Hypomagnesemia

Etiology

Hypomagnesemia can be secondary to decreased intake, as seen in the following:[5]

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

It also can be secondary to the following medications:[1]

• 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

It can also result from redistribution from the extracellular to the intracellular compartment:[7]

• 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, including but not limited to the following conditions:[1]

• 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 to be 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 1,000 mmol of magnesium.[11] Magnesium is the second most abundant intracellular cation after potassium and a co-factor in many biochemical reactions. About 99% is located 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 kidney (primarily through the proximal tubule, the thick ascending loop of Henle, and the distal tubule), small bowel (primarily through the jejunum and ileum), and bone. Hypomagnesemia occurs when something, whether a drug or a disease condition, alters the homeostasis of magnesium.

Magnesium is important for many functions, including the following:

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

Acquired Hypomagnesemia

Magnesium deficiency also can cause hypocalcemia, as the two are interrelated. Decreased magnesium causes impaired magnesium-dependent adenyl cyclase generation of cyclic adenosine monophosphate (cAMP), decreasing parathyroid hormone (PTH) release. In turn, calcium levels are decreased as well, 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[14]

Gitelman syndrome: It 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 have the tendency 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.

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.

EAST (SeSAME) syndrome: It 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.[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. Specific signs and symptoms are outlined below.

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. It may occur in the absence of hypocalcemia and alkalosis and is thought to be due to the lowering of 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 at magnesium levels 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

It is recommended to check the following in a patient suspected of having hypomagnesemia:

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

Please note that there is no clinically available "ionized" magnesium test.

If unsure, the distinction between gastrointestinal and renal losses can be made 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

Once hypomagnesemia is confirmed, the etiology can usually be obtained from the history. History may include the causes mentioned above.

On examination, vertical nystagmus and tetany may be observed. The following signs can be checked:

• 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.

Genetic testing may be considered if there is positive family history, unexplained hypomagnesemia, or if discovered early in infancy.

Table 1. Some genetic disorders causing hypomagnesemia[22]

Treatment / Management

The treatment of patients with hypomagnesemia is based on a patient’s kidney function, the severity of their symptoms, and hemodynamic stability. If a patient is hemodynamically unstable in an acute hospital setting, 1 to 2 grams of magnesium sulfate can be given in about 15 minutes. For symptomatic, severe hypomagnesemia in a stable patient, 1 to 2 grams of magnesium sulfate can be given over one hour. Non-emergent repletion of the adult patient is generally 4 to 8 grams 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 grams).[11][23](B3)

For an asymptomatic patient who is not hospitalized and can tolerate medications by mouth, sustained-release oral replacement should be tried first.

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, serum electrolyte levels must be rechecked (whether in an inpatient or outpatient setting) to ensure effective treatment. Although serum magnesium levels rise quickly with treatment, intracellular magnesium takes longer to replete. Thus, patients with normal renal function should try to continue magnesium repletion for two 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. Studies recommend reducing the magnesium dose by 50% and closely monitoring magnesium levels in these patients.

Selected food sources should also be kept in mind while giving supplements to patients with adequate intake.

Table 2. Foods sources of magnesium[24]

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

In patients with concurrent hypocalcemia, calcium should be replaced before initiating magnesium replacement. This is 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 levels of potassium and/or calcium. Furthermore, many other electrolyte and hormonal abnormalities can present with similar symptoms. Hypomagnesemia may need to be distinguished from the following:

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

Prognosis

The 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, it is associated with increased length of ICU stay, mortality, and need for mechanical ventilation.[27]

Complications

It is important to treat hypomagnesemia. Dangerously low levels of magnesium have the potential to 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. Moreover, it may also cause chondrocalcinosis.[14]