Version July 2025
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]). The threshold plasma magnesium level that defines hypomagnesemia may vary among clinical laboratories.
Symptomatic magnesium depletion is often associated with multiple biochemical abnormalities such as hypokalemia, hypocalcemia, and metabolic alkalosis. As a result, it is often difficult to ascribe specific clinical manifestations solely to hypomagnesemia.
This topic reviews the clinical manifestations of magnesium depletion. The causes, evaluation, and treatment of magnesium depletion are discussed elsewhere:
●(See "Hypomagnesemia: Causes of hypomagnesemia".)
●(See "Hypomagnesemia: Evaluation and treatment".)
CLINICAL MANIFESTATIONS —
Acute manifestations of hypomagnesemia include neuromuscular manifestations, cardiovascular manifestations, abnormalities of calcium metabolism, and hypokalemia.
Neuromuscular manifestations — Neuromuscular hyperexcitability may be the presenting complaint of patients with magnesium deficiency. Hypocalcemia, which is often observed in patients with magnesium deficiency, may contribute to these clinical findings. Neuromuscular hyperexcitability may manifest as:
●Tetany – Patients may develop positive Trousseau and Chvostek signs, muscle spasms, and muscle cramps [1,2]. Tetany can occur in the absence of hypocalcemia and alkalosis and is presumably due to lowering of the threshold for nerve stimulation [3,4].
●Seizures – Hypomagnesemic neonates, children, and adults can develop seizures that may be generalized and tonic clonic in nature or multifocal motor. The effects of magnesium deficiency on brain neuronal excitability may be mediated by increased glutamate-activated depolarization in the brain [5].
●Involuntary movements – Patients with hypomagnesemia can manifest athetoid or choreiform movements [6].
In addition to neuromuscular hyperexcitability, patients with hypomagnesemia may manifest apathy, delirium, or coma [7].
Vertical nystagmus is a rare but diagnostically useful sign of severe hypomagnesemia. In the absence of a structural lesion of the cerebellar and vestibular pathways, the only recognized metabolic causes are Wernicke encephalopathy and severe magnesium deficiency [8].
Weakness of the respiratory muscles is a major concern in critically ill patients with hypomagnesemia and may be a variable in the genesis of respiratory failure [4].
Cardiovascular manifestations — Magnesium has complex effects on myocardial ion fluxes. As magnesium is an obligate cofactor in all reactions that require adenosine triphosphate (ATP), magnesium deficiency impairs the activity of Na-K-ATPase [9].
Magnesium depletion induces the following changes in the electrocardiogram, which usually reflect abnormal cardiac repolarization:
●Widening of the QRS complex and peaking of T waves have been described with modest magnesium loss [10].
●Prolongation of the PR interval, progressive widening of the QRS complex, and diminution of the T wave can be seen with more severe magnesium depletion [11].
●Frequent atrial and ventricular premature systoles may be present, and sustained atrial fibrillation may also develop.
●Hypomagnesemia exacerbates digoxin cardiotoxicity [12]. Because cardiac glycosides and magnesium depletion both inhibit Na-K-ATPase, their additive effects on intracellular potassium depletion may account for their enhanced toxicity in combination [13].
●The clinical disturbance of greatest potential importance, however, is the association of hypomagnesemia with ventricular arrhythmias, particularly during myocardial ischemia or cardiopulmonary bypass. A discussion of these issues can be found elsewhere. (See "Significance of hypomagnesemia in cardiovascular disease".)
Abnormalities of calcium metabolism — Hypocalcemia is a classical sign of hypomagnesemia. In hypomagnesemic patients, symptomatic hypocalcemia is almost always associated with plasma magnesium levels below 1 mEq/L (0.5 mmol/L or 1.2 mg/dL). Mild hypomagnesemia (plasma magnesium concentration between 1.1 and 1.3 mEq/L) can also lower the plasma calcium concentration, but the change is quite small (0.2 mg/dL or 0.05 mmol/L) [14]. Occasionally, patients with normal plasma magnesium concentrations may have hypocalcemia that improves with magnesium therapy, possibly due to cellular magnesium depletion.
The major factors resulting in hypocalcemia in hypomagnesemic patients are hypoparathyroidism, parathyroid hormone (PTH) resistance, and vitamin D deficiency. (See 'Hypoparathyroidism and parathyroid hormone resistance' below and 'Vitamin D deficiency' below.)
Hypoparathyroidism and parathyroid hormone resistance — Low magnesium levels impair PTH release in response to hypocalcemia. Immunoreactive PTH levels in most hypomagnesemic-hypocalcemic patients are either normal or low (and in some cases undetectable), indicating inappropriately low PTH secretion [15-17]. Thus, a state of hypoparathyroidism exists in most hypomagnesemic-hypocalcemic patients. In the majority of these patients, parenteral magnesium supplementation leads to a rapid rise in plasma PTH levels [15,17].
In addition to diminished hormonal secretion, bone resistance to PTH also plays a role [17]. Studies in isolated perfused bone have shown that, for unknown reasons, magnesium depletion interferes with the generation of cyclic adenosine monophosphate (AMP) in response to perfusion with PTH [18]. Severe hypomagnesemia may interfere with G protein activation in response to PTH, thereby minimizing the stimulation of adenylate cyclase.
