You are in: eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders HypomagnesemiaArticle Last Updated: Jul 24, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
 
Author: Mahendra Agraharkar, MD, MBBS, FACP, President, Space City Associates of Nephrology; Medical Director, Acute Dialysis Unit and Chronic Home Dialysis Unit, Gambro Healthcare Reliant Dialysis Center Mahendra Agraharkar is a member of the following medical societies: American College of Physicians, American Society of Nephrology, and National Kidney Foundation Coauthor(s): Helbert Rondon-Berrios, MD, Nephrology Fellow, Renal-Electrolye Division, University of Pittsburgh Medical Center; Mark Fahlen, MD, Staff Physician, Gould Medical Group Editors: James H Sondheimer, MD, Director of Hemodialysis Unit, Harper Hospital; Associate Professor, Department of Internal Medicine, Division of Nephrology, Wayne State University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Christie Thomas, MD, FACP, FAHA, FASN, Department of Internal Medicine, Division of Nephrology, Professor, University of Iowa Hospitals and Clinics; Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine; Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System Author and Editor Disclosure Synonyms and related keywords: magnesium, Mg, magnesium deficiency, magnesium depletion, mineral deficiency, dietary magnesium deprivation, primary intestinal hypomagnesemia, primary renal magnesium wasting, Gitelman syndrome, magnesium wasting, Bartter syndrome, diuretic therapy, diuretics, excessive lactation, severe sweating, hungry bone syndrome, hyperadrenergic states, acute alcoholism, chronic alcoholism, hypocalcemia BACKGROUND AND PATHOPHYSIOLOGYSection 2 of 11
 
Magnesium is the fourth most abundant cation in the body and the second most abundant intracellular cation after potassium. Magnesium plays a fundamental role in many functions of the cell, including energy transfer, storage, and use; protein, carbohydrate, and fat metabolism; maintenance of normal cell membrane function; and the regulation of parathyroid hormone (PTH) secretion. Systemically, magnesium lowers blood pressure and alters peripheral vascular resistance. Abnormalities of magnesium levels can result in disturbances in nearly every organ system and can cause potentially fatal complications (eg, ventricular arrhythmia, coronary artery vasospasm, sudden death). This article addresses the basic physiological principles of magnesium distribution and handling, causes of hypomagnesemia, disorders related to magnesium depletion, assessment of magnesium status, and treatment of magnesium deficiency. Magnesium homeostasis The total body magnesium level of an average adult is 25 g or 1000 mmol. Approximately 60% is present in bone, 20% in muscle, and 20% in soft tissue and the liver. Approximately 99% of the total body magnesium is intracellular, with only 1% in the extracellular space; 80% of plasma magnesium is ionized or complexed to filterable ions (eg, oxalate, phosphate, citrate) and is available for glomerular filtration, while 20% is protein-bound. Normal plasma magnesium concentration is 1.7-2.1 mg/dL (0.7-0.9 mmol or 1.4-1.7 mEq/L). The main controlling factors in magnesium homeostasis appear to be gastrointestinal absorption and renal excretion. The average American diet contains approximately 360 mg (ie, 15 mmol) of magnesium; healthy individuals need to ingest 0.15-0.2 mmol/kg/d to stay in balance. Magnesium is ubiquitous in nature and is especially plentiful in green vegetables, cereal, grain, nuts, legumes, and chocolate. Vegetables, fruits, meats, and fish have intermediate values. Food processing and cooking may deplete magnesium content, thus accounting for the apparently high percentage of the population whose magnesium intake is less than the daily allowance. The plasma magnesium concentration is kept within narrow limits. Extracellular magnesium is in equilibrium with that in the bone, kidneys, intestine, and other soft tissues. In contrast to other ions, magnesium is treated differently in 2 major respects: (1) no hormonal modulation of urinary magnesium excretion occurs and (2) bone, the principal reservoir of magnesium, does not readily exchange with circulating magnesium in the extracellular fluid space. This inability to mobilize magnesium stores means that in states of negative magnesium balance, initial losses come from the extracellular space; equilibrium with bone stores does not begin for several weeks. Magnesium absorption Magnesium is absorbed principally in the small intestine, through both a saturable transport system and passive diffusion through bulk flow of water. Absorption of magnesium depends on the amount ingested. When the dietary content