2 Other factors that could influence reabsorption are hypercalcaemia and the Magnesium homoeostasis rate of sodium chloride reabsorption. While the distribution of magnesium may flow between In cases of negative magnesium imbalance, the initial losses will have come from the ECF with a rapid fall in Lancet 1998; 352: 391–96 serum [Mg2+]. This leads to a reduction in urinary [Mg2+] Departments of Medicine, Universidad Central de Venezuela, and unless there is magnesium wasting for other reasons. Division of Nephrology and Renal Transplantation, Hospital Equilibration with the bone stores usually takes several Universitario de Caracas (Prof J R Weisinger MD); and Research weeks. Centre, Centro Nacional de Diálisis y Trasplante, MSAS, Caracas, Venezuela (E Bellorín-Font MD) Correspondence to: Prof José B Weisinger, Servicio de Nefrologia y Trasplante Renal, Hospital Universitario de Caracas, AP 47365, Los Chaguaramos 1041, Caracaus, Venezuela (e-mail: [email protected])
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Hypomagnesaemia Causes of magnesium deficiency Hypomagnesaemia (figure 1) is often found in inpatients (eg, 65% of those intensive care and up to 12% of these 391
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Panel 1: Differential diagnosis of magnesium deficiency Gastrointestinal losses Prolonged nasogastric suction Acute and chronic diarrhoea Malabsorption syndromes Steatorrhoea Extensive bowel resection Primary intestinal hypomagnesaemia Acute pancreatitis Severe malnutrition Intestinal fistulae Renal losses Chronic parenteral fluid therapy Volume expanded states Hypercalcaemia and hypercalciuria Osmotic diuresis (diabetes, urea, mannitol) Drugs Diuretics [thiazide or loop], alcohol, aminoglycoside antibiotics, cisplatin, amphotericin B, cyclosporine, foscarnet, pentamidine Phosphate depletion Hungry-bone syndrome Correction of chronic systemic acidosis Postobstructive nephropathy Renal transplantation Diuretic phase of acute renal failure Primary renal tubular magnesium wasting
on general wards).3 The usual reason is loss of magnesium from the gastrointestinal tract or the kidney (panel 1). Depletion by gastrointestinal causes occurs during acute or chronic diarrhoea, in the presence of malabsorption steatorrhoea, and after extensive bowel resection. There is also a rare inborn error of metabolism (primary intestinal hypomagnesaemia) characterised by a selective defect in magnesium adsorption, and hypomagnesaemia can also be observed in acute pancreatitis. Urinary Mg2+ loss is often the basis for magnesium depletion either because of sodium reabsorption in the same tubular segments (magnesium transport passively follows that of sodium) or because of a primary defect in renal tubular magnesium reabsorption. Thiazide and loop diuretics inhibit Mg2+ reabsorption but here, any hypomagnesaemia is usually mild because of increased proximal tubular reabsorption of Mg2+ induced by the volume depletion. Renal Mg2+ reabsorption is related to urine flow so long-term parenteral fluid therapy and volume expansion could result in magnesium deficiency. Hypercalcaemia and hypercalciuria decrease renal Mg2+ reabsorption so magnesium wasting may be observed in hypercalcaemic states such as hyperparathyroidism or malignancy. Diabetes mellitus is the most common cause of hypomagnesaemia, probably secondary to glycosuria and osmotic diuresis. Of the drugs implicated in hypomagnesaemia alcohol is very common, hypomagnesaemia being found in 30% of alcoholic patients admitted to hospital.4 Other nephrotoxic drugs include aminoglycoside antibiotics, cisplatin, amphotericin B, cyclosporin, foscarnet, and pentamidine. They hypomagnesaemia can persist for a long time after the acute tubular damage has been reversed. Two conditions are associated with a primary renal tubular Mg2+ wasting. One is characterised by hypercalciuria, nephrocalcinosis, and a tubular 392
Glossary of abbreviations [Mg2+] Ca ⫻ P product >70 abnormal Magnesium concentration; 1 mmol/L=2 meq/L=2·43 mg/dL [P] Phosphorus concentration, measured as phosphate; 1 mmol/L=3·125 mg/dL PTH Parathyroid hormones TBMg Total body magnesium TBP Total body phosphorus
acidification defect; the other, Gitelman’s syndrome, is associated with hypocalciuria and a defect in the gene encoding for the thiazide-sensitive Na+/Cl– cotransporter. Hypomagnesaemia may also accompany other disorders, including phosphate depletion, hungry-bone syndrome after parathyroidectomy, correction of chronic systemic acidosis, postobstructive nephropathy, renal transplantation, and the diuretic phase of acute tubular necrosis.
