Hypomagnesemia

Magnesium is the second-most abundant intracellular cation and, overall, the fourth-most abundant cation.[4]  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.

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.

Magnesium homeostasis

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).[5]

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, 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.[6, 7, 8]  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 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%); see the image below. The PCT accounts for only 15-25% of absorbed magnesium, and the distal convoluted tubule (DCT), for another 5-10%.[9]  There is no significant reabsorption of magnesium in the collecting duct.[10, 11]  Inherited disorders of magnesium transport, although rare, may present through an array of underlying biochemical abnormalities.[12, 13]

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.[14, 15]

Twenty-four members of the family have been described in mammals.[16]  In humans, mutations in the claudin-16 (previously known as paracellin-1) and claudin-19 genes cause a 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 kidney failure.[17, 18, 19]  Mutations in claudin-19 are also associated with severe ocular involvement.[16]

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.[20, 21]  Mutations in TRPM6 have been identified as the underlying defect in patients with hypomagnesemia with secondary hypocalcemia (HSH),[9, 22, 23, 24]  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[25]  and thus, with hypomagnesemia; cancer medications that are EGF receptor inhibitors (eg, cetuximab, panitumumab) can also cause hypomagnesemia.[26, 27, 28, 29]  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, with the highest incidence in non–small cell lung cancer and the lowest incidence in colorectal cancer.[30]

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.[31]  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.[32, 33]  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.[5]  For example, 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 kidney 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).[34]

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.[35]  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.[36, 37]

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 effect. 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.[38]

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). Whether these effects have an important role in normal magnesium hemostasis remains unknown.

Related metabolic abnormalities

Hypokalemia is common in patients with hypomagnesemia, occurring in 40-60% of cases.[1] 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).[35]

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 thick ascending limb of Henle (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.[39] 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.

Arrhythmia

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 can cause cardiac arrhythmia.[40, 41, 42] Changes in electrocardiogram findings include prolongation of conduction and slight ST depression, although those 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.[43]

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.[40]

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.[44] 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 recommends that magnesium sulfate be added to the regimen used to manage torsade de pointes or refractory ventricular fibrillation.

Hypertension

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.[45] 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.[46, 47] 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 noted in a study of 2316 patients.[48] Disappointingly, 2 other large studies failed to confirm this benefit.[49, 50]

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.[51] Intravenous magnesium given after the termination of cardiopulmonary bypass has resulted in significantly lower incidence rates of supraventricular and ventricular dysrhythmia, in relatively small trials of adult[52, 53] and pediatric[54] patients. Considering the above data, carefully assessing magnesium status in patients with CAD and supplementing patients deficient in magnesium seems prudent. The routine use of magnesium supplements in myocardial infarction remains controversial in the era of thrombolytics and percutaneous coronary interventions.

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 has been induced in volunteers. Other manifestations include the following:

• Convulsions
• Apathy
• Muscle cramps
• Hyperreflexia
• Acute organic brain syndromes
• Depression
• Generalized weakness
• Anorexia
• 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 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.

Osteoporosis

Magnesium deficiency has also been implicated in osteoporosis.[55] 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.[56] (Magnesium intake frequently is lower than the recommended dietary intake in many groups, especially elderly persons.)[57]

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.[58]

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 is associated with hypomagnesuria and, theoretically, could play a role in predisposition to urinary calculus formation.

Diabetes

Patients with diabetes mellitus are often magnesium deficient, expressed by hypomagnesemia.[59, 60, 61, 62] Magnesium deficiency decreases insulin sensitivity and secretion.[63, 64] 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.[65, 66] Magnesium deficiency may be a link with both inflammation or vascular stiffness in certain populations.[67, 68]

Generally, modern people tend to live in a state of chronic dietary magnesium deficiency.[69] 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.[70] 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.

Miscellaneous conditions

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.[71]  

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,[72] but it has been shown to reduce bronchial hyperreactivity to methacholine and other measures of allergy.[73]  

Magnesium deficiency has also been linked to chronic fatigue syndrome (myalgic encephalomyelitis), sudden death in athletes, impaired athletic performance, and sudden infant death syndrome. Risk prediction for pre-eclampsia can be improved by measuring ionized magnesium, rather than the total magnesium concentration in blood.[74]

Hypomagnesemia can result from decreased intake, redistribution of magnesium from the extracellular to the intracellular space, or increased renal or gastrointestinal loss. An additional element of variability is the difference between total versus ionized magnesium concentration, the latter being influenced by plasma protein concentration and the acid-base status[74] . In some cases, more than one of these may be present.

