What is hypophosphatemia?

Hypophosphatemia: Definition, Causes, and Clinical Implications

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. 1, 2 It can be classified based on severity as mild (2.0-2.5 mg/dL), moderate (1.0-2.0 mg/dL), or severe (<1.0 mg/dL), with each level carrying increasing risk of clinical complications 3.

Pathophysiology and Mechanisms

Hypophosphatemia occurs through three main mechanisms:

1. Decreased intestinal absorption

   • Inadequate dietary intake
   • Malabsorption syndromes
   • Vitamin D deficiency
   • Use of phosphate binders (antacids)

2. Increased renal excretion (renal phosphate wasting)

   • FGF23-mediated disorders (most common genetic cause)
   • Primary or secondary hyperparathyroidism
   • Renal tubular defects
   • Medication-induced (diuretics, steroids)

3. Intracellular shift of phosphate

   • Refeeding syndrome
   • Diabetic ketoacidosis treatment
   • Respiratory alkalosis
   • Hungry bone syndrome

Clinical Manifestations

Most patients with mild hypophosphatemia are asymptomatic. However, moderate to severe hypophosphatemia can lead to:

• Musculoskeletal system: Muscle weakness, rhabdomyolysis, osteomalacia, rickets in children
• Cardiovascular system: Decreased cardiac contractility, arrhythmias, heart failure
• Respiratory system: Respiratory muscle weakness, respiratory failure
• Neurological system: Altered mental status, seizures, coma
• Hematological system: Hemolysis, impaired leukocyte function
• Metabolic effects: Insulin resistance, metabolic acidosis

Diagnostic Approach

When hypophosphatemia is detected, a systematic approach should be followed:

1. Confirm true hypophosphatemia and determine severity

2. Calculate fractional excretion of phosphate (FEP) or tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR)

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

3. Evaluate calcium status to categorize renal phosphate wasting:

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

4. Measure FGF23 levels (if available)

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

5. Rule out other causes:

   • Measure serum bicarbonate, urinary calcium, amino acids, glucose, and low-molecular-weight protein markers to exclude metabolic acidosis, hypercalciuria, and renal Fanconi syndrome 1

Common Clinical Scenarios

X-linked Hypophosphatemia (XLH)

• Most common genetic cause of hypophosphatemia (80% of genetic cases) 1
• Characterized by PHEX gene mutations leading to elevated FGF23 levels
• Clinical features include rickets, lower limb deformities, dental abnormalities, and growth failure in children
• In adults: osteomalacia, pseudofractures, early osteoarthritis, spinal degeneration, and enthesopathies 1

Refeeding Syndrome

• Occurs when nutrition is reintroduced too aggressively after a period of malnutrition
• Characterized by hypophosphatemia, hypokalemia, and hypomagnesemia
• Risk factors: BMI <16 kg/m², >15% weight loss in 3-6 months, little/no intake for >10 days 1
• Can lead to cardiac arrhythmias, respiratory failure, and neurological complications

Medication-Induced Hypophosphatemia

• Intravenous iron therapy (especially ferric carboxymaltose) can cause "6H-syndrome": high FGF23, hyperphosphaturia, hypophosphatemia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism 1
• Other medications: antacids, diuretics, steroids 4

Tumor-Induced Osteomalacia

• Rare paraneoplastic syndrome caused by tumors secreting FGF23
• Most commonly seen with prostate cancer and lung cancer 1

Management Approach

Treatment depends on severity, underlying cause, and presence of symptoms:

Mild to Moderate Hypophosphatemia (1.0-2.5 mg/dL)

• Oral phosphate supplementation: 750-1,600 mg elemental phosphorus daily in 2-4 divided doses 3
• Monitor for side effects: Diarrhea, abdominal discomfort, hypocalcemia

Severe Hypophosphatemia (<1.0 mg/dL)

• Intravenous phosphate: 0.16 mmol/kg administered at 1-3 mmol/hour until level reaches 2 mg/dL 2
• Close monitoring: Check phosphate levels within 24 hours of initiating therapy and every 1-2 days until stable 3
• Monitor for complications: Hypocalcemia, hyperkalemia, nephrocalcinosis

For X-linked Hypophosphatemia

• Burosumab (anti-FGF23 antibody): First-line treatment in children with XLH 3
• Conventional therapy: Oral phosphate (20-60 mg/kg/day) and active vitamin D (calcitriol 0.50-0.75 μg daily or alfacalcidol 0.75-1.5 μg daily) 3

For Refeeding Syndrome

• Gradual reintroduction of nutrition with appropriate phosphate supplementation
• Close monitoring of electrolytes, especially within the first 72 hours 1

Important Clinical Pitfalls

1. Failure to recognize refeeding syndrome risk: Always assess risk in malnourished patients before aggressive nutritional support

2. Overzealous phosphate replacement: Can cause severe hypocalcemia and hyperphosphatemia

3. Inadequate monitoring: Phosphate levels should be checked within 24 hours of initiating therapy and regularly thereafter

4. Missing underlying causes: Always investigate the root cause of hypophosphatemia rather than simply correcting the level

5. Ignoring other electrolyte abnormalities: Hypophosphatemia often coexists with other electrolyte disorders, particularly in refeeding syndrome

6. Delayed treatment of severe hypophosphatemia: Can lead to life-threatening complications including respiratory failure, cardiac dysfunction, and altered mental status

By understanding the mechanisms, clinical implications, and appropriate management of hypophosphatemia, clinicians can effectively address this common electrolyte disorder and prevent its potentially serious consequences.