Approach

Magnesium deficiency is a state of decreased total body magnesium content. Only 1% of the total body magnesium content is located in the extracellular fluid; hence, the serum magnesium level is a poor indicator of total body magnesium content and availability. A serum magnesium <1.5 mEq/L is termed hypomagnesemia.[1]

Patients with abnormalities of magnesium homeostasis typically fall into one of three groups:

  • Patients with magnesium deficiency (low total body magnesium content) and a resultant hypomagnesemia (low serum magnesium concentration)

  • Patients with hypomagnesemia (low serum magnesium concentration) in the absence of magnesium deficiency (i.e., a normal total body magnesium content)

  • Patients with magnesium deficiency (low total body magnesium content) but no evidence of hypomagnesemia (i.e., a normal serum magnesium concentration).

Magnesium deficiency should be suspected in patients with a relevant chronic disease causing abnormalities in magnesium homeostasis, symptoms of magnesium deficiency, or persistent associated electrolyte abnormalities such as hypocalcemia or hypokalemia.[4][44] However, often it may only be detected following a blood test.

Clinical features of magnesium deficiency and/or hypomagnesemia

Most patients with mild magnesium deficiency and/or hypomagnesemia are asymptomatic. Although symptoms tend to appear once the serum magnesium falls below 1 mEq/L, there is no direct correlation between serum magnesium and the severity of the symptoms.

The symptoms are nonspecific and include:

  • Neuromuscular irritability similar to that produced by hypocalcemia, manifesting with extensor plantar reflexes, positive Trusseau and Chvostek signs, and, in severe cases, tetany; hypoparathyroidism should be considered if these signs are present

  • Cardiovascular features such as rapid heartbeats and an elevated blood pressure, tachycardia, and/or ventricular arrhythmias[14]

  • CNS symptoms of vertigo, ataxia, depression, and seizure activity.

Elucidating the cause

Malnutrition

  • General inspection may reveal signs of generalized malnutrition, including loss of subcutaneous fat, apathy and lethargy, pallor, depigmentation, enlarged abdomen, winged scapula, flaky skin, and bipedal edema. Food deprivation, a malabsorption syndrome, neglect, an eating disorder with consumption of a diet low in magnesium, or decreased food intake due to a prolonged postoperative course should be considered.

  • Signs of specific vitamin and mineral deficiencies may also be noted, and suggest reduced intake or a malabsorption syndrome.

  • Increased prominence of superficial cutaneous vasculature, peripheral neuropathy, alterations in normal dentition, and halitosis suggest alcohol abuse.

  • Magnesium malabsorption should be considered if there is a history suggestive of celiac disease or short gut syndrome. Both conditions may also present with symptoms and signs of associated vitamin deficiencies or chronic diarrhea. A skin rash consistent with dermatitis herpetiformis suggests celiac disease. A history of extensive bowel resection, abdominal radiation injury, or gastroschisis suggests short gut syndrome.

Pregnancy

  • Should prompt suspicion as the cause of magnesium deficiency due to increased magnesium demand and volume status. Preeclampsia should also be considered and excluded. Seizures in a pregnant woman should prompt suspicion of eclampsia.

Volume depletion

  • Diarrhea results in gastrointestinal magnesium loss. Causes to consider include gastroenteritis, inflammatory bowel disease, and Whipple disease. Tenesmus should prompt suspicion of inflammatory bowel disease. A travel history should be obtained to assess traveler's diarrhea. A history of laxative abuse should be sought.

  • Abdominal tenderness with distension may indicate gastroenteritis or laxative abuse. Tenderness without distension may indicate inflammatory bowel disease or pancreatitis (which typically produces epigastric tenderness). Patients with acute pancreatitis have a history of epigastric pain, fever, tachycardia with a prior history of cholelithiasis, or high alcohol intake. Patients with chronic pancreatitis usually have a history of alcohol abuse, with epigastric abdominal pain radiating to the back, steatorrhea, malnutrition, and associated diabetes mellitus.

  • Acute-onset polyuria, polydipsia, weakness, weight loss, nausea, vomiting, or abdominal pain should prompt suspicion of diabetic ketoacidosis. A history of an associated acute medical illness or suboptimal insulin therapy may also be present.

  • Most patients with renal disease do not have symptoms related to magnesium abnormalities. However, patients in the recovery phase of acute tubular necrosis develop diuresis that may lead to magnesium deficiency and/or hypomagnesemia. A history of hypotension, fluid depletion, or exposure to nephrotoxic agents may be present. There may be a history of renal tubular acidosis, or of recent relief of an obstructive uropathy, leading to postobstructive diuresis.

