🔻 Hypophosphatemia

Comprehensive Guide to Diagnosis and Management

🔬 Calcium-Phosphate Homeostasis Overview

Understanding the System: Hypophosphatemia results from decreased intestinal absorption, increased renal losses (via PTH or FGF23), or intracellular shifts. The kidneys (red) reabsorb 85-90% of filtered phosphate. FGF23 disorders cause severe phosphate wasting and rickets/osteomalacia.

🚨 EMERGENCY PROTOCOL: Severe Hypophosphatemia (<1.0 mg/dL)

1 IV Phosphate: 0.08-0.16 mmol/kg over 6 hours (max 0.24 mmol/kg)
2 Monitor Closely: Check PO₄, Ca, K, Mg q4-6h
3 Watch for Complications: Hypocalcemia, hyperkalemia, renal failure
4 Correct Other Electrolytes: K⁺, Mg²⁺ often low
5 Respiratory Support: Monitor for muscle weakness

⚠️ Critical Manifestations: Respiratory failure, rhabdomyolysis, hemolytic anemia, cardiac dysfunction!

📊 Clinical Presentation by Severity

Mild (2.0-2.5 mg/dL)

  • Usually asymptomatic
  • Mild fatigue
  • Bone pain (chronic)

Moderate (1.0-2.0 mg/dL)

  • Weakness, myalgias
  • Impaired leukocyte function
  • Paresthesias
  • Confusion

Severe (<1.0 mg/dL)

  • Respiratory failure
  • Rhabdomyolysis
  • Hemolytic anemia
  • Seizures, coma
  • Heart failure

🔬 Clinical Manifestations

🫁 Respiratory

  • Diaphragm weakness
  • Respiratory failure
  • Difficulty weaning ventilator

💪 Muscular

  • Proximal myopathy
  • Rhabdomyolysis
  • Dysphagia

🩸 Hematologic

  • Hemolytic anemia
  • ↓2,3-DPG (↓O₂ delivery)
  • Impaired WBC function
  • Platelet dysfunction

🦴 Skeletal

  • Osteomalacia (adults)
  • Rickets (children)
  • Bone pain
  • Fractures

🧠 Neurologic

  • Confusion, irritability
  • Paresthesias
  • Seizures (rare)
  • Metabolic encephalopathy

❤️ Cardiac

  • Cardiomyopathy
  • Heart failure
  • Arrhythmias

🔍 Etiology and Pathophysiology

📉 Decreased Absorption

  • Malnutrition/Alcoholism (most common)
  • Malabsorption syndromes
  • Chronic diarrhea
  • Vitamin D deficiency
  • Phosphate binders (excessive)
  • Antacids (aluminum, magnesium)

🚰 Increased Renal Losses

  • Primary hyperparathyroidism
  • FGF23 disorders (XLH, TIO)
  • Fanconi syndrome
  • Post-kidney transplant
  • Volume expansion
  • Diuretics
  • Glucocorticoids

➡️ Intracellular Shifts

  • Refeeding syndrome
  • Insulin administration
  • Respiratory alkalosis
  • Hungry bone syndrome
  • Rapid cell proliferation
  • Treatment of DKA

⚠️ REFEEDING SYNDROME - High Risk Patients

Risk Factors:

  • BMI <16 kg/m²
  • Weight loss >15% in 3-6 months
  • Little/no intake for >10 days
  • Low baseline K⁺, PO₄, or Mg²⁺
  • Chronic alcoholism
  • Anorexia nervosa

Prevention Protocol:

  • Start feeding at 10-20 kcal/kg/day
  • Increase slowly over 4-7 days
  • Thiamine 200-300 mg daily BEFORE feeding
  • Monitor PO₄, K⁺, Mg²⁺ daily × 1 week
  • Supplement prophylactically

🧬 FGF23-Mediated Disorders

X-Linked Hypophosphatemia (XLH)

  • PHEX gene mutation
  • ↑FGF23 → renal PO₄ wasting
  • Rickets, short stature, bone deformities
  • Dental abscesses
  • Treatment: Burosumab (anti-FGF23 antibody)

Tumor-Induced Osteomalacia (TIO)

  • Mesenchymal tumors secrete FGF23
  • Severe muscle weakness, bone pain
  • Often occult tumors (difficult to locate)
  • Treatment: Tumor resection if possible
  • Burosumab if unresectable

Common Features: ↑FGF23, ↓1,25(OH)₂D (inappropriately low), renal phosphate wasting, normal PTH/calcium

