Hypomagnesemia

Etiology

Hypomagnesemia can be secondary to decreased intake.[5] This is the case as seen in the following:

• Starvation
• Alcohol use disorder (with a reported prevalence of 30%)[6]
• Anorexia nervosa
• Terminal cancer
• Critically ill patients who are receiving total parenteral nutrition

Hypomagnesemia can also be secondary to the following medications:

• Loop and thiazide diuretics
• Proton pump inhibitors
• Aminoglycoside antibiotics
• Amphotericin B
• Pentamidine
• Digitalis
• Chemotherapeutic drugs, such as cisplatin, cyclosporine
• Antibodies that bind to epidermal growth factor (EGF) receptors (cetuximab, matuzumab, panitumumab)
• Laxative abuse [1] 

This condition can also result from redistribution from the extracellular to the intracellular compartment.[7] The following are in this category:

• Treatment of diabetic ketoacidosis by insulin
• Refeeding syndrome
• Correction of metabolic acidosis
• Acute pancreatitis
• Ethanol withdrawal syndrome

Lastly, hypomagnesemia can be induced by gastrointestinal and renal losses.[1] This includes but is not limited to the following conditions:

• Acute diarrhea
• Chronic diarrhea (Crohn disease, ulcerative colitis)
• Hungry bone syndrome (an increased magnesium uptake by renewing bone following parathyroidectomy or thyroidectomy, causing a decrease in serum magnesium)
• Acute pancreatitis
• Gastric bypass surgery
• Genetic disorders
• Gitelman syndrome
• Bartter syndrome
• Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
• Renal malformations and early-onset diabetes mellitus caused by HNF1-beta mutation
• Autosomal recessive isolated hypomagnesemia caused by EGF mutation
• Autosomal dominant isolated hypomagnesemia caused by Na-K-ATPase gamma subunit, Kv1.1, and cyclin M2 mutations
• Intestinal hypomagnesemia with secondary hypocalcemia
• Acquired tubular dysfunction
• Post-kidney transplant
• Recovery from acute tubular necrosis
• Postobstructive diuresis

Epidemiology

The risk of hypomagnesemia depends on multiple characteristics in various healthcare settings. The reported prevalence in the general population is 2.5% to 15%. In hospitalized patients, it ranges from 12% to 20%.[8][9] The prevalence is even higher in critically ill patients, estimated at 65% in a study.[1] 

In a study of 100 critically ill children (mean age 4.9 years) admitted to a pediatric intensive care unit in India, the prevalence was about 55%. A study revealed a 30% prevalence in patients with chronic alcohol use disorder.[10]  No recent studies have identified which age groups are at higher risk of hypomagnesemia.

Pathophysiology

An adult human body contains 25 g or 1000 mmol of magnesium.[11] Magnesium is the second most abundant intracellular cation after potassium and a cofactor in many biochemical reactions. About 99% of magnesium is in bone (60%) and soft tissues (40%).[11]

Magnesium directly affects various other electrolytes, including sodium, calcium, and potassium. As described above, low magnesium levels can occur secondary to renal and gastrointestinal losses.[12][13]

Magnesium homeostasis involves the following:

• The kidney (primarily through the proximal tubule, the thick ascending loop of Henle, and the distal tubule)
• Small bowel (primarily through the jejunum and ileum)
• Bone

Hypomagnesemia occurs when a drug or a disease condition alters magnesium homeostasis.

Magnesium is essential for many functions, including the following:

• Cofactor activity for more than 300 enzymatic reactions
• Platelet function (clotting and thrombus formation)
• Maintenance of vascular tone
• Platelet-activated thrombosis
• Muscle contraction and relaxation
• Insulin regulation
• Neurotransmission
• Cardiac conduction
• Bone formation

Acquired Hypomagnesemia

Magnesium deficiency also can cause hypocalcemia, as the 2 are interrelated. Decreased magnesium causes impaired magnesium-dependent adenyl cyclase generation of cyclic adenosine monophosphate (cAMP), decreasing parathyroid hormone (PTH) release, and decreasing calcium levels—as PTH regulates calcium levels.

