Hypomagnesemia: Evaluation and treatment

INTRODUCTION — 

Hypomagnesemia is defined as a serum magnesium concentration that is below the normal range (eg, less than 1.7 mg/dL [1.4 mEq/L or 0.7 mmol/L] in adults), which may vary among clinical laboratories [1]. Hypomagnesemia can be induced by increased gastrointestinal losses or increased urinary magnesium excretion.

This topic will review the evaluation and treatment of hypomagnesemia. The regulation of magnesium balance and the causes and clinical manifestations of hypomagnesemia are presented in detail elsewhere:

●(See "Regulation of magnesium balance".)

●(See "Hypomagnesemia: Causes of hypomagnesemia".)

●(See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

WHEN TO SUSPECT HYPOMAGNESEMIA — 

Because plasma magnesium is not a routine laboratory measurement in most patients, hypomagnesemia is often undetected. Clinical settings in which hypomagnesemia should be suspected include the following:

●Patients with chronic diarrhea or malabsorption. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Diarrhea and malabsorption'.)

●Patients with alcohol use disorder. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Alcohol use disorder'.)

●Patients receiving medications that are known to cause hypomagnesemia (table 1). (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Proton pump inhibitors' and "Hypomagnesemia: Causes of hypomagnesemia", section on 'Medications'.)

●Patients with unexplained hypokalemia or hypocalcemia. (See "Causes of hypokalemia in adults", section on 'Hypomagnesemia' and "Etiology of hypocalcemia in adults", section on 'Disorders of magnesium metabolism'.)

●Patients with neuromuscular disturbances, such as tremor, tetany, seizures, weakness, apathy, delirium, or coma. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Neuromuscular manifestations'.)

●Patients with ventricular arrhythmias. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Cardiovascular manifestations'.)

EVALUATION — 

Patients with hypomagnesemia should be evaluated by history and laboratory testing to identify the underlying cause and determine if the patient is experiencing any symptoms related to hypomagnesemia. If the cause is not apparent, measurement of urinary magnesium excretion can be helpful to distinguish between gastrointestinal and urinary phosphate losses.

Exclude spurious hypomagnesemia — Spurious hypomagnesemia may occur with ethylenediaminetetraacetic acid (EDTA) contamination of the blood sample or with severe hypoalbuminemia. These should be excluded to avoid unnecessary testing and treatment of hypomagnesemia. EDTA contamination may be suspected in a patient with concurrent unexplained hyperkalemia or hypocalcemia.

History and initial laboratory testing — Patients with hypomagnesemia should be evaluated to identify the underlying cause, which is usually apparent from the history (table 1). In addition, patients should be assessed for the presence of any clinical manifestations related to hypomagnesemia. (See "Hypomagnesemia: Causes of hypomagnesemia" and "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

We perform the following initial evaluation:

●We assess the patient for symptoms associated with hypomagnesemia, including tremor, tetany, convulsions, weakness, apathy, delirium, and coma. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Neuromuscular manifestations'.).

●We review the patient’s medications to assess for drugs that can potentially cause hypomagnesemia (table 1). (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Proton pump inhibitors' and "Hypomagnesemia: Causes of hypomagnesemia", section on 'Medications'.):

●We review the patient’s family history for a history of hypomagnesemia, which could suggest an inherited cause of hypomagnesemia. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Inherited causes of renal magnesium wasting'.)

●We review serum chemistries for other electrolyte abnormalities, such as hypokalemia and hypocalcemia.

●If an arrythmia or cardiac complication is suspected, we obtain an electrocardiogram (ECG) to determine if changes related to hypomagnesemia are present. These include widening of the QRS and peaking of T waves with moderate magnesium depletion, and widening of the PR interval, diminution of T waves, and atrial and ventricular arrhythmias with severe depletion [2]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Cardiovascular manifestations'.)

Assessment of urinary magnesium excretion — If the cause of hypomagnesemia is still not apparent from the history and initial laboratory testing, measurement of urinary magnesium excretion can be helpful to distinguish between gastrointestinal and urinary magnesium losses.

Magnesium excretion can be measured either from a 24-hour urine collection or by calculation of the fractional excretion of filtered magnesium (FEMg) from a random urine specimen.

The latter can be calculated from the following formula (calculator 1 and calculator 2):

The terms "U" and "P" refer to the urine and plasma concentrations of magnesium (Mg) and creatinine (Cr). The plasma magnesium concentration is multiplied by 0.7 since only approximately 70 percent of the circulating magnesium is free (not bound to albumin) and therefore able to be filtered across the glomerulus.