Causes of hypomagnesemia related to decreased magnesium intake include the following[5] :

• Starvation
• Alcohol dependence
• Total parenteral nutrition

Causes related to the redistribution of magnesium from the extracellular to the intracellular space include the following:

• Hungry bone syndrome
• Treatment of diabetic ketoacidosis
• Alcohol withdrawal syndromes
• Refeeding syndrome ^[75]
• Acute pancreatitis

Causes related to gastrointestinal magnesium loss include the following:

• Diarrhea
• Vomiting and nasogastric suction
• Gastrointestinal fistulas and ostomies
• Hypomagnesemia with secondary hypocalcemia (HSH)

Hypomagnesemia due to renal magnesium loss can result from inherited renal tubular defects[17, 19, 76, 77]  or medications,[78] including the following:

• Gitelman syndrome
• 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
• HSH
• Diuretics - Loop diuretics, osmotic diuretics, and long-term use of thiazides
• Antimicrobials - Amphotericin B, aminoglycosides, pentamidine, capreomycin, viomycin, foscarnet
• Chemotherapeutic agents - Cisplatin, cetuximab ^[79]
• Immunosuppressants - Tacrolimus, cyclosporine
• Proton-pump inhibitors ^{[80, 81, 82, 83]}
• Ethanol ^[84]
• Hypercalcemia
• Chronic metabolic acidosis
• Volume expansion
• Primary hyperaldosteronism ^[85]
• Recovery phase of acute tubular necrosis
• Postobstructive diuresis

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,[86] 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.[87, 88]

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[89] or critical illnesses in general are associated with low magnesium levels,[90] without pancreatitis necessarily being present.

Gastrointestinal losses

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, described with increasing frequency, is the association with proton pump inhibitors (PPIs), widely used to reduce gastric acid secretion.[80, 81, 82, 91, 83]  The likely mechanism is decreased gastrointestinal absorption.

In 2011 the US Food and Drug Administration (FDA) issued a safety warning that prolonged use of PPIs (in most cases, for longer than 1 year) can lead to hypomagnesemia. The FDA advised healthcare professionals to consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as in patients also taking other medications (eg, diuretics) that may cause hypomagnesemia and in those taking digoxin, as hypomagnesemia can increase the likelihood of serious adverse effects from digoxin. The FDA recommended considering periodic measurement of serum magnesium levels in those patients.[92]

In a population-based case-control study of 366 patients hospitalized with hypomagnesemia and 1464 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).[93]

HSH is a rare autosomal-recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia.[94] Pathophysiology involves impaired intestinal absorption of magnesium[95] accompanied by renal magnesium wasting; see Renal losses, below.

Renal losses

Urinary magnesium losses may result from hereditary conditions, medications, and other causes. Inherited tubular disorders that result in urinary magnesium wasting include the following:

• Gitelman syndrome
• 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
• Hypomagnesemia with secondary hypocalcemia (HSH)

Gitelman syndrome

Gitelman syndrome is an autosomal-recessive condition caused by mutations of the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCCT).[96] This syndrome is characterized by hypokalemia, hypomagnesemia, and hypocalciuria.[97]

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 point to magnesium wasting as a primary abnormality.[98] Some studies have indicated that magnesium wasting in Gitelman syndrome may be due to down-regulation of TRPM6 in the DCT.

Bartter syndrome

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.[17, 19, 76] Other symptoms that have been reported in patients with FHHNC include urinary tract infections, nephrolithiasis, incomplete distal tubular acidosis, and ocular abnormalities.[99]

FHHNC is caused by mutations in the gene CLDN16, which encodes for paracellin-1 (claudin-16),[18] 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.[100, 101, 102]

Autosomal-dominant hypocalcemia with hypercalciuria

ADHH is another disorder of urinary magnesium wasting.[36] 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.[37] 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.[103]

Isolated dominant hypomagnesemia with hypocalciuria

IDH with hypocalciuria[31] 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.[32, 33] 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.[104] 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.[6]

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.[94]  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.[22, 23, 24] Patients usually present within the first 3 months of life with the neurologic signs 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.

Medications

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.[105]

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.[106]

Urinary magnesium wasting due to immunosuppressive regimens that include calcineurin inhibitors (eg, cyclosporine, tacrolimus) is partly the reason that hypomagnesemia frequently develops after kidney transplantation. Other causal factors in these patients include post-transplantation volume expansion, metabolic acidosis, insulin resistance, decreased GI absorption due to diarrhea, low dietary magnesium intake, and use of drugs such as diuretics or proton pump inhibitors.[107]

In contrast, aminoglycosides are thought to induce the action of the CaSR on the TAL and DCT, producing magnesium wasting.[108] 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.[109] 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.

