- Author: Tibor Fulop, MD, FASN, FACP; Chief Editor: Vecihi Batuman, MD, FASN more...
Abnormalities of magnesium levels, such as hypomagnesemia, can result in disturbances in nearly every organ system and can cause potentially fatal complications (eg, ventricular arrhythmia, coronary artery vasospasm, sudden death). (See Pathophysiology.) Despite the well-recognized importance of magnesium, low and high levels have been documented in ill patients, as a result of which, magnesium has occasionally been called the "forgotten cation."[2, 3]
Magnesium is the second-most abundant intracellular cation and, overall, the fourth-most abundant cation. It 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. (See Etiology, Presentation, and Workup.)
Almost all enzymatic processes using phosphorus as an energy source require magnesium for activation. Magnesium is involved in nearly every aspect of biochemical metabolism (eg, DNA and protein synthesis, glycolysis, oxidative phosphorylation). Almost all enzymes involved in phosphorus reactions (eg, adenosine triphosphatase [ATPase]) require magnesium for activation. Magnesium serves as a molecular stabilizer of RNA, DNA, and ribosomes. Because magnesium is bound to adenosine triphosphate (ATP) inside the cell, shifts in intracellular magnesium concentration may help to regulate cellular bioenergetics, such as mitochondrial respiration.
Extracellularly, magnesium ions block neurosynaptic transmission by interfering with the release of acetylcholine. Magnesium ions also may interfere with the release of catecholamines from the adrenal medulla. Magnesium has been proposed as an endogenous endocrine modulator of the catecholamine component of the physiologic stress response.
The total body magnesium content of an average adult is 25 g, or 1000 mmol. Approximately 60% of the body's magnesium is present in bone, 20% is in muscle, and another 20% is in soft tissue and the liver. Approximately 99% of total body magnesium is intracellular or bone-deposited, with only 1% present in the extracellular space. Seventy percent 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 1.4-1.8 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 or 30 mEq) 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, cereals, grains, 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 bones and soft tissues (eg, those of the kidneys and intestines). In contrast with other ions, magnesium is treated differently in two major respects: (1) bone, the principal reservoir of magnesium, does not readily exchange magnesium with circulating magnesium in the extracellular fluid space and (2) only limited hormonal modulation of urinary magnesium excretion occurs.[5, 6, 7] 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 is absorbed principally in the small intestine, through a saturable transport system and via 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 the intake is high (25 mmol/d).
The exact mechanism by which alterations in fractional magnesium absorption occur has yet to be determined. Presumably, only ionized magnesium is absorbed. Increased luminal phosphate or fat may precipitate magnesium and decrease its absorption.
In the gut, calcium and magnesium intakes influence each other's absorption; a high calcium intake may decrease magnesium absorption, and a 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
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 (TAL) of the loop of Henle is the major site of reabsorption (60-70%). The PCT accounts for only 15-25% of absorbed magnesium, and the distal convoluted tubule (DCT), for another 5-10%. There is no significant reabsorption of magnesium in the collecting duct.[9, 10] Inherited disorders of magnesium transport, although rare, may present through an array of underlying biochemical abnormalities.[11, 12]
In the TAL, magnesium is passively reabsorbed with calcium through paracellular tight junctions; the driving force behind this reabsorption is a lumen-positive electrochemical gradient, which results from the reabsorption of sodium chloride. Claudins are the major components of tight-junction strands in the TAL, where the reabsorption of magnesium occurs.[13, 14] Twenty-four members of the family have been described. Mutations in the claudin-16 (previously known as paracellin-1) and claudin-19 genes cause a human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), which is characterized by excessive renal magnesium and calcium wasting, polyuria, recurrent urinary tract infections, bilateral nephrocalcinosis, and progressive renal failure.[16, 17, 18] Mutations in claudin-19 are also associated with severe ocular involvement.
