INTRODUCTION — Hypomagnesemia is a common problem, occurring in nearly 12 percent of hospitalized patients . A higher incidence, as much as 60 to 65 percent, has been found among intensive care unit patients .
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".)
OVERVIEW OF CLINICAL MANIFESTATIONS — The major clinical manifestations of hypomagnesemia include:
●Neuromuscular manifestations, including neuromuscular hyperexcitability (eg, tremor, tetany, convulsions), weakness, apathy, delirium, and coma. (See 'Neuromuscular' below.)
●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' below.)
●Abnormalities of calcium metabolism, including hypocalcemia, hypoparathyroidism, parathyroid hormone (PTH) resistance, and decreased synthesis of calcitriol. (See 'Calcium metabolism' below.)
●Hypokalemia. (See 'Hypokalemia' below.)
Magnesium depletion is also associated with several other disorders, such as nephrolithiasis [3,4], insulin resistance and the metabolic syndrome , and hypertension. Patients with primary hypertension (formerly called "essential" hypertension) may have reduced free magnesium concentrations in red blood cells , and magnesium supplementation can reduce blood pressure . In addition, magnesium deficiency has been implicated in both migraine headaches and asthma, and some studies suggest that magnesium therapy is effective in these disorders [8,9]. Low magnesium levels have been associated with higher mortality in hemodialysis patients  and with a higher risk of new-onset diabetes after liver and kidney transplantation [11-13].
NEUROMUSCULAR — Neuromuscular hyperexcitability may be the presenting complaint of patients with magnesium deficiency. Hypocalcemia is often observed in patients with magnesium deficiency and may contribute to the clinical findings. Neuromuscular hyperexcitability may manifest as:
●Tetany – Patients may develop positive Trousseau and Chvostek signs, muscle spasms, and muscle cramps [14,15]. Tetany can occur in the absence of hypocalcemia and alkalosis and is presumably due to lowering of the threshold for nerve stimulation [2,16].
●Seizures – Hypomagnesemic patients can develop seizures that may be generalized and tonic clonic in nature or multifocal motor. This has been observed in neonates and children, as well as adults. The effects of magnesium deficiency on brain neuronal excitability may be mediated by increased glutamate-activated depolarization in the brain .
●Involuntary movements – Patients with hypomagnesemia can manifest athetoid or choreiform movements .
In addition to neuromuscular hyperexcitability, patients with hypomagnesemia may manifest apathy, delirium, or coma . 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 . 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 .
CARDIOVASCULAR — Magnesium has complex effects on myocardial ion fluxes, among which its effect on the sodium pump (Na-K-ATPase) is probably the most important. As magnesium is an obligate cofactor in all reactions that require adenosine triphosphate (ATP), it is essential for the activity of Na-K-ATPase . During magnesium deficiency, Na-K-ATPase function is impaired.
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 .
●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 .
●Frequent atrial and ventricular premature systoles may be present, and sustained atrial fibrillation may also develop.
●Hypomagnesemia facilitates the development of digoxin cardiotoxicity . 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 .
●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".)
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) . Occasionally, patients with normal plasma magnesium concentrations may have hypocalcemia that improves with magnesium therapy, possibly due to cellular magnesium depletion. (See 'Normomagnesemic magnesium depletion' below.)
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.)
Dietary magnesium depletion in animals has been shown to lead to a decrease in skeletal growth and increased 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. Since both PTH and calcitriol are trophic for bone, impaired secretion or skeletal resistance may result in osteoporosis . In addition, magnesium is mitogenic for cell growth, and, therefore, magnesium depletion may result in a decrease in bone formation.
Hypoparathyroidism and parathyroid hormone resistance — Low magnesium levels impair PTH release in response to hypocalcemia. Immunoreactive PTH levels in most hypomagnesemic-hypocalcemic patients have been either normal or low (and in some cases undetectable), indicating inappropriately low PTH secretion [28-30]. 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 [28,30].
Failure of hormone secretion cannot explain all of the hypocalcemia that is observed, and bone resistance to PTH also plays a role . Studies in isolated perfused bone have shown that magnesium depletion interferes with the generation of cyclic adenosine monophosphate (AMP) in response to perfusion with PTH . Why this occurs is not clear. It is possible that severe hypomagnesemia may interfere with G protein activation in response to PTH, thereby minimizing the stimulation of adenylate cyclase.