In patients with magnesium depletion, PTH resistance may be a more important cause of hypocalcemia than diminished PTH secretion. In general, PTH-induced release of calcium from bone is substantially impaired at plasma magnesium concentrations below 0.8 mEq/L (0.4 mmol/L or 1 mg/dL), while diminished PTH secretion requires more severe hypomagnesemia. Failure of the serum calcium level to increase during the initial days of magnesium repletion, at a time when serum PTH concentrations are normal or elevated, is also consistent with end-organ resistance to PTH in the magnesium-depleted patient [17].
Vitamin D deficiency — Plasma levels of calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D) are low in hypocalcemic, hypomagnesemic subjects and can contribute to the decreased calcium concentration. The most likely explanation for low calcitriol levels is decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the kidney due to both low PTH levels and a direct renal effect of hypomagnesemia [19].
Normomagnesemic magnesium depletion — Hypocalcemia responsive to magnesium administration in the absence of detectable hypomagnesemia has been reported in a small number of patients [17,20,21]. In one prospective study, hypocalcemia unexplained by other known causes like hypoalbuminemia, hypoparathyroidism, or pancreatitis was found in 30 of 82 hospitalized patients with alcohol use disorder [21]. Approximately half of the hypocalcemic patients had hypomagnesemia, but 87 percent of the normomagnesemic patients with unexplained hypocalcemia had low mononuclear cell magnesium levels. The serum calcium normalized in 11 of these patients after intravenous infusions of 32 to 64 mEq of elemental magnesium per day for three to five days.
Thus, these findings do not conclusively demonstrate that intracellular magnesium depletion is the cause of unexplained hypocalcemia in patients with a normal plasma magnesium levels. Most patients with chronic alcohol use disorder and diarrhea have tissue magnesium depletion that is independent of the presence or absence of hypocalcemia [22]. Sepsis, hypoalbuminemia, stress, and vitamin D deficiency are among the many factors in these patients that can lower the total and ionized calcium. In addition, there were no untreated time controls in this study, and it is possible that resolution of the hypocalcemia may have occurred without magnesium repletion as the clinical status of the patients improved after admission. Nevertheless, it seems reasonable to consider a trial of magnesium replacement in patients with normal kidney function who have persistent, unexplained hypocalcemia and are at risk for magnesium deficiency. (See "Hypomagnesemia: Evaluation and treatment".)
Effects on bone metabolism — Dietary magnesium depletion in animals decreases skeletal growth and increases skeletal fragility. In humans, epidemiologic studies suggest a correlation between bone mass and dietary magnesium intake. Several mechanisms may account for a decrease in bone mass in magnesium deficiency. Impaired secretion or skeletal resistance to PTH and calcitriol, which are trophic for bone, may result in osteoporosis [23]. In addition, magnesium is mitogenic for cell growth, and, therefore, magnesium depletion may result in a decrease in bone formation.
Hypokalemia — Hypokalemia is common in hypomagnesemic patients, occurring in 40 to 60 percent of cases [24]. This relationship is in part due to underlying disorders that cause both magnesium and potassium loss, such as diarrhea and diuretic therapy. (See "Hypomagnesemia: Causes of hypomagnesemia".)
Renal potassium wasting due to increased potassium secretion in the connecting and cortical collecting tubules also contributes to hypokalemia [25]. Potassium secretion from the tubular cells, which is mediated by luminal potassium (ROMK) channels, is inhibited by intracellular magnesium. Hypomagnesemia is associated with reduced intracellular magnesium which releases the inhibitory effect of magnesium on potassium efflux [25-27]. Given the very high intracellular potassium concentration, loss of magnesium's inhibitory effect on potassium efflux promotes potassium secretion from the cell into the lumen resulting in enhanced urinary potassium losses. The hypokalemia in this setting is relatively refractory to potassium supplementation and requires correction of the magnesium deficit [28].
OTHER MANIFESTATIONS —
Magnesium depletion is also associated with several other disorders, such as nephrolithiasis [29,30], insulin resistance and the metabolic syndrome [31], hypertension [32], migraine headaches [33], asthma [34,35], fractures, posttransplant diabetes mellitus [36-38], progression of diabetic kidney disease [39], higher viral titers in Ebstein-Barr virus infection [40], and higher mortality in patients on hemodialysis [41]. Some studies suggest that magnesium therapy is effective in the treatment of hypertension, migraines, and asthma [32-35].
SUMMARY
●Clinical manifestations – The major clinical manifestations of hypomagnesemia include the following:
•Neuromuscular manifestations, including neuromuscular hyperexcitability (eg, tremor, tetany, convulsions), weakness, apathy, delirium, and coma. (See 'Neuromuscular manifestations' above.)
•Cardiovascular manifestations, including 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. (See 'Cardiovascular manifestations' above.)
•Abnormalities of calcium metabolism, including hypocalcemia, hypoparathyroidism, parathyroid hormone (PTH) resistance, and decreased synthesis of calcitriol. (See 'Abnormalities of calcium metabolism' above.)
•Hypokalemia. (See 'Hypokalemia' above.)
●Other manifestations – Magnesium depletion is also associated with several other disorders, such as nephrolithiasis, insulin resistance and the metabolic syndrome, hypertension, migraine headaches, asthma, fractures, posttransplant diabetes mellitus, progression of diabetic kidney disease, higher viral titers in Ebstein-Barr virus infection, and higher mortality in patients on hemodialysis. (See 'Other manifestations' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to earlier versions of this topic review.
