You are in: eMedicine Specialties > Emergency Medicine > ENDOCRINE AND METABOLIC HypophosphatemiaArticle Last Updated: May 24, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 9
  Author: Thomas Mailhot, MD, Staff Physician, Department of Emergency Medicine, University of Southern California, Los Angeles County Thomas Mailhot is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Emergency Medicine Residents Association Coauthor(s): Allison J Richard, MD, Instructor of Clinical Emergency Medicine, Keck School of Medicine, University of Southern California; Consulting Staff, Department of Emergency Medicine, LAC-USC Medical Center Editors: Robin R Hemphill, MD, MPH, Associate Professor, Director, Disaster Preparedness, Department of Emergency Medicine, Vanderbilt University Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard A Bessen, MD, Professor of Medicine, Department of Emergency Medicine, UCLA School of Medicine; Program Director, Harbor-UCLA Medical Center; John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center; Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital Author and Editor Disclosure Synonyms and related keywords: phosphate, intracellular anion, ATP, 2, 3-diphosphoglycerate, 2, 3-DPG, serum phosphate, phosphorus, refeeding syndrome, hypophosphatemia INTRODUCTIONSection 2 of 9
  BackgroundPhosphate is the most abundant intracellular anion and is essential for membrane structure, energy storage, and transport in all cells. In particular, phosphate is necessary to produce ATP, which provides energy for nearly all cell functions. Phosphate is an essential component of DNA and RNA. Phosphate is also necessary in red blood cells for production of 2,3-diphosphoglycerate (2,3-DPG), which facilitates release of oxygen from hemoglobin. Approximately 85% of the body's phosphorus is in bone as hydroxyapatite, while most of the remainder (15%) is present in soft tissue. Only 0.1% of phosphorus is present in extracellular fluid, and it is this fraction that is measured with a serum phosphorus level. Reducing available phosphate may compromise any organ system, alone or in combination. The critical role phosphate plays in every cell, tissue, and organ explains the systemic nature of injury caused by phosphate deficiency. Serum phosphate or phosphorus normally ranges from 2.5-4.5 mg/dL (0.81-1.45 mmol/L) in adults. Hypophosphatemia is defined as mild (2-2.5 mg/dL, or 0.65-0.81 mmol/L), moderate (1-2 mg/dL, or 0.32-0.65 mmol/L), or severe ( <1 mg/dL, or 0.32 mmol/L). Mild to moderately severe hypophosphatemia is usually asymptomatic. Major clinical sequelae usually occur only in severe hypophosphatemia. As in the case of other intracellular ions (eg, potassium, magnesium), a decrease in the level of serum phosphate (hypophosphatemia) should be distinguished from a decrease in total body storage of phosphate (phosphate deficiency). PathophysiologyPhosphorus homeostasis is complex and regulated by the actions of several hormones. Parathyroid hormone causes phosphate to be released from bone and inhibits renal reabsorption of phosphorus, resulting in phosphaturia. Vitamin D aids in the intestinal reabsorption of phosphorus. Thyroid hormone and growth hormone act to increase renal reabsorption of phosphate. Finally, a new class of phosphate-regulating factors, the so-called phosphatonins have been shown to be important in phosphate-wasting diseases. Hypophosphatemia is caused by the intracellular shift of phosphate from serum, increased urinary excretion of phosphate, decreased intestinal absorption of phosphate, or decreased dietary intake. Hypophosphatemia may be transient, reflecting intracellular shift with minimal clinical consequences. The disease also may reflect a deeper state of total body phosphate depletion with significant sequelae. Intracellular shift Respiratory alkalosis moves phosphate into cells by activating phosphofructokinase, which stimulates intracellular glycolysis. Glycolysis leads to phosphate consumption as phosphorylated glucose precursors are produced. Any cause of hyperventilation (eg, sepsis, anxiety, pain, heatstroke, alcohol withdrawal, diabetic ketoacidosis [DKA], hepatic encephalopathy, salicylate toxicity) can precipitate hypophosphatemia. Since respiratory alkalosis is one of the most common causes of hypophosphatemia, discovery of hypophosphatemia should prompt a search for the serious causes of hyperventilation. Administering carbohydrate lowers serum phosphate by stimulating the release of insulin, which moves phosphate and glucose into cells. This so-called refeeding syndrome occurs when starving or chronically malnourished patients are refed or given intravenous (IV) glucose, and typically produces a hypophosphatemic state by treatment day 3 or 4. In addition, during refeeding cells switch to an anabolic state, resulting in further phosphate depletion as this essential substrate is incorporated into cells and cell products. Catecholamines and beta-receptor agonists also stimulate phosphate uptake into cells. Certain rapidly growing malignancies (eg, acute leukemia, lymphomas) may consume phosphate preferentially, leading to hypophosphatemia. In most cases of intracellular phosphate shift, serum phosphate normalizes once the precipitating cause is removed. Increased urinary excretion Since parathyroid hormone stimulates the kidneys to excrete phosphate, hypophosphatemia is a common sequela of primary and secondary hyperparathyroidism. Urinary loss of phosphate also occurs with acute volume expansion due to a dilution of serum calcium, which in turn triggers an increase in the release of parathyroid