of magnesium is typical, approximately 30-40% is absorbed. Under conditions of low magnesium intake (ie, 1 mmol/d), approximately 80% is absorbed, while only 25% is absorbed when intake is high (25 mmol/d). The exact mechanism for alterations in fractional magnesium absorption has yet to be determined. Presumably, only ionized magnesium is absorbed. Increased luminal phosphate or fat may precipitate magnesium and decrease absorption. Calcium and magnesium absorption may have a relationship in the gut, whereby a high calcium intake may decrease magnesium absorption and low magnesium intake may increase calcium absorption. PTH appears to increase magnesium absorption. Glucocorticoids, which decrease the absorption of calcium, appear to increase the transport of magnesium. Vitamin D may increase magnesium absorption, but its role is controversial. Renal handling of magnesium The kidneys play a major role in magnesium homeostasis and in the maintenance of plasma magnesium concentration. See Media file 1. Approximately 80% of plasma magnesium is ultrafiltrable. Under normal circumstances, approximately 95% of filtered magnesium is reabsorbed by various parts of the nephron. Unlike most ions, the majority of magnesium is not reabsorbed in the proximal convoluted tubule (PCT). Micropuncture studies, in which small pipettes are placed into different nephron segments, indicate that the thick ascending limb of the loop of Henle (TAL) is the major site of reabsorption (60-70%). The PCT accounts for another 15-25%, and the distal convoluted tubule (DCT) accounts for 5-10% of reabsorption. There is no significant reabsorption of magnesium in the collecting duct. In TAL, magnesium is passively reabsorbed with calcium through paracellular tight junctions; the driving force of this reabsorption being a lumen-positive electrochemical gradient, resulting from the reabsorption of sodium chloride. Paracellin-1, also known as claudin-16, has been identified as the renal tight junction protein in TAL, where the reabsorption of magnesium occurs. Mutations in the paracellin-1 gene cause a human hereditary disease familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) characterized by excessive renal magnesium and calcium wasting, bilateral nephrocalcinosis, and progressive renal failure. Magnesium is reabsorbed in the distal convoluted tubule (DCT) via an active, transcellular process that is thought to involve TRPM6, a member of the transient receptor potential (TRP) family of cation channels. Recently, mutations in TRPM6 were identified as the underlying defect in patients with hypomagnesemia with secondary hypocalcemia (HSH), an autosomal recessive disorder that manifests in early infancy with generalized convulsions refractory to anticonvulsant treatment or other symptoms of increased neuromuscular excitability like muscle spasms or tetany. Laboratory evaluation reveals extremely low serum magnesium and serum calcium levels. The mechanism of basolateral transport into the interstitium is unknown. Magnesium has to be extruded against an unfavorable electrochemical gradient. Most physiological studies favor a sodium-dependent exchange mechanism driven by low intracellular sodium concentrations generated by the Na+/K+-ATPase. A mutation in the gamma-subunit of Na+/K+-ATPase is responsible for isolated dominant hypomagnesemia (IDH), an autosomal-dominant condition associated with few symptoms other than chondrocalcinosis. Patients always have hypocalciuria and variable but usually mild hypomagnesemic symptoms. This mutation in the gamma-subunit is thought to produce a disturbed routing of the Na+/K+-ATPase complex to the basolateral membrane, leading to reduced expression of the Na+/K+-ATPase on the cell surface. Consequently, the entry of K+ is reduced and the cell depolarizes to some extent, leading to closing of TRPM6 channel and magnesium wasting. Factors affecting renal handling of magnesium Several factors are responsible, as follows:
Volume status influences renal handling of magnesium. Expansion of the extracellular fluid volume increases the excretion of calcium, sodium, and magnesium. Magnesium reabsorption in the loop of Henle is reduced, probably due to increased delivery of sodium and water to TAL and a decrease in the potential difference that is the driving force for magnesium reabsorption. Changes in the glomerular filtration rate (GFR) also influence tubular magnesium reabsorption. When the GFR and, thus, the filtered load of magnesium in chronic renal failure are reduced, fractional reabsorption is also reduced such that the plasma magnesium value remains normal until the patient reaches end-stage renal disease (ESRD). Electrolyte and acid-base abnormalities also influence