In the distal convoluted tubule (DCT), magnesium is reabsorbed via an active, transcellular process that is thought to involve TRPM6, a member of the transient receptor potential (TRP) family of cation channels.[19, 20] Mutations in TRPM6 have been identified as the underlying defect in patients with hypomagnesemia with secondary hypocalcemia (HSH),[8, 21, 22, 23] an autosomal-recessive disorder that manifests in early infancy with generalized convulsions refractory to anticonvulsant treatment or with other symptoms of increased neuromuscular excitability, such as muscle spasms or tetany. Laboratory evaluation reveals extremely low serum magnesium and serum calcium levels.
Interestingly, mutations of the epithelial growth factor (EGF) have been associated with reduced expression of TRPM6 and thus, with hypomagnesemia; colorectal cancer treatment with cetuximab/panitumumab (EGF receptor inhibitors) also causes hypomagnesemia.[25, 26, 27, 28]
In a meta-analysis of 10 randomized controlled trials involving a total of 7,045 patients with advanced cancers, the overall incidence of grade 3/4 hypomagnesemia among patients treated with cetuximab was 3.9% (95% confidence interval [CI], 2.6–4.3). Compared with patients who received control medication, those who received cetuximab had a significantly increased risk of grade 3/4 hypomagnesemia (relative risk, 8.60; 95% CI, 5.08–14.54). The increased risk varied with tumor type.
The mechanism of basolateral transport into the interstitium is unknown. Magnesium has to be extruded against an unfavorable electrochemical gradient. Most physiologic studies favor a sodium-dependent exchange mechanism driven by low intracellular sodium concentrations; these concentrations are generated by Na+/K+ - ATPase, also known as the sodium-potassium pump.
A mutation in the gene FXYD2 encoding 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.[31, 32] Consequently, the entry of K+ is reduced and the cell depolarizes to some extent, leading to closing of the TRPM6 channel and magnesium wasting.
A variety of factors influence the renal handling of magnesium. For example, the 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 the 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).
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 the TAL. When calcium or magnesium activates the receptor, there is a resultant enhancement in the formation of arachidonic acid ̶ derived 20-hydroxyeicosatetraenoic acid (20-HETE), which reversibly inhibits apical potassium channels (ROMK2 channels).
Secretion of potassium into the lumen via these channels has 2 functions: it provides potassium for sodium chloride reabsorption by the Na-K-2Cl cotransporter (NKCC2), and it makes the lumen electropositive, which permits passive calcium and magnesium reabsorption. Thus, inhibition of ROMK2 channels in the TAL will reduce active sodium transport and passive calcium and magnesium reabsorption.
Activating mutations of the CaSR result in autosomal-dominant hypocalcemia with hypercalciuria (ADHH), a condition characterized by hypocalcemia, hypercalciuria, and hypomagnesemia and by low, but detectable, levels of PTH.[35, 36]
Phosphate depletion can also increase urinary magnesium excretion, through a mechanism that is not clear.
Chronic metabolic acidosis results in renal magnesium wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. Chronic metabolic acidosis decreases renal TRPM6 expression in the DCT, increases magnesium excretion, and decreases serum magnesium concentration, whereas chronic metabolic alkalosis results in the exact opposite effects.
No single hormone has been implicated in the control of renal magnesium reabsorption. In experimental studies, a number of hormones have been shown to alter magnesium transport in the TAL. These include PTH, calcitonin, glucagon, arginine vasopressin (AVP), and the beta-adrenergic agonists, all of which are coupled to adenylate cyclase in the 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 the phosphorylation of paracellular pathway proteins). It is not known if these effects have an important role in normal magnesium hemostasis.
Related metabolic abnormalities
Hypokalemia is a common event in patients with hypomagnesemia, occurring in 40-60% of cases. This is partly due to underlying disorders that cause magnesium and potassium losses, including diuretic therapy and diarrhea.
