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hypophosphatemia

Etiology: 1) chronic alcoholism & withdrawal* - refeeding after starvation - insulin promotes phosphate uptake by cells 2) decreased intestinal absorption a) malnutrition b) vitamin D deficiency, vitamin D resistance c) malabsorption & steatorrhea d) vomiting & nasogastric suction e) secretory diarrhea 3) critical illness - sepsis (gram-negative) 4) associated with increases in serum Ca+2 elevation a) primary hyperparathyroidism b) PTH-producing tumor c) familial hypocalciuric hypercalcemia 5) renal tubular acidosis type 2 (Fanconi syndrome)* 6) chronic hemodialysis 7) decreased dietary phosphate intake (occasional)* 8) osteomalacia - rickets - oncogenic osteomalacia 9) hypokalemia 10) acute gout 11) respiratory tract infection 12) osteoblastic metastases 13) osmotic diuresis - diuretic phase of severe burns* 14) genetic disorders a) familial hyperphosphaturic hypophosphatemia b) renal hypophosphatemia with intracerebral calcifications c) X-linked hypophosphatemia d) hereditary hypophosphatemia, type II e) Fanconi syndrome f) Wilson's disease g) hereditary fructose intolerance h) others (see OMIM correlations) 15) therapeutic hyperthermia* 16) hyperalimentation* - administration of intravenous fructose 17) neuroleptic malignant syndrome* 18) recovery from exhaustive exercise* 19) diabetes mellitus a) polyuria, glucosuria, ketonuria & acidemia increase renal phosphorus excretion b) hypophosphatemia in patients with diabetic ketoacidosis may only become apparent after ketoacidosis is corrected [3] 20) increased intracellular uptake a) hungry bone syndrome after parathyroidectomy b) refeeding syndrome c) treatment of diabetic ketoacidosis with insulin d) respiratory alkalosis* e) acute leukemia 21) increased urine loss - hyperparathyroidism - hypophosphatemic rickets - osteopenic osteomalacia - volume expansion - heavy metal intoxication - multiple myeloma - osmotic diuresis - metabolic acidosis - renal transplantation - FGF23-mediated mechanisms 22) 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 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 Pathology: 1) phosphate trapping a) results from reduction of intracellular phosphate b) intravenous fructose is most common cause 2) insulin promotes phosphate uptake by cells 3) symptomatic muscle weakness (serum phosphorus < 2 mg/dL) 4) serum phosphorus < 1 mg/dL (severe hypophosphatemia) a) rhabdomyolysis (serum phosphorus < 1 mg/dL) - occurs in alcoholics - rarely in treatment of diabetic ketoacidosis - may occur with hyperalimentation - may correct hypophosphatemia b) cardiomyopathy (serum phosphorus < 1 mg/dL) - occurs with severe hypophosphatemia - decreased cardiac output - hypotension - reduced pressor response to catecholamines - reduced threshold to ventricular arrhythmias c) 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 d) 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 e) leukocyte dysfunction - impaired phagocytosis & opsinization - increased susceptibility to bacterial & fungal infections f) thrombocytopenia g) skeletal demineralization - osteopenia - bone pain - syndrome resembling osteomalacia (oncogenic osteomalacia) h) 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 i) 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 Clinical manifestations: severe hypophosphatemia (serum phosphate < 1 mg/dL) 1) heart failure 2) arrhythmias [3] 3) muscle weakness, myalgias, rhabdomyolysis 4) respiratory failure 5) hemolytic anemia 6) delirium, metabolic encephalopathy, seizures, coma Laboratory: 1) complete blood count (CBC) a) anemia b) thrombocytopenia 2) peripheral blood smear may show evidence of hemolytic anemia 3) arterial blood gas 4) serum chemistries a) serum Ca+2 b) serum phosphosphorus - symptoms seldom occur if serum phosphorus > 2.0 mg/dL [3] 5) 24-hour urine phosphorus a) hyperphosphaturia suggests renal phosphate wasting b) normal or low urine phosphate suggest extra-renal cause of hypophosphatemia 6) fractional excretion of phosphorus > 5% is consistent with renal phosphate wasting (RTA type 2) 7) CSF examination (if neurologic signs) is normal Management: 1) oral phosphate replacement (serum phosphate > 2.0 mg/dL) a) milk contains 33 mmol/L (100 mg/dL) of phosphorous b) Neutra-Phos 2 tabs TID/QID c) sodium biphosphate (Fleets enema) given orally c) potassium phosphate 2) intravenous potassium phosphate a) reserve for patients with serum phosphorus < 1.5 mg/dL (0.5 mmol/L); < 1,0 mg/dL [3]; < 2.0 mg/dL [3] b) 15 mmol in 100 mL of normal saline over 60 minutes c) alcoholics who are hypophosphatemic, hypokalemic & hypomagnesemic 1] 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 2] monitor serum K+, serum Mg+2, serum phosphorus, serum Ca+2 q6 hours [3] 3) dipyridamole may be of use in hyperphosphaturia a) PTH-mediated b) familial hyperphosphaturic hypophosphatemia 4) burosumab for X-linked hypophosphatemia [7]

Related

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

Specific

hungry bone syndrome hypophosphatasia phosphate depletion syndrome X-linked hypophosphatemia

General

electrolyte disorder sign/symptom disorder of phosphorus metabolism

Database Correlations

OMIM correlations

References

  1. Guide to Clinical Laboratory Tests, 3rd ed, NW Teitz (ed) WB Saunders, 1995
  2. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 2259-62
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021.
  4. Liamis G, Milionis HJ, Elisaf M. Medication-induced hypophosphatemia: a review. QJM. 2010 Jul;103(7):449-59. PMID: 20356849
  5. Felsenfeld AJ, Levine BS. Approach to treatment of hypophosphatemia. Am J Kidney Dis. 2012 Oct;60(4):655-61. Review. PMID: 22863286
  6. Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab. 2012 Mar;97(3):696-706. PMID: 22392950 Free PMC Article
  7. NEJM Knowledge+ Endocrinology