What are the causes and treatments of hypophosphatemia?

Causes and Treatment of Hypophosphatemia

Hypophosphatemia is primarily caused by renal phosphate wasting, inadequate intake, decreased intestinal absorption, or intracellular shifting of phosphate, and should be treated with oral phosphate supplements combined with active vitamin D (calcitriol) for most cases, while reserving intravenous phosphate for severe, symptomatic cases.

Classification of Hypophosphatemia

Hypophosphatemia is classified by severity as:

• Mild: phosphate level < LLN - 2.5 mg/dL
• Moderate: 2.0 - 2.5 mg/dL
• Severe: 1.0 - 2.0 mg/dL
• Life-threatening: < 1.0 mg/dL 1

Causes of Hypophosphatemia

1. Renal Phosphate Wasting

• X-linked hypophosphatemia (XLH): Most common form (~80% of all hypophosphatemic rickets), caused by inactivating mutations in PHEX gene 2
• Other genetic disorders: Autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria (HHRH) 2
• Tumor-induced osteomalacia: Caused by tumors producing excess FGF23 2
• Medication-induced: Ferric carboxymaltose (FCM) treatment can cause severe and prolonged hypophosphatemia (47-75% incidence) 2
• Renal tubular disorders: Fanconi syndrome with acidosis, glucosuria, aminoaciduria, and low molecular mass proteinuria 2

2. Inadequate Intake or Absorption

• Malabsorptive disorders: Bariatric surgery, inflammatory bowel disease, celiac disease 2
• Nutritional deficiency: Dietary phosphate deficiency or impaired bioavailability 2
• Vitamin D deficiency: Leading to decreased intestinal phosphate absorption 3

3. Intracellular Shifting

• Acute conditions: Refeeding syndrome, diabetic ketoacidosis, sepsis, alkalosis 3, 4
• Alcoholism: Common cause of hypophosphatemia in hospitalized patients 4

4. Other Causes

• Hyperparathyroidism: Causing increased renal phosphate excretion 3
• Recurrent blood loss: Leading to increased erythropoiesis and cellular phosphate uptake 2

Clinical Presentation

Symptoms correlate with severity:

• Mild/Moderate: Often asymptomatic or nonspecific symptoms like fatigue
• Moderate/Severe: Proximal muscle weakness, bone pain, myalgia 2
• Severe: Skeletal muscle weakness, myocardial dysfunction, rhabdomyolysis, altered mental status, respiratory failure 3, 5

Diagnostic Approach

1. Measure fractional phosphate excretion: If >15% with hypophosphatemia, confirms renal phosphate wasting 3
2. Categorize based on serum calcium:
   • High calcium: Consider primary hyperparathyroidism
   • Low calcium: Consider secondary hyperparathyroidism
   • Normal calcium: Consider primary renal phosphate wasting 3
3. Genetic testing: For suspected XLH, PHEX gene analysis should be performed 2
4. FGF23 levels: Elevated in XLH and tumor-induced osteomalacia 2

Treatment Approach

General Principles

• Treatment goal is to improve symptoms and prevent complications rather than normalize serum phosphate levels 1
• Identify and treat the underlying cause whenever possible 3

Specific Treatments

1. Mild to Moderate Hypophosphatemia:

   • Oral phosphate supplements (sodium or potassium phosphate) 1, 6, 7
   • Combine with active vitamin D (calcitriol) to enhance intestinal absorption 1
   • Avoid taking with calcium-rich foods which impair absorption 1

2. Severe or Symptomatic Hypophosphatemia:

   • Intravenous phosphate at 0.16 mmol/kg administered at a rate of 1-3 mmol/h until level reaches 2 mg/dL 3
   • Monitor serum phosphate, calcium, potassium, and renal function during replacement 1

3. Specific Conditions:

   • XLH: Long-term oral phosphate and calcitriol; consider burosumab (FGF23 antibody) particularly in children 2, 1
   • Tumor-induced osteomalacia: Surgical removal of the tumor when possible 8
   • FCM-induced hypophosphatemia: Consider alternative iron formulations in high-risk patients 2
   • Total parenteral nutrition: Include 12-15 mM phosphorus per 250g of dextrose 6, 7

Monitoring and Follow-up

• Check serum phosphorus, calcium, and other electrolytes within 24 hours of initiating therapy 1
• Continue monitoring every 1-2 days until stable, then weekly until normalized 1
• For chronic disorders like XLH, regular follow-up every 3-6 months 1

Complications and Cautions

• Excessive phosphate supplementation can cause hyperphosphatemia, hypocalcemia, and nephrocalcinosis 1
• Use phosphate supplements cautiously in patients with chronic kidney disease 1
• Monitor for secondary hyperparathyroidism during treatment 1
• FCM should be avoided in patients with recurrent blood loss or malabsorptive disorders due to risk of severe hypophosphatemia 2

By identifying the underlying cause and implementing appropriate treatment strategies, hypophosphatemia can be effectively managed to prevent serious complications and improve patient outcomes.