The mechanism for hypomagnesemia-induced hypokalemia relates to the intrinsic biophysical properties of renal outer medullary K (ROMK) channels mediating K+ secretion in the TAL and the distal nephron. ROMK channels represent the first (Kir1.1) of 7 subfamilies making up the 2-transmembrane segment inward-rectifier potassium channel family. The channels are designated as inward rectifiers because they have a greater inward conductance of potassium ions than they do an outward conductance of them 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 blocking 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, thus causing the greater outward conductance of K+ ions through the channel pore. Therefore, a decrease in intracellular magnesium concentration in the TAL and collecting duct cells results in increased K+ secretion through the ROMK channels.
Evidence also suggests that this wasting may be due to a hypomagnesemia-induced decline in adenosine triphosphate (ATP) and the subsequent removal of ATP inhibition of the ROMK channels responsible for secretion in the 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 cyclic adenosine monophosphate (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.
The cardiovascular effects of magnesium deficiency include effects on electrical activity, myocardial contractility, potentiation of digitalis effects, and vascular tone. Epidemiologic studies also show an association between magnesium deficiency and coronary artery disease (CAD).
Hypomagnesemia is now recognized to cause cardiac arrhythmia.[39, 40] 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 Na+/K+ -ATPase. The resulting decrease in intracellular potassium disturbs the resting membrane potential and repolarization phase of the myocardial cells, enhancing the inhibitory effect of digoxin. Intravenous magnesium supplementation may be a helpful adjunct when attempting rate control for atrial fibrillation with 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, as well as 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 the 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.
It has been suggested that magnesium plays a role in blood pressure regulation, its therapeutic efficacy in the hypertensive syndromes of pregnancy having been demonstrated in the 19th century. Hypertension appears to be uniformly characterized by a decrease in intracellular free magnesium that, due to increased vascular tone and reactivity, causes an increase in total peripheral resistance.
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 epidemiologic studies have failed to confirm a relationship, and results from clinical trials examining the hypotensive effects of magnesium supplementation have been conflicting. Noticeably, in the DASH study (Dietary Approaches to Stop Hypertension), a diet rich in fruits and vegetables (rich in potassium and magnesium) resulted in lowering of blood pressure. Larger, carefully performed, randomized clinical trials are needed to confirm these findings.
Coronary artery disease
In epidemiologic studies, patients with CAD have a higher incidence of magnesium deficiency than do control subjects.[44, 45] 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, which are 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. Research is conflicting regarding the benefits of intravenous administration of magnesium in the setting of acute myocardial infarction. A 16% reduction in all-cause mortality was noticed in a study of 2316 patients. Disappointingly 2 other large studies failed to confirm this benefit.[47, 48]
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 the patient to arrhythmia. Intravenous magnesium given after the termination of cardiopulmonary bypass has resulted in significantly fewer incidences of supraventricular and ventricular dysrhythmia in relatively small trials of adult[50, 51] and pediatric patients. Considering the above data, carefully assessing magnesium status in patients with CAD and supplementing patients deficient in magnesium seem prudent. The use of routine magnesium supplements in myocardial infraction remains controversial in the era of thrombolytics and percutaneous coronary interventions.
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 has been induced in volunteers. Other manifestations include the following:
Acute organic brain syndromes
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 the excitability of muscles and nerves. The cellular basis for these changes is due to increased intracellular calcium content, by mechanisms similar to those described above for hypertension.
Magnesium deficiency has also been implicated in osteoporosis. The magnesium content in trabecular bone is significantly reduced in patients with osteoporosis, and magnesium intake in people with osteoporosis reportedly is lower than it is in control subjects. (Magnesium intake frequently is lower than the recommended dietary intake in many groups, especially elderly persons.)
Postmenopausal women are encouraged to consume at least 1000 mg of elemental 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, because the formation of calcitriol involves a magnesium-dependent hydroxylase enzyme, calcitriol concentrations are reduced in magnesium deficiency, possibly affecting calcium reabsorption.
Magnesium supplementation may be beneficial in osteoporosis and may increase bone density, arrest vertebral deformity, and decrease osteoporotic pain. In the large joints, chondrocalcinosis is associated with long-term magnesium depletion.
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 is associated with hypomagnesuria and, theoretically, could play a role in predisposition to urinary calculus formation.
