What is hypophosphatemia?

Hypophosphatemia: Definition, Diagnosis, and Management

Hypophosphatemia is defined as serum phosphate levels below the age-related reference range, typically less than 2.5 mg/dL (0.8 mmol/L) in adults, and is classified into four categories: mild (<2.5 mg/dL), moderate (2.0-2.5 mg/dL), severe (1.0-2.0 mg/dL), and life-threatening (<1.0 mg/dL). 1

Pathophysiology and Causes

Hypophosphatemia results from three main mechanisms:

1. Inadequate intake or decreased intestinal absorption

   • Malnutrition
   • Alcoholism
   • Vitamin D deficiency
   • Antacid use (phosphate binding)

2. Increased urinary excretion

   • Genetic disorders (X-linked hypophosphatemic rickets)
   • Acquired renal disorders
   • Hyperparathyroidism
   • Oncogenic osteomalacia
   • Fanconi syndrome

3. Intracellular shift of phosphate

   • Refeeding syndrome
   • Diabetic ketoacidosis
   • Respiratory alkalosis
   • IV iron therapy (particularly ferric carboxymaltose)

Clinical Manifestations

Most patients with mild hypophosphatemia are asymptomatic. However, severe hypophosphatemia can cause significant morbidity and mortality:

• Neuromuscular: Muscle weakness, altered mental status, seizures, delirium
• Cardiovascular: Cardiac dysfunction, arrhythmias
• Respiratory: Respiratory muscle weakness, respiratory failure
• Hematologic: Impaired red blood cell function, hemolysis
• Musculoskeletal: Rhabdomyolysis, bone pain, osteomalacia (chronic)

Diagnostic Approach

When hypophosphatemia is identified:

1. Measure fractional phosphate excretion:

   • 15% in the presence of hypophosphatemia confirms renal phosphate wasting 2

2. Evaluate serum calcium levels to categorize renal phosphate wasting:

   • High calcium: Primary hyperparathyroidism
   • Low calcium: Secondary hyperparathyroidism
   • Normal calcium: Primary renal phosphate wasting

3. Additional testing to identify underlying causes:

   • Serum bicarbonate, urinary calcium
   • Urinary amino acids, glucose, and low-molecular-weight proteins (for Fanconi syndrome)
   • PTH and vitamin D levels
   • Assessment for refeeding syndrome risk factors

Management

Treatment approach depends on severity, symptoms, and underlying cause:

Mild Asymptomatic Hypophosphatemia

• Observation with monitoring of serum phosphate levels
• Address underlying causes

Moderate to Severe or Symptomatic Hypophosphatemia

1. Oral Supplementation (preferred for most cases):

   • 750-1,600 mg elemental phosphorus daily in 2-4 divided doses 1
   • Potassium phosphates are preferred except in patients with renal impairment, hyperkalemia, or those taking potassium-sparing medications

2. Intravenous Supplementation (for severe cases <1.0 mg/dL or symptomatic patients):

   • 0.16 mmol/kg administered at 1-3 mmol/hour until level reaches 2 mg/dL 2
   • Close monitoring for complications (hypocalcemia, hyperkalemia, nephrocalcinosis)

3. Specific Situations:

   • Refeeding Syndrome: Gradual reintroduction of nutrition with phosphate supplementation and close electrolyte monitoring, especially in first 72 hours 3
   • IV Iron-Induced: Cessation of ferric carboxymaltose and treatment of secondary hyperparathyroidism with vitamin D supplementation 1
   • Chronic Hypophosphatemia: Oral phosphate supplements plus active vitamin D (calcitriol 0.50-0.75 μg daily or alfacalcidol 0.75-1.5 μg daily) 1

Prevention of Complications

• Monitor for life-threatening complications in severe cases (respiratory failure, cardiac dysfunction)
• Ensure adequate calcium intake (minimum 1g daily) and recommend low-sodium diet to reduce calciuria
• Correct vitamin D deficiency if present
• For patients on long-term nutritional supplementation, laboratory monitoring every 6 months is recommended 3

Special Considerations

• Phosphate supplementation may paradoxically worsen hypophosphatemia in some cases by raising PTH levels and increasing phosphaturia 1
• Target phosphorus levels: 2.5-4.5 mg/dL (0.81-1.45 mmol/L) for adults 1
• Phospha 250™ Neutral is an FDA-approved medical food for the dietary management of hypophosphatemia, but should only be used under medical supervision 4

Early recognition and appropriate management of hypophosphatemia are essential to prevent potentially life-threatening complications, particularly in hospitalized and critically ill patients where the prevalence can be significantly higher.