What is Hypomagnesemia

Hypomagnesemia is defined as a serum magnesium level less than < 1.8 mg/dL (< 0.70 mmol/L) ¹. Magnesium is a mineral that is vital for energy production, muscle contraction, nerve function, and the maintenance of strong bones. Hypomagnesemia causes include inadequate magnesium intake (may be seen with malnutrition) and malabsorption or excess loss of magnesium by the kidneys due to hypercalcemia or drugs such as furosemide. Hypomagnesemia clinical features are often due to accompanying hypokalemia and hypocalcemia and include lethargy, tremor, tetany, seizures, and arrhythmias. Hypomagnesemia treatment is with magnesium replacement.

Magnesium, an abundant mineral in the body, is naturally present in many foods, added to other food products, available as a dietary supplement, and present in some medicines (such as antacids and laxatives). Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation ². Magnesium is required for energy production, oxidative phosphorylation, and glycolysis. It contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm ².

An adult body contains approximately 25 g magnesium, with 50% to 60% present in the bones and most of the rest in soft tissues ³. Less than 1% of total magnesium is in blood serum, and these levels are kept under tight control. Normal serum magnesium concentrations range between 0.75 and 0.95 millimoles (mmol)/L ⁴. Magnesium homeostasis is largely controlled by the kidney, which typically excretes about 120 mg magnesium into the urine each day ⁵. Urinary excretion is reduced when magnesium status is low ⁶.

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. In healthy adults, plasma magnesium ranges from 1.7-2.3 mg/dL. Approximately 30% of total plasma magnesium is protein-bound and approximately 70% is filterable through artificial membranes (15% complexed, 55% free magnesium (Mg2+) ions). With a glomerular filtration rate (GFR) of approximately 150 L per day and an ultrafiltrable magnesium concentration of 14 mg/L, the filtered magnesium load is approximately 2,100 mg per day.

Normally, only 3% of filtered magnesium appears in urine; thus, 97% is reabsorbed by the renal tubules. In contrast to sodium and calcium, only approximately 25-30% of filtered magnesium is reabsorbed in the proximal tubule. Approximately 60-65% of filtered magnesium is reabsorbed in the thick ascending loop of Henle and 5% is reabsorbed in the distal nephron ⁷. Relatively little is known about cellular magnesium transport mechanisms ⁸.

Hypomagnesemia occurs when something, whether a drug or a disease condition, alters the homeostasis of magnesium.

Magnesium deficiency also can cause hypocalcemia, as the two are inter-related. Decreased magnesium causes impaired magnesium-dependent adenyl cyclase generation of cyclic adenosine monophosphate (cAMP), which decreases the release of parathyroid hormone (PTH). In turn, calcium levels are decreased as well, as parathyroid hormone (PTH) regulates calcium levels.

Normally, only about 1% of total body magnesium is present inside cells or in bone and this makes it difficult to get an accurate measurement of total magnesium content from blood tests alone ². The most commonly used and readily available method for assessing magnesium status is measurement of serum magnesium concentration, even though serum levels have little correlation with total body magnesium levels or concentrations in specific tissues ¹. Other methods for assessing magnesium status include measuring magnesium concentrations in erythrocytes, saliva, and urine; measuring ionized magnesium concentrations in blood, plasma, or serum; and conducting a magnesium-loading (or “tolerance”) test. No single method is considered satisfactory ⁹. Some experts [4] but not others ² consider the tolerance test (in which urinary magnesium is measured after parenteral infusion of a dose of magnesium) to be the best method to assess magnesium status in adults. To comprehensively evaluate magnesium status, both laboratory tests and a clinical assessment might be required ¹.

Hypomagnesemia key points

• Hypomagnesemia may occur in alcoholics, in patients with uncontrolled diabetes, and with hypercalcemia or use of loop diuretics.
• Symptoms include anorexia, nausea, vomiting, lethargy, weakness, personality change, tetany (eg, positive Trousseau or Chvostek sign, spontaneous carpopedal spasm, hyperreflexia), tremor, and muscle fasciculations.
• Treat with magnesium salts when magnesium deficiency is symptomatic or persistently < 1.25 mg/dL (< 0.50 mmol/L).
• Give oral magnesium salts unless patients have seizures or other severe symptoms, in which case, give 2 to 4 g of magnesium sulfate IV over 5 to 10 min.

