What are the common causes of hypophosphatemia (low serum phosphorus)?

Common Causes of Hypophosphatemia

Hypophosphatemia results from three primary mechanisms: increased renal phosphate excretion, decreased intestinal absorption, and transcellular shifts from extracellular to intracellular compartments. 1, 2

Mechanism-Based Classification

Increased Renal Phosphate Wasting

This is the most clinically significant category and requires measurement of fractional phosphate excretion (>15% confirms renal wasting). 1

FGF23-Mediated Causes (Non-Suppressed FGF23)

• X-linked hypophosphatemia (XLH): The most common genetic cause, accounting for approximately 80% of FGF23-mediated cases, characterized by elevated or inappropriately normal FGF23 levels despite hypophosphatemia 3
• Intravenous iron therapy: Ferric carboxymaltose (FCM) causes the "6H-syndrome" (high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcemia, secondary hyperparathyroidism) with incidence of 47-75% following FCM administration 3
• Tumor-induced osteomalacia: Ectopic FGF23 production from mesenchymal tumors 3
• Alcohol-induced FGF23 syndrome: Acquired form in chronic alcohol use 3
• Malignancy-associated: Ectopic FGF23 syndrome in advanced prostate or lung cancer 3
• Other genetic disorders: Autosomal-dominant/recessive hypophosphatemic rickets, fibrous dysplasia, neurofibromatosis 1 3

Non-FGF23-Mediated Renal Wasting (Suppressed FGF23)

• Primary hyperparathyroidism: High serum calcium with elevated PTH 1
• Secondary hyperparathyroidism: Low serum calcium (vitamin D deficiency) with elevated PTH 1
• Fanconi syndrome: Non-selective proximal tubular dysfunction with losses of bicarbonate, amino acids, glucose, and low-molecular-weight proteins 3
• Dent disease, cystinosis, hereditary hypophosphatemic rickets with hypercalciuria: Genetic tubular disorders 3
• Diuretics: Precipitate renal phosphate losses 4

Decreased Intestinal Absorption

• Inadequate dietary intake: Particularly in malnourished patients 1, 2
• Malabsorption syndromes: Inflammatory bowel disease, celiac disease, bariatric surgery 3
• Elemental formula use: Impaired phosphate bioavailability documented in infants/children on amino acid-based formulas (Neocate®), causing rickets and fractures 5
• Vitamin D deficiency: Impairs intestinal phosphate absorption 1

Transcellular Shifts (Extracellular to Intracellular)

• Refeeding syndrome: Most critical cause—rapid phosphate shift when nutrition (especially glucose) is reintroduced after prolonged fasting (>72 hours), with prevalence particularly high in malnourished, elderly, and alcoholic patients 4, 6
• Respiratory alkalosis: Drives phosphate intracellularly 1, 2
• Insulin therapy: Promotes cellular phosphate uptake 2
• Hungry bone syndrome: Post-parathyroidectomy 2

High-Risk Clinical Settings

Hospitalized Patients

• ICU patients: 60-80% prevalence, associated with prolonged mechanical ventilation, respiratory failure, cardiac arrhythmias 4
• Kidney replacement therapy: Prevalence rises to 80% during prolonged KRT modalities 4
• Diarrhea: Contributes through intestinal losses 4

Vulnerable Populations

• Recurrent blood loss: Abnormal uterine bleeding, hereditary hemorrhagic telangiectasia, GI bleeding requiring repeat iron infusions (especially FCM) 3
• Chronic alcoholics: Multiple mechanisms including poor intake, malabsorption, and alcohol-induced FGF23 syndrome 3, 6
• Elderly patients: More vulnerable to electrolyte disturbances and complications 6

Diagnostic Approach

Calculate fractional phosphate excretion or TmP/GFR to distinguish renal from non-renal causes. 3, 1

Key Discriminating Tests

• FGF23 levels: Distinguish FGF23-mediated (elevated/normal) from primary tubular defects (suppressed) 3
• Serum calcium and PTH: Categorize renal wasting into hyperparathyroid (high calcium), vitamin D deficiency (low calcium), or primary renal wasting (normal calcium) 1
• Urinary losses: Check calcium, amino acids, glucose, bicarbonate, low-molecular-weight proteins to exclude Fanconi syndrome 3
• Medication history: Critical for identifying IV iron (especially FCM), diuretics 3, 4

Critical Pitfalls

• FCM-induced hypophosphatemia: Can be severe, prolonged (up to 6 months), and cause osteomalacia/fractures with repeat dosing—avoid FCM in patients with recurrent blood loss or malabsorptive disorders requiring repeat infusions 3
• Refeeding syndrome: Requires prophylactic phosphate monitoring and supplementation when refeeding malnourished patients, with stepwise glucose introduction 6
• Normal phosphate in infants: Serum phosphate may be normal in first 3-4 months of life despite XLH 3
• Elemental formula: Monitor mineral metabolism carefully in children on amino acid-based formulas 5