What are the causes of hypomagnesaemia (low serum magnesium levels) in patients with gastrointestinal disorders, renal disease, or those taking medications such as proton pump inhibitors (PPIs) or diuretics?

Etiology of Hypomagnesemia

Primary Mechanisms of Magnesium Loss

Hypomagnesemia results from three fundamental mechanisms: inadequate intake, increased gastrointestinal losses, or increased renal losses, with drug-induced causes (particularly PPIs and diuretics) being increasingly recognized as major contributors. 1, 2

Gastrointestinal Causes

Direct intestinal losses occur through:

• Diarrhea and high-output stomas: Each liter of jejunostomy fluid contains approximately 100 mmol/L sodium along with substantial magnesium, creating significant ongoing losses 3
• Short bowel syndrome: Patients with jejunostomy experience particularly severe magnesium depletion due to reduced intestinal transit time and absorption surface 3, 4
• Malabsorption syndromes: Including inflammatory bowel disease (13-88% prevalence of deficiency) 3, 5
• Inadequate dietary intake: Though less common as an isolated cause 1, 2

A critical but often overlooked mechanism: Volume depletion from GI losses triggers secondary hyperaldosteronism, which paradoxically increases renal magnesium wasting even as the body is depleted—creating a vicious cycle where the more sodium-depleted the patient becomes, the more magnesium is lost through the kidneys 3

Renal Causes

Medication-induced renal wasting represents the most common cause in hospitalized patients:

• Proton pump inhibitors (PPIs): Increasingly recognized as causing hypomagnesemia through unclear mechanisms, likely involving impaired intestinal absorption 4, 2, 6
• Loop diuretics (furosemide): Inhibit sodium chloride transport in the ascending loop of Henle, causing renal magnesium wasting, hypokalemia, metabolic alkalosis, and hypercalciuria 1, 3
• Thiazide diuretics: Inhibit the sodium chloride cotransporter in the distal convoluted tubule, causing similar electrolyte abnormalities but with hypocalciuria instead 1
• Calcineurin inhibitors (cyclosporine, tacrolimus): Cause direct renal tubular magnesium wasting 5, 7
• Other nephrotoxic drugs: Aminoglycosides, amphotericin B, cisplatin 7

Genetic renal disorders:

• Gitelman syndrome: Associated with hypokalemia, metabolic alkalosis, renal magnesium wasting, and hypocalciuria 1
• Bartter syndrome type 3: Requires magnesium supplementation targeting plasma levels >0.6 mmol/L 3, 5
• Familial renal magnesium wasting: Associated with hypercalciuria, nephrocalcinosis, and nephrolithiasis 1

Redistribution and Special Populations

Critically ill patients have hypomagnesemia prevalence of 60-65%, particularly those on continuous renal replacement therapy (CRRT), especially when regional citrate anticoagulation is used (citrate chelates ionized magnesium) 3, 8

Refeeding syndrome: Malnourished patients starting nutrition require magnesium monitoring even for mild deficiency during the first 72 hours 3

Diagnostic Approach to Determine Etiology

The first step is measuring fractional excretion of magnesium (FEMg) and urinary calcium-creatinine ratio 1:

• FEMg <2%: Indicates appropriate renal conservation, suggesting GI losses or inadequate intake 1
• FEMg >2% (with normal renal function): Indicates renal magnesium wasting from medications, genetic disorders, or tubular dysfunction 1

For patients with high GI losses, 24-hour urinary magnesium measurement better reflects total body status than serum levels, as less than 1% of total body magnesium is in blood 3, 5

Urinary calcium helps differentiate renal causes:

• Hypercalciuria: Suggests loop diuretics, Bartter syndrome, or familial renal magnesium wasting 1
• Hypocalciuria: Suggests thiazide diuretics or Gitelman syndrome 1

Critical Clinical Pitfall

Never attempt magnesium correction without first addressing volume depletion in patients with GI losses. Secondary hyperaldosteronism from sodium and water depletion increases renal retention of sodium at the expense of both magnesium and potassium—supplementation will fail as ongoing renal losses exceed replacement 3. Rehydration with IV saline to correct hyperaldosteronism is the crucial first step before any magnesium supplementation 3, 7.

Serum magnesium does not accurately reflect total body stores—normal levels can coexist with significant intracellular depletion, so patients at risk with typical symptoms should be considered for treatment even with normal serum levels 3, 8.