Signs of hypervolemia

  • These include jugular venous distension and peripheral edema, and may indicate hyperaldosteronism, cirrhosis, or obstructive uropathy.

  • Hypervolemia, polyuria, and polydipsia in association with paresthesia, headache, and muscular weakness may indicate hyperaldosteronism.

  • Jaundice, ascites, hepatomegaly, or small liver suggest liver disease. The patient may have a known history of cirrhosis.

  • There may be a history of excessive administration of intravenous fluids.

Weight loss

  • A history of increased appetite, weight loss, heat intolerance, and hair loss should prompt suspicion of hyperthyroidism. Exam may reveal a fine tremor, goiter, and exophthalmos.

  • If the patient has had a recent parathyroidectomy for hyperparathyroidism, or a thyroidectomy for hyperthyroidism, hungry bone syndrome should be considered. Hungry bone syndrome is usually asymptomatic, but may present with bone pain.

Primary renal magnesium wasting is rare, but should be suspected if there is a positive family history with symptoms of polyuria, polydipsia, and/or volume depletion. Associated growth retardation with severe cramps involving the arms and legs should prompt suspicion of Gitelman syndrome. Associated growth and intellectual disability with or without sensorineural deafness should prompt suspicion of Bartter syndrome.

Initial investigations

Serum magnesium

  • Assessment of serum magnesium level can be routinely conducted in medical clinical laboratories.[45] However, there is no simple, rapid, and accurate laboratory test to determine total body magnesium status in humans.[2] Hypomagnesemia is generally defined as a serum magnesium <1.5 mEq/L.[1]

  • A low serum magnesium level may be due to underlying magnesium deficiency, magnesium redistribution, or modest acute losses that deplete circulating magnesium without affecting magnesium stores. A normal serum magnesium level does not exclude magnesium deficiency.

  • Intracellular magnesium determination: assessment of total and free intracellular magnesium contents can be useful to determine the possibility of tissue magnesium deficiency, and should be considered. As the determination is laborious and time-consuming, and prone to possible misinterpretation depending on the procedure used, this type of determination is not commonly performed as it requires specialized lab settings.

Serum calcium, potassium, and sodium

  • Abnormalities in magnesium homeostasis may coexist with other electrolyte abnormalities. Magnesium deficiency and hypomagnesemia should be considered as causes of hypocalcemia or refractory hypokalemia.

  • Symptoms of hypomagnesemia and hypocalcemia are similar, and the two abnormalities may coexist. Calcium competes with magnesium for uptake in the loop of Henle, and an increase in the filtered calcium load can impair magnesium reabsorption. Hypomagnesemia, in turn, leads to parathyroid hormone (PTH) resistance and a decrease in PTH secretion, both of which result in hypocalcemia.

  • Hypokalemia is commonly seen in patients with hypomagnesemia, partly because the associated underlying disorders can produce both these disturbances. However, there is also evidence that hypomagnesemia can lead to increased renal potassium wasting.

  • Hypernatremia may be present if hyperaldosteronism is the cause. Increased aldosterone level increases sodium retention by the kidneys. This leads to an expansion of intravascular volume, which impairs passive magnesium transport, resulting in renal magnesium wasting.

Urinary magnesium

  • Indicated to identify renal magnesium wasting or as a test for magnesium deficiency in patients with a normal serum magnesium.

  • Magnesium depletion in patients with a normal serum magnesium should be considered in patients with unexplained hypocalcemia or hypokalemia and a history consistent with magnesium loss.[41] The best test to diagnose this syndrome is not, as yet, clear.

  • Decreased 24-hour urinary magnesium excretion or decreased excretion following an infused magnesium load may indicate extrarenal magnesium losses. However, these parameters are not specific.[45]

Therapeutic trial of magnesium supplementation

  • This should be considered in patients with unexplained or refractory hypocalcemia or hypokalemia.[41] Magnesium supplementation may produce resolution of hypokalemia or hypocalcemia.[41]

ECG

  • All patients require an ECG to search for characteristic changes associated with hypomagnesemia. These include widening of the QRS complex, prolonged QT interval, peaked or diminished T waves, and prolonged PR interval.[41]​ A sinus tachycardia, ventricular extrasystolic beats, or ventricular tachycardias (especially torsades de pointes) may also be detected.