Clinical manifestations Most of the symptoms of moderate to severe hypomagnesaemia (panel 2) are non-specific and symptomatic magnesium depletion is usually associated with additional ion abnormalities such as hypocalcaemia, hypokalaemia, and metabolic alkalosis.5 Hypocalcaemia is typical in severe hypomagnesaemia, and its degree seems to be related to the severity of the magnesium depletion, usually appearing at a serum [Mg2+] below 0·49 mmol/L. Patients may present evidence of neuromuscular hyperexcitability, with positive Chvostek and Trousseau signs or spontaneous carpopedal spasm. Most hypocalcaemic/hypomagnesaemic patients have a low or normal (PTH) concentration, suggesting impaired synthesis or secretion of PTH. Magnesium supplementation leads to a rapid rise in plasma PTH. Many observations are compatible with a primary role for PTH resistance, where severe hypomagnesaemia may alter signal transduction from the PTH receptor to catalytic adenylate cyclase.6 Hypokalaemia is also a frequent feature of magnesium deficiency (40–60% of cases). In magnesium deficiency potassium secretion in the loop of Henle and the cortical collecting tubule increases. The hypokalaemia here does not respond to potassium replacement, and the magnesium deficit itself has to be corrected.7 Magnesium is vital to carbohydrate metabolism and the generation of both anaerobic and aerobic energy, and it influences glucose catabolism and insulin sensitivity. Thus metabolic alterations secondary to deficiency could increase the risk of atherosclerosis, since experimental magnesium deficiency has resulted in hypertriglyceridaemia and hypercholesterolaemia. Panel 2: Clinical manifestations of magnesium depletion Neuromuscular Trousseau and Chvostek signs Carpopedal spasm Seizures Vertigo and ataxia Muscular weakness Depression, psychosis
Cardiovascular Widening of QRS complex, prologation of PR interval, inversion of T wave, U waves Severe ventricular arrhythmias Sensitivity to cardiac glycosides
Metabolic Carbohydrate intolerance Hyperinsulinism Atherosclerosis
Bone Osteoporosis and osteomalacia
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Magnesium depletion may produce acute electrocardiographic changes such as widening of the QRS complex and the appearance of peak T waves. In severe depletion the PR interval is prolonged, with progressive widening of the QRS, T-wave inversion, and the appearance of U waves. Hypomagnesaemia has been implicated in severe ventricular arrhythmias, especially during myocardial ischaemia and cardiopulmonary bypass procedures. There is also an association between hypomagnesaemia and sensitivity to cardiac glycosides. Persistent magnesium deficiency has been implicated as a risk factor for osteoporosis and osteomalacia, especially in patients with chronic alcoholism, diabetes mellitus, and malabsorption syndromes.8
Diagnosis There is no consensus on what is an abnormally low plasma [Mg2+]. However, a concentration below 0·75 mmol/L usually indicates some degree of magnesium depletion. If gastrointestinal or renal losses cannot be distinguished, measurement of 24 h Mg2+ excretion or the fractional excretion should help. In some patients a magnesium-tolerance test (measuring urinary Mg2+ excretion over 24 h after an intravenous magnesium load9,10) can be useful.
