What Causes Low Phosphorus (Hypophosphatemia)
Hypophosphatemia results from three primary mechanisms: excessive renal phosphate loss (most common in hospitalized patients), decreased intestinal absorption, or intracellular phosphate shifts—with renal phosphate wasting accounting for the majority of cases, particularly in ICU settings where prevalence reaches 60-80%. 1, 2
Primary Mechanisms
Excessive Renal Phosphate Loss
- Renal phosphate wasting is the most common cause in hospitalized patients, occurring through multiple pathways 2:
- Hyperparathyroidism (both primary and secondary) causes PTH-mediated renal phosphate loss 2
- Vitamin D deficiency leads to secondary hyperparathyroidism and subsequent renal phosphate wasting 2
- FGF23-mediated disorders, including X-linked hypophosphatemia (XLH), account for approximately 80% of hereditary hypophosphatemic rickets cases 1, 2
- Tumor-induced osteomalacia produces ectopic FGF23 secretion, causing phosphaturic syndromes 1
- Fanconi syndrome causes generalized proximal tubular dysfunction with phosphate, amino acid, glucose, and protein wasting 1
Decreased Intestinal Absorption
- Malabsorptive disorders including inflammatory bowel disease, celiac disease, and bariatric surgery reduce phosphate absorption 1
- Inadequate dietary intake, particularly in malnourished patients, creates a chronically phosphate-deficient state 1
- Post-kidney transplant patients experience reduced intestinal phosphorus absorption 1
Intracellular Phosphate Shifts
- Refeeding syndrome is a critical cause where glucose infusion triggers acute insulin release that drives phosphate intracellularly, particularly dangerous in malnourished elderly patients 1, 3
- Parenteral nutrition, especially glucose-containing solutions, can provoke rapid drops in plasma phosphate 1
- Insulin administration in diabetic patients causes intracellular phosphate shifts 1
High-Risk Clinical Settings and Iatrogenic Causes
Hospital-Acquired Hypophosphatemia
- Kidney replacement therapy (KRT) causes hypophosphatemia in 60-80% of ICU patients, rising to 80% during prolonged continuous renal replacement therapy (CRRT) when standard phosphate-free dialysis solutions are used 1, 3, 2
- Diuretics precipitate hypophosphatemia through increased urinary losses 1, 3, 2
- Intravenous iron formulations, particularly ferric carboxymaltose (FCM), cause hypophosphatemia in 47-75% of patients through FGF23-mediated hyperphosphaturia, creating the "6H-syndrome" (high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcemia, secondary hyperparathyroidism) 1, 2
- Immunosuppressive drugs, particularly post-transplant, cause hypophosphatemia in 5% of kidney transplant patients at 1 year 1
Specific Drug-Induced Causes
- Iatrogenic proximal tubulopathy from drug toxicity can cause renal phosphate wasting 1
- Diarrhea contributes through intestinal losses 1, 3
Genetic and Hereditary Causes
- X-linked hypophosphatemia (XLH) accounts for approximately 80% of genetic hypophosphatemic disorders, characterized by elevated or inappropriately normal FGF23 levels despite hypophosphatemia 1
- Dent disease (CLCN5 mutations) and hereditary hypophosphatemic rickets with hypercalciuria (SLC34A3 mutations) are rare genetic causes 1
- Cystinosis leads to cysteine accumulation in proximal tubules causing phosphate wasting 1
High-Risk Patient Populations
- Geriatric patients face compounded risk due to progressive muscle mass loss, osteoporosis, higher rates of malnutrition, and polypharmacy 1
- Severely malnourished patients require stepwise substrate increases with strict electrolyte monitoring to prevent refeeding syndrome 1
- ICU patients have 60-80% prevalence of hypophosphatemia due to multiple contributing factors 3, 2
- Diabetic patients undergoing insulin administration are at risk for intracellular phosphate shifts 1
Critical Pitfalls to Avoid
- FCM-induced hypophosphatemia can persist up to 6 months and cause osteomalacia with repeated use—avoid in patients with recurrent blood loss or malabsorptive disorders, and if unavoidable, provide phosphate supplementation before and after iron infusion with close monitoring 1, 2
- Persistent hypophosphatemia unresponsive to supplements should raise suspicion for tumor-induced osteomalacia or other underlying FGF23-mediated disorders 2
- Never ignore persistent hypophosphatemia, as it can cause osteomalacia, fractures, rhabdomyolysis, cardiac arrhythmias, respiratory failure requiring prolonged mechanical ventilation, and neurological complications 1, 2
- Always exclude metabolic acidosis, hypercalciuria, and generalized Fanconi syndrome by measuring serum bicarbonate and urinary calcium, amino acids, glucose, and low-molecular-weight proteins 1
- During continuous renal replacement therapy, proactive supplementation with phosphate-containing dialysis solutions prevents the 60-80% incidence of hypophosphatemia 2