Renal magnesium excretion should be reduced in patients with plasma magnesium depletion. Thus, in patients with hypomagnesemia:

●A daily excretion of more than 10 to 30 mg (in a 24-hour urine specimen) or a fractional excretion of magnesium above 3 to 4 percent indicates renal magnesium wasting. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Increased urinary losses'.)

●By contrast, a 24-hour urinary magnesium excretion less than 10 mg or a fractional excretion of magnesium less than 2 percent usually indicates an extrarenal source of magnesium losses (typically gastrointestinal). (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Increased gastrointestinal losses'.)

In one study of 74 hypomagnesemic patients, for example, the mean fractional excretion of magnesium in patients with hypomagnesemia of extrarenal origin was 1.4 percent (range 0.5 to 2.7 percent) [3]. By comparison, the fractional excretion of magnesium in those with renal magnesium loss was 15 percent (range of 4 to 48 percent). (See "Hypomagnesemia: Causes of hypomagnesemia".)

Genetic testing — Genetic testing for inherited causes of hypomagnesemia is reasonable for patients with unexplained hypomagnesemia. We have a low threshold for genetic testing in children and young adults or individuals who have no other systemic diseases and are not taking any medications that could cause hypomagnesemia. If the decision is made to pursue genetic testing, we begin by ordering an inherited kidney disease gene panel. If the result of the kidney disease gene panel is negative, individual testing for rarer genes that are not on panels can be considered.

TREATMENT — 

Treatment of hypomagnesemia should be focused on addressing the underlying cause. Some patients will require magnesium supplementation depending upon the presence of symptoms of hypomagnesemia and the plasma magnesium concentration.

Treatment of the underlying cause — Patients with hypomagnesemia should be treated for the underlying cause, if possible. As examples:

●Alcohol use disorder – In patients with hypomagnesemia related to alcohol use disorder, hypomagnesemia may be reversible with abstinence from alcohol and improved nutrition. Magnesium supplementation may be required. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Alcohol use disorder' and "Nutritional status in patients with sustained heavy alcohol use".)

●Drug-induced hypomagnesemia – In patients with drug-induced hypomagnesemia, discontinuation of the offending agent often leads to resolution of hypomagnesemia. However, in some patients, such as those who receive a platinum agent (eg, cisplatin, carboplatin) for several months, urinary magnesium wasting may persist even after discontinuation of therapy. In such patients, chronic magnesium replacement therapy is often necessary. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Proton pump inhibitors' and "Hypomagnesemia: Causes of hypomagnesemia", section on 'Medications' and "Cisplatin nephrotoxicity", section on 'Hypomagnesemia'.)

●Inherited causes of renal magnesium wasting - There are no available therapies that specifically address the genetic defects causing inherited renal magnesium wasting. Most patients will require lifelong magnesium repletion.

●Diabetes mellitus – In patients with hypomagnesemia in the setting of diabetes mellitus, correction of hyperglycemia may reverse the hypomagnesemia. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Uncontrolled diabetes mellitus'.)

Magnesium repletion

Patients with normal or near-normal kidney function — In patients with normal or near-normal kidney function, the route and dose of magnesium repletion should be selected on the basis of the severity of the clinical manifestations and the degree of hypomagnesemia (algorithm 1).

Patients with severe symptoms — Symptomatic patients, such as those with tetany, arrhythmias, or seizures should receive intravenous (IV) magnesium (algorithm 1). Such patients should have continuous cardiac monitoring. Our approach is as follows:

●Hemodynamically unstable patients – In hemodynamically unstable patients (including those with arrhythmias consistent with torsade de pointes or hypomagnesemic hypokalemia), we administer 1 to 2 grams of magnesium sulfate (8 to 16 mEq [4 to 8 mmol] of elemental magnesium) over 2 to 15 minutes [4,5]. If the patient remains hemodynamically unstable after this initial bolus, a repeat bolus can be administered.

Once the patient is stable, we follow with an infusion of 4 to 8 grams of magnesium sulfate (32 to 64 mEq [16 to 32 mmol] of elemental magnesium) given slowly over 12 to 24 hours. We repeat the dose as necessary to maintain the plasma magnesium concentration above 1 mg/dL (0.8 mEq/L or 0.4 mmol/L).