Hypermagnesaemia Hypermagnesaemia (a plasma [Mg2+] above 0·95 mmol/L would be considered abnormal) is rare and usually iatrogenic—eg, after intravenous magnesium or when magnesium-containing cathartics or antacids have been given. Those most at risk are the elderly and patients with bowel disorders or renal insufficiency.13 A new syndrome of hypokalaemic metabolic alkalosis with hypomagnesuric hypermagnesaemia and severe hypocalciuria has been recently described.14 Clinical manifestations of hypermagnesaemia include hypotension, bradycardia, respiratory depression, depressed mental status, and ECG abnormalities. Treatment should include discontinuation of magnesium in whatever form and haemodialysis may be necessary in severe cases.
Phosphorus homoeostasis
The average diet provides 800–1400 mg phosphorus daily. 60–80% will be absorbed in the gut, mainly by passive transport but there is also active transport stimulated by 1,25dihydroxyvitamin D3 (1,25[OH]2 D3). Normal plasma phosphorus, usually expressed as phosphate-ranges between 0·89 and 1·44 mmol/L (2·8–4·5 mg/dL). Concentrations are higher in children, decreasing to adult values in late adolescence.15,16 Treatment Phosphorus is freely filtered in the The choice of route of magnesium glomerulus. More than 80% of the repletion varies with the severity of the filtered load is reabsorbed in the proximal clinical findings. An acute infusion of tubule and a small amount in the distal magnesium could decreased magnesium tubule. Proximal reabsorption occurs by reabsorption in the loop of Henle, most passive transport coupled to sodium (Naof the infused magnesium ending up in P cotransport). Two different Na-P the urine. For this reason, oral Figure 2: Normal range for plasma transporters have been identified in replacement is preferred, especially in the phosphate rabbit, mouse, and human kidney.17 symptom-free patients. Commercial Cotransport is regulated mainly by preparations, contain magnesium chloride or lactate and phosphorus intake and PTH.18 Phosphorus restriction provide 2·5–3·5 mmol per tablet. In severe increases reabsorption and intake decreases it.19 Acute hypomagnesaemia 15–20 mmol in divided doses could be adaptation to a low or high phosphorus diet involves the indicated, while 5–15 mmol may be enough for mild insertion or retrieval of Na-P transporters from the brushasymptomatic cases. border membrane. Chronic adaptation to a lowSymptomatic moderate-to-severe magnesium phosphate diet involves synthesis of new transport deficiency should be treated by parenteral administration. proteins.17 The mechanisms which initiate phosphate Patients with tetany or severe ventricular arrhythmia transport adaptation may include changes in ATP or should receive 25 mmol magnesium intravenously over calcium concentration within the cells. 12–24 hours. In cases of seizure or acute arrhythmia 4–8 PTH induces phosphaturia by inhibition of Na-P mmol should be administered as an intravenous load in cotransport. The effect is exerted mainly in the proximal 5–10 minutes, followed by 25 mmol per day. The aim tubule. The hormone binds to specific receptors in the should be to keep the plasma [Mg2+] above 0·4 mmol/L. basolateral membrane, resulting in activation of two If the patient is also hypocalcaemic magnesium treatment pathways—the adenylate-cyclase/cyclic AMP/proteinshould be maintained for 3–5 days. kinase-A and the phospholipase-C/calcium/proteinMagnesium has also been used as a therapeutic agent kinase-C systems, both of which are involved in the (ie, in the absence of hypomagnesaemia) in patients with inhibition of Na-P cotransport.20 One of the most pre-eclampsia, ischaemic heart disease, cardiac interesting renal effects of phosphate deficiency is arhythmias, urolithiasis, and bronchial asthma.11 In one resistance to the phosphaturic action of PTH. The recent placebo-controlled study, magnesium prevented cellular mechanisms involved in the adaptive response of the increase in action potential duration and the phosphate transport during phosphate deprivation are not prolongation of membrane repolarisation that occur in clearly defined. Studies from our laboratory have the ischaemic myocardium.12 Nevertheless, clinical trials demonstrated resistance of adenylate cyclase to PTH in acute myocardial infarction have proved controversial activation, probably due to an alteration in signal and this theapy should only be considered in high-risk transduction from the receptor to catalytic adenylate coronary patients, especially those who are not candidates cyclase.18,20 Other studies have demonstrated an for reperfusion. association with low intracellular ATP levels.21 THE LANCET • Vol 352 • August 1, 1998
