What causes chronically low magnesium levels?

Causes of Chronically Low Magnesium

Chronically low magnesium results from three primary mechanisms: inadequate intake, excessive gastrointestinal losses, or excessive renal losses—with the most common causes being gastrointestinal malabsorption (particularly short bowel syndrome and chronic diarrhea), medication-induced renal wasting (especially diuretics and proton pump inhibitors), and alcohol use disorder. 1, 2, 3

Gastrointestinal Causes

Malabsorption Syndromes

• Short bowel syndrome, particularly in patients with jejunostomy, causes the most severe and intractable magnesium losses through direct loss in intestinal fluid (which contains approximately 100 mmol/L of magnesium) combined with reduced absorption time. 2, 3
• Chronic diarrhea and steatorrhea lead to both direct magnesium loss and reduced intestinal transit time, which impairs absorption since magnesium is best absorbed when intestinal transit is slowest. 2, 4
• Inflammatory bowel disease causes magnesium deficiency in 13-88% of patients through a combination of malabsorption, increased losses, and reduced intake. 2
• Continuous nasogastric suctioning, bowel fistulas, and chronic vomiting result in direct magnesium depletion. 4

Inadequate Intake

• Protein-calorie malnutrition and prolonged starvation deplete magnesium stores over weeks to months. 5, 4
• Intravenous fluid administration without magnesium supplementation or total parenteral nutrition with inadequate magnesium content causes iatrogenic deficiency. 4
• Alcohol use disorder combines multiple mechanisms: poor dietary intake, increased gastrointestinal losses, and direct renal magnesium wasting. 1, 4

Renal Causes

Medication-Induced Renal Wasting

• Loop diuretics (furosemide) and thiazide diuretics are the most common medication causes, inhibiting magnesium reabsorption in the thick ascending limb and distal convoluted tubule respectively. 6, 4
• Proton pump inhibitors cause renal magnesium wasting through mechanisms that remain incompletely understood. 7
• Aminoglycosides (particularly gentamicin), cisplatin, cetuximab, pentamidine, and foscarnet directly damage renal tubular magnesium handling. 3, 4
• Immunosuppressants used in transplant patients cause chronic magnesium wasting. 3

Genetic Renal Disorders

• Gitelman syndrome presents with hypokalemia, metabolic alkalosis, renal magnesium wasting, hypomagnesemia, and hypocalciuria (distinguishing it from Bartter syndrome). 6
• Bartter syndrome presents with hypokalemia, metabolic alkalosis, renal magnesium wasting, hypomagnesemia, and hypercalciuria. 6
• Familial renal magnesium wasting syndromes are associated with hypercalciuria, nephrocalcinosis, and nephrolithiasis. 6

Secondary Hyperaldosteronism

• Volume depletion from any cause triggers secondary hyperaldosteronism, which increases renal retention of sodium at the expense of both magnesium and potassium, creating a vicious cycle where ongoing sodium depletion perpetuates magnesium wasting. 2, 7
• This mechanism is particularly important in patients with high-output stomas, chronic diarrhea, or diuretic use. 2

Critical Illness and Iatrogenic Causes

• Continuous renal replacement therapy causes hypomagnesemia in 60-65% of critically ill patients, with the risk substantially increased when regional citrate anticoagulation is used (citrate chelates ionized magnesium). 2, 3, 7
• Post-obstructive diuresis, post-acute tubular necrosis recovery, and the early post-renal transplant period all cause transient renal magnesium wasting. 4

Endocrine and Metabolic Causes

• Diabetes mellitus causes magnesium deficiency through osmotic diuresis (hyperglycemia increases renal magnesium losses) combined with reduced intake and gastrointestinal dysfunction. 4
• Primary hyperaldosteronism directly increases renal magnesium excretion. 3
• 22q11.2 deletion syndrome is associated with hypoparathyroidism and chronic hypomagnesemia. 2, 3

Diagnostic Approach to Determine the Cause

Step 1: Calculate Fractional Excretion of Magnesium

• Fractional excretion of magnesium <2% indicates appropriate renal conservation and points to gastrointestinal losses or inadequate intake as the cause. 6
• Fractional excretion >2% in a patient with normal kidney function indicates renal magnesium wasting (medications, genetic disorders, or endocrine causes). 6

Step 2: Measure Urinary Calcium-Creatinine Ratio

• Hypercalciuria with renal magnesium wasting suggests Bartter syndrome, loop diuretics, or familial renal magnesium wasting. 6
• Hypocalciuria with renal magnesium wasting suggests Gitelman syndrome or thiazide diuretics. 6

Step 3: Review Medication History

• Systematically review for diuretics, proton pump inhibitors, aminoglycosides, chemotherapy agents, and immunosuppressants. 3, 4

Step 4: Assess for Volume Depletion

• Check for signs of sodium and water depletion that would trigger secondary hyperaldosteronism (orthostatic hypotension, elevated BUN/creatinine ratio, concentrated urine). 2

Critical Clinical Pitfalls

• Serum magnesium levels do not accurately reflect total body magnesium status, as less than 1% of total body magnesium is found in the blood—patients can have severe intracellular depletion with normal serum levels. 2, 3
• Hypomagnesemia causes refractory hypokalemia and hypocalcemia that will not correct until magnesium is repleted, as magnesium deficiency impairs multiple potassium transport systems and parathyroid hormone secretion. 3, 7, 6
• Attempting to correct magnesium without first addressing volume depletion and secondary hyperaldosteronism will fail, as ongoing renal losses will exceed supplementation. 2
• Most magnesium salts are poorly absorbed and may paradoxically worsen diarrhea, perpetuating the deficiency. 2