hypophosphatemia

Etiology

• chronic alcoholism & withdrawal*
  • refeeding after starvation
    • insulin promotes phosphate uptake by cells
• decreased intestinal absorption
  • malnutrition
  • vitamin D deficiency, vitamin D resistance
  • malabsorption & steatorrhea
  • vomiting & nasogastric suction
  • secretory diarrhea
• critical illness
  • sepsis (gram-negative)
• associated with increases in serum Ca+2 elevation
  • primary hyperparathyroidism
  • PTH-producing tumor
  • familial hypocalciuric hypercalcemia
• renal tubular acidosis type 2 (Fanconi syndrome)*
• chronic hemodialysis
• decreased dietary phosphate intake (occasional)*
• osteomalacia
  • rickets
  • oncogenic osteomalacia
• hypokalemia
• acute gout
• respiratory tract infection
• osteoblastic metastases
• osmotic diuresis
  • diuretic phase of severe burns*
• genetic disorders
  • familial hyperphosphaturic hypophosphatemia
  • renal hypophosphatemia with intracerebral calcifications
  • X-linked hypophosphatemia
  • hereditary hypophosphatemia, type II
  • Fanconi syndrome
  • Wilson's disease
  • hereditary fructose intolerance
  • others (see OMIM correlations)
• therapeutic hyperthermia*
• hyperalimentation*
  • administration of intravenous fructose
• neuroleptic malignant syndrome*
• recovery from exhaustive exercise*
• diabetes mellitus
  • polyuria, glucosuria, ketonuria & acidemia increase renal phosphorus excretion
  • hypophosphatemia in patients with diabetic ketoacidosis may only become apparent after ketoacidosis is corrected
• increased intracellular uptake
  • hungry bone syndrome after parathyroidectomy
  • refeeding syndrome
  • treatment of diabetic ketoacidosis with insulin
  • respiratory alkalosis*
  • acute leukemia
• increased urine loss
  • hyperparathyroidism
  • hypophosphatemic rickets
  • osteopenic osteomalacia
  • volume expansion
  • heavy metal intoxication
  • multiple myeloma
  • osmotic diuresis
  • metabolic acidosis
  • renal transplantation
  • FGF23-mediated mechanisms
• drugs
  • aluminum-containing antacids*
  • acetaminophen poisoning
  • acetazolamide
  • amino acids
  • anesthetic agents
  • beta-2 adrenergic agonists
    • albuterol
  • calcitonin
  • carbamazepine
  • diuretics
    • acetazolamide
    • metolazone
  • epinephrine
  • estramustine
  • estrogens
  • ferric carboxymaltose (FGF23-mediated)
  • fructose
  • glucocorticoids
  • glucose
  • hydrochlorothiazide (prolonged treatment)
  • ifosfamide
  • insulin*
  • isoniazid
  • oral contraceptives
  • phenytoin
  • phosphate binders
  • salicylate poisoning
  • sucralfate
  • tenofovir
  • xanthines

* causes of severe hypophosphatemia

Pathology

• phosphate trapping
  • results from reduction of intracellular phosphate
  • intravenous fructose is most common cause
• insulin promotes phosphate uptake by cells
• symptomatic muscle weakness (serum phosphorus < 2 mg/dL)
• serum phosphorus < 1 mg/dL (severe hypophosphatemia)
  • rhabdomyolysis (serum phosphorus < 1 mg/dL)
    • occurs in alcoholics
    • rarely in treatment of diabetic ketoacidosis
    • may occur with hyperalimentation
    • may correct hypophosphatemia
  • cardiomyopathy (serum phosphorus < 1 mg/dL)
    • occurs with severe hypophosphatemia
    • decreased cardiac output
    • hypotension
    • reduced pressor response to catecholamines
    • reduced threshold to ventricular arrhythmias
  • respiratory insufficiency (serum phosphorus < 1 mg/dL)
    • malnourished patients receiving parenteral nutrition
    • occurs over 8-10 days
    • failure of diaphragm function
    • hypoxia
    • respiratory acidosis
    • seldom occurs in alcoholics
  • erythrocyte dysfunction: (serum phosphorus < 1 mg/dL)
    • due to decrease in 2,3-DPG
    • enhances affinity of hemoglobin for oxygen
    • decreases delivery of O2 to tissues
    • may account for CNS dysfunction with hypophosphatemia
    • hemolytic anemia may occur
  • leukocyte dysfunction
    • impaired phagocytosis & opsinization
    • increased susceptibility to bacterial & fungal infections
  • thrombocytopenia
  • skeletal demineralization
    • osteopenia
    • bone pain
    • syndrome resembling osteomalacia (oncogenic osteomalacia)
  • metabolic acidosis
    • reduced urinary secretion of H+ as Na H2PO4
    • reduction of Na+/H+ antiporter activity in proximal tubule
      • reduces excretion of H+ into the tubular lumen
      • reduces reabsorption of filtered HCO3-
    • reduced production of NH3
  • nervous system dysfunction
    • generally occurs in the setting of hyperalimentation or refeeding-induced hypophosphatemia
    • occurs over 8-10 days
    • hyperventilation may contribute
    • paresthesias & numbness
    • muscular weakness
    • dysarthria
    • confusion
    • obtundation
    • seizures
    • coma
    • ascending motor paralysis with or without sensory changes resembling Guillain-Barre syndrome

Physiology

• phosphate is primarily excreted through the renal glomeruli & reabsorbed mostly in the proximal tubules.
• PTH decreases proximal tubule reabsorbtion of phosphorus
• calcitriol stimulates phosphate absorption in the small intestine

Clinical manifestations

severe hypophosphatemia (serum phosphate < 1 mg/dL)

• heart failure
• arrhythmias
• muscle weakness, myalgias, rhabdomyolysis
• respiratory failure
• hemolytic anemia
• delirium, metabolic encephalopathy, seizures, coma

Laboratory

• complete blood count (CBC)
  • anemia
  • thrombocytopenia
• peripheral blood smear may show evidence of hemolytic anemia
• arterial blood gas
• serum chemistries
  • serum Ca+2
  • serum phosphosphorus
    • symptoms seldom occur if serum phosphorus > 2.0 mg/dL
• 24-hour urine phosphorus
  • hyperphosphaturia suggests renal phosphate wasting
  • normal or low urine phosphate suggest extra-renal cause of hypophosphatemia
• fractional excretion of phosphorus > 5% is consistent with renal phosphate wasting (RTA type 2)
• CSF examination (if neurologic signs) is normal

Management

• oral phosphate replacement (serum phosphate > 2.0 mg/dL)
  • milk contains 33 mmol/L (100 mg/dL) of phosphorous
  • Neutra-Phos 2 tabs TID/QID
  • sodium biphosphate (Fleets enema) given orally
  • potassium phosphate
• intravenous potassium phosphate
  • reserve for patients with serum phosphorus < 1.5 mg/dL (0.5 mmol/L); < 1,0 mg/dL; < 2.0 mg/dL
  • 15 mmol in 100 mL of normal saline over 60 minutes
  • alcoholics who are hypophosphatemic, hypokalemic & hypomagnesemic
    • D5 1/2 NS containing 9 mmol K-Phos & 4.2 mmol MgSO4 (2.0 mL of a 50% magnesium solution) at 100 mL/hr
    • monitor serum K+, serum Mg+2, serum phosphorus, serum Ca+2 q6 hours
• dipyridamole may be of use in hyperphosphaturia
  • PTH-mediated
  • familial hyperphosphaturic hypophosphatemia
• burosumab for X-linked hypophosphatemia

More general terms

• electrolyte disorder
• sign/symptom
• disorder of phosphorus metabolism

More specific terms

• hungry bone syndrome
• hypophosphatasia
• phosphate depletion syndrome
• X-linked hypophosphatemia

Additional terms

• inorganic phosphate; inorganic phosphorous
• phosphorus (inorganic phosphate) in serum

Database

• OMIM: https://mirror.omim.org/entry/307800
• OMIM: https://mirror.omim.org/entry/307810
• OMIM: https://mirror.omim.org/entry/241519
• OMIM: https://mirror.omim.org/entry/146350
• OMIM: https://mirror.omim.org/entry/193100
• OMIM: https://mirror.omim.org/entry/241520
• OMIM: https://mirror.omim.org/entry/241530