Magnesium also affects the electrical activity of the myocardium and vascular tone, which is why patients with hypomagnesemia are at risk for cardiac arrhythmias. In addition, when magnesium is low, there is inhibition of renal outer medullary potassium channels, leading to increased urinary excretion and depletion of intracellular potassium levels; this reduces the threshold required for generating an action potential in the cardiac myocyte. Moreover, reduced intracellular potassium levels also prolong the time to repolarize the cell membrane, increasing the risk of arrhythmias.

Inherited Hypomagnesemias

Gitelman syndrome: This condition is caused by recessive mutations in the gene that codes for the thiazide-sensitive sodium chloride cotransporter (SLC12A3) in the distal convoluted tubule (DCT). Transcellular reabsorption of magnesium in the DCT is impaired, leading to increased calcium reabsorption, and the subsequent hypocalciuria and fluid loss tend to lower blood pressure. In addition, fluid loss activates the renin-angiotensin-aldosterone system, and increased aldosterone causes increased potassium secretion in exchange for sodium and subsequent hypokalemia.[14]

Hypercalciuric hypomagnesemias: Mutations affect the reabsorption of magnesium and calcium ions in the thick ascending limb of Henle (TAL), leading to hypercalciuric hypomagnesemia that ultimately results in nephrocalcinosis or chronic kidney disease.[14]

EAST (SeSAME) syndrome: This condition is caused by loss-of-function mutations in the gene encoding the potassium channel, KCNJ10 (Kir4.1), on the basolateral membrane of the DCT. It results in hypomagnesemia, salt wasting, metabolic alkalosis, and hypokalemia. The mechanism, however, is poorly understood.[14][15]

History and Physical

Patients with symptomatic magnesium depletion can present in many ways. The major clinical manifestations include neuromuscular and cardiovascular manifestations and other electrolyte abnormalities.

Early presentation of hypomagnesemia includes nausea, vomiting, loss of appetite, fatigue, and weakness.[5] Patients may complain of dysphagia, muscular weakness, and other symptoms, as described below.[7]

Neuromuscular Manifestations

• Neuromuscular hyperexcitability (often the first clinical manifestation)[11]
• Tremors
• Tetany, including positive Trousseau and Chvostek signs, muscle spasms, and muscle cramps. Tetany may occur in the absence of hypocalcemia and alkalosis and is presumably due to lowering the threshold for nerve stimulation.[16]
• Choreoathetosis [17]
• Seizures
• Vertical nystagmus
• Apathy
• Delirium
• Depression
• Agitation
• Psychosis
• Delirium
• Coma

Cardiovascular Manifestations

• Electrocardiogram changes, including widening of the QRS complex, peaked T waves (with mild to moderate deficiency), prolongation of the PR interval, and diminution of the T wave (with severe deficiency)[18]
• Atrial and ventricular premature systoles
• Atrial fibrillation
• Ventricular arrhythmias, including torsades de pointes
• Cardiac ischemia
• Increased risk of digoxin toxicity by inhibiting Na-K-ATPase and depleting intracellular potassium [19]

Other Electrolyte and Hormone Abnormalities

• Hypocalcemia
• Symptoms typically occur when magnesium levels are below 1 mEq/L (0.5 mmol/L or 1.2 mg/dL).
• Milder hypomagnesemia (between 1.1 and 1.3 mEq/L) lowers the plasma calcium concentration only slightly (0.2 mg/dL or 0.05 mmol/L)[20]
• Hypoparathyroidism
• Hypokalemia (about 60% of cases)

A case report describes symptoms of cerebellar ataxia, generalized convulsions, intermittent downbeat nystagmus, and supraventricular tachycardia in a 59-year-old man with severe hypomagnesemia.[21]

Evaluation

 Check the following in a patient suspected of having hypomagnesemia:

• Serum magnesium, phosphate, and calcium level
• A basic metabolic panel, including serum creatinine/kidney function and glucose levels
• Electrocardiogram to rule out arrhythmias

There is currently no clinically available "ionized" magnesium test. When in doubt, distinguishing between gastrointestinal and renal losses can be achieved by measuring the 24-hour urinary magnesium excretion. In addition, one can calculate the fractional excretion of magnesium (on a random urine specimen) with the following formula, where U and P refer to the urine and plasma concentrations of magnesium (Mg) and creatinine (Cr).

• FEMg = [(UMg x PCr) / (PMg x UCr x 0.7)] x 100

After confirming hypomagnesemia, typically obtain the etiology from the patient's history, which may include the mentioned causes.

