Hypophosphatemic Disorders

Basics

Description

Hypophosphatemia is defined by serum phosphorus values below the age-appropriate normal range. Hypophosphatemia may be acute or chronic. Effects on various body systems depend on the severity and duration of hypophosphatemia. Symptoms and signs are nonspecific, most commonly involving generalized muscle weakness and fatigue but can include severe neurologic, cardiovascular, and respiratory compromise with acute severe hypophosphatemia, whereas with chronic hyposphatemia, patients develop rickets and osteomalacia.

ALERT
  • Normal phosphorus concentrations in infants and children are significantly higher than in adults.
  • Hypophosphatemia can be missed if an adult normal range is used for pediatric patients.

Epidemiology

  • Acute hypophosphatemia is a common laboratory finding in the hospital, especially in the intensive care unit (ICU) setting, resulting from a variety of mechanisms.
  • Chronic hypophosphatemia is less common but is clinically important as an etiology of rickets.
    • Vitamin D deficiency may cause hypophosphatemia and remains the most common form of rickets around the world, even in industrialized nations.
    • X-linked hypophosphatemic (XLH) rickets is the most common inherited cause of rickets (prevalence ≈1 in 20,000).
    • Other genetic forms of rickets are more rare.
  • Isolated dietary phosphate deficiency is rare; dietary phosphate deficiency usually involves generalized malnutrition or inadequate phosphate availability in parenteral or enteral nutrition formulations.

Risk Factors

  • Nutritional
    • Vitamin D deficiency
    • Malnutrition/refeeding syndrome
    • Chronic diarrhea
    • Amino-acid based elemental enteral formulas
  • Medications affecting phosphate absorption
    • Antacids
    • Sevelamer
    • Lanthanum carbonate
    • Excess calcium salts
  • Other:
    • Medications affecting renal phosphate transport
    • Medications or toxins causing generalized proximal renal tubulopathy
    • Treatment of diabetic ketoacidosis (DKA)
    • Acute respiratory alkalosis
    • Post renal transplant
    • Hungry bone syndrome with hypocalcemia after parathyroidectomy for hyperparathyroidism

Genetics

Genetic forms are less common than acquired forms:

  • PHEX (XLH, X-linked dominant)
  • FGF23 (fibroblast growth factor 23, autosomal dominant hypophosphatemic rickets [ADHR])
  • DMP1 (autosomal recessive [AR] hypophosphatemic rickets [ARHR])
  • ENPP1 (ARHR, generalized arterial calcification of infancy [GACI])
  • FAM20C (AR hypophosphatemia, Raine syndrome)
  • SCL34A3 (NPT2c, AR hereditary hypophosphatemic rickets with hypercalciuria [HHRH]; nephrolithiasis also occurs in heterozygotes)
  • CYP27B1 (1α-hydroxylase deficiency, AR)
  • VDR (vitamin D receptor, AR)
  • Somatic mutations sometimes associated with hypophosphatemia:
    • GNAS (McCune-Albright syndrome [MAS], fibrous dysplasia, somatic activating mutations)
    • HRAS/NRAS (somatic activating mutations causing epidermal nevus syndrome)
  • Others, including various genetic causes of renal Fanconi syndrome

Pathophysiology

  • Decreased nutritional intake or malabsorption
  • Redistribution of extracellular phosphate into the intracellular compartment (causes acute hypophosphatemia only)
    • Insulin mediated (during treatment of DKA)
    • Refeeding syndrome
    • Acute respiratory alkalosis
  • Increased renal phosphate loss
    • FGF23-mediated
    • Parathyroid hormone (PTH)-mediated
    • Medications altering phosphate transport
    • Primary proximal renal tubulopathies

Etiology

See genetic causes and “Differential Diagnosis.”

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