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Panel 3: Causes of hypophosphataemia Internal redistribution Respiratory alkalosis (pain, anxiety, salicylate poisoning, sepsis, heatstroke) Recovery from malnutrition Recovery from diabetic ketoacidosis Hormonal and other agents (insulin, glucagon, epinephrine, cortisol, glucose, fructose, lacatate) Sepsis Hungry bone syndrome Increased urinary excretion Hyperparathyroidism Disorders of vitamin-D metabolism (D deficiency, D-dependent rickets, X-linked hypophosphataemic rickets) Kidney transplantation Volume expansion Malabsorption Renal tubular defects Alcohol abuse Carbonic anhydrase inhibition Metabolic or respiratory acidosis Decreased intestinal absorption Severe dietary phosphorus restriction Antacid abuse Vitamin D deficiency Chronic diarrhoea Steatorrhoea
Hypophosphataemia Hypophosphataemia (figure 2), defined as a plasma phosphate below 0·97 mmol/L is observed in 0·25–2·15% of general admissions to hospitals,22,23 but the frequency has been as high as 25% in selected series.24
Causes Pathophysiological and mechanisms include internal redistribution, increased urinary excretion, and decreased intestinal absorption (panel 3). Combinations of these abnormalities are also common. Internal redistribution is the most frequent cause of hypophosphataemia.16 The associated clinical conditions are acute respiratory alkalosis, increased insulin during glucose administration, recovery from diabetic ketoacidosis, and refeeding of malnourished patients. These conditions stimulate glycolysis, leading to the formation of phosphorylated glucose compounds and a intracellular shift of phosphorus.25 In the hungry-bone syndrome, after parathyroidectomy for correction of hyperparathyroidism, massive deposition of phosphorus and calcium in the bone results in hypocalcaemia and hypophosphataemia. Hypophosphataemia due to respiratory alkalosis is common in states associated with severe hyperventilation such as pain, anxiety, and sepsis. Serum phosphorus may decrease below 0·32 mmol/L but the patient usually has no symptoms and the phosphorus concentration rapidly returns to normal after the cause has been removed. Hyperventilation is a frequent precipitating cause of symptomatic hypophosphataemia in patients with severe phosphorus depletion, such as alcoholic and malnourished patients. Increased urinary excretion of phosphorus: hypophosphataemia as a consequence of renal losses is usually seen in primary hyperparathyroidism. These patients present hypercalcaemia and moderate hypophosphataemia and decreased renal tubular reabsorption. 394
Decreased vitamin-D synthesis or vitamin-D resistance cause hypocalcaemia and secondary hyperparathyroidism. The hypophosphataemia resulting from the PTH increase is aggravated by a decrease in intestinal absorption of phosphorus. Vitamin-D deficiency may occur as a consequence of poor sun exposure and inadequate intake. Also, in hepatic insufficiency 25-hydroxylation of vitamin D in the liver is impaired, decreasing the substrate for 1␣-hydroxylase in the kidney and leading to reduced synthesis of 1,25(OH)2 D3. Familial disorders of vitamin D metabolism associated with hypophosphataemia include vitamin-D-resistant rickets and X-linked vitamin-D-resistant rickets.16 Hypophosphataemia due to urinary losses is observed in up to 30% of patients with malignant neoplasms,26 after osmotic diuresis, inhibition of carbonic anhydrase with acetazolamide, acute volume expansion, and renal transplantation (panel 3). In Fanconi’s syndrome there is a general dysfunction of the proximal tubule that results in increase phosphaturia, glysosuria, hypouricaemia, aminoaciduria, and type-2 renal tubular acidosis.27 Modest dietary restriction of phosphorus does not lead to hypophosphataemia and phosphate depletion. However, if phosphorus restriction is severe and prolonged, or if intestinal absorption is reduced by the chronic use of phosphate binders, the constant intestinal secretion of phosphorus may induce phosphate depletion. Chronic diarrhoea and steatorrhoea may also reduce intestinal absorption. In these cases the concomitant decrease in vitamin-D absorption enhances phosphaturia, and negative phosphorus balance.