renal magnesium handling. Hypercalcemia and hypermagnesemia inhibit magnesium reabsorption through activation of the calcium-sensing receptor (CaSR), a member of the family of G-protein-coupled receptors. The CaSR is expressed in the basolateral membrane of TAL. When calcium or magnesium activates the receptor, there is a resultant enhancement in the formation of arachidonic acid-derived 20-HETE, which reversibly inhibits apical potassium channels (ROMK2). No single hormone has been implicated in the control of renal magnesium reabsorption. A number of hormones have been shown to alter magnesium transport in the thick ascending limb in experimental studies. These include PTH, calcitonin, glucagon, AVP, and the beta-adrenergic agonists, all of which are coupled to adenylate cyclase in TAL. Postulated mechanisms include an increase in luminal positive voltage (via activation of basolateral membrane chloride conductance and NKCC2) and an increase in paracellular permeability (possibly by phosphorylation of paracellular pathway proteins). It is not known if these effects have any important role in normal magnesium hemostasis. CAUSES OF HYPOMAGNESEMIASection 3 of 11
Causes of hypomagnesemia
Decreased intake Alcoholics and individuals on magnesium-deficient diets or on parenteral nutrition for prolonged periods can become hypomagnesemic without abnormal gastrointestinal or kidney function. The addition of 4-12 mmol of magnesium per day to total parenteral nutrition has been recommended to prevent hypomagnesemia. Redistribution from extracellular to intracellular The transfer of magnesium from extracellular to intracellular fluid or bone is a frequent cause of decreased serum magnesium levels. This depletion may occur as part of the hungry bone syndrome, in which magnesium is removed from the extracellular fluid space and deposited into bone following parathyroidectomy or thyroidectomy. Hypomagnesemia may also occur following insulin therapy for diabetic ketoacidosis and may be related to the anabolic effects of insulin driving magnesium back into cells. Hyperadrenergic states, such as alcohol withdrawal, may cause intracellular shifting of magnesium and may increase circulating levels of free fatty acids that combine with free plasma magnesium. The hypomagnesemia that sometimes is observed after surgery is attributed to the latter. Hypomagnesemia is a manifestation of the refeeding syndrome, a condition where previously malnourished patients are fed with high carbohydrate loads, resulting in a rapid fall in phosphate, magnesium, and potassium, along with an increasing ECF volume, leading to a variety of complications. Acute pancreatitis can also cause hypomagnesemia. The mechanism probably is similar to that of the associated hypocalcemia, the saponification of magnesium and calcium in necrotic fat. Gastrointestinal losses Impaired gastrointestinal absorption is a common underlying basis for hypomagnesemia, especially when the small bowel is involved, due to disorders associated with malabsorption, chronic diarrhea, or steatorrhea, or as a result of small intestinal bypass surgery. Because there is some magnesium absorption in the colon, patients with ileostomies can develop hypomagnesemia. Hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia. Pathophysiology is related to impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the distal convoluted tubule. Recently, mutations in the TRPM6 gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, were identified as the underlying genetic defect. Renal losses Several inherited tubular disorders are responsible for urinary magnesium wasting. Gitelman syndrome is an autosomal recessive condition caused by mutations of the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCCT). This syndrome is characterized by hypokalemia, hypomagnesemia, and hypocalciuria. Hypomagnesemia is found in most patients with Gitelman syndrome and is assumed to be secondary to the primary defect in NCCT, but the mechanisms underlying hypomagnesemia are poorly understood. Recently, some studies pointed out that magnesium wasting in Gitelman syndrome may be due to down-regulation of TRPM6 in the DCT. Classic Bartter syndrome (Type III Bartter syndrome) is caused by mutations in CLCNKB encoding the basolaterally located renal chloride channel ClC-Kb, which mediates chloride efflux from the tubular epithelial cell to the interstitium along the TAL and DCT. It is unknown how hypomagnesemia is produced in this syndrome. In familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive disorder, there is profound renal magnesium and calcium wasting. The hypercalciuria often leads to nephrocalcinosis, resulting in progressive renal failure. Other symptoms that have