Food Sources of Magnesium

Magnesium is widely distributed in plant and animal foods and in beverages. Green leafy vegetables, such as spinach, legumes, nuts, seeds, and whole grains, are good sources ². In general, foods containing dietary fiber provide magnesium. Magnesium is also added to some breakfast cereals and other fortified foods. Some types of food processing, such as refining grains in ways that remove the nutrient-rich germ and bran, lower magnesium content substantially ⁶. Selected food sources of magnesium are listed in Table 2.

Tap, mineral, and bottled waters can also be sources of magnesium, but the amount of magnesium in water varies by source and brand (ranging from 1 mg/L to more than 120 mg/L) ¹⁰.

Approximately 30% to 40% of the dietary magnesium consumed is typically absorbed by the body ⁵.

Table 1. Recommended Dietary Allowances (RDAs) for Magnesium

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	30 mg*	30 mg*
7–12 months	75 mg*	75 mg*
1–3 years	80 mg	80 mg
4–8 years	130 mg	130 mg
9–13 years	240 mg	240 mg
14–18 years	410 mg	360 mg	400 mg	360 mg
19–30 years	400 mg	310 mg	350 mg	310 mg
31–50 years	420 mg	320 mg	360 mg	320 mg
51+ years	420 mg	320 mg

Footnote: *Adequate Intake (AI)

[Source ¹¹ ]

Table 2. Selected Food Sources of Magnesium

Food	Milligrams (mg) per serving	Percent DV*
Almonds, dry roasted, 1 ounce	80	20
Spinach, boiled, ½ cup	78	20
Cashews, dry roasted, 1 ounce	74	19
Peanuts, oil roasted, ¼ cup	63	16
Cereal, shredded wheat, 2 large biscuits	61	15
Soymilk, plain or vanilla, 1 cup	61	15
Black beans, cooked, ½ cup	60	15
Edamame, shelled, cooked, ½ cup	50	13
Peanut butter, smooth, 2 tablespoons	49	12
Bread, whole wheat, 2 slices	46	12
Avocado, cubed, 1 cup	44	11
Potato, baked with skin, 3.5 ounces	43	11
Rice, brown, cooked, ½ cup	42	11
Yogurt, plain, low fat, 8 ounces	42	11
Breakfast cereals, fortified with 10% of the DV for magnesium	40	10
Oatmeal, instant, 1 packet	36	9
Kidney beans, canned, ½ cup	35	9
Banana, 1 medium	32	8
Salmon, Atlantic, farmed, cooked, 3 ounces	26	7
Milk, 1 cup	24–27	6–7
Halibut, cooked, 3 ounces	24	6
Raisins, ½ cup	23	6
Chicken breast, roasted, 3 ounces	22	6
Beef, ground, 90% lean, pan broiled, 3 ounces	20	5
Broccoli, chopped and cooked, ½ cup	12	3
Rice, white, cooked, ½ cup	10	3
Apple, 1 medium	9	2
Carrot, raw, 1 medium	7	2

Footnote: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed Daily Values to help consumers compare the nutrient contents of products within the context of a total diet. The Daily Value for magnesium used for the values in Table 2 is 400 mg for adults and children age 4 years and older ¹². This Daily Value, however, is changing to 420 mg as the updated Nutrition and Supplement Facts labels are implemented ¹³. The updated labels must appear on food products and dietary supplements beginning in January 2020, but they can be used now ¹⁴. FDA does not require food labels to list magnesium content unless a food has been fortified with this nutrient. Foods providing 20% or more of the Daily Value are considered to be high sources of a nutrient, but foods providing lower percentages of the Daily Value also contribute to a healthful diet.

[Source ¹¹ ]

Hypomagnesemia causes

Common causes of hypomagnesemia include:

• Alcohol use – due to inadequate intake and excessive renal excretion
• Burns that affect a large area of the body
• Acute pancreatitis
• Acute diarrhea
• Chronic diarrhea
• Critically ill patients who are receiving total parenteral nutrition (TPN)
• Excessive urination (polyuria), such as in uncontrolled diabetes and during recovery from acute kidney failure
• Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
• Gastric bypass surgery
• High blood calcium level (hypercalcemia)
• Hungry bone syndrome (an increased magnesium uptake by renewing bone following parathyroidectomy or thyroidectomy, causing a decrease in serum magnesium)
• Hyperaldosteronism (disorder in which the adrenal gland releases too much of the hormone aldosterone into the blood)
• Inherited tubular disorders (Gitelman syndrome, Bartter syndrome)
• Malabsorption syndromes, such as celiac disease and inflammatory bowel disease (Crohn disease & ulcerative colitis)
• Malnutrition
• Medicines including loop and thiazide diuretics, amphotericin B, cisplatin, cyclosporine, diuretics, digitalis, proton pump inhibitors, and aminoglycoside antibiotics
• Pregnancy (especially 3rd trimester; excessive renal excretion, other factors; usually physiologic)
• Lactation (increased magnesium requirements)
• Primary renal losses – rare disorders that cause inappropriately high magnesium excretion (eg, Gitelman syndrome)
• Other rare genetic renal diseases
• Small-bowel bypass
• Starvation
• Steatorrhea
• Sweating
• Secondary renal losses:
  • Loop and thiazide diuretics
  • Hypercalcemia
  • After removal of parathyroid tumor
  • Diabetic ketoacidosis
  • Hypersecretion of aldosterone, thyroid hormones, or vasopressin
  • Nephrotoxins (eg, amphotericin B, cisplastin, cyclosporine, aminoglycosides)

