Causes of Hypophosphatemia
Hypophosphatemia results from three primary mechanisms: inadequate intake/absorption, excessive renal losses, and intracellular shifts of phosphate from the extracellular compartment. 1
Primary Mechanisms
1. Inadequate Intake or Intestinal Absorption
- Dietary deficiency combined with phosphate-binding antacids represents one of the most severe forms of phosphate depletion 2
- Malnutrition and starvation deplete phosphate stores, particularly when fasting exceeds 72 hours 3
- Decreased intestinal absorption can occur through various gastrointestinal disorders 1
- Diarrhea contributes through direct intestinal phosphate losses 4
2. Excessive Renal Phosphate Wasting
FGF23-Mediated Disorders (Non-Suppressed FGF23):
- X-linked hypophosphatemia (XLH) accounts for approximately 80% of hereditary hypophosphatemic rickets cases 5
- Autosomal dominant and recessive hypophosphatemic rickets (OMIM#193100, #241520, #613312) 5
- Tumor-induced osteomalacia from FGF23-secreting tumors 5
- Intravenous iron therapy (ferric carboxymaltose or iron isomaltoside) causing "6H-syndrome" (high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcemia, secondary hyperparathyroidism) 5
- Alcohol-induced FGF23 syndrome and ectopic FGF23 syndrome in advanced malignancies (prostate, lung cancer) 5
- Fibrous dysplasia, neurofibromatosis 1, osteoglophonic dysplasia 5
Primary Renal Tubular Defects (Suppressed FGF23):
- Fanconi syndrome including cystinosis, Dent disease, and hereditary hypophosphatemic rickets with hypercalciuria (HHRH) 5
- Vitamin D deficiency causing secondary hyperparathyroidism 1
- Primary hyperparathyroidism with elevated PTH driving renal phosphate wasting 1
Post-Kidney Transplant:
- Hyperphosphaturia occurs in 50-80% of patients within the first 3 months post-transplant, caused by persistent hyperparathyroidism, immunosuppressive drugs, diuretics, and possibly circulating phosphaturic substances 5
3. Intracellular Phosphate Shifts
Refeeding Syndrome:
- Refeeding after prolonged fasting triggers severe hypophosphatemia as phosphate shifts intracellularly when glucose/nutrition is reintroduced 3
- High amino acid dosage in parenteral nutrition creates a refeeding-like syndrome, particularly in preterm infants 5
- Malnourished patients are at highest risk when nutritional rehabilitation begins 5
Metabolic Conditions:
- Diabetic ketoacidosis during treatment with insulin and glucose 6, 7
- Respiratory alkalosis driving intracellular phosphate movement 8, 2
- Alcohol withdrawal in chronic alcoholism 6, 8, 2
High-Risk Clinical Settings
Hospitalized Patients
- Intensive care unit patients have 60-80% prevalence of hypophosphatemia 4
- Kidney replacement therapy (KRT) increases prevalence to 80% during prolonged modalities 4
- Post-surgical patients, particularly after partial hepatectomy 6
- Parenteral nutrition without adequate phosphate supplementation 6, 7
Vulnerable Populations
- Preterm infants with intrauterine growth restriction on parenteral nutrition with inappropriately low phosphate intake 5
- Very low birth weight and small for gestational age infants have high phosphorus needs for growth 5
- Elderly patients with comorbidities and vulnerable homeostasis 3
- Chronic alcoholics with severe, prolonged phosphate depletion 2
Medication-Induced Causes
- Diuretics precipitate hypophosphatemia through renal losses 4
- Immunosuppressive agents post-transplant 5
- Phosphate-binding antacids when combined with inadequate dietary intake 2
Critical Diagnostic Distinction
The key discriminant is FGF23 level: In true hypophosphatemia, FGF23 should be suppressed (low or low-normal range). Non-suppressed FGF23 with hypophosphatemia indicates FGF23-mediated disorders (XLH, tumor-induced osteomalacia, drug-induced), while suppressed FGF23 indicates primary renal tubular defects or inadequate intake 5. Fractional phosphate excretion >15% in the presence of hypophosphatemia confirms renal phosphate wasting 1.