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86 Electrolyte & Blood Pressure 6:86-95, 2008 Review article

1)

Magnesium Metabolism

Jang Won Seo, M.D. and Tae Jin Park, M.D.

Department of Internal Medicine, College of Medicine and Kidney Research Institute, Hallym University, Seoul, Korea

Magnesium is the second most common intracellular divalent cation. Magnesium balance in the body is controlled by a dynamic interplay among intestinal absorption, exchange with bone, and renal excretion. Intestinal magnesium absorption proceeds in both a passive paracellular and an active transcellular manner. Regulation of serum magnesium concentrations is achieved mainly by control of renal magnesium re absorption. Only 20% of filtered magnesium is reabsorbed in the proximal tubule, whereas 60% is reclaim ed in the cortical thick ascending limb (TAL) and another 510% in the distal convoluted tubule (DCT). The passive paracellular transport of magnesium in the TAL is closely related with the mutations in claudin16/paracellin1 and is responsible for familial hypomagnesemia with and nephro . The active transcellular transport of magnesium in the DCT was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary . This channel regulates the apical entry of magnesium into epithelia and alters wholebody magnesium homeostasis by controlling urinary excretion. TRPM6 is regulated at the transcriptional level by acidbase status, 17β , and both FK506 and cyclosporine. The molecular identity of the protein responsible for the basolateral exit of magnesium from the epithelial cell remains unidentified.

Key Words : magnesium; homeostasis; paracellular transport; transcellular transport; transient receptor potential channels

Introduction cation, and energy metabolism 2) .

Magnesium is the major intracellular divalent cation Magnesium metabolism and plays an essential physiological role in many func 1. Body content and distribution of magnesium tions of the body 1) . Magnesium is essential for the syn The normal adult human body contains approximately thesis of nucleic acids and proteins, and is an important 1,000 mmols of magnesium (2226 g). The distribution of cofactor for a wide range of enzymes, transporters. magnesium within the body is shown in Fig. 1 3) . Magnesium has important effects on the cardiovascular About 60% of the magnesium is present in bone, of system. Intracellular magnesium forms a key complex which 30% is exchangeable and functions as a reservoir with ATP and has a key role in many other important to stabilize the serum concentration. About 20% is found biological processes such as protein synthesis, cell repli in skeletal muscle, 19% in other soft tissues and less than 1% in the . Intracellular magnesium is Received November 12, 2008. Accepted November 19, 2008. maintained within narrow concentration limits except in Corresponding author: Jang Won Seo, M.D. Department of Internal Medicine, College of Medicine and Kidney extreme situations such as hypoxia or prolonged magne Research Institute, Hallym University, Seoul, Korea Tel: +82226395786, Fax: +82226779756 sium depletion. Very little is known about the mecha Email: [email protected] JW Seo et al. : Magnesium Metabolism 87 nisms involved in the regulation of intracellular magne spinach and broccoli (which are rich in magnesiumcon sium 4) . taining chlorophyll), cereal, grain, nuts, banana, and le gumes. Fruits, meats, chocolates, and fish have interme Magnesium balance diate values, and dairy products are poor in magnesium 5, The recommended daily allowance (RDA) for magne 6) . Fig. 2 illustrates the metabolism of magnesium in a sium in adults is 4.5 mg/kg/day, lower than the previous healthy adult 1) . The average magnesium intake of a nor recommendation of 610 mg/kg/day. The daily require mal adult is approximately 12 mmol/day. In addition to ment is higher in pregnancy, lactation and following de this, approximately 2 mmol/day of magnesium is secreted bilitating illness. Recent dietary surveys show that the into the intestinal tract in bile and pancreatic and intestinal average intake in many western countries is less than the juices. From this pool 6 mmol (about 30%) is absorbed RDA 5) . Magnesium intake depends on the magnesium giving a net absorption of 4 mmol/day. concentration in drinking water and food composition. Intestinal absorption of magnesium Magnesium is plentiful in green leafy vegetables such as About 3040% of the dietary magnesium content is ab sorbed, mainly in the jejunum and ileum. Fractional in testinal absorption of magnesium is inversely related to intake; 65% at low intake and 11% at high intake. Most of the absorption occurs in the jejunum, ileum, and colon. At normal intake, absorption is primarily passive. During low magnesium intake a saturable component of magne sium absorption can be demonstrated 7) . Factors control ling magnesium absorption are not well understood. Studies suggest a role for (PTH) in regulating magnesium absorption. Intestinal magnesium absorptive efficiency is stimulated by 1,25dihydroxyvita

min D (1,25(OH) 2D) and can reach 70% during magne Fig. 1. Distribution of chemical forms of magnesium in serum. sium deprivation, but the role of and its active Of total body magnesium, 67% is found in bone and hard tissue; 1) 31% is found inside cells; and approximately 2% is found in metabolite 1,25(OH) 2D is controversial . serum 3) .

Fig. 2. Distribution of magnesium in the body 1) . 88 JW Seo et al. : Magnesium Metabolism

fects in transient receptor potential melastatin 6 (TRPM6) Magnesium reabsorption in the kidney cause hypomagnesemia with secondary hypocalcemia The kidney plays a major role in magnesium homeo (HSH). This channel regulates the apical entry of magne stasis and the maintenance of plasma magnesium con sium into epithelia and alters wholebody magnesium ho centration. Urinary magnesium excretion normally match meostasis by controlling urinary excretion. TRPM6 is es net intestinal absorption and is ~4 mmol/d (100 mg/ regulated at the transcriptional level by acidbase status, day). Regulation of serum magnesium concentration is 17β estradiol, and both FK506 and cyclosporine. The mo achieved mainly by control of renal magnesium reabsorp lecular identity of the protein responsible for the baso tion. Under normal circumstances, when 80% of the total lateral exit of magnesium from the epithelial cell remains plasma magnesium is ultrafiltrable, 84 mmol of magne unidentified 13) . Factors influencing renal magnesium ex sium is filtered daily and 95% of this reabsorbed, leaving cretion are listed in Table 2. The plasma magnesium con about 35 mmol to appear in the urine. Under normal centration is a major determinant of urinary magnesium circumstances, approximately only 20% of filtered mag excretion. Hypomagnesemia is associated with an increase nesium is reabsorbed in the proximal tubule, whereas 60% in magnesium excretion due to an increase in the filtered is reclaimed in the cortical thick ascending limb (TAL) load and reduced reabsorption in TAL 1) . of loop of Henle and the remaining 510% in the distal Assessment of magnesium status convoluted tubule (DCT) 8, 9) . Magnesium transport in the proximal tubule appears At present, there is no simple, rapid, and accurate labo to be primarily a unidirectional passive process depend ratory test to indicate the total body magnesium status. ing on sodium/water reabsorption and the luminal magne The most commonly used method for assessing magne sium concentration. Magnesium transport in the TAL is sium status is the serum magnesium concentration. The directly related to sodium chloride reabsorption and the total serum magnesium concentration is not the best meth positive luminal voltage in the segment 4) . In the TAL, od to evaluate magnesium status as changes in serum pro approximately 25% of the filtered sodium chloride is re tein concentrations may affect the total concentration absorbed through the active transcellular transport (so without necessarily affecting the ionized fraction or total diumchloride transport) and passive para body magnesium status. The correlation between serum cellular diffusion 10) . This creates a favorable luminal pos total magnesium and total body magnesium status is itive potential at the TAL where most of the magnesium poor 5, 14) . is reabsorbed. Magnesium reabsorption in the TAL occurs via a paracellular route that requires both a lumenpositive Table 1. Factors Affecting Tubular Reabsorption of Magnesium 1) potential, created by NaCl reabsorption, and the tight Plasma magnesium concentration/magnesium status junction protein, claudin16/paracellin1. Glomerular filtration rate The mutations in claudin16/paracellin1 are respon Volume status Hormones sible for familial hypomagnesemia with hypercalciuria Parathyroid hormone and (FHHNC). Magnesium reabsorption Antidiuretic hormone in the TAL is increased by PTH but inhibited by hyper Insulin calcemia, both of which activate the sensing re depletion ceptor (CaSR) in this nephron segment. Magnesium re Acid base status Hypercalcemia 11, 12) absorption in the DCT is active and transcellular . The active transcellular transport of magnesium in the Miscellaneous factors DCT was similarly enhanced by the realization that de JW Seo et al. : Magnesium Metabolism 89

Table 2. Classification and Characteristics of Inherited Disorders of Renal Magnesium Wasting 1)

AR, autosomal recessive; AD, autosomal dominant; TRPM6, transient receptor potential melastatin 6.

Measurement of ultrafiltrable magnesium may be more hypomagnesaemic patients had magnesium requested 15) . meaningful than the total magnesium as it is likely to Thus, it has been suggested that magnesium should be reflect ionized magnesium concentration, but methods are determined routinely in all acutely ill patients especially not available for routine use. In the last few years, ion in those with conditions, diseases, or treatment that may selective electrodes for magnesium have been developed predispose to 11) . and several commercial analyzers are now available for the measurement of ionized magnesium concentration. 1. Etiology and pathogenesis of hypomagnesemia Measurement of ionized magnesium has been found to Hypomagnesemia may result from one or more of the be useful in several clinical situations. In summary, no following mechanisms: redistribution, reduced intake, re single method is satisfactory to assess magnesium status. duced intestinal absorption, increased gastrointestinal The simplest, most useful, and readily available tests are loss, and increased renal loss. the measurement of serum total magnesium and the mag nesium tolerance test 3, 5) . Ionized magnesium measure 1) Hypomagnesemia due to redistribution ment may become more readily available with the devel Hypomagnesemia due to the shift of magnesium from opment of reliable analyzers. extracellular fluid into cells or bone is seen in refeeding of starved patients (refeeding syndrome), during treatment Hypomagnesemia and magnesium deficiency of metabolic acidosis, and in hungry bone syndrome The terms hypomagnesemia and magnesium deficiency which is seen after parathyroidectomy or in patients with are commonly used interchangeably. However, total body diffuse osteoblastic metastases 1) . magnesium depletion can be present with normal serum magnesium concentrations and there can be significant 2) Gastrointestinal causes hypomagnesemia without total body deficit 1) . Hypomag Magnesium deficiency entirely due to reduced dietary nesemia is frequently undetected. Measurement of serum intake in otherwise healthy subjects is very uncommon. magnesium concentration in 1,000 samples received for Hypomagnesemia may be seen in patients who are main electrolyte determination showed that only 10% of the tained on magnesiumfree intravenous fluids or total pa 90 JW Seo et al. : Magnesium Metabolism renteral nutrition, especially in those patients who have fication, features and molecular defects in some of the a marginal or reduced serum magnesium to start off syndromes are listed in Table 2 1) . And renal regulation with 11) . An inherited disorder of isolated magnesium mal of magnesium homeostasis is illustrated in Fig. 3 13) . absorption associated with hypocalcemia, tetany, and seiz ures has been described in infants as well as in older in 4) Drugs dividuals 16) . Children with this condition usually present A variety of drugs including antibiotics and chemo at 45 weeks of age with generalized convulsions asso therapeutic agents cause magnesium wasting. Loop diu ciated with protein losing enteropathy, hypoalbuminae retics inhibit magnesium transport in TAL and cause mag mia, and anasarca. The disorder is caused by a mutation nesium depletion, especially during longterm use 19, 20) . in the TRPM6 gene which codes for an ion channel, re Shortterm administration of diuretics which act sulting in defective carrier mediated transport in the small on the DCT, where less that 5% of magnesium is ab intestine 10) . sorbed, does not produce magnesium wasting. However, long term administration may produce substantial magne 3) Renal causes sium depletion due to secondary hyperaldosteronism, in Proximal tubular magnesium reabsorption is propor creased sodium load, and interaction with calcium metab tional to sodium reabsorption, and a reduction in sodium olism 21) . reabsorption during longterm intravenous fluid therapy Hypomagnesemia is a frequent of cispla may result in magnesium deficiency 1) . tin treatment and may be acute or chronic. Cisplatin, for (1) Renal disease example, frequently causes magnesium wasting with hy Hypomagnesemia is occasionally observed in chronic pocalciuria and , resembling Gitelman syn renal failure due to an obligatory renal magnesium loss 17) . drome 22) , a disease caused by defective electroneutral Na – It is also seen during the phase of acute renal Cl cotransporter in the DCT. Cisplatin increases the trans failure, in postobstructive and after renal trans epithelial voltage in the DCT 23) , consistent with a plantation 18) . ‘Gitelmanlike’ effect. The incidence of hypomagnesemia (2) Inherited disorders increases with cumulative dose. In the acute phase, poor Several different congenital disorders of renal tubular dietary intake and the use of diuretics are contributing reabsorption of magnesium have been described but there factors. Chronic hypomagnesemia starts to develop 3 is no consensus on their classification 9, 10) . The classi weeks after the initial chemotherapy and usually persists

Fig. 3. Renal regulation of magnesium homeostasis. Model of thick ascending limb (TAL) and distal convoluted tubule (DCT), showing predominant magnesium transport pathways 9) . CLCKb, voltagedependent chloride channel; claudin16, paracellin; NKA, Na +,K +ATPase; NKCC2, Na +/K +/2Cl cotransporter; ROMK, inwardly rectifying potassium channel; TSC, thiazidesensitive Na +/Cl cotransporter. JW Seo et al. : Magnesium Metabolism 91 for several months 24) . Management of hypomagnesemia and Manifestations of hypomagnesemia and magnesium deficiency magnesium deficiency 1. Prophylaxis of hypomagnesemia Many patients with hypomagnesemia and magnesium In patients likely to develop magnesium deficiency, deficiency remain asymptomatic. As magnesium defi prophylactic measures should be taken to prevent the de ciency is usually secondary to other disease processes or velopment or progression of hypomagnesemia and mag drugs, the features of the primary disease process may nesium deficiency. Highrisk patients such as chronic al complicate or mask magnesium deficiency. Signs and coholics, patients receiving total parenteral nutrition, long symptoms of magnesium deficiency are usually not seen term diuretic therapy or other drugs causing magnesium until serum magnesium decreases to 0.5 mmol/L or low loss, and those with chronic diarrheal and steatorrheal er 1) . Manifestations may depend more on the rate of de states should have serum magnesium monitored regularly velopment of magnesium deficiency and/or on the total and, if necessary, supplemented with magnesium. Patients body deficit rather than the actual serum magnesium con on parenteral nutrition should receive prophylactic doses centration 18) . Clinical manifestations of severe or moder of 48 mmol/day of magnesium. Higher doses may be ate magnesium deficiency are listed in Table 3. required in malnourished patients and in those with on going magnesium loss 1) .

Table 3. Clinical Features of Hypomagnesemia and Mag- 2. Treatment of hypomagnesemia nesium Deficiency 1) Mild, asymptomatic hypomagnesemia may be treated Electrolyte disturbance Hypokalemia with oral magnesium salts [MgCl 2, MgO, Mg(OH) 2] in Hypocalcemia divided doses totaling 2030 mmol/d (4060 mEq/d). Neuromuscular and central nervous system 12) Carpopedal spasm Diarrhea may occur with larger doses . Assessment of Convulsions renal function before replacement therapy is important, Muscle cramps and magnesium therapy in patients with any renal failure Muscle , fasciculations, tremors Vertigo should be undertaken cautiously. During intravenous re Nystagmus placement therapy it is important to monitor serum con , Athetoid movements & choreform movements centrations of magnesium, potassium, and other major Cardiovascular cations as well as deep tendon reflexes. If there is deterio Atrial tachycardias, fibrillation Supraventricular ration in renal function, the dose of magnesium should Ventricular arrhythmias be halved and serum magnesium monitored more fre Torsade de pointes quently. sensitivity Complications of magnesium deficiency If or signs of magnesium intoxi Altered glucose homeostasis cation (hypotension, bradycardia or depression of tendon Atherosclerotic vascular disease 1) Hypertension reflexes) develop, therapy should be stopped . More se vere hypomagnesemia should be treated parenterally, pref Osteoporosis Miscellaneous erably with MgCl 2, which can be administered safely Migraine through a continuous infusion of 50 mmol/d (100 mEq Asthma Mg 2+ /d) if renal function is normal. MgSO may be given Chronic syndrome 4 Impaired athletic performance IV instead of MgCl 2, although the sulfate anions may bind calcium in serum and urine and aggravate hypocalcemia. 92 JW Seo et al. : Magnesium Metabolism

Serum magnesium should be monitored at intervals of the ECF in patients who suffered trauma, shock, sepsis, 1224 hours during therapy, which may continue for sev , or severe burns 12) . Hypermagnesemia com eral days because of impaired renal conservation of mag monly occurs due to the excessive administration of mag nesium (only 5070% of the daily IV magnesium dose nesium salts or magnesiumcontaining drugs, especially is retained) and delayed repletion of intracellular deficits, in patients with reduced renal function. Hypermagnesemia which may be as high as 11.5 mmol/kg (23 mEq/kg) 12) . may rarely be due to redistribution from cells 27) . (Table 4) Hypermagnesemia

Hyermagnesemia is rarely seen in the absence of renal 1) Excessive intake insufficiency, as normal kidneys can excrete large amounts Magnesium containing are commonly used (250 mmol/d) of magnesium. Prevalence of Hypermagne as laxatives, antacids, and as rectal enemas. Hypermagne semia varies from 5.7% to 9.3% 15, 25) . The highest serum semia has often been described with the use of magnesium magnesium concentrations reported so far are 18 mmol/L containing cathartics for treatment of drug overdose, in in a 33 week old premature infant and 13.4 mmol/L in patients taking magnesiumcontaining cathartics and ant a 78 year old woman who swallowed water from the Dead acids for therapeutic purposes and following rectal admin Sea 25, 26) . Severe hypermagnesemia in fact seems to be istration of magnesium, even in the presence of normal a feature in patients who drown in the Dead Sea 26) . renal function 28) .