●Hemodynamically stable patients – In hemodynamically stable patients, our approach depends on the severity of the hypomagnesemia:

•If the plasma magnesium is <1 mg/dL (0.8 mEq/L or 0.4 mmol/L), we administer 1 to 2 grams of magnesium sulfate (8 to 16 mEq [4 to 8 mmol] of elemental magnesium) over 30 to 60 minutes. We follow this with an infusion of 4 to 8 grams of magnesium sulfate (32 to 64 mEq [16 to 32 mmol] of elemental magnesium) given slowly over 12 to 24 hours [6]. We repeat the dose as necessary to maintain the plasma magnesium concentration above 1 mg/dL (0.8 mEq/L or 0.4 mmol/L).

•If the plasma magnesium is ≥1 mg/dL (0.8 mEq/L or 0.4 mmol/L), we administer 4 to 8 grams of magnesium sulfate (32 to 64 mEq [16 to 32 mmol] of elemental magnesium) given slowly over 12 to 24 hours [6]. We repeat the dose as necessary to maintain the plasma magnesium concentration above 1 mg/dL (0.8 mEq/L or 0.4 mmol/L).

●Children – In children, we use a slow infusion of magnesium sulfate; the dose is 25 to 50 mg/kg magnesium sulfate (0.2 to 0.4 mEq/kg [0.1 to 0.2 mmol/kg] of elemental magnesium) with a maximum single dose of 2 grams magnesium sulfate (16 mEq [8 mmol] of elemental magnesium). The dose may be repeated every 6 hours as needed based on serum magnesium levels.

●Monitoring – The magnesium concentration should be measured 6 to 12 hours after each dose of IV magnesium. Repeat doses are given based upon the follow-up measurement. Of note, plasma magnesium levels do not correlate well with total body stores, as the majority of magnesium is intracellular; plasma concentrations may be transiently elevated for a few hours after administration of an IV dose.

(Conversion relationships: 1 g magnesium sulfate = 98.6 mg elemental magnesium = 8.12 mEq elemental magnesium = 4.06 mmol elemental magnesium) (table 2).

Patients with no or minimal symptoms — For hypomagnesemic patients with no or minimal symptoms, we prefer to give oral magnesium replacement. However, many patients are unable to take oral magnesium or have side effects such as gastrointestinal discomfort and diarrhea. Thus, many hospitalized patients with hypomagnesemia are given IV rather than oral magnesium supplementation, even if symptoms are minimal or absent.

Oral repletion — A number of oral magnesium salts are available (table 2). Each differs in the content of elemental magnesium, but all suffer from limited bioavailability. A typical daily dose in a patient with normal kidney function is 240 to 1000 mg (20 to 80 mEq [10 to 40 mmol]) of elemental magnesium in divided doses.

Sustained-release preparations have the advantage that they are slowly absorbed and thereby minimize renal excretion of the administered magnesium. Available sustained-release preparations include magnesium chloride containing 64 to 71.5 mg elemental magnesium (eg, MagDelay, SlowMag) and magnesium L-lactate containing 84 mg elemental magnesium (eg, Mag-Tab SR). Six to eight tablets (30 to 56 mEq [15 to 28 mmol]) should be taken daily in divided doses for severe magnesium depletion. Two to four tablets (10 to 28 mEq [5 to 14 mmol]) may be sufficient for mild hypomagnesemia. The use of sustained-release preparations may permit the use of lower doses, which minimizes the associated diarrhea (the major dose-limiting side effect).

If a sustained-release preparation is not available, magnesium oxide 800 to 1600 mg (20 to 40 mmol [40 to 80 mEq]) daily in divided doses may be used for moderate to severe hypomagnesemia. Diarrhea frequently occurs with magnesium oxide therapy.

Intravenous repletion — In some hospitalized patients, oral magnesium supplementation may be unavailable or not tolerable (eg, in postoperative patients who cannot take medications orally). Even if such patients with hypomagnesemia are asymptomatic or minimally symptomatic, IV magnesium therapy can be used (algorithm 1). Clinicians should be aware of the inefficiencies of IV magnesium as described below. (See 'Inefficiency of intravenous magnesium supplementation' below.)

For routine IV repletion or maintenance in the inpatient setting, we use the following regimen in which the dose and rate of repletion depends upon the plasma magnesium concentration [6,7]: severe (eg, <1 mg/dL), moderate (1 to 1.4 mg/dL), and mild (1.5 to 1.7 mg/dL combined with suspicion of magnesium depletion) depletion with an estimated repletion dose:

●If the plasma magnesium is less than 1 mg/dL (0.8 mEq/L or 0.4 mmol/L), give 4 to 8 grams of magnesium sulfate (32 to 64 mEq [16 to 32 mmol] of elemental magnesium) over 12 to 24 hours and repeat as needed.