Clinical manifestations Symptomatic hypophosphataemia is usually observed when plasma phosphorus falls below 0·32 mmol/L, particularly with concurrent phosphate depletion. The most frequent risk factors or causes are alcoholism and alcohol withdrawal, recovery from diabetic ketoacidosis, total parenteral nutrition without phosphate supplementation, and chronic ingestion of phosphatebinding antacids. Hyperventilation is frequently a precipitating factor. The clinical manifestations of hypophosphataemia are diverse and include altered bone and mineral metabolism and disorders of the skeletal muscle, cardiac, respiratory, haematological, and central nervous systems. The most prominent renal alterations of mineral metabolism are hypercalciuria and increased urinary magnesium excretion. Tubular phosphate reabsorption is enhanced by mechanisms that include an increase in NaP cotransport and resistance to PTH.20,28 Proximal myopathy, dysphagia and ileus are common alterations of skeletal and smooth muscle. Rhabdomyolysis may complicate severe cases.29 If it is massive, hypophosphataemia may be masked by the release of phosphate from damaged muscle. Alcoholic patients with phosphate depletion are at high risk of rhabdomyolysis. Respiratory failure due to weakness of respiratory muscles is another consequence of phosphate depletion that may complicate and delay recovery of patients under mechanical ventilation. In addition, there may be important impairment of cardiac contractility; this has been attributed to a decrease in ATP concentration in myocardial cells.30 Haemolysis, thrombocytopenia, and impaired phagocytosis and granulocyte chemotaxis are related to
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decreased intracellular ATP. Erythrocyte concentrations of 2,2-diphosphoglycerate decrease, enhancing the affinity of haemoglobin for oxygen and reducing oxygen release from tissues. Metabolic encephalopathy probably due to tissue ischaemia has also been described in severe hypophosphataemia. Symptoms may progress from irritability to confusion and coma.
Treatment When serum [P] is between 0·48 and 0·72 mmol/L with no clinical evidence of phosphate deficit there is no need for phosphorus administration. However, if risk factors for phosphate depletion are present, or if serum phosphorus falls below 0·32 mmol/L, replacement is advised. The safest mode of therapy is oral. 1000 mg phosphorus per day will usually correct phosphate depletion. Cow’s milk contains about 1 mg of phosphorus per mL. Oral phosphate can also be administered in tablets of sodium or potassium phosphate in doses of 2–3 g daily. Intravenous replacement of phosphorus carries a high risk of severe hypocalcaemia and this route should be reserved for patients with severe symptomatic hypophosphataemia and phosphate depletion. The administration must be by infusion in normal saline (2·5 mg/kg body weight over 6 h). Serum phosphate should be measured every 6 hours and, once it has recorded, replacement should be continued orally.16
Hyperphosphataemia Causes Hyperphosphataemia (figure 2) can occur as a consequence of increased exogenous phosphorus load or absorption in the gastrointestinal tract, increased endogenous load, decreased urinary excretion and pseudohyperphosphataemia (panel 4). Panel 4: Causes of hyperphosphataemia Increased exogenous load Intravenous infusion Oral supplementation Cow’s-milk feeding to premature babies Vitamin D intoxication Phosphate-containing enemas Acute phosphorus poisoning Increased endogenous load Tumour-lysis syndrome Rhabdomyolysis Bowel infarction Malignant hyperthermia Haemolysis Acid-base disorders (lactic acidosis, diabetic ketoacidosis, respiratory acidosis) Reduced urinary excretion Renal failure Hypoparathyroidism Acromegaly Tumoral calcinosis Vitamin D intoxication Bisphosphonate therapy Magnesium deficiency Pseudohyperphosphataemia Multiple myeloma Haemolysis in vitro Hypertriglyceridaemia