been reported in patients with FHHNC include urinary tract infections, nephrolithiasis, incomplete distal tubular acidosis, and ocular abnormalities. This syndrome is caused by mutations in the gene CLDN16, which encodes for paracellin-1 (claudin-16), a member of the claudin family of tight junction proteins that form the paracellular pathway for calcium and magnesium reabsorption in TAL. Autosomal dominant hypocalcemia with hypercalciuria (ADHH) is another disorder of urinary magnesium wasting. Individuals who are affected present with hypocalcemia, hypercalciuria, and polyuria, and about 50% of these patients have hypomagnesemia. ADHH is produced by mutations of the CASR gene, the gene that encodes for the calcium-sensing receptor (CaSR) located basolaterally in TAL and DCT, which is involved in renal calcium and magnesium reabsorption. Activating mutations shift the set point of the receptor to a level of enhanced sensitivity by increasing the apparent affinity of the mutant receptor for extracellular calcium and magnesium. This results in diminished PTH secretion and decreased reabsorption of divalent cations in the TAL and DCT, which leads to loss of urinary calcium and magnesium. Isolated dominant hypomagnesemia with hypocalciuria (IDH) is an autosomal dominant condition associated with few symptoms other than chondrocalcinosis. Patients always have hypocalciuria and variable but usually mild hypomagnesemic symptoms. A mutation in the gene FXYD2 coding for the gamma-subunit of the basolateral Na+/K+-ATPase in the DCT has been identified. This mutation in the gamma-subunit is thought to produce a disturbed routing of the Na+/K+-ATPase complex to the basolateral membrane, leading to reduced expression of the Na+/K+-ATPase on the cell surface. Consequently, the entry of potassium is reduced and the cell depolarizes to some extent, leading to closing of TRPM6 channel and magnesium wasting. Isolated recessive hypomagnesemia with normocalcemia (IRH) is an autosomal recessive disorder in which the individuals who are affected present with symptoms of hypomagnesemia early during infancy. Hypomagnesemia due to increased urinary magnesium excretion appears to be the only abnormal biochemical finding. IRH is distinguished from the autosomal dominant form by the lack of hypocalciuria. The mechanism of hypomagnesemia remains unknown. Hypomagnesemia with secondary hypocalcemia (HSH), also called primary intestinal hypomagnesemia, is an autosomal recessive disorder that is characterized by very low serum magnesium and low calcium levels. Patients usually present within the first 3 months of life with neurologic symptoms of hypomagnesemic hypocalcemia, including seizures, tetany, and muscle spasms. Untreated, the disorder may result in permanent neurologic damage or may be fatal. Hypocalcemia is secondary to parathyroid failure and peripheral parathyroid hormone resistance as a result of sustained magnesium deficiency. Usually, the hypocalcemia is resistant to calcium or vitamin D therapy. Normocalcemia and relief of clinical symptoms can be attained by administration of high oral doses of magnesium, up to 20 times the normal intake. As large oral amounts of magnesium may induce severe diarrhea and noncompliance in some patients, parenteral magnesium administration has to sometimes be considered. Several drugs such as loop diuretics, including furosemide, bumetanide, or ethacrynic acid, produce large increases in magnesium excretion through inhibition of electrical gradient necessary for magnesium reabsorption in TAL. Long-term thiazide diuretic therapy also may cause magnesium deficiency. Chronic thiazide administration enhanced magnesium excretion and specifically reduced renal expression levels of the epithelial magnesium channel TRPM6. Many nephrotoxic drugs, including aminoglycoside antibiotics, cisplatin, amphotericin B, cyclosporine, and pentamidine, can produce urinary magnesium wasting by a variety of mechanisms; some of them still unknown. For instance, tacrolimus causes hypomagnesemia through down-regulation of TRPM6 channels. Other causes of renal magnesium wasting include aldosterone excess, most likely through chronic volume expansion, causing increased magnesium excretion; hypercalcemia due to stimulation of CaSR and inhibition of magnesium reabsorption; hypophosphatemia for unknown reasons; and alcohol, most likely due to alcohol-induced tubular dysfunction that is reversible within 4 weeks of abstinence. Finally, magnesium wasting can be seen as part of the tubular dysfunction seen with recovery from acute tubular necrosis or during a postobstructive diuresis. CLINICAL MANIFESTATIONS OF MAGNESIUM DEFICIENCYSection 4 of 11