🔬 Diagnostic Approach

Step-by-Step Evaluation

1 Confirm Hypophosphatemia: PO₄ <2.5 mg/dL (fasting preferred)
2 Check Urine Phosphate:
  • 24hr urine PO₄ <100 mg = GI losses/shifts
  • 24hr urine PO₄ >100 mg = renal losses
  • FePO₄ >5% = inappropriate renal wasting
3 If Renal Losses, Check:
  • PTH: ↑ in hyperparathyroidism
  • 25-OH Vitamin D: Screen for deficiency
  • 1,25(OH)₂ Vitamin D: Inappropriately low in FGF23 disorders
  • FGF23: ↑ in XLH, TIO
4 Additional Testing:
  • Glucose, aminoaciduria (Fanconi syndrome)
  • Imaging for tumors if TIO suspected
  • Genetic testing for hereditary disorders

🧮 Phosphate Replacement Calculator

Estimated Deficit: 7.0 mmol
IV Dose: 0.10 mmol/kg = 7.0 mmol over 6 hours
Oral: Neutra-Phos 2 packets TID × 2-3 days

💊 Treatment Strategies

Acute Replacement

Route Formulation Dosing Considerations
IV (Severe) Sodium phosphate
Potassium phosphate		 0.08-0.16 mmol/kg over 6 hrs
Max: 0.24 mmol/kg		 • Monitor Ca, K q4-6h
• Risk: hypocalcemia, hyperkalemia
• Use K-phos if K low
Oral (Mild-Moderate) Neutra-Phos
K-Phos
Fleet Phospho-soda		 1-2 g (32-64 mmol) daily
Divided TID-QID		 • GI upset common (diarrhea)
• Take with meals
• Slower correction

Chronic Management by Etiology

Nutritional Deficiency

  • Diet: High phosphate foods (dairy, meat, nuts, beans)
  • Supplements: 1-3 g daily in divided doses
  • Vitamin D: If deficient (enhances absorption)
  • Address underlying: Alcoholism, malabsorption

Primary Hyperparathyroidism

  • Definitive: Parathyroidectomy
  • Medical: Phosphate supplements (limited efficacy)
  • Monitor: Can worsen hypercalcemia

X-Linked Hypophosphatemia (XLH)

Traditional Therapy:
  • Phosphate 1-3 g/day in 4-5 doses
  • Calcitriol 0.5-1 mcg/day
  • Monitor for nephrocalcinosis
  • Suboptimal outcomes
Burosumab (Game Changer):
  • Anti-FGF23 monoclonal antibody
  • 0.4-2.0 mg/kg SC q2 weeks
  • Normalizes phosphate
  • Improves growth, rickets, pain
  • FDA approved for XLH and TIO

Tumor-Induced Osteomalacia

  • Localize tumor: Octreotide scan, FDG-PET, MRI
  • Surgical resection: Curative if tumor found
  • If unresectable: Burosumab or phosphate + calcitriol
  • Monitor: FGF23 levels post-resection

🎯 Key Clinical Pearls

  • Symptoms appear at PO₄ <2.0 mg/dL; severe at <1.0 mg/dL
  • Respiratory muscle weakness → difficulty weaning from ventilator
  • Rhabdomyolysis risk highest when PO₄ <1.0 mg/dL
  • Refeeding syndrome: Most common in malnourished patients - PREVENT!
  • Always give thiamine BEFORE feeding malnourished patients
  • Check urine phosphate to distinguish GI vs renal losses
  • FePO₄ >5% = inappropriate renal wasting (should conserve if low)
  • Primary hyperparathyroidism: Most common cause of renal losses
  • FGF23 disorders: Low 1,25(OH)₂D despite hypophosphatemia (paradox!)
  • IV phosphate: Never exceed 0.24 mmol/kg - risk of acute hypocalcemia
  • Oral phosphate causes diarrhea - divide doses, take with meals
  • Alcoholics: Triple threat - poor intake, ↑renal losses, vitamin D deficiency
  • Post-parathyroidectomy: Hungry bone syndrome can cause severe hypophosphatemia
  • Burosumab revolutionized treatment of XLH - consider for refractory cases

📚 Special Populations

Critical Care

  • Common in ICU (30-50%)
  • Ventilator weaning difficulty
  • Check before extubation
  • IV replacement if <1.5 mg/dL
  • Monitor for refeeding syndrome

Post-Transplant

  • Persistent hyperparathyroidism
  • FGF23 remains elevated
  • Usually resolves in months
  • Oral supplements usually sufficient

Pediatric

  • Rickets presentation
  • Growth retardation
  • Consider genetic causes
  • XLH most common inherited form
  • Burosumab if XLH confirmed

🔄 Monitoring and Follow-up

Replacement Monitoring

During IV Replacement: PO₄, Ca, K, Mg q4-6h
Oral Replacement: Daily × 3-5 days, then weekly
Chronic Therapy: Monthly initially, then q3-6 months
XLH on Burosumab: PO₄ monthly, adjust dose to maintain normal