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Hypophosphatemia in Emergency Medicine

  • Author: Luda Khait, MD, MS; Chief Editor: Erik D Schraga, MD  more...
 
Updated: Dec 22, 2014
 

Background

Phosphate 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. If severe hypophosphatemia is present for longer than 2-3 days, serious complications can be seen, including rhabdomyolysis, respiratory failure, acute hemolytic anemia, and fatal arrhythmias.[1] It has also been shown to increase mortality by four-fold.[2] Approximately 5% of hospitalized patients have hypophosphatemia, mostly those patients with diabetic ketoacidosis, chronic obstructive pulmonary disease, malignancy, states of malnutrition, and sepsis

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).

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Pathophysiology

Normal physiology and homeostasis of phosphate is complicated and is controlled by many different hormones. In general, homeostasis of phosphate is regulated by the amount of phosphate in the plasma, which is mostly composed of inorganic phosphate. The kidneys and to a lesser extent, the small intestines, are the main regulators of phosphorous homeostasis.[3]

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, such as oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia, and tumoral calcinosis.[4]

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

Increasing intracellular pH will cause stimulation of glycolysis, in turn producing phosphate-containing intermediates, driving phosphorous intracellularly and lowering the extracellular concentration.[5] One of the more common ways to raise intracellular pH is through hyperventilation causing a respiratory alkalosis. 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, neuroleptic malignant syndrome [NMS]) can precipitate hypophosphatemia. Also, patients requiring mechanical ventilation for asthma or COPD may develop respiratoryalkalosis.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, when clinically appropriate.[6, 7]

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.[8]

Patients with uncontrolled diabetes and prolonged hyperglycemia can chronically lose phosphate via osmotic diuresis (secondary to glycosuria) and develop acute hypophosphatemia once insulin is administered, driving phosphorous into the cell. Along those same lines, diabetic ketoacidosis is also an important cause of hypophosphatemia. Metabolic acidosis and insulin deficiency will mobilize intracellular phosphate stores, causing them to shift to the extracellular space and leading to urinary losses.[9] Treatment of DKA with insulin causes phosphate to move back into cells resulting in a decrease of serum phosphate levels. Routine replacement of phosphate in the setting of DKA is not proven to decrease morbidity or mortality. However, because patients in DKA are often hypokalemic and hypophosphatemic, some clinicians replete these losses with potassium phosphate salts.

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.

Certain medications and disease states can also promote hypophosphatemia. In the emergency department, many patients present with acute respiratory distress secondary to asthma or COPD exacerbations requiring aggressive nebulized albuterol treatments. As stated previously, activation of the beta-adrenergic receptor can move phosphate into the cells. One study showed evidence of acute hypophosphatemia with aggressive administration of nebulized albuterol (2.5 mg/dL every 30 min). The serum phosphate level was found to decrease by 1.25 mg/dL after 3 hours of therapy.[10] In salicylate overdose, the first clinical manifestation is respiratory alkalosis, leading to hypophosphatemia.[7]

Increased urinary excretion

Increased urinary excretion is the most common cause of hypophosphatemia. Since parathyroid hormone stimulates the kidneys to excrete phosphate, hypophosphatemia is a common sequela of primary and secondary hyperparathyroidism. Parathyroid hormone increases renal losses of phosphate by decreasing the activity of the sodium-phosphate transporters.[11]

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.[12] 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.[13]

There is also evidence that shows estrogen to be a downregulator of a renal sodium phosphate cotransporter, causing significant hypophosphatemia in patients.[14]

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). Also, the intestine "senses" luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption.[15]

Decreased dietary intake

Decreased dietary intake of phosