Hypophosphatemic Disorders

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DESCRIPTION

  • Hypophosphatemia is defined by serum phosphorus values below an age-appropriate normal range.
  • Hypophosphatemia may be acute or chronic. The severity and duration of hypophosphatemia determine its effects on various body systems. Symptoms and signs are often nonspecific, most commonly generalized muscle weakness and fatigue.
    • With acute severe hypophosphatemia, severe neurologic, cardiovascular, and respiratory compromise can be seen.
    • With chronic hypophosphatemia, patients may develop rickets and osteomalacia.
  • Normal phosphorus concentrations for infants and children are significantly higher than adults.
ALERT

Hypophosphatemia can be missed if an adult normal range is used for pediatric patients.

EPIDEMIOLOGY

  • Acute hypophosphatemia is a common laboratory finding in hospitalized patients, especially in intensive care unit settings
  • Chronic hypophosphatemia is less common and clinically important as an etiology of rickets.
    • Vitamin D deficiency may be associated with hypophosphatemia.
    • The most common inherited form of rickets is X-linked hypophosphatemic rickets (XLH) (prevalence: ~1 in 20,000).
    • Other genetic forms of rickets are more rare.
  • Isolated dietary phosphate deficiency is rare; usually involves generalized malnutrition or inadequate phosphate bioavailability

RISK FACTORS

  • Nutritional
    • Vitamin D deficiency
    • Malnutrition/refeeding syndrome
    • Chronic diarrhea
    • Amino acid–based elemental enteral formula
  • Medications affecting phosphate absorption (phosphate binders)
    • Antacids
    • Sevelamer
    • Lanthanum carbonate
    • Excess calcium salts
  • Other:
    • Medications affecting renal phosphate transport (e.g., diuretics, tyrosine kinase inhibitors, parathyroid hormone [PTH] analogues)
    • Medications or toxins causing generalized proximal renal tubulopathy (e.g., tenofovir, aminoglycosides, cisplatin, ifosfamide)
    • Bisphosphonates, denosumab
    • Treatment of diabetic ketoacidosis (DKA)
    • Acute respiratory alkalosis
    • Postrenal transplant
    • Hungry bone syndrome with hypocalcemia after parathyroidectomy for hyperparathyroidism

Genetics

Genetic forms of hypophosphatemia/hypophosphatemic rickets (HR) are less common than acquired forms:

  • Fibroblast growth factor 23 (FGF23) mediated:
    • PHEX (XLH, X-linked dominant)
    • Autosomal dominant (AD) HR (FGF23)
    • Autosomal recessive (AR) HR
      • DMP1 (ARHR)
      • ENPP1 (generalized arterial calcification of infancy [GACI] and ARHR)
      • FAM20C (Raine syndrome and ARHR)
    • GNAS (somatic activating mutations: McCune-Albright syndrome [MAS], fibrous dysplasia)
    • HRAS/NRAS (somatic activating mutations: epidermal nevus syndrome)
  • Non-FGF23 mediated:
    • CYP27B1 (1α-hydroxylase deficiency, AR)
    • VDR (vitamin D receptor, AR)
    • SCL34A3 (NPT2c, AR; hereditary HR with hypercalciuria [HHRH]; nephrolithiasis also occurs in heterozygotes)
    • SGK3 (serum- and glucocorticoid-inducible kinase 3)
    • SLC34A1 (NPT2a; hypophosphatemia with osteoporosis and nephrolithiasis)
    • SLC9A3R1 (NHERF1; hypophosphatemia with osteoporosis and nephrolithiasis)
    • Others, including various genetic causes of renal Fanconi syndrome
      • SLC34A1 (NPT2a)
      • Dent disease (chloride channel 5 [CLCN5] or OCRL1)
      • Nephropathic cystinosis (CTNS, lysosomal cystine transporter cystinosin)

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
    • PTH-mediated
      • Hyperparathyroidism
      • Vitamin D deficiency
    • Medications altering phosphate transport
    • Primary proximal renal tubule disorders including Fanconi syndromes

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