Chemotherapeutic agents that are EGF receptor inhibitors (eg, cetuximab, panitumumab) can cause hypomagnesemia.[26, 27, 28, 29]  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, with the highest incidence in non–small cell lung cancer and the lowest incidence in colorectal cancer.[30]

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) ^[84]

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.

Cystic fibrosis

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.[110]

COVID-19

Hypomagnesemia has been associated with increased risk for severe disease and death in patients with COVID-19.[111]   In a study of 1064 patients hospitalized with COVID-19, Guerrero-Romero et al reported that a magnesium-to-calcium ratio ≤0.20 was a biomarker for increased mortality risk in patients with severe COVID-19 disease.[112]

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.[113]

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.[114]

The risk of hypomagnesemia can be summarized as follows:

• 2% in the general population
• 0-20% in hospitalized patients
• 50-60% in intensive care unit (ICU) patients
• 30-80% in persons with alcoholism
• 25% in outpatients with diabetes

Age-related demographics

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.

For patient education information, see the Magnesium Directory, as well as the Magnesium fact sheet from the National Institutes of Health Office of Dietary Supplements. 

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).[115]

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.[116]

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%.[114]

 

At least 10 inherited disorders of magnesium handling cause hypomagnesemia.[117] Consequently, a careful family history is important, particularly when acquired causes of hypomagnesemia have been excluded.

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.

Neuromuscular manifestations of hypomagnesemia may include the following[5] :

• Muscular weakness
• Tremors
• Seizure
• Paresthesias
• Tetany
• Positive Chvostek sign and Trousseau sign
• Vertical and horizontal nystagmus

Cardiovascular manifestations may include the following electrocardiographic abnormalities and arrhythmias:

• Nonspecific T-wave changes - U waves
• Prolonged QT and QU interval
• Repolarization alternans
• Premature ventricular contractions - Monomorphic ventricular tachycardia
• Torsade de pointes
• Ventricular fibrillation
• Enhanced digitalis toxicity

Metabolic manifestations may include the following:

• Hypokalemia
• Hypocalcemia

At serum magnesium levels less than 1 mEq/L, patients develop the following signs:

• Tremor
• Hyperactive deep-tendon reflexes
• Hyperreactivity to sensory stimuli
• Muscular fibrillations
• Positive Chvostek and Trousseau signs
• Carpopedal spasms progressing to tetany
• Vertical nystagmus

Mental status changes may become evident and may include irritability, disorientation, depression, and psychosis. Cardiac arrhythmias and reversible respiratory muscle failure can also occur in severe hypomagnesemia.

In a fashion analogous to hypermagnesemia, the rate of development of hypomagnesemia may be more important than the absolute value in terms of symptom development.

Patients whose clinical condition suggests magnesium depletion should have their serum magnesium level measured. Most laboratories use a reference range of 1.5 to 2.5 mg/dL for serum magnesium. Hypomagnesemia reliably indicates reduced total body stores of magnesium.

However, while measurement of serum magnesium is relatively easy, and it has become the method of choice to estimate magnesium content, its ability to evaluate total body stores of magnesium is limited. A person may be intracellularly magnesium depleted and exhibit signs of magnesium deficiency, yet have normal serum levels of magnesium. In this setting, serum magnesium tends to remain within the normal range due to recruitment of intracellular stores, until the point where the intracellular stores cannot keep up.

Unfortunately, no quick, simple, and accurate test is available to measure magnesium at the intracellular level, which is where the major physiologic role of magnesium occurs. Excluding magnesium deposited in bone, which is poorly mobilized, the extracellular fluid space contains only 2% of total body magnesium, and levels there may not always accurately reflect the intracellular magnesium status.

A surrogate for direct intracellular magnesium is the measurement of magnesium retention after acute magnesium loading. A magnesium deficiency is indicated if a patient has 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). 

This method is useful only when the clinical suggestion of magnesium deficiency is strong (eg, the patient has unexplained cardiovascular or neuromuscular abnormalities) but serum magnesium levels are normal. It is not helpful in the setting of renal magnesium wasting (as seen with diuretics) or in the presence of renal dysfunction.

However, the utility of this test is uncertain. Patients with malnutrition, cirrhosis, diarrhea, or long-term diuretic use typically have a positive result, 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.