●If the plasma magnesium is 1 to 1.4 mg/dL (0.8 to 1.2 mEq/L or 0.4 to 0.6 mmol/L), give 2 to 4 grams of magnesium sulfate (16 to 32 mEq [8 to 16 mmol] of elemental magnesium) over 4 to 12 hours.

●If the plasma magnesium is 1.5 to 1.7 mg/dL (1.2 to 1.4 mEq/L or 0.6 to 0.7 mmol/L), give 1 to 2 grams of magnesium sulfate (8 to 16 mEq [4 to 8 mmol] of elemental magnesium) over one to two hours.

In stable hospitalized patients receiving magnesium therapy, the plasma magnesium concentration should be measured daily or more frequently if indicated. Repeat doses are given based upon the follow-up measurement.

Duration of therapy — Serum magnesium levels usually rise quickly with therapy, but intracellular stores take longer to replete. It is therefore advisable in patients with normal kidney function to continue magnesium repletion for at least one to two days after the serum magnesium concentration normalizes.

Patients with impaired kidney function — In general, great caution should be exercised in treating patients who have acute or chronic kidney injury with magnesium-containing medications. However, patients with reduced kidney function may require magnesium repletion if they have severe hypomagnesemia (ie, <1 mg/dL [0.8 mEq/L or 0.4 mmol/L]).

There are no published data to guide therapy in such patients, and it is critical that the plasma magnesium concentration be followed closely (ie, after each magnesium dose). In addition, the patient should be monitored for signs of hypermagnesemia such as facial flushing, decreased tendon reflexes, hypotension, and atrioventricular block. (See "Hypermagnesemia: Causes, symptoms, and treatment", section on 'Symptoms of hypermagnesemia'.)

In the absence of published data, we take the following approach:

●A symptomatic patient who has moderately reduced kidney function (ie, estimated glomerular filtration rate of 15 to 30 mL/min/1.73 m²) and severe hypomagnesemia should be treated with 2 to 4 grams of IV magnesium sulfate given slowly over 4 to 12 hours. The plasma magnesium should be checked prior to subsequent doses and daily if doses are given less frequently.

●Asymptomatic patients who have severe hypomagnesemia and moderately decreased kidney function may be treated with approximately one-half the dose of the selected oral preparation that is recommended for the patient with normal kidney function. The plasma magnesium concentration should be measured before giving a subsequent dose.

It would be extremely unusual for a patient with no kidney function (ie, on dialysis) to have severe magnesium depletion in the absence of an extrarenal loss such as diarrhea. In such cases, treating the diarrhea may be sufficient to correct the hypomagnesemia.

Inefficiency of intravenous magnesium supplementation — Plasma magnesium concentration inhibits magnesium reabsorption in the loop of Henle, the major site of active magnesium transport (see "Regulation of magnesium balance"). Thus, when an IV magnesium infusion is given, an abrupt but temporary elevation in the plasma magnesium concentration will partially inhibit the stimulus to magnesium reabsorption in the loop of Henle. Thus, up to 50 percent of the infused magnesium will be excreted in the urine. In addition, magnesium uptake by the cells is slow, and therefore adequate repletion requires sustained correction of the hypomagnesemia.

Adjunctive therapies

Potassium-sparing diuretics — Patients with renal magnesium wasting may benefit from the addition of a potassium-sparing diuretic such as amiloride or triamterene. These drugs have been shown to effectively reduce urinary magnesium excretion in animal studies [8]. The mechanism is unknown, but these drugs may decrease magnesium excretion by increasing its reabsorption in the distal nephron [9]. (See "Effect of diuretics on magnesium handling by the kidney".)

However, data on the efficacy of potassium-sparing diuretics for the treatment of hypomagnesemia in humans is limited. In one series of 12 healthy human subjects treated with a thiazide diuretic, amiloride at a dose of 20 mg daily increased plasma magnesium by only 5 percent on average [10]. Similarly, in a randomized crossover trial of patients with Gitelman syndrome, six weeks of treatment with amiloride reduced urinary magnesium excretion but had no effect on plasma magnesium concentration [11].

Sodium-glucose cotransporter 2 (SGLT2) inhibitors — The addition of an SGLT2 inhibitor (eg, dapagliflozin, empagliflozin, canagliflozin) may be used as adjunctive therapy in patients with hypomagnesemia that is refractory to oral magnesium supplementation, particularly if the underlying cause is renal magnesium wasting.

