What causes hypophosphatemia (low phosphate levels)?

Causes of Hypophosphatemia

Hypophosphatemia is caused by three primary mechanisms: inadequate intake or intestinal absorption, redistribution from extracellular to intracellular compartments, and excessive renal phosphate wasting. 1

Mechanisms of Hypophosphatemia

1. Inadequate Intake or Intestinal Absorption

• Malnutrition and starvation 2
• Malabsorptive disorders including:
  • Inflammatory bowel disease
  • Celiac disease
  • Post-bariatric surgery 2
• Vitamin D deficiency leading to decreased intestinal phosphate absorption 1
• Chronic use of phosphate binders (aluminum, calcium, or magnesium-containing antacids) 2

2. Redistribution from Extracellular to Intracellular Compartments

• Refeeding syndrome - carbohydrate reintroduction after caloric deprivation causes insulin release, driving phosphate into cells 1
• Diabetic ketoacidosis treatment - insulin administration causes cellular uptake of phosphate 3
• Respiratory alkalosis - hyperventilation shifts phosphate intracellularly 4
• Recovery phase of metabolic acidosis 5
• Hungry bone syndrome after parathyroidectomy 4

3. Excessive Renal Phosphate Wasting

FGF23-Mediated Causes:

• Genetic disorders:
  • X-linked hypophosphatemic rickets (XLH) - most common genetic cause (80% of cases) 1
  • Autosomal dominant hypophosphatemic rickets 1
  • Autosomal recessive hypophosphatemic rickets 1
• Tumor-induced osteomalacia - tumors producing excess FGF23 1
• Iron therapy with intravenous ferric carboxymaltose - causes "6H-syndrome" (high FGF23, hyperphosphaturia, hypophosphataemia, hypovitaminosis D, hypocalcaemia, secondary hyperparathyroidism) 1, 2
• Advanced malignancies (especially prostate and lung cancer) causing ectopic FGF23 syndrome 1
• Alcohol-induced FGF23 syndrome 1

Non-FGF23 Mediated Causes:

• Primary hyperparathyroidism - elevated PTH increases phosphate excretion 4
• Secondary hyperparathyroidism due to vitamin D deficiency 4
• Renal tubular disorders:
  • Fanconi syndrome 1
  • Dent disease 1
  • Hereditary hypophosphatemic rickets with hypercalciuria 1
• Kidney replacement therapy (KRT) - especially continuous or prolonged intermittent KRT modalities 1
  • Prevalence of hypophosphatemia can rise to 80% during prolonged KRT 1

Clinical Severity Classification

Hypophosphatemia is classified by severity 2, 3:

• Mild: 2.0-2.5 mg/dL (0.65-0.81 mmol/L)
• Moderate: 1.0-2.0 mg/dL (0.32-0.65 mmol/L)
• Severe: <1.0 mg/dL (<0.32 mmol/L)

Diagnostic Approach

When evaluating hypophosphatemia, the following approach is recommended:

1. Measure fractional excretion of phosphate (FEP) 4

   • FEP >15% with hypophosphatemia confirms renal phosphate wasting
   • FEP <5% suggests non-renal causes

2. Assess FGF23 levels 1

   • Elevated or inappropriately normal FGF23 with hypophosphatemia suggests FGF23-mediated disorders
   • Low FGF23 suggests primary renal tubular defects

3. Check for metabolic acidosis, hypercalciuria, and other markers of renal tubular dysfunction to rule out Fanconi syndrome 1

4. Consider genetic testing for suspected hereditary disorders, particularly PHEX gene analysis for XLH 1, 2

Clinical Implications

Severe hypophosphatemia can lead to significant complications 4, 3:

• Respiratory muscle weakness and respiratory failure
• Cardiac dysfunction and arrhythmias
• Rhabdomyolysis
• Hemolytic anemia
• Neurological manifestations (confusion, seizures, coma)
• Impaired immune function
• Metabolic encephalopathy

In hospitalized patients, hypophosphatemia is associated with:

• Prolonged mechanical ventilation 1
• Increased risk of cardiac arrhythmias 1
• Extended hospital stays 1
• Overall negative impact on patient outcomes 1

Prevention in High-Risk Settings

For patients undergoing kidney replacement therapy:

• Use dialysis solutions containing phosphate to prevent hypophosphatemia 1
• Monitor electrolytes closely during intensive or prolonged KRT 1

For patients at risk of refeeding syndrome:

• Introduce nutrition gradually with appropriate phosphate supplementation 1
• Monitor phosphate levels frequently during refeeding 2

Understanding these diverse causes of hypophosphatemia is essential for proper diagnosis and management, ultimately improving patient outcomes by preventing the serious complications associated with severe phosphate depletion.