What causes hypophosphatemia (decreased phosphate levels)?

Causes of Hypophosphatemia (Decreased Phosphate Levels)

Hypophosphatemia results from three primary mechanisms: excessive renal phosphate wasting, inadequate intestinal absorption, or transcellular shifts of phosphate into cells. 1, 2

Primary Mechanisms

1. Renal Phosphate Wasting (Most Common Chronic Cause)

FGF23-Mediated Renal Losses:

• X-linked hypophosphatemia (XLH) accounts for approximately 80% of genetic hypophosphatemic disorders, characterized by elevated or inappropriately normal FGF23 levels despite hypophosphatemia 3
• Ferric carboxymaltose (FCM) causes hypophosphatemia in 47-75% of patients through FGF23-mediated hyperphosphaturia, creating the "6H-syndrome" (high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcemia, secondary hyperparathyroidism) 4, 5
• Other genetic causes include autosomal-dominant/recessive hypophosphatemic rickets, DMP1 and ENPP1 mutations, and Raine syndrome 3
• Tumor-induced osteomalacia produces ectopic FGF23 secretion 3

Primary Renal Tubular Defects (Low FGF23):

• Fanconi syndrome causes generalized proximal tubular dysfunction with phosphate, amino acid, glucose, and protein wasting 3
• Cystinosis leads to cysteine accumulation in proximal tubules 3
• Dent disease (CLCN5 mutations) and hereditary hypophosphatemic rickets with hypercalciuria (SLC34A3 mutations) 3
• Iatrogenic proximal tubulopathy from drug toxicity 3

PTH-Mediated Losses:

• Primary hyperparathyroidism causes persistent hyperparathyroidism with ongoing phosphaturia through PTH-mediated renal phosphate loss 5, 6
• Secondary hyperparathyroidism from vitamin D deficiency 6

2. Decreased Intestinal Absorption

• Malabsorptive disorders including inflammatory bowel disease, celiac disease, and bariatric surgery reduce phosphate absorption 5
• Vitamin D deficiency impairs intestinal phosphate absorption 6
• Post-kidney transplant patients experience reduced intestinal phosphorus absorption 5
• Phosphate-binding antacids consumed with phosphate-deficient diets cause severe depletion 7

3. Transcellular Shifts (Acute Hypophosphatemia)

Critical Clinical Settings:

• Refeeding syndrome causes significant phosphate depletion, especially in malnourished patients, as glucose and insulin drive phosphate into cells 1, 5, 2
• Diabetic ketoacidosis treatment with insulin shifts phosphate intracellularly 2, 8
• Respiratory alkalosis from hyperventilation 8
• Post-surgical states, particularly after partial hepatectomy 2

4. Hospital-Acquired Causes

• Kidney replacement therapy (KRT) causes hypophosphatemia in 60-80% of ICU patients, rising to 80% during prolonged continuous renal replacement therapy (CRRT) 1, 5
• Diuretics precipitate hypophosphatemia through urinary losses 1
• Immunosuppressive drugs, particularly post-transplant, cause hypophosphatemia in 5% of kidney transplant patients at 1 year 5
• Diarrhea contributes through intestinal losses 1

5. Other Contributing Factors

• Chronic alcoholism represents one of the most severe phosphate deficiency states through multiple mechanisms: poor intake, increased urinary losses, and transcellular shifts 2, 8, 7
• Malnutrition and starvation reduce phosphate intake 2
• Chronic obstructive pulmonary disease patients are at increased risk 8
• Malignancy-associated hypophosphatemia 8

Key Diagnostic Discriminants

To determine the cause, measure fractional phosphate excretion:

• If >15% in the presence of hypophosphatemia, renal phosphate wasting is confirmed 6
• FGF23 levels are the key discriminant: elevated/normal FGF23 indicates FGF23-mediated losses (XLH, FCM, tumors), while low/suppressed FGF23 indicates primary tubular defects 3
• Serum calcium helps categorize renal wasting: high calcium suggests primary hyperparathyroidism, low calcium suggests secondary hyperparathyroidism, normal calcium suggests primary renal phosphate wasting 6

Critical Pitfalls

• Persistent hypophosphatemia can cause osteomalacia, fractures, rhabdomyolysis, cardiac arrhythmias, respiratory failure, and neurological complications 5
• 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 4, 5
• Always exclude metabolic acidosis, hypercalciuria, and generalized Fanconi syndrome by measuring serum bicarbonate and urinary calcium, amino acids, glucose, and low-molecular-weight proteins 3