Subsequent investigations and identification of cause

The following procedures may point to possible diagnoses.

  • A trial of discontinuation of causative medications may produce resolution of symptoms and hypomagnesemia.

  • A diagnostic interview may help identify alcohol dependence. The alcohol level (breath and blood) may be elevated.

  • Stool culture and examination is required if clinical features suggest infectious diarrhea due to a nonviral cause. The underlying organism may be detected in bacterial infection, and parasites or ova may be detected in parasitic infections.

  • Serum BUN and creatinine may be elevated in patients with renal disease. A BUN:creatinine ratio of ≥10 with a fractional excretion of sodium and chloride >2% suggests acute tubular necrosis (ATN). Urinalysis for sediment reveals tubular epithelial cells, epithelial cell casts, or muddy brown casts in ATN.

  • Urinalysis should be performed in pregnant patients. Proteinuria >300 mg per 24 hours (suggested by 1+ proteinuria on dipstick) in association with hypertension is diagnostic of preeclampsia.

  • Patients with suspected diabetic ketoacidosis require measurement of serum sodium, potassium, magnesium, calcium, and glucose. Serum magnesium, sodium, and calcium are decreased. Serum potassium is elevated, but the total body potassium is usually depleted. Plasma glucose is elevated, and urine ketones are positive. ABG reveals a metabolic acidosis, with a pH ranging from 7 to 7.3 and a bicarbonate level ranging from 10 to 15 mEq/L.

  • Serum iron or vitamins A, B1, B2, B6, B12, C, D, and E may be decreased in malabsorption syndromes. An increased INR suggests vitamin K deficiency. An immunoglobulin A-tissue transglutaminase (IgA-tTG) test should be performed if celiac disease is suspected. A small bowel biopsy can be performed if the results of this test are equivocal. Colonoscopy and esophagogastroduodenoscopy should be performed to define intestinal anatomy, length, and health of remaining bowel in patients with short gut syndrome.

  • Elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with an ALT:AST ratio ≥1 indicates hepatocellular damage in patients with cirrhosis. Alkaline phosphatase and gamma-GT are elevated in cirrhotic patients with cholestasis. Abdominal ultrasound can be considered to assess liver damage and portal circulation. A liver biopsy may also be helpful.

  • Serum amylase and lipase are elevated in acute pancreatitis. Use serum lipase testing in preference to serum amylase.[46]​ Serum lipase and amylase have similar sensitivity and specificity, but lipase levels remain elevated for longer (up to 14 days after symptom onset vs. 5 days for amylase), providing a higher likelihood of picking up the diagnosis in patients with a delayed presentation.[47]

  • Abdominal CT scan can be performed if chronic pancreatitis is suspected, and reveals characteristic signs. Direct pancreatic function tests can be considered, and show decreased function in chronic pancreatitis.

  • Elevated erythrocyte sedimentation rate may indicate inflammatory bowel disease. Stool testing for fecal occult blood is often positive, and fecal leukocytes are also present. Colonoscopy should be considered, and reveals the characteristic abnormalities and distribution pattern of the underlying cause.

Tests for the rarer causes are only performed if clinical features suggest the diagnosis. These include the following procedures.

  • Upper gastrointestinal endoscopy with or without small bowel biopsy should be considered to diagnose Whipple disease.

  • An elevated serum aldosterone level indicates hyperaldosteronism. Low serum renin activity indicates primary disease, whereas elevated activity indicates secondary disease. CT or MRI of adrenal glands may detect a macroadenoma.

  • A decreased or undetectable PTH level in the presence of hypocalcemia indicates hypoparathyroidism. Vitamin D level should be considered if the alternative diagnosis of vitamin D deficiency is suspected.

  • A decreased thyroid-stimulating hormone (TSH) level with increased serum free T4 indicates hyperthyroidism. Radioactive iodine intake should also be performed; it is elevated in Graves disease, normal in toxic multinodular goiter, and decreased in acute or subacute thyroiditis. Positive TSH-receptor antibodies are diagnostic of Graves disease, but are rarely required for diagnosis.

  • Decreased serum phosphate, in combination with low magnesium and calcium levels, may indicate hungry bone syndrome. Bone biopsy reveals extensive bone remineralization.

  • Decreased serum bicarbonate with elevated serum chloride suggests renal tubular acidosis (RTA). The serum potassium is decreased in proximal and classic distal RTA, but elevated in hyperkalemic distal RTA.

  • Genetic testing reveals the underlying causative mutations of primary renal magnesium wasting.

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