During the examination, look for vertical nystagmus and tetany. Check for the following signs:

• Chvostek sign: Tapping on facial nerve leads to twitching of facial muscles
• Trousseau sign: Carpopedal spasm induced by inflated blood pressure cuff

If the fractional excretion of magnesium is above 2% in someone with normal renal function, the hypomagnesemia is likely secondary to renal magnesium wasting from drugs such as diuretics, aminoglycosides, or cisplatin.

Consider genetic testing if there is a positive family history, unexplained hypomagnesemia, or if the discovery of the condition is early in infancy (see Table 1. Various Genetic Disorders That Cause Hypomagnesemia).

Table 1. Various Genetic Disorders That Cause Hypomagnesemia [22]

Treatment / Management

Treating patients with hypomagnesemia is based on the state of kidney function, the severity of symptoms, and hemodynamic stability. If a patient is hemodynamically unstable in an acute hospital setting, 1 to 2 g of magnesium sulfate can be given in about 15 minutes. For symptomatic, severe hypomagnesemia in a stable patient, 1 to 2 g of magnesium sulfate can be given over 1 hour. Non-emergent repletion of the adult patient is generally 4 to 8 g of magnesium sulfate given slowly over 12 to 24 hours. In pediatric patients, the dose is 25 to 50 mg/kg (with a maximum of 2 g).[11][23](B3)

Try sustained-release oral replacement first in an asymptomatic patient who is not hospitalized and can tolerate medications by mouth.

Asymptomatic patients can benefit from oral sustained-release magnesium preparations (magnesium chloride containing 64-71.5 mg or magnesium L-lactate containing 84 mg elemental magnesium).

After repletion, recheck serum electrolyte levels (whether in an inpatient or outpatient setting) to ensure effective treatment. Although serum magnesium levels rise quickly with treatment, intracellular magnesium takes longer to replenish. Thus, patients with normal renal function should try to continue magnesium repletion for 2 days after the level normalizes.

Use caution in repleting magnesium in patients with abnormal kidney function (defined as creatinine clearance less than 30 mL/min/1.73 m²). These patients are at risk of hypermagnesemia. Study findings recommend reducing the magnesium dose by 50% and closely monitoring magnesium levels in these patients.

Selected food sources (see Table 2. Food Sources of Magnesium) should also be considered while giving supplements to patients with adequate intake.

Table 2. Food Sources of Magnesium [24]

The underlying cause of persistent hypomagnesemia should be addressed and treated. For example, if patients consistently have low electrolyte levels due to renal losses, they may benefit from amiloride, a potassium- and magnesium-sparing diuretic.

In patients with concurrent hypocalcemia, replace calcium before initiating magnesium replacement to avoid increased urinary excretion of calcium caused by sulfate from magnesium sulfate, making complex with ionized calcium.[25]

Potassium-sparing diuretics (amiloride or triamterene) should be considered in patients with diuretic-induced hypomagnesemia (when diuretic therapy cannot be discontinued) or chronic renal magnesium wasting.[1](B3)

Differential Diagnosis

Always check for other electrolyte abnormalities when suspecting or treating hypomagnesemia. Low magnesium levels can, in turn, cause low potassium and calcium levels. Furthermore, many additional electrolyte and hormonal abnormalities can present with similar symptoms. Distinguish hypomagnesemia from the following:

• Hypoparathyroidism (genetic and idiopathic)
• Acrodysostosis
• Pseudohypoparathyroidism [26]
• Blomstrand chondrodysplasia

Prognosis

Hypomagnesemia prognosis depends on the underlying cause of hypomagnesemia. Patients with hypomagnesemia from an identifiable cause have a good prognosis for complete recovery. However, in critically ill patients, this condition is associated with increased length of ICU stay, mortality, and need for mechanical ventilation.[27]

Complications

Treating hypomagnesemia is essential. Dangerously low magnesium levels can potentially cause fatal cardiac arrhythmias, such as torsades de pointes (polymorphous ventricular tachycardia with marked QT prolongation). Moreover, hypomagnesemia in patients with acute myocardial infarction puts them at a higher risk of ventricular arrhythmias within the first 24 hours. Furthermore, hypomagnesemia may also cause chondrocalcinosis.[14]