1. Causes of hypermagnesemia 2) Renal failure A notable example of a cause of hypermagnesemia is Hypermagnesemia is common in patients with end prolonged retention of even normal amounts of magne stage renal disease, in those undergoing and in siumcontaining cathartics in patients with intestinal , acute renal failure 27) . In chronic renal failure, serum mag obstruction, or perforation. Extensive soft tissue injury or nesium concentration is usually maintained until the glo necrosis can also deliver large amounts of magnesium into merular filtration rate falls below 30 mL/min. However, severe hypermagnesemia may result, especially if magne 1) Table 4. Causes of Hypermagnesemia siumcontaining medications are used. In patients under Redistribution going regular dialysis, the serum magnesium concen Acute acidosis Excessive intake tration is directly related to the dialysate magnesium Oral concentration. Hypermagnesemia is also seen in patients Antacids Cathartics undergoing continuous ambulatory peritoneal dialysis Swallowing salt water 29) Rectal (CAPD) . Purgation Parenteral Urethral irrigation 3) Miscellaneous causes Renal failure therapy causes mild hypermagnesemia as well Chronic renal failure Acute renal failure as hypercalcaemia 20) . Modest elevations in serum magne Others sium concentration have been reported in familial hypo Lithium therapy calciuric hypercalcaemia. Mild hypermagnesemia has also Familial hypocalciuric hypercalcemia Hypothyroidism been seen in hypothyroidism, Addison's disease, and milk Addison’s disease alkali syndrome 27) . Milk alkali syndrome Depression JW Seo et al. : Magnesium Metabolism 93

12) Table 5. Clinical Manifestations of Hypermagnesemia 1) pansion, may be an early sign of hypermagnesemia . A Neuromuscular moderate increase in serum magnesium concentration of 23 mmol/L results in mild reduction in supine as well Lethargy Respiratory depression as erect blood pressure. A higher concentration of magne Absent tendon reflexes sium may cause severe symptomatic hypotension 30) . Para Paralytic ileus Bladder paralysis doxical bradycardia; prolongation of PR, QRS, and QT /paralysis intervals; heart block; may be seen at serum magnesium Cardiovascular levels approaching 10 mmol/L, asystole 12) . Hypotension Bradycardia Inhibition of AV and interventricular conduction 3. Hypocalcaemia Heart block Cardiac arrest Magnesium intoxication causes a reduction in serum Others calcium concentration. This has most commonly been re , ported in patients receiving magnesium therapy for preg nancyinduced hypertension 31) . Hypermagnesemia, acting via the CaSR, causes hypocalcemia and hypercalciuria Effects of hypermagnesemia due to both parathyroid suppression and impaired cortical of hypomagnesemia are not usu TAL calcium reabsorption 12) . ally apparent until serum magnesium is in excess of 2 mmol/L; however, the serum concentration at which signs 4. Other effects 1) and symptoms appear varies widely . (Table 5) Hypermagnesemia may cause smooth muscle paralysis resulting in paralytic ileus. Other nonspecific manifes 1. Neuromuscular manifestations tations of magnesium intoxication include nausea, vomit The most prominent clinical manifestations of hyper ing, lethargy, and weakness may progress to respiratory magnesemia are vasodilation and neuromuscular block failure and paralysis. Other findings may include gastro ade, which may appear at a serum magnesium concen intestinal hypomotility or ileus; facial flushing and papil tration of greater than 2 mmol/L (>4 mEq/L; >4.8 mg/ lary dilation 12) . dL) 12) . Neuromuscular symptoms are the most common Management of hypermagnesemia presenting problem of hypermagnesemia and magnesium intoxication. Magnesium prevents the release of presyn Most cases of hypermagnesemia can be prevented. The aptic acetylcholine from both sympathetic and neuro possibility of hypermagnesemia should be anticipated in 26) muscular junctions . Hypermagnesemia causes blockage any patient receiving magnesium treatment, especially if of neuromuscular transmission and depresses the con the patient has reduced renal function, serum magnesium duction system of the heart and the sympathetic ganglia. concentration should be monitored daily. When hyper Clinically, one of the earliest effects of magnesium in magnesemia is found, we should identify and interrupting toxication is the disappearance of deep tendon reflexes. the source of magnesium and magnesium therapy should This is often seen at magnesium concentrations of 2.04.5 be withdrawn. This is all that is needed in most patients mmol/L. may be observed at serum concen with mild to moderate hypermagnesemia 1) . 1) trations of 2 mmol/L or above . Use of magnesiumfree cathartics or enemas may be helpful in clearing ingested magnesium from the gastro 2. Cardiovascular manifestations intestinal tract. 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