Magnesium deficiency is a state of decreased total body magnesium content. Only 1% of the total body magnesium 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 <0.9 mmol/L (<1.8 mEq/L) is termed hypomagnesaemia.
Patients with abnormalities of magnesium homoeostasis typically fall into one of three groups:
Patients with magnesium deficiency (low total body magnesium content) and a resultant hypomagnesaemia (low serum magnesium concentration)
Patients with hypomagnesaemia (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 hypomagnesaemia (i.e., a normal serum magnesium concentration).
Magnesium deficiency should be suspected in patients with a relevant chronic disease causing abnormalities in magnesium homoeostasis, symptoms of magnesium deficiency, or persistent associated electrolyte abnormalities such as hypocalcaemia or hypokalaemia. However, often it may only be detected following a blood test.
Clinical features of magnesium deficiency and/or hypomagnesaemia
Most patients with mild magnesium deficiency and/or hypomagnesaemia are asymptomatic. Although symptoms tend to appear once the serum magnesium falls below 0.5 mmol/L (1 mEq/L), there is no direct correlation between serum magnesium and the severity of the symptoms.
The symptoms are non-specific and include:
Neuromuscular irritability similar to that produced by hypocalcaemia, manifesting with extensor plantar reflexes, positive Trusseau's and Chvostek's signs, and, in severe cases, tetany; hypoparathyroidism should be considered if these signs are present
Cardiovascular features such as rapid heartbeats and an increased blood pressure, tachycardia, and/or ventricular arrhythmias
CNS symptoms of vertigo, ataxia, depression, and seizure activity.
Elucidating the cause
General inspection may reveal signs of generalised malnutrition, including loss of subcutaneous fat, apathy and lethargy, pallor, depigmentation, enlarged abdomen, winged scapula, flaky skin, and bipedal oedema. 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 coeliac disease or short gut syndrome. Both conditions may also present with symptoms and signs of associated vitamin deficiencies or chronic diarrhoea. A skin rash consistent with dermatitis herpetiformis suggests coeliac disease. A history of extensive bowel resection, abdominal radiation injury, or gastroschisis suggests short gut syndrome.
Should prompt suspicion as the cause of magnesium deficiency, due to increased magnesium demand and volume status. Pre-eclampsia should also be considered and excluded. Seizures in a pregnant woman should prompt suspicion of eclampsia.
Diarrhoea results in gastrointestinal magnesium loss. Causes to consider include gastroenteritis, inflammatory bowel disease, and Whipple's disease. Tenesmus should prompt suspicion of inflammatory bowel disease. A travel history should be obtained to assess traveller's diarrhoea. 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, steatorrhoea, 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 hypomagnesaemia. 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 post-obstructive diuresis.
Signs of hypervolaemia
These include jugular venous distension and peripheral oedema, and may indicate hyperaldosteronism, cirrhosis, or obstructive uropathy.
Hypervolaemia, polyuria, and polydipsia in association with paraesthesia, 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.
A history of increased appetite, weight loss, heat intolerance, and hair loss should prompt suspicion of hyperthyroidism. Examination may reveal a fine tremor, goitre, 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's syndrome. Associated growth and developmental delay, with or without sensorineural deafness, should prompt suspicion of Bartter's syndrome.
Assessment of serum magnesium level can be routinely conducted in medical clinical laboratories. However, there is no simple, rapid, and accurate laboratory test to determine total body magnesium status in humans. Hypomagnesaemia is generally defined as a serum magnesium <0.9 mmol/L (<1.8 mEq/L).
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.
Serum calcium, potassium, and sodium
Abnormalities in magnesium homoeostasis may co-exist with other electrolyte abnormalities. Magnesium deficiency and hypomagnesaemia should be considered as causes of hypocalcaemia or refractory hypokalaemia.
Symptoms of hypomagnesaemia and hypocalcaemia are similar, and the two abnormalities may co-exist. Calcium competes with magnesium for uptake in the loop of Henle, and an increase in the filtered calcium load can impair magnesium reabsorption. Hypomagnesaemia, in turn, leads to parathyroid hormone (PTH) resistance and a decrease in PTH secretion, both of which result in hypocalcaemia.
Hypokalaemia is commonly seen in patients with hypomagnesaemia, partly because the associated underlying disorders can produce both these disturbances. However, there is also evidence that hypomagnesaemia can lead to increased renal potassium wasting.
Hypernatraemia 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.
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 hypocalcaemia or hypokalaemia and a history consistent with magnesium loss. 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.
Therapeutic trial of magnesium supplementation
All patients require an ECG to search for characteristic changes associated with hypomagnesaemia. These include widening of the QRS complex, prolonged QT interval, peaked or diminished T waves, and prolonged PR interval. 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 hypomagnesaemia.
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 infective diarrhoea due to a non-viral cause. The underlying organism may be detected in bacterial infection, and parasites or ova may be detected in parasitic infections.
Serum urea and creatinine may be elevated in patients with renal disease. A urea: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 pre-eclampsia.
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 mmol/L (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 elevated INR suggests vitamin K deficiency. An immunoglobulin A-tissue transglutaminase (IgA-tTG) test should be performed if coeliac disease is suspected. A small bowel biopsy can be performed if the results of this test are equivocal. Colonoscopy and oesophagogastroduodenoscopy 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. Abdominal computed tomographic (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 faecal occult blood is often positive, and faecal 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's disease.
An elevated serum aldosterone level indicates hyperaldosteronism. Low serum renin activity indicates primary disease, whereas increased activity indicates secondary disease. CT or magnetic resonance imaging (MRI) of adrenal glands may detect a macroadenoma.
A decreased or undetectable PTH level in the presence of hypocalcaemia 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 elevated serum free T4 indicates hyperthyroidism. Radioactive iodine intake should also be performed; it is elevated in Graves' disease, normal in toxic multinodular goitre, 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 remineralisation.
Decreased serum bicarbonate with increased serum chloride suggests renal tubular acidosis (RTA). The serum potassium is decreased in proximal and classic distal RTA, but increased in hyperkalaemic distal RTA.
Genetic testing reveals the underlying causative mutations of primary renal magnesium wasting.
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