Patients with diabetes mellitus are often magnesium deficient, expressed by hypomagnesemia.[57, 58, 59, 60] Magnesium deficiency decreases insulin sensitivity and secretion.[61, 62] Moreover, magnesium deficiency is inherently related to the pathogenesis and development not only of diabetic microangiopathy but also of lifestyle-related diseases, such as hypertension and hyperlipidemia.[63, 64] Magnesium deficiency may be a link with both inflammation or vascular stiffness in certain populations.[65, 66]
Generally, modern people tend to live in a state of chronic dietary magnesium deficiency. There is a possibility that one of the major factors contributing to the drastic increase of type 2 diabetes mellitus is the drastically 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 that in the future, clinical trials will be performed to investigate the efficacy of magnesium supplementation therapy.
Magnesium deficiency has also been implicated in many other conditions. Low intracellular magnesium levels in the brain have been reported in migraine headache. However, the exact value of magnesium supplementation for migraine prophylaxis is not currently well defined.
In addition, magnesium status may have an influence on asthma, because magnesium deficiency is associated with increased contractility of smooth muscle cells. Magnesium supplementation in asthma remains controversial, but it has been shown to reduce bronchial hyperreactivity to methacholine and other measures of allergy.
Magnesium deficiency has also been linked to chronic fatigue syndrome, sudden death in athletes, impaired athletic performance, and sudden infant death syndrome.
Hypomagnesemia can result from decreased intake, redistribution of magnesium from the extracellular to the intracellular space, or increased renal or gastrointestinal loss. In some cases, more than one of these may be present.
Causes of hypomagnesemia related to decreased magnesium intake include the following :
Total parenteral nutrition
Causes related to the redistribution of magnesium from extracellular to intracellular space include the following:
Hungry bone syndrome
Treatment of diabetic ketoacidosis
Alcohol withdrawal syndromes
Causes related to gastrointestinal magnesium loss include the following:
Vomiting and nasogastric suction
Gastrointestinal fistulas and ostomies
Hypomagnesemia with secondary hypocalcemia (HSH)
Classic Bartter syndrome (type III Bartter syndrome)
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)
Autosomal-dominant hypocalcemia with hypercalciuria (ADHH)
Isolated dominant hypomagnesemia (IDH) with hypocalciuria
Isolated recessive hypomagnesemia (IRH) with normocalcemia
Diuretics - Loop diuretics, osmotic diuretics, and long-term use of thiazides
Antimicrobials - Amphotericin B, aminoglycosides, pentamidine, capreomycin, viomycin, and foscarnet
Chemotherapeutic agents - Cisplatin, cetuximab 
Immunosuppressants - Tacrolimus and cyclosporine
Proton-pump inhibitors [75, 76, 77]
Chronic metabolic acidosis
Recovery phase of acute tubular necrosis
Decreased magnesium 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 of magnesium from extracellular to intracellular
The transfer of magnesium from extracellular space to intracellular fluid or bone is a frequent cause of decreased serum magnesium levels. This depletion may occur as part of hungry bone syndrome, in which magnesium is removed from the extracellular fluid space and deposited in bone following parathyroidectomy or total thyroidectomy or any similar states of massive mineralization of the bones.[80, 81]
Hypomagnesemia may also occur following insulin therapy for diabetic ketoacidosis and may be related to the anabolic effects of insulin driving magnesium, along with potassium and phosphorus, 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 in which previously malnourished patients are fed high carbohydrate loads, resulting in a rapid fall in phosphate, magnesium, and potassium, along with an expanding extracellular fluid space volume, leading to a variety of complications.
Acute pancreatitis can also cause hypomagnesemia. The mechanism may represent saponification of magnesium in necrotic fat, similar to that of hypocalcemia. However, postoperative states or critical illnesses in general are associated with low magnesium levels, without pancreatitis necessarily being present.
Impaired gastrointestinal magnesium 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 bypass surgery on the small intestine. Because there is some magnesium absorption in the colon, patients with ileostomies can develop hypomagnesemia.