Magnesium depletion usually results from inadequate intake plus impairment of renal conservation or gastrointestinal absorption. There are numerous causes of clinically significant magnesium deficiency. Hypomagnesemia is common among hospitalized patients and frequently occurs with other electrolyte disorders, including hypokalemia and hypocalcemia. Hypomagnesemia is related to decreased intake in patients with malnutrition or long-term chronic alcoholism. Decreased oral intake is frequently compounded by increased urinary excretion exacerbated by diuretic use, which increase urinary excretion of magnesium.

Drugs can cause hypomagnesemia. Examples include chronic (> 1 yr) use of a proton pump inhibitor and concomitant use of diuretics. Amphotericin B can cause hypomagnesemia, hypokalemia, and acute kidney injury. The risk of each of these is increased with duration of therapy with amphotericin B and concomitant use of another nephrotoxic agent. Liposomal amphotericin B is less likely to cause either kidney injury or hypomagnesemia. Hypomagnesemia generally resolves with cessation of therapy.

Cisplatin can cause increased magnesium losses by the kidneys as well as generalized decrease in kidney function. Magnesium loses can be severe and persist despite discontinuation of cisplatin. Discontinuation of cisplatin is still recommended if signs of renal toxicity occur during therapy.

Hypomagnesemia signs and symptoms

Every organ in the body, especially the heart, muscles, and kidneys, needs the mineral magnesium. Magnesium also contributes to the makeup of teeth and bones. Magnesium is needed for many functions in the body, including the physical and chemical processes in the body that convert or use energy (metabolism).

When the level of magnesium in the body drops below normal, symptoms of low magnesium may develop.

Patients with symptomatic hypomagnesemia can present in many ways. Clinical manifestations are anorexia, nausea, vomiting, lethargy, weakness, personality change, tetany (eg, positive Trousseau or Chvostek sign or spontaneous carpopedal spasm, hyperreflexia), and tremor and muscle fasciculations.

Trousseau sign is the precipitation of carpal spasm by reduction of the blood supply to the hand with a tourniquet or blood  pressure cuff inflated to 20 mm Hg above systolic blood  pressure applied to the forearm for 3 min.

Chvostek sign is an involuntary twitching of the facial muscles elicited by a light tapping of the facial nerve just anterior to the exterior auditory meatus.

The neurologic signs, particularly tetany, correlate with development of concomitant hypocalcemia, hypokalemia, or both. Myopathic potentials are found on electromyography but are also compatible with hypocalcemia or hypokalemia.

Common hypomagnesemia symptoms include:

• Abnormal eye movements (nystagmus)
• Convulsions
• Fatigue
• Muscle spasms or cramps
• Muscle weakness
• Numbness

The major clinical manifestations of hypomagnesemia include neuromuscular and cardiovascular manifestations and other electrolyte abnormalities. Specific signs and symptoms are outlined below.

Neuromuscular Manifestations

• Tremors
• Tetany, including positive Trousseau and Chvostek signs, muscle spasms, muscle cramps
• Seizures
• Vertical nystagmus
• Apathy
• Delirium
• Coma

Magnesium also affects the electrical activity of the myocardium and vascular tone, which is why patients with hypomagnesemia are at risk for cardiac arrhythmias.

Cardiovascular Manifestations

• Electrocardiogram changes, including widening of the QRS complex, peaked T waves, prolongation of the PR interval
• Atrial and ventricular premature systoles
• Atrial fibrillation
• Ventricular arrhythmias, including torsades de pointes
• Cardiac ischemia

Other Electrolyte and Hormone Abnormalities

• Hypocalcemia
• Hypoparathyroidism
• Hypokalemia

Hypomagnesemia complications

Untreated, hypomagnesemia can lead to:

• Cardiac arrest
• Respiratory arrest
• Death

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 higher risk of ventricular arrhythmias within the first 24 hours.

