What are the causes and effects of hypophosphatemia (low phosphate levels)?

Causes of Hypophosphatemia (Low Phosphate Levels)

Hypophosphatemia is primarily caused by inadequate intake or intestinal absorption, redistribution from extracellular to intracellular compartments, and excessive renal phosphate wasting. 1

Major Etiological Categories

1. Inadequate Intake or Absorption

• Vitamin D deficiency leading to decreased intestinal phosphate absorption 1
• Malnutrition or starvation 2
• Use of phosphate-binding antacids 3
• Malabsorption syndromes

2. Intracellular Shift (Redistribution)

• Refeeding syndrome - when nutrition is reintroduced after starvation 1
• Diabetic ketoacidosis (DKA) treatment 2
• Respiratory alkalosis
• Administration of intravenous glucose 3
• Hungry bone syndrome after parathyroidectomy
• Rapid cellular proliferation (e.g., in acute leukemia) 4

3. Increased Renal Excretion

• Genetic disorders:

  • X-linked hypophosphatemic rickets (XLH) - due to PHEX gene mutations 5, 1
  • Autosomal dominant hypophosphatemic rickets 1
  • Hypophosphatemia with nephrocalcinosis (SLC34A1 mutations) 5
  • X-linked recessive hypophosphatemic rickets (CLCN5 mutations) 5

• Acquired disorders:

  • Tumor-induced osteomalacia (elevated FGF23) 1
  • Primary hyperparathyroidism 6
  • Secondary hyperparathyroidism 6
  • Fanconi syndrome (proximal tubular dysfunction) 5, 1
  • Iatrogenic proximal tubulopathy (drug toxicity) 5
  • Iron therapy with intravenous ferric carboxymaltose 1
  • Alcohol-induced FGF23 syndrome 1

4. Iatrogenic and Hospital-Related Causes

• Kidney replacement therapy, especially continuous or prolonged intermittent modalities 1
• Medications (diuretics, steroids) 3
• Post-surgical states, particularly after partial hepatectomy 2
• Gram-negative septicemia 3

Clinical Manifestations and Effects

Biochemical Features

• Decreased serum phosphate (<2.5 mg/dL) 6
• Often accompanied by elevated alkaline phosphatase (ALP) levels 5
• In XLH: renal phosphate wasting with low TmP/GFR 5
• Serum calcium usually in lower normal range in phosphate wasting disorders 5

Clinical Impact

• Mild hypophosphatemia (2.0-2.5 mg/dL): Often asymptomatic 1, 2
• Moderate hypophosphatemia (1.0-1.9 mg/dL): May cause muscle weakness 2
• Severe hypophosphatemia (<1.0 mg/dL): Can lead to life-threatening complications 1, 2
  • Respiratory muscle weakness
  • Cardiac dysfunction
  • Rhabdomyolysis
  • Altered mental status
  • Impaired red blood cell function (decreased ATP and 2,3-DPG) 7, 8
  • Increased mortality (20-30% in hospitalized patients with severe hypophosphatemia) 3

Long-term Effects

• In children: Rickets, impaired growth, and bone deformities 5, 9
• In adults: Osteomalacia, pseudofractures, early osteoarthritis, and enthesopathies 5
• Impaired chondrocyte apoptosis in growth plates, leading to abnormal bone development 9

Diagnostic Approach

1. Measure serum phosphate levels - normal range is 3.0-4.5 mg/dL in adults and 4.0-7.0 mg/dL in children 5, 7, 8

2. Calculate fractional excretion of phosphate or TmP/GFR:

   • If >15% in the presence of hypophosphatemia, confirms renal phosphate wasting 6
   • Note: TmP/GFR can be falsely low with insufficient phosphate intake until serum levels normalize 5

3. Based on serum calcium levels, categorize renal phosphate wasting as:

   • High calcium: Primary hyperparathyroidism
   • Low calcium: Secondary hyperparathyroidism
   • Normal calcium: Primary renal phosphate wasting 6

4. Consider measuring FGF23 levels for suspected FGF23-mediated disorders 1

5. Genetic testing for hereditary disorders (e.g., PHEX gene for XLH) 1

Prevention and Management

The approach to treatment depends on the severity, cause, and chronicity of hypophosphatemia:

1. For mild to moderate acute hypophosphatemia:

   • Increase dietary phosphate intake
   • Oral phosphate supplementation (750-1,600 mg daily in 2-4 divided doses) 1

2. For severe or symptomatic hypophosphatemia:

   • Intravenous phosphate (0.16 mmol/kg) at a rate of 1-3 mmol/hour until level reaches 2 mg/dL 6
   • Monitor serum phosphate within 24 hours of initiating therapy 1

3. For chronic hypophosphatemia (e.g., XLH):

   • Long-term oral phosphate combined with active vitamin D (calcitriol 0.50-0.75 μg daily or alfacalcidol 0.75-1.5 μg daily) 1
   • Consider burosumab (FGF23 antibody) particularly in children 1
   • Ensure adequate calcium intake (minimum 1g per day) 1
   • Regular monitoring of blood levels of ALP, calcium, phosphate, creatinine, PTH, and vitamin D 1

4. For specific causes:

   • Refeeding syndrome: Introduce nutrition gradually with appropriate phosphate supplementation 1
   • FCM-induced hypophosphatemia: Consider alternative iron formulations for future use 1
   • Vitamin D deficiency: Correct with appropriate supplementation 1

Remember that severe hypophosphatemia can be life-threatening and requires prompt intervention to prevent significant morbidity and mortality.