SGLT2 inhibitors have been observed to induce mild increases in serum magnesium levels in patients with type 2 diabetes, and this appears to be a class effect [12,13]. In addition, there are reports describing the use of SGLT2 inhibitors to treat refractory hypomagnesemia in patients with or without diabetes [14-16]. In all cases, patients had a sustained improvement in serum magnesium levels, and some were able to discontinue or reduce the dose of their magnesium supplementation. The mechanism behind these beneficial effects is unclear. SGLT2 inhibitors have been shown to increase epidermal growth factor (EGF) expression in the thick ascending limb, which may have a beneficial effect on magnesium reabsorption [17]. (See "Effect of diuretics on magnesium handling by the kidney", section on 'Osmotic diuretics'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

●When to suspect hypomagnesemia – Because plasma magnesium is not a routine laboratory measurement in most patients, hypomagnesemia is often undetected. Clinical settings in which hypomagnesemia should be suspected include the following (see 'When to suspect hypomagnesemia' above):

•Chronic diarrhea or malabsorption

•Alcohol use disorder

•Treatment with medications that can cause hypomagnesemia

•Unexplained hypokalemia or hypocalcemia

•Neuromuscular disturbances, such as tremor, tetany, seizures, weakness, apathy, delirium, or coma

•Ventricular arrhythmias

●Evaluation – In patients with hypomagnesemia, we take the following approach to evaluation:

•Exclude spurious hypomagnesemia – Spurious hypomagnesemia may occur with ethylenediaminetetraacetic acid (EDTA) contamination of the blood sample or with severe hypoalbuminemia. These should be excluded to avoid unnecessary testing and treatment of hypomagnesemia. (See 'Exclude spurious hypomagnesemia' above.)

•History and initial laboratory testing – Patients with hypomagnesemia should be evaluated to identify the underlying cause, which is usually apparent from the history (table 1). In addition, patients should be assessed for the presence of any clinical manifestations related to hypomagnesemia. (See 'History and initial laboratory testing' above.)

•Assess urinary magnesium excretion - If the cause of hypomagnesemia is still not apparent from the history and initial laboratory testing, measurement of urinary magnesium excretion can be helpful to distinguish between gastrointestinal and urinary magnesium losses. Magnesium excretion can be measured either from a 24-hour urine collection or by calculation of the fractional excretion of filtered magnesium (FEMg) from a random urine specimen (calculator 1 and calculator 2).

-A daily excretion of more than 10 to 30 mg (in a 24-hour urine specimen) or a fractional excretion of magnesium above 3 to 4 percent indicates renal magnesium wasting.

-By contrast, a 24-hour urinary magnesium excretion less than 10 mg or a fractional excretion of magnesium less than 2 percent usually indicates an extrarenal source of magnesium losses (typically gastrointestinal).

•Genetic testing – Genetic testing for inherited causes of hypomagnesemia is reasonable for patients with unexplained hypomagnesemia. We have a low threshold for genetic testing in children and young adults or individuals who have no other systemic diseases and are not taking any medications that could cause hypomagnesemia. (See 'Genetic testing' above.)

●Treatment – Treatment of hypomagnesemia should be focused on addressing the underlying cause. Some patients will require magnesium supplementation depending upon the presence of symptoms of hypomagnesemia and the plasma magnesium concentration. (See 'Treatment of the underlying cause' above.)

•Magnesium repletion – The route of magnesium repletion varies with the severity of the clinical manifestations (algorithm 1):

-Severe symptoms – Patients with hypomagnesemia and severe signs and symptoms require intravenous (IV) magnesium with cardiac monitoring. (See 'Patients with severe symptoms' above.)

-No or minimal symptoms – For patients with hypomagnesemia who are asymptomatic or minimally symptomatic, we suggest magnesium supplementation (Grade 2C). Oral supplementation is preferred in outpatients (table 2); because of adverse effects with oral magnesium, IV magnesium is often used among hospitalized patients. (See 'Patients with no or minimal symptoms' above.)

-Impaired kidney function – Caution should be exercised in treating patients who have acute or chronic kidney injury with magnesium-containing medications. There are no data to guide therapy in such patients. Plasma magnesium concentration should be followed closely, and the patient should be monitored for signs of hypermagnesemia. (See 'Patients with impaired kidney function' above.)

•Adjunctive therapies – Potassium-sparing diuretics (amiloride, triamterene) or sodium-glucose cotransporter 2 (SGLT2) inhibitors can be used as adjunctive therapies in patients with renal magnesium wasting and/or refractory hypomagnesemia. (See 'Adjunctive therapies' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Gunjeet K Kala Ahluwalia, MD, who contributed to earlier versions of this topic review.