Severe hypomagnesemia may cause generalized tonic-clonic seizures, especially in children.

Hypomagnesemia diagnosis

Your health care provider will do a physical exam and ask about your symptoms.

Tests that may be ordered include an electrocardiogram (ECG).

A blood test will be ordered to check your magnesium level. Normal magnesium range is 1.3 to 2.1 mEq/L (0.65 to 1.05 mmol/L).

Hypomagnesemia is diagnosed by measurement of serum magnesium concentration < 1.8 mg/dL (< 0.70 mmol/L). Severe hypomagnesemia usually results in concentrations of < 1.25 mg/dL (< 0.50 mmol/L). Associated hypocalcemia and hypocalciuria are common. Hypokalemia with increased urinary potassium excretion and metabolic alkalosis may be present.

Magnesium deficiency should be suspected even when serum magnesium concentration is normal in patients with unexplained hypocalcemia or refractory hypokalemia. Magnesium deficiency should also be suspected in patients with unexplained neurologic symptoms and alcoholism, with chronic diarrhea, or after cyclosporine use, cisplatinum-based chemotherapy, or prolonged therapy with amphotericin B or aminoglycosides.

Other blood and urine tests that may be done include:

• Serum magnesium, phosphate, calcium level
• Basic metabolic panel, including serum creatinine/kidney function, glucose levels
• Potassium blood test
• Urine magnesium test

Once hypomagnesemia is confirmed, the cause usually can be obtained from the history. If unsure, the distinction between gastrointestinal losses 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).

• Fractional excretion of magnesium = [ urine x plasma concentrations of magnesium (Mg) and creatinine (Cr)]/[ (0.7 x P) x U ] x 100

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.

Hypomagnesemia treatment

The treatment of patients with hypomagnesemia is based on a patient’s kidney function, the severity of their symptoms, and their hemodynamic stability. If a patient is hemodynamically unstable in an acute hospital setting, 1 to 2 grams of magnesium sulfate IV can be given in about 15 minutes. When seizures persist, the dose may be repeated up to a total of 10 g over the next 6 hours. In patients in whom seizures stop, 10 g in 1 L of 5% D/W (dextrose water) can be infused over 24 hours, followed by up to 2.5 g q 12 hours to replace the deficit in total magnesium stores and prevent further drops in serum magnesium. For symptomatic, severe hypomagnesemia in a stable patient, 1 to 2 grams of magnesium sulfate IV can be given over one hour. Non-emergent repletion of the adult patient is generally 4 to 8 grams of magnesium sulfate IV or IM given slowly over 12 to 24 hours. In pediatric patients, the dose is 25 to 50 mg/kg (with a maximum of 2 grams) ¹⁵. The serum magnesium concentration should be monitored frequently during magnesium therapy, particularly when magnesium is given to patients with renal insufficiency or in repeated parenteral doses. In these patients, treatment is continued until a normal serum magnesium concentration is achieved.

Concurrent hypokalemia or hypocalcemia should be specifically addressed in addition to hypomagnesemia. These electrolyte disturbances are difficult to correct until magnesium has been repleted. Additionally, hypocalcemia can be worsened by isolated treatment of hypomagnesemia with intravenous magnesium sulfate because sulfate binds ionized calcium.

For an asymptomatic patient who is not hospitalized and can tolerate medications by mouth, sustained-release oral replacement should be tried first. Treatment with oral magnesium salts is indicated when magnesium deficiency is symptomatic or the magnesium concentration is persistently < 1.25 mg/dL (< 0.50 mmol/L). Patients with alcoholism are treated empirically. In such patients, deficits approaching 12 to 24 mg/kg are possible.

About twice the amount of the estimated deficit should be given in patients with intact renal function, because about 50% of the administered magnesium is excreted in urine. Oral magnesium salts (eg, magnesium gluconate 500 to 1000 mg po tid) are given for 3 to 4 days. Oral treatment is limited by the onset of diarrhea.

Patients with hypomagnesemia should be encouraged to eat the following foods:

• Green vegetables, such as spinach
• Beans
• Peas
• Nuts
• Seeds
• Unrefined grains

After repletion, serum electrolyte levels must be rechecked (whether in an inpatient or outpatient setting) to ensure that the treatment was effective. 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.

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.

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