An emerging association is, described with increasing frequency, the association with proton pump inhibitors (PPIs), widely used to reduce gastric acid secretion,[75, 76, 77, 84] presumably due to decreased gastrointestinal absorption. As of March 2011, the US Federal Drug Administration (FDA) issued a safety warning on PPIs, including a recommendation to periodically monitor serum levels.
In a population-based case-control study of 366 patients hospitalized with hypomagnesemia and 1,464 matched controls, Zipursky and colleagues found that current use of PPIs was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio [OR], 1.43; 95% confidence index [CI] 1.06–1.93). The increased risk was significant among patients receiving diuretics, (adjusted OR, 1.73; 95% CI 1.11–2.70) but not among those who were not receiving diuretics (adjusted OR, 1.25; 95% CI 0.81–1.91).
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 DCT. Mutations in the gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, have been identified as the underlying genetic defect.[21, 22, 23]
Inherited tubular disorders that result in urinary magnesium wasting include the following:
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)
Autosomal-dominant hypocalcemia with hypercalciuria (ADHH)
Isolated dominant hypomagnesemia (IDH) with hypocalciuria
Isolated recessive hypomagnesemia (IRH) with normocalcemia
Hypomagnesemia with secondary hypocalcemia (HSH)
Urinary magnesium losses may also result from various medications, as well as other causes.
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 the NCCT, but some data points to magnesium wasting as a primary abnormality. Some studies have indicated that magnesium wasting in Gitelman syndrome may be due to down-regulation of TRPM6 in the DCT.
The electrical gradient in the thick ascending limb of the loop of Henle (TAL) generated by the active transport of sodium, potassium, and chloride by Na-K-Cl cotransporter (NKCC2) aids in the reabsorption of magnesium. Mutation in NKCC2 is seen in antenatal Bartter syndrome and leads to renal magnesium wasting and hypomagnesemia. Classic Bartter syndrome is caused by mutations in CLCNKB ’s encoding of 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.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
In FHHNC, an autosomal-recessive disorder, profound renal magnesium and calcium wasting occurs. The hypercalciuria often leads to nephrocalcinosis, resulting in progressive renal failure.[16, 18, 72] Other symptoms that have been reported in patients with FHHNC include urinary tract infections, nephrolithiasis, incomplete distal tubular acidosis, and ocular abnormalities.
FHHNC 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 the TAL. FHHNC with ophthalmologic disease indicates potential claudin-19 mutation.[92, 93, 94]
Autosomal-dominant hypocalcemia with hypercalciuria
ADHH is another disorder of urinary magnesium wasting. Affected individuals 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. In other cases, a basolateral protein (cyclin M2 protein) mutation has been described.
Isolated dominant hypomagnesemia with hypocalciuria
IDH with hypocalciuria 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, which codes 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.[31, 32] Consequently, the entry of potassium is reduced and the cell depolarizes to some extent, leading to closing of the TRPM6 channel and magnesium wasting.
Isolated recessive hypomagnesemia with normocalcemia
IRH with normocalcemia is an autosomal-recessive disorder in which affected individuals 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. It is caused by a mutation in the EGF gene, resulting inadequate stimulation of renal epidermal growth factor receptor (EGFR), and thereby insufficient activation of the epithelial Mg2+ channel TRPM6, which results in magnesium wasting.
Hypomagnesemia with secondary hypocalcemia
HSH, also called primary intestinal hypomagnesemia, is an autosomal-recessive disorder that is characterized by very low serum magnesium levels and low calcium levels. Mutations in the gene encoding for TRPM6, the active magnesium transporter in the DCT, have been identified.[22, 23] Patients usually present within the first 3 months of life with the neurologic symptoms of hypomagnesemic hypocalcemia, including seizures, tetany, and muscle spasms.
Untreated, HSH 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 must sometimes be considered. Alternatively, continuous nocturnal nasogastric magnesium infusions have been proven to efficiently reduce gastrointestinal adverse effects.