hormone. Osmotic diuresis, such as seen in hyperosmolar hyperglycemic syndrome (HHS), also produces increased urinary excretion of phosphorus. Diuretics, including loop diuretics, thiazides, and carbonic anhydrase inhibitors (eg, acetazolamide) interfere with the ability of the proximal tubule to reabsorb phosphorus, thus producing hyperphosphaturia and potentially leading to hypophosphatemia. Patients with transplanted kidneys, congenital defects (X-linked hypophosphatemia [XLH] and autosomal dominant hypophosphatemic rickets [ADHR]), or Fanconi syndrome (proximal tubule dysfunction) also may excrete excess urinary phosphate. Decreased intestinal absorption Phosphate may be lost via the gut, as in chronic diarrhea, malabsorption syndromes, severe vomiting, or NG suctioning. Phosphate may also be bound in the gut, thereby preventing absorption (eg, chronic use of sucralfate, or phosphate-binding antacids, including aluminum hydroxide, aluminum carbonate, and calcium carbonate). Decreased dietary intake This is a rare cause of hypophosphatemia because of the ubiquity of phosphate in foods. Certain conditions such as anorexia nervosa or chronic alcoholism may lead to hypophosphatemia in part via this mechanism. Manifestations of phosphate deficiency Weakness of skeletal or smooth muscle is the most common clinical manifestation of phosphate deficiency. It can involve any muscle group, alone or in combination, ranging from ophthalmoplegia to proximal myopathy to dysphagia or ileus. Hypophosphatemia also causes rhabdomyolysis via ATP depletion and the consequent inability of muscle cells to maintain membrane integrity. Patients undergoing acute alcohol withdrawal are especially vulnerable to rhabdomyolysis secondary to hypophosphatemia, which is caused by the rapid uptake of phosphate into muscle cells. Rhabdomyolysis occurs more rarely in patients being treated for DKA or being refed after starvation. Respiratory insufficiency may occur in some patients with severe hypophosphatemia, particularly when the underlying cause is malnourishment. Impaired cardiac contractility occurs, leading to generalized signs of myocardial depression. Blood pressure and stroke volume have been shown to improve when serum phosphorus is corrected. The hypophosphatemic myocardium also has a reduced threshold for ventricular arrhythmias. Phosphate deficiency commonly impairs neurologic function, which may be manifested by confusion, seizures, and coma. Peripheral neuropathy and ascending motor paralysis, similar to Guillain-Barré syndrome, may occur. Extrapontine myelinolysis has also been reported. Hematologic function may be impaired. The hemolytic anemia associated with severe hypophosphatemia has been attributed to the inability of erythrocytes to maintain integrity of cell membranes in the face of ATP depletion, leading to their destruction in the spleen. Phosphate deficiency also compromises oxygen delivery to the tissues due to decreases in erythrocyte 2,3-DPG and the resulting leftward shift in the oxygen-hemoglobin dissociation curve. Diminished oxygen delivery to the brain may be the cause of some of the neurologic manifestations mentioned above. Leukocyte function is affected, which results in impaired chemotaxis and phagocytosis. Manifestations of phosphate deficiency may occur singly or simultaneously. FrequencyUnited StatesHypophosphatemia may occur in as many as 2-3% of hospitalized patients and as many as 30% of patients admitted to ICUs. Certain subgroups, including HIV-positive patients and patients with falciparum malaria, have higher rates of hypophosphatemia than the general public (17% and 38.5%, respectively, in 2 separate studies), although the significance of this is unknown. Fortunately, severe hypophosphatemia is rare, occurring in no more than 0.5% of hospitalized patients. Sex
Age
CLINICALSection 3 of 9
History
Physical
Causes
DIFFERENTIALSSection 4 of 9
Alcoholic Ketoacidosis Anxiety CBRNE - Botulism Diabetic Ketoacidosis Guillain-Barré Syndrome Hyperventilation Syndrome
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| Drug Name | Phosphate salt |
|---|---|
| Description | IV preparations are available as sodium phosphate (Na2HPO4 and NAH2PO4) or potassium phosphate (K2HPO4 and KH2PO4). Response to IV phosphorus supplementation varies widely and may be associated with hyperphosphatemia and hypocalcemia. Rate of infusion and choice of initial dosage should be based on severity of hypophosphatemia and presence of symptoms. When treating hypophosphatemia with potassium phosphate, potassium level may limit amount of phosphate that can be given safely. One Canadian group recently reported administering 30 mmol of potassium phosphate via central line over 3 h for severe hypophosphatemia and 15 mmol of potassium phosphate via central line over 3 h for moderate hypophosphatemia. Another study reported safely administering IV phosphate at a rate of 14.5 mmol of phosphate ions over 1 h. |
| Adult Dose | 8 mmol of potassium phosphate IV q6h initially (32 mmol/24h) Aggressive IV replacement: 15 mmol of potassium phosphate over 6 h |
| Pediatric Dose | 0.25-0.5 mmol/kg IV over 4-6 h; repeat if symptomatic hypophosphatemia persists |
| Contraindications | Hyperphosphatemia; hypocalcemia; hypomagnesemia; hyperkalemia; renal failure |
| Interactions | Magnesium- and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels; potassium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in patients with renal insufficiency or metabolic alkalosis; admixture of phosphate and calcium in IV fluids can result in calcium-phosphate precipitation |
Article Last Updated: May 24, 2006