Several findings suggest that PTH resistance may be of greater importance than diminished secretion in most patients. In general, PTH-induced release of calcium from bone is substantially impaired when the plasma magnesium concentration falls below 0.8 mEq/L (1 mg/dL or 0.4 mmol/L); by comparison, diminished PTH secretion appears to require more severe hypomagnesemia. In addition, magnesium therapy produces a rise in PTH secretion that occurs significantly earlier than restoration of PTH responsiveness . This observation is compatible with a primary role for PTH resistance.
Vitamin D deficiency — Low plasma levels of calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D) have been noted in hypocalcemic, hypomagnesemic subjects and can contribute to the decreased calcium concentration. Several factors may explain low calcitriol levels. Patients with magnesium deficiency and hypocalcemia frequently have low serum levels of 25-hydroxyvitamin D. The major reason, however, appears to be a decrease in the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the kidney . This results from both impaired PTH secretion, as mentioned above, and a direct effect of magnesium depletion on the kidney.
Normomagnesemic magnesium depletion — A small number of patients have been reported with hypocalcemia responsive to magnesium administration in the absence of detectable hypomagnesemia [30,33,34]. In most of these patients, other findings suggested the presence of magnesium depletion, such as alcoholism or diarrhea. In a prospective study of 82 patients with alcohol-related admission diagnoses, for example, 30 had unexplained hypocalcemia (8 mg/dL or 2 mmol/L); 14 were hypomagnesemic while 16 had a normal plasma magnesium concentration . However, both of the hypocalcemic groups had low mononuclear cell magnesium levels, a finding also seen in normocalcemic patients, and both groups showed normalization of the plasma calcium concentration after the administration of 32 to 64 mEq of elemental magnesium per day for three to five days.
These findings, however, do not conclusively demonstrate that intracellular magnesium depletion is the cause of unexplained hypocalcemia in patients with a normal plasma magnesium concentration. Most patients with chronic alcoholism and diarrhea have tissue magnesium depletion that is independent of the presence or absence of hypocalcemia . 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".)
HYPOKALEMIA — Hypokalemia is a common event in hypomagnesemic patients, occurring in 40 to 60 percent of cases . 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".)
There is also evidence of renal potassium wasting in hypomagnesemic patients that is due to increased potassium secretion in the connecting tubule and the cortical collecting tubule . The following sequence may explain how this might occur. Potassium secretion from the cell into the lumen by the cells of the connecting tubule and cortical collecting tubule is mediated by luminal potassium (ROMK) channels, a process that is inhibited by intracellular magnesium. Hypomagnesemia is associated with a reduction in the intracellular magnesium concentration, which releases this inhibitory effect on potassium efflux [37-39]. Given the very high cell potassium concentration, this change would promote potassium secretion from the cell into the lumen and enhanced urinary losses. The hypokalemia in this setting is relatively refractory to potassium supplementation and requires correction of the magnesium deficit .
SUMMARY AND RECOMMENDATIONS
●Hypomagnesemia is a common problem, occurring in nearly 12 percent of hospitalized patients. A higher incidence, as much as 60 to 65 percent, has been found among intensive care unit patients. (See 'Introduction' above.)
●The major clinical manifestations of hypomagnesemia include (see 'Overview of clinical manifestations' above):
•Neuromuscular manifestations, including neuromuscular hyperexcitability (eg, tremor, tetany, convulsions), weakness, apathy, delirium, and coma. (See 'Neuromuscular' 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' above.)
•Abnormalities of calcium metabolism, including hypocalcemia, hypoparathyroidism, parathyroid hormone (PTH) resistance, and decreased synthesis of calcitriol. (See 'Calcium metabolism' above.)
•Hypokalemia. (See 'Hypokalemia' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to earlier versions of this topic review.
4 : Association Between Serum Magnesium and the Prevalence of Kidney Stones: a Cross-sectional Study.
9 : Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis.
12 : Posttransplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation.
17 : Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices.
26 : Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism.
30 : Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency.
31 : Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency. Studies in isolated perfused bone.
38 : Mg(2+)-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes.
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