Magnesium is critically important in maintaining normal cell function, and symptomatic magnesium depletion is often associated with multiple biochemical abnormalities, including hypokalemia, hypocalcemia, and metabolic acidosis. As a result, hypomagnesemia is sometimes difficult to attribute solely to specific clinical manifestations. The organ systems commonly affected by magnesium deficiency are the cardiovascular system and the central and peripheral nervous systems. The skeletal, hematologic, gastrointestinal, and genitourinary systems are affected less often. Clinical manifestations of hypomagnesemia
RELATED METABOLIC ABNORMALITIESSection 5 of 11
Hypokalemia is a common event in patients with hypomagnesemia, occurring in 40-60% of cases. This is partly due to underlying disorders that cause both magnesium and potassium losses, including diuretic therapy or diarrhea. The mechanism for hypomagnesemia-induced hypokalemia relates to the intrinsic biophysical properties of ROMK channels mediating K+ secretion in the TAL and distal nephron. ROMK channels represent the first subfamily (Kir1.1) of 7 total subfamilies comprising the 2-transmembrane segment inward rectifier potassium channel family. Inward rectifiers are inwardly rectifying meaning that they have a greater inward conductance of potassium ions than an outward conductance of potassium ions at negative membrane potentials (if external and internal K+ concentrations are equivalent). The mechanism for this differential conductance results from the binding and subsequent cytoplasmic block of the outward K+ movement through the inward rectifier conduction pathway by cytoplasmic magnesium and polyamines. A reduction in intracellular magnesium (in the absence of polyamines) results in the loss of inward rectification and, hence, the greater outward conductance of K+ ions through the channel pore. Thus, a decrease in intracellular magnesium concentration in TAL and collecting duct cells results in increased K+ secretion through ROMK channels. Evidence also suggests this wasting may be due to hypomagnesemia causing a decline in ATP and the subsequent removal of ATP inhibition of the ROMK channels responsible for secretion in TAL and collecting duct. The classic sign of severe hypomagnesemia ( <1.2 mg/dL) is hypocalcemia. The mechanism is multifactorial. Parathyroid gland function is abnormal, largely because of impaired release of PTH. Impaired magnesium-dependent adenyl cyclase generation of cAMP mediates the decreased release of PTH. Skeletal resistance to this hormone in magnesium deficiency has also been implicated. Hypomagnesemia also alters the normal heteroionic exchange of calcium and magnesium at the bone surface, leading to an increased bone release of magnesium ions in exchange for an increased skeletal uptake of calcium from the serum. CARDIOVASCULAR MANIFESTATIONS OF MAGNESIUM DEFICIENCYSection 6 of 11
The cardiovascular effects of magnesium deficiency include effects on electrical activity, myocardial contractility, potentiation of digitalis effects, and vascular tone. Epidemiological studies also show an association between magnesium deficiency and coronary artery disease (CAD). Arrhythmia Hypomagnesemia is now recognized to cause cardiac arrhythmia. Changes in electrocardiogram findings include prolongation of conduction and slight ST depression, although these changes are nonspecific. Patients with magnesium deficiency are particularly susceptible to digoxin-related arrhythmia. Intracellular magnesium deficiency and digoxin excess act together to impair the sodium-potassium pump. The resulting decrease in intracellular potassium disturbs the myocardial cell resting membrane potential and repolarization phase, enhancing the inhibitory effect of digoxin. Non–digitalis-associated arrhythmias are myriad. The clinical disturbance of greatest importance is the association of mild hypomagnesemia with ventricular arrhythmia in patients with cardiac disease. At-risk patients include those with acute myocardial ischemia, congestive heart failure, or recent cardiopulmonary bypass and acutely ill patients in the intensive care unit. The ionic basis of the effect of magnesium depletion on cardiac arrhythmia may be related to impairment of the membrane sodium-potassium pump and increased outward movement of potassium through the potassium channels in cardiac cells, leading to shortening of the action potential and increasing susceptibility to cardiac arrhythmia. Torsade de pointes, a repetitive polymorphous ventricular tachycardia with prolongation of the QT interval, has been reported in conjunction with hypomagnesemia, and the American Heart Association now recommends that magnesium sulfate be added to the regimen used to manage torsade de pointes or refractory ventricular fibrillation. Hypertension Magnesium has been suggested to play a role in blood pressure regulation since its therapeutic efficacy in the hypertensive syndromes of pregnancy was demonstrated in the 19th century. Hypertension appears to be uniformly characterized by a decrease in intracellular free magnesium causing an increase in total peripheral resistance due to increased vascular tone and reactivity. At a cellular level, increased intracellular calcium content is believed to account for this increased tone and reactivity. This increased cytosolic calcium concentration may be secondary to decreased activation of calcium channels, which may enhance calcium current into cells, decrease calcium efflux from cells, increase cellular permeability to calcium, or decrease sarcoplasmic reticulum reuptake of intracellularly released calcium. Whatever the cause, intracellular accumulation leads to activation of actin-myosin contractile proteins, which increase vascular tone and total peripheral resistance. In contrast to experimental cellular physiology data supporting a role for magnesium deficiency in hypertension, results from clinical epidemiological studies have failed to confirm a relationship, and results from clinical trials examining the hypotensive effects of magnesium supplementation have been conflicting. Large, carefully performed, randomized clinical trials are needed. Coronary artery disease In epidemiological studies, patients with CAD have a higher incidence of magnesium deficiency compared to control subjects. Mounting evidence suggests that magnesium deficiency may play a role in the pathogenesis, initiation, morbidity, and mortality associated with myocardial infarction. In experimental animals, arterial atherogenesis varied inversely with dietary magnesium intake. In humans, the level of serum magnesium is inversely related to the serum cholesterol concentration. Therefore, magnesium deficiency is associated with hypertension and hypercholesterolemia, both well-recognized risk factors for atherogenesis and CAD. Magnesium deficiency is also known to be accompanied by thrombotic tendencies, increased platelet aggregatability, and increased coronary artery responsiveness to contractile stimuli. These factors are important in the initiation of acute myocardial infarction. The incidence of cardiac arrhythmia also correlates with the degree of magnesium deficiency in patients with CAD. Preliminary data suggest that magnesium supplementation may reduce the frequency of potentially fatal ventricular arrhythmia, although this finding has not been conclusively proven. Hypomagnesemia can also develop during cardiopulmonary bypass and predispose to arrhythmia, and intravenous magnesium given after the termination of cardiopulmonary bypass has resulted in significantly fewer incidences of supraventricular and ventricular dysrhythmia in a randomized prospective trial of 100 patients. Considering the above data, carefully assessing magnesium status in patients with CAD and supplementing patients deficient in magnesium seem prudent. Before magnesium is administered routinely in the setting of acute myocardial infarction, large well-designed trials are still needed. HYPOMAGNESEMIA AND OTHER SYSTEMSSection 7 of 11
Neuromuscular manifestations The earliest manifestations of magnesium deficiency are usually neuromuscular and neuropsychiatric disturbances, the most common being hyperexcitability. Neuromuscular irritability, including tremor, fasciculations, tetany, Chvostek and Trousseau signs, and convulsions, has been noted when hypomagnesemia is induced in volunteers. Other manifestations include convulsions, apathy, muscle cramps, hyperreflexia, acute organic brain syndromes, depression, generalized weakness, anorexia, and vomiting. Magnesium is required for stabilization of the axon. The threshold of axon stimulation is decreased and nerve conduction velocity is increased when serum magnesium is reduced, leading to an increase in excitability of muscles and nerves. The cellular basis for these changes is due to increased intracellular calcium content by mechanisms similar to those described in Cardiovascular Manifestations of Magnesium Deficiency. Magnesium and bone Magnesium deficiency has also been implicated in osteoporosis. The magnesium content in trabecular bone is significantly less in patients with osteoporosis, and magnesium intake in people with osteoporosis reportedly is lower than in control subjects. Magnesium intake frequently is lower than the recommended dietary intake in many groups, especially elderly persons. Postmenopausal women are also encouraged to consume at least 1000 mg of calcium per day, which leads to altered dietary calcium-to-magnesium ratios. This calcium supplementation may reduce the efficacy of magnesium absorption and further aggravate the consequences of diminished estrogen and the greater demineralizing effects of PTH. The H+-K+-ATPase pump in the cells of the periosteum is magnesium dependent, which may lead to decreased pH in the bone extracellular fluid and increased demineralization. In addition, the formation of calcitriol involves a magnesium-dependent hydroxylase enzyme, and concentrations are reduced in magnesium deficiency, possibly affecting calcium reabsorption. Results from recent studies suggest that magnesium supplementation may be beneficial in osteoporosis. Magnesium supplementation reportedly increases bone density, arrests vertebral deformity, and decreases osteoporotic pain. Magnesium and nephrolithiasis Urinary magnesium is an inhibitor of urinary crystal formation in vivo, and some studies have shown a lower urinary excretion of magnesium in patients with stones. Magnesium deficiency due to etiologies other than renal wasting are associated with hypomagnesuria and, theoretically, could play a role in predisposition to urinary calculus formation. Magnesium and diabetes Patients with diabetes mellitus are often magnesium deficient, expressed by hypomagnesemia. Magnesium deficiency decreases insulin sensitivity and insulin secretion. Moreover, magnesium deficiency is inherently related to the pathogenesis and the development of not only diabetic microangiopathy but also lifestyle-related diseases, such as hypertension and hyperlipidemia. Generally, modern people tend to live in the state of chronic deficiency of dietary magnesium. There is a possibility that one of the major factors contributing to the drastic increase of type 2 diabetes mellitus is the drastic decreased intake of grains, such as barley or cereals rich in magnesium. This implies an association between the volume of dietary magnesium intake and the onset of type 2 diabetes, raising expectations in the future for clinical trials that would prove the clinical efficacy of magnesium supplementation therapy. MISCELLANEOUS CONDITIONSSection 8 of 11
Magnesium deficiency has also been implicated in many other conditions. Low brain intracellular magnesium has been reported in migraine headache. Magnesium status may also have an influence on asthma because magnesium deficiency is associated with increased contractility of smooth muscle cells. In one epidemiological study, reduced magnesium intake, as assessed by a questionnaire, was associated with hyperreactivity of airways to methacholine, which led the authors to conclude that magnesium intake is related independently to lung function and, therefore, may be involved in the etiology of asthma. Magnesium deficiency has also been linked to chronic fatigue syndrome, sudden death in athletes, impaired athletic performance, and sudden infant death syndrome. ASSESSMENT AND TREATMENT OF MAGNESIUM DEPLETIONSection 9 of 11
Assessment of magnesium status The majority of patients with clinical manifestations of magnesium deficiency have hypomagnesemia. Measurement of serum magnesium is relatively easy, becoming the method of choice to estimate magnesium content, although its use in evaluating total body stores is limited. Other methods of magnesium assessment include red cell, mononuclear cell, or skeletal muscle intracellular content; 24-hour urinary excretion; fractional excretion of magnesium; and intracellular free magnesium ion concentration with fluorescent dye or nuclear magnetic resonance spectroscopy. Two caveats should be considered when serum magnesium is used to diagnose magnesium deficiency. First, most methods measure total magnesium concentration, while only free magnesium is biologically active. Because 30% of magnesium is bound to albumin and is, therefore, inactive, hypoalbuminemic states may lead to spuriously low magnesium values. Second, the major physiological role of magnesium occurs at an intracellular level. Serum contains only 0.3% of total body magnesium and may not always accurately reflect the intracellular magnesium status. A person may have normal serum levels of magnesium but be intracellularly depleted and exhibit signs of magnesium deficiency. Unfortunately, no quick, simple, and accurate test is available to measure intracellular magnesium. A surrogate for direct intracellular magnesium is the measurement of magnesium retention after acute magnesium loading. This method is useful only when the clinical suggestion of magnesium deficiency is strong in the setting of normomagnesemia (eg, unexplained cardiovascular or neuromuscular abnormalities). Patients have magnesium deficiency if they have reduced excretion ( <80% over 24 h) of an infused magnesium load (2.4 mg/kg of lean body weight given over the initial 4 h). However, the utility of this test is uncertain. Patients with malnutrition, cirrhosis, diarrhea, or long-term diuretic use typically have a positive test, whether or not they have signs or symptoms referable to magnesium depletion. It seems prudent, therefore, to simply administer magnesium to these patients if they have unexplained hypocalcemia and/or hypokalemia. If hypomagnesemia is confirmed, the diagnosis can usually be obtained from the history. If no cause is apparent, the distinction between gastrointestinal and renal losses can be made by measuring the 24-hour urinary magnesium excretion or the fractional excretion of magnesium on a random urine specimen. The latter can be calculated from the following formula: FEMg = [ (UMg x PCr) / (PMg x UCr x 0.7) ] x 100 The terms U and P refer to the urine and plasma concentrations of magnesium (Mg) and creatinine (Cr). The plasma magnesium concentration is multiplied by 0.7, since only about 70% of the circulating magnesium is free (not bound to albumin) and, therefore, able to be filtered across the glomerulus. The normal renal response to magnesium depletion is to lower magnesium excretion to very low levels. Thus, daily excretion of more than 1 mmol or a calculated fractional excretion of magnesium above 3% in a subject with normal renal function indicates renal magnesium wasting. Treatment of magnesium depletion The route of magnesium repletion varies with the severity of the clinical manifestations. As an example, the hypocalcemic-hypomagnesemic patient with tetany or the patient suspected of having hypomagnesemic-hypokalemic ventricular arrhythmias should receive 50 mEq of intravenous magnesium given slowly over 8-24 hours. This dose can be repeated as necessary to maintain the plasma magnesium concentration above 1.0 mg/dL (0.4 mmol/L or 0.8 mEq/L). In the normomagnesemic patient with hypocalcemia, it has been suggested to repeat this dose daily for 3-5 days. It must be appreciated that the plasma magnesium concentration is the major regulator of magnesium reabsorption in the loop of Henle, the major site of active magnesium transport. Thus, an abrupt elevation in the plasma magnesium concentration will partially remove the stimulus to magnesium retention, and up to 50% of the infused magnesium will be excreted in the urine. Furthermore, magnesium uptake by the cells is slow, and repletion requires sustained correction of the hypomagnesemia. For these reasons, oral replacement should be given in the asymptomatic patient, preferably with a sustained-release preparation. There are 2 such preparations currently available: Slow-Mag, containing magnesium chloride, and Mag-Tab, containing magnesium lactate. These preparations provide 5-7 mEq (2.5-3.5 mmol or 60-84 mg) of magnesium per tablet. Six to 8 tablets should be taken daily in divided doses for severe magnesium depletion. Two to 4 tablets may be sufficient for mild, asymptomatic disease. Patients with concomitant hypokalemia or hypocalcemia should also receive potassium and calcium replacement because these disorders may take several days to correct when treated with magnesium alone. Patients undergoing intravenous magnesium replacement should be monitored for evidence of acute hypermagnesemia (eg, respiratory depression, areflexia). Patients with renal dysfunction are at a markedly increased risk, and 25-50% of the normal dose should be given to those patients with plasma creatinine levels greater than 2 mg/dL. Intravenous calcium chloride or gluconate is the antidote, and 2 ampules should be administered immediately if these complications develop. Patients with mild magnesium depletion are predisposed to magnesium deficiency, remaining asymptomatic despite developing hypomagnesemia. Whenever possible, the underlying cause of active magnesium loss should be corrected. Patients with diuretic-induced hypomagnesemia who cannot discontinue diuretic therapy may benefit from the addition of a potassium-sparing diuretic (eg, amiloride). These drugs may decrease magnesium excretion by increasing its reabsorption in the collecting tubule. These drugs also may be useful in Bartter or Gitelman syndrome or in cisplatin nephrotoxicity. These patients should also be placed on a magnesium-rich diet, which includes such foods as meat, green vegetables, dairy products, nuts, cereals, and seafood. These patients should be examined frequently for evidence of magnesium deficiency and monitored for regular serum magnesium. If hypomagnesemia persists, these patients should be treated with an oral sustained-release preparation. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Article Last Updated: Jul 24, 2006 | |||||||