Another caveat to estimating serum magnesium levels is that although only free magnesium is biologically active, most methods of assessing the serum content measure total magnesium concentration. Because 30% of magnesium is bound to albumin and is therefore inactive, hypoalbuminemic states may lead to spuriously low magnesium values.

The majority of patients with clinical manifestations of magnesium deficiency have hypomagnesemia. Magnesium assessment can also be made via the following, which are mostly limited to research purposes.

• Red cell content
• Mononuclear cell content
• Skeletal muscle intracellular content
• 24-hour urinary excretion
• Fractional excretion (FE) of magnesium
• Intracellular free magnesium ion concentration with fluorescent dye or nuclear magnetic resonance spectroscopy

Protein, potassium, phosphate, and calcium

Because extracellular magnesium is protein bound, the patient's protein status is an important consideration in interpreting magnesium levels.

Hypomagnesemia contributes to hypokalemia. This condition may be due to a hypomagnesemia-induced decline in adenosine triphosphate (ATP) and the subsequent removal of ATP inhibition of the renal outer medullary K (ROMK) channels responsible for secretion in the thick ascending limb of Henle and collecting duct. In addition, hypophosphatemia has been found in patients with hypomagnesemia.

Hypocalcemia is caused by magnesium depletion, but the reason is not known. Some studies link hypomagnesemia to decreased parathyroid hormone levels and end-organ resistance to parathyroid hormone. Alterations in vitamin D metabolism can contribute to hypocalcemia.

Electrocardiography

Electrocardiographic (ECG) findings in hypomagnesemia are nonspecific, and include the following:

• ST segment depression
• Tall, peaked T waves
• Flat T waves or depression in the precordium
• U waves
• Loss of voltage
• PR prolongation
• Widened QRS complex

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 FE 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

In the above equation, 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 capable of being filtered across the glomerulus. The normal renal response to magnesium depletion is to reduce magnesium excretion to very low levels. Thus, daily excretion of more than 2 mEq (1 mmol or 24 mg) or a calculated FE of magnesium above 3% in a subject with normal renal function indicates renal magnesium wasting.

For the most part, the signs and symptoms of hypomagnesemia are reversible with magnesium replacement. Sources of magnesium loss (eg, diuretic use) may also need to be addressed. Hypomagnesemia often leads to hypocalcemia, a phenomenon largely explained by inhibition of parathyroid hormone bioactivity. Hypocalcemia does not resolve until the magnesium deficiency has been corrected.

 

The route of magnesium repletion varies with the severity of the clinical manifestations. For example, the hypocalcemic-hypomagnesemic patient with tetany or the patient who is 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 that this dose be repeated 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 for magnesium retention, and up to 50% of the infused magnesium will be excreted in the urine.

Furthermore, because magnesium is subject to slow equilibration between serum and the intracellular spaces and tissues (eg, bone, red blood cells, muscle), the serum magnesium level may appear artificially high if measured too soon after a magnesium dose is administered. Significant magnesium depletion requires sustained correction of the hypomagnesemia.

For these reasons, oral replacement should be given in the asymptomatic patient, preferably with a sustained-release preparation, given the ability of magnesium to induce diarrhea. Bioavailability of oral preparations is assumed to be 33% in the absence of intestinal malabsorption. Several preparations are available: Mag-Ox 400, containing magnesium oxide; 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. Mag-Ox 400 contains 242 mg (20 mEq) of elemental magnesium, but absorption is less efficacious.

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. In the presence of hypocalcemia, tetany can occur during the administration of magnesium sulfate if calcium is not supplemented, as ionized calcium levels can drop acutely from complexing of calcium with sulfate ions and increased urinary excretion.[118]

Sulfate ions also cause the generation of more negative transepithelial potential difference in renal tubules, which promotes kaliuresis and thereby can worsen hypokalemia. Patients undergoing intravenous magnesium replacement should be monitored for evidence of acute hypermagnesemia (eg, respiratory depression, areflexia). Patients with renal dysfunction are particularly at increased risk for hypermagnesemia during treatment, and only 25-50% of the normal dose magnesium dose should be given to patients when plasma creatinine levels are greater than 2 mg/dL.

