How should I evaluate and manage an adult with hypophosphatemia?

Evaluation and Management of Adult Hypophosphatemia

Begin by determining the mechanism of hypophosphatemia through measurement of fractional phosphate excretion (FE-PO4), serum calcium, PTH, and 25-hydroxyvitamin D levels to distinguish between renal phosphate wasting, redistribution, and decreased intake/absorption. 1

Initial Diagnostic Approach

Confirm True Hypophosphatemia

• Obtain a fasting blood draw in adults to accurately assess phosphate homeostasis, as serum phosphate concentration varies significantly with food intake throughout the day 2
• Hypophosphatemia is defined as serum phosphate <2.5 mg/dL (0.8 mmol/L) 1
• Measure serum phosphate, calcium, PTH, and 25-hydroxyvitamin D to evaluate for metabolic bone disease 3

Calculate Fractional Phosphate Excretion

• If FE-PO4 >15% in the presence of hypophosphatemia, renal phosphate wasting is confirmed 1
• Obtain 24-hour urine collection for calcium and phosphate excretion in adults 2
• Calculate TmP/GFR (maximum rate of renal tubular reabsorption of phosphate normalized to GFR) 2

Differential Diagnosis Based on Mechanism

Renal Phosphate Wasting (FE-PO4 >15%)

Categorize based on serum calcium levels: 1

• High serum calcium: Primary hyperparathyroidism 1
• Low serum calcium: Secondary hyperparathyroidism due to vitamin D deficiency 1
• Normal serum calcium: Primary renal phosphate wasting disorders 1

Primary Renal Phosphate Wasting with Normal Calcium

Measure intact FGF23 levels to distinguish FGF23-mediated disorders from primary tubular defects: 2

• Non-suppressed or elevated FGF23: Consider X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia 2
• Low or suppressed FGF23: Consider Fanconi syndrome, Dent disease, cystinosis, or hereditary hypophosphatemic rickets with hypercalciuria 2

Exclude Fanconi Syndrome

• Measure serum bicarbonate, urinary amino acids, glucose, and low-molecular-weight protein markers to exclude proximal renal tubular wasting not restricted to phosphate 2

X-Linked Hypophosphatemia Specific Evaluation

In adults with suspected XLH, look for: 2

• History of lower-limb deformities
• Clinical, biochemical, or radiological signs of osteomalacia (pseudofractures, early osteoarthritis, spinal stenosis)
• Dental abscesses and enthesopathies
• Isolated renal phosphate wasting with phosphate below age-related reference range
• Family history of X-linked inheritance

Confirm XLH diagnosis with genetic testing for PHEX gene mutations when available 2

Common Causes in Hospitalized Patients

Be aware that severe hypophosphatemia in hospitalized adults is frequently multifactorial: 4

• Medications (82% of cases): IV glucose, antacids, diuretics, steroids 4
• Postoperative state (42.5% of cases), especially with IV glucose administration 4
• Gram-negative septicemia (second most common cause) 4
• Redistribution: Refeeding syndrome, treatment of diabetic ketoacidosis, respiratory alkalosis 5, 6

Management Strategy

Severity Assessment

Classify hypophosphatemia severity to guide treatment intensity: 7, 1

• Mild-moderate (1.8 mg/dL to lower end of normal): Often asymptomatic 1, 5
• Severe (<1.0 mg/dL): Risk of life-threatening complications 4, 6

Clinical Manifestations Requiring Treatment

Severe hypophosphatemia becomes clinically significant when there is underlying phosphate depletion: 6

• Skeletal muscle weakness and rhabdomyolysis 1, 5, 6
• Respiratory failure (especially in ventilated patients) 5, 6
• Myocardial dysfunction and left ventricular dysfunction 5, 6
• Hemolysis 5, 6
• Altered mental status 1, 6

Treatment Approach

Oral Phosphate Supplementation

For chronic renal phosphate wasting or symptomatic patients without life-threatening manifestations: 2, 1

• Administer 750-1,600 mg elemental phosphorus daily in 2-4 divided doses using sodium-based or potassium-based salts 2
• Increase dose gradually to avoid gastrointestinal adverse effects 2
• Combine with active vitamin D (calcitriol or alfacalcidol) to counter calcitriol deficiency, prevent secondary hyperparathyroidism, and increase phosphate absorption 2
• Do not give phosphate supplements with calcium-containing foods or supplements, as precipitation reduces absorption 2
• Maintain normal calcium intake (minimum 1g per day) and low-sodium diet 2

Intravenous Phosphate Replacement

Reserve IV phosphate for life-threatening hypophosphatemia (serum phosphate <2.0 mg/dL) or patients with clinical sequelae: 7, 1, 5

Dosing based on severity: 7

• Serum phosphate 1.8 mg/dL to lower normal: 0.16-0.31 mmol/kg
• Serum phosphate 1.0-1.7 mg/dL: 0.32-0.43 mmol/kg
• Serum phosphate <1.0 mg/dL: 0.44-0.64 mmol/kg (maximum 45 mmol as single dose)

Administration guidelines: 7

• Check serum potassium and calcium before administration; normalize calcium first 7
• Only administer if serum potassium <4 mEq/dL (use alternative phosphorus source if ≥4 mEq/dL) 7
• Maximum infusion rate via peripheral line: 6.8 mmol/hour 7
• Maximum infusion rate via central line: 15 mmol/hour 7
• Do not infuse with calcium-containing IV fluids 7
• Monitor serum phosphorus, potassium, calcium, and magnesium concentrations 7

Alternative dosing from research literature: Administer 0.16 mmol/kg at 1-3 mmol/hour until level reaches 2 mg/dL 1

Special Considerations for XLH in Adults

Conventional therapy (oral phosphate + active vitamin D) is first-line for adults with XLH: 2

• Phosphate supplements: 750-1,600 mg elemental phosphorus daily in 2-4 divided doses 2
• Active vitamin D to increase calcium absorption 2
• Correct 25(OH) vitamin D deficiency as in general population 2
• Consider thiazide diuretics to increase renal calcium reabsorption, though long-term effects unknown 2

Burosumab may be considered for adults with skeletal pain and osteomalacia based on clinical trial data showing benefit at 6-12 months 2

Critical Pitfalls to Avoid

• Do not aggressively replace moderate hypophosphatemia (>1.5 mg/dL) with IV phosphate unless symptomatic, as there is little evidence of significant clinical consequences except in ventilated patients 5
• Avoid bisphosphonates in patients with hypophosphatasia (low alkaline phosphatase), as they can cause atypical femur fractures 3
• Do not overlook medication-induced hypophosphatemia in hospitalized patients, particularly IV glucose, antacids, and diuretics 4
• Monitor for hypercalciuria and nephrocalcinosis in patients on conventional therapy with oral phosphate and active vitamin D 2
• Recognize that mortality increases with severity: 20% mortality with phosphate 1.1-1.5 mg/dL and 30% with phosphate ≤1.0 mg/dL 4
• In patients with moderate renal impairment (eGFR 30-60 mL/min/1.73 m²), start at the low end of the dose range for IV phosphate 7