Several drugs, such as loop diuretics (including furosemide, bumetanide, and ethacrynic acid), produce large increases in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in the TAL. Long-term thiazide diuretic therapy also may cause magnesium deficiency, through enhanced magnesium excretion and, specifically, reduced renal expression levels of the epithelial magnesium channel TRPM6.
Many nephrotoxic drugs, including cisplatin, amphotericin B, cyclosporine, tacrolimus and pentamidine, can produce urinary magnesium wasting by a variety of mechanisms, some of which are still unknown. For instance, tacrolimus causes hypomagnesemia through down-regulation of TRPM6 channels.
On the other side, aminoglycosides are thought to induce the action of the CaSR on the TAL and DCT, producing magnesium wasting. Cisplatin- and amphotericin B–induced magnesium deficiency is associated with hypocalciuria, which suggests injury to the DCT. In a rat model Ledeganck et al showed that cisplatin treatment results in EGF and TRPM6 down-regulation, causing renal Mg2+ wasting. Some data suggest that magnesium loss associated with cisplatin treatment is mainly the result of lowered intestinal absorption rather than, as presently thought, the result of increased renal elimination.
Other renal causes
Other causes of renal magnesium wasting, and the likely mechanisms, include the following:
Aldosterone excess - Chronic volume expansion, thereby increasing magnesium excretion
Hypercalcemia - Stimulation of the CaSR and inhibition of magnesium reabsorption
Hypophosphatemia - Unknown
Alcohol ingestion - Alcohol-induced tubular dysfunction (which is reversible within 4 weeks of abstinence) 
Finally, magnesium wasting can be seen as part of the tubular dysfunction that is observed with recovery from acute tubular necrosis or during a postobstructive diuresis.
Serum magnesium levels decrease with age in patients with cystic fibrosis (CF), and hypomagnesemia occurs in more than half of patients with advanced CF. In part, hypomagnesemia in these patients may result from use of aminoglycoside antibiotics, which can induce both acute and chronic renal magnesium-wasting. In addition, limited data suggest that CF may impair intestinal magnesium balance.
Occurrence in the United States
Although the incidence of hypomagnesemia in the general population has been estimated at less than 2%, some studies have estimated that 75% of Americans do not meet the recommended dietary allowance of magnesium.
In a Mayo Clinic review, magnesium levels of less than 1.7 mg/dL were noted in 13,320 of 65,974 hospitalized adult patients (20.2%). Hypomagnesemia was common in patients with hematologic/oncological disorders.
The risk of hypomagnesemia can be summarized as follows:
2% in the general population
10-20% in hospitalized patients
50-60% in intensive care unit (ICU) patients
30-80% in persons with alcoholism
25% in outpatients with diabetes
Although no comprehensive studies have addressed the actual incidence of hypomagnesemia stratified by age group, neonates may be more predisposed to develop the condition. The mechanism for this is unknown, although several studies suggest that neonates have an increased requirement for intracellular magnesium in growing tissues.
Patients should be counseled regarding modification of risks of hypomagnesemia. Such modifications may include maintaining a proper diet, ceasing alcohol consumption, improving diabetic controls, and taking supplements if the cause of hypomagnesemia is still present.
Hypomagnesemia has been linked to poor outcome in several different patient populations. In a study of 21,534 patients on maintenance dialysis, patients with the lowest serum magnesium levels (<1.30 mEq/L) were at highest risk for death (hazard ratio, 1.63; 95% confidence index, 1.30-1.96).
Hypomagnesemia is a common development in critically ill sepsis patients, and indicates a poor prognosis. Although evidence is derived largely from observational studies, it shows a significant association between hypomagnesemia and with increased need for mechanical ventilation, prolonged intensive care unit stays, and increased mortality in this patient population.
In a Mayo Clinic review of 65,974 hospitalized adult patients, hypomagnesemia on admission was associated with increased in-hospital mortality. Death rates were 2.2% in patients with magnesium levels of 1.5-1.69 mg/dL and 2.4% in those with levels below 1.5 mg/dL; by comparison, mortality in patients with levels of 1.7-1.89 mg/dL were 1.8%.
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