Intravenous calcium chloride or gluconate represent the antidotes for hypermagnesemia, and 1-2 ampules should be administered immediately if symptomatic or otherwise serious hypermagnesemia develops. Calcium chloride (1000 mg, 13.6 mEq of calcium) should be infused via a central venous catheter over 10 minutes; however, calcium gluconate 1-3 g (4.56-13.7 mEq of elemental calcium) can be infused via a peripheral intravenous catheter over 3-10 minutes.[119]

Diuretic-induced hypomagnesemia

Patients with diuretic-induced hypomagnesemia who cannot discontinue diuretic therapy may benefit from the addition of a potassium-sparing diuretic (eg, amiloride or triamterene) or from changing plain thiazide-type diuretic medications to thiazide diuretic/potassium-sparing diuretic combinations. These drugs may decrease magnesium excretion by increasing its reabsorption in the collecting tubule. These drugs also may be useful in Bartter and 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. In addition, these patients should be examined frequently for evidence of magnesium deficiency and should be monitored for regular serum magnesium. If hypomagnesemia persists, these patients should be treated with an oral sustained-release preparation.

Dietary surveys have found that almost half of people in the United States consistently consume less than recommended amounts of magnesium. Men aged 71 years and older and adolescent males and females are most likely to have low intakes.[120]  

Green vegetables such as spinach are good sources of magnesium, which is contained in the chlorophyll molecule. Some legumes (beans and peas), nuts and seeds, and whole, unrefined grains are also good sources of magnesium.[113] The National Institutes of Health has produced a magnesium fact sheet that lists recommended dietary allowances for magnesium, which vary by age and sex, and selected food sources of magnesium.

Treatment for hypomagnesemia depends on the degree of deficiency and the patient's clinical symptoms and signs. Therapy can be oral for patients with mild symptoms or intravenous for patients with severe symptoms or those unable to tolerate oral administration. Some patients with hypomagnesemia caused by renal magnesium wasting may benefit from certain diuretics that have magnesium-sparing properties, such as spironolactone and amiloride.

Class Summary

Magnesium can be administered either orally in an oxide or gluconate form or parenterally as a sulfate salt.

Magnesium oxide (Mag-Ox, MagGel 600, Uro-Mag)

This agent is used for the treatment of magnesium deficiencies or magnesium depletion from malnutrition, restricted diet, alcoholism, or magnesium-depleting drugs.

Magnesium gluconate (Magtrate, Mag-G, Magonate)

Five hundred milligrams of magnesium gluconate contain 27 mg of elemental magnesium.

Magnesium sulfate

One gram of magnesium sulfate contains 8.12 mEq of magnesium (98 mg of elemental magnesium).

Class Summary

These medications are used to avoid the loss of potassium in urine.

Amiloride

Amiloride is a potassium-sparing diuretic that also has some mild hypocalciuric activity. It reduces the magnesium loss caused by thiazides. Amiloride is a pyrazine-carbonyl-guanidine that is chemically unrelated to other known antikaliuretic or diuretic agents. It possesses weak (compared with thiazide diuretics) natriuretic, diuretic, antihypertensive, and hypocalciuric effects.

In some clinical studies, amiloride activity increased the effects of thiazide diuretics. Amiloride is not an aldosterone antagonist, and its effects are observed even in the absence of aldosterone.

Amiloride exerts its potassium-sparing effect through the inhibition of sodium reabsorption at the DCT, the cortical collecting tubule, and the collecting duct. This decreases the net negative potential of the tubular lumen and reduces the secretion, and subsequent excretion, of potassium and hydrogen.

Amiloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion peaks after between 6-10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3-4 hours, and the drug's plasma half-life ranges from 6-9 hours.

Amiloride is not metabolized by the liver; it is excreted unchanged by the kidneys. About 50% of a dose of amiloride is excreted in urine and 40% is excreted in stool, within 72 hours. The drug has little effect on the GFR or on renal blood flow. Because the liver does not metabolize amiloride HCl, drug accumulation is not anticipated in patients with hepatic dysfunction; however, accumulation can occur if hepatorenal syndrome develops.

Amiloride rarely should be used alone. Used as single agents, potassium-sparing diuretics, including amiloride, result in an increased risk of hyperkalemia (approximately 10% with amiloride). Amiloride should be used alone only when persistent hypokalemia has been documented and only with careful titration of the dose and close monitoring of serum electrolytes.

Spironolactone (Aldactone)

Spironolactone is a potassium-sparing diuretic that acts on the distal convoluted tubule of the kidney as an aldosterone antagonist.

Triamterene (Dyrenium)

Triamterene interferes with potassium/sodium exchange (active transport) in the distal tubule, cortical collecting tubule, and collecting duct by inhibiting sodium/potassium adenosine triphosphatase (ATPase). This agent decreases calcium and magnesium excretion.