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An increased exogenous phosphorus load means that the amount of phosphorus that enters the intravascular compartment overwhelms renal excretory capacity. This can happen with administration of high quantities of phosphate or by vitamin D overdose. Premature babies fed cow’s milk may also develop hyperphosphataemia and this is an important factor in the pathogenesis of neonatal tetany.16 Hyperphosphataemia arising from endogenous sources may be seen in the tumour-lysis syndrome, rhabdomyolysis, bowel infarction, malignant hyperthermia, and severe haemolysis. Tumour-lysis syndrome is seen in rapidly growing malignancies (eg, leukaemia) but hyperphosphataemia is most frequently observed in association with chemotherapy,31 and serum potassium and urate are sometimes raised too. In rhabdomyolysis massive muscle-cell breakdown releases myoglobin that induces acute renal failure and aggravate the hyperphosphataemia. During recovery the serum calcium may rise due to mobilisation of abnormal softtissue calcium deposits. Acid-base disorders release phosphorus from endogenous stores. Examples are organic metabolic acidosis (increased lactic acid production, diabetic ketoacidosis), even when the TBP is low, and respiratory acidosis, when there is a shift of phosphorus from the cell interior in response to high ambient concentrations of carbon dioxide. Renal failure is the most common cause of hyperphosphataemia in clinical practice. Decreased urinary phosphate excretion follows a reduction in the filtered phosphorus load. In mild-to-moderate renal failure the retention of phosphorus is compensated by an increase in PTH, which inhibits tubular phosphate reabsorption, but in severe renal failure hyperphosphataemia is a constant finding. The mechanisms whereby phosphorus induces an increase in PTH secretion are not completely defined. One suggestion was that the excess phosphate would induce hypocalcaemia which in turn would increase PTH secretion. Also phosphorus retention decreases calcitriol synthesis,32 which induces hyperparathyroidism by lowering plasma calcium and decreasing the direct inhibitory effect of calcitriol on PTH secretion.33 However, studies in animals with severe renal insufficiency and secondary hyperparathyroidism show that a low phosphate intake results in a significant decrease in serum PTH, independent of changes in serum calcium or 1,25(OH)2 D3 levels.34 It seems more likely that phosphorus directly increases the rate of PTH secretion.35 Hypoparathyroidism, acromegaly, and thyrotoxicosis also reduce urinary phosphorus excretion. Another cause of hyperphosphataemia is tumoral calcinosis syndrome,36 with abnormal calcifications around large joints and normal PTH levels. Spurious (pseudo) hyperphosphataemia may be seen in multiple myeloma (myeloma proteins bind phosphate and interfere with the colorimetric measurement of serum phosphate), and other causes are in vitro haemolysis and extreme hypertriglyceridaemia.
Clinical manifestations Hypocalcaemia and tetany may occur with rapid increases in plasma phosphate. A rise in the serum calcium ⫻ phosphorus product above 70 results in deposition of calcium in soft tissues, decreasing circulating calcium levels. Serum calcium also falls because phosphate inhibits renal 1␣-hydroxylase so that 395
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less 1,25(OH)2 D3 is produced. Ectopic calcification is a frequent complication in patients with chronic renal failure receiving supplements of vitamin D when correction of hyperphosphataemia is inadequate.
Treatment The most effective measure to correct hyperphosphataemia is reduction of intestinal absorption by a moderate decrease in protein intake and the ingestion of phosphate-binding salts of aluminium, magnesium, or calcium. In patients with renal failure, calcium salts are preferred bcause aluminium accumulation can have dangerous consequences. Our work has been supported in part by grants S1-1223, RP-IV-C139, and G-97000808 of the Consejo Nacional de Investigaciones Cientificas y Technológicas de Venezuela (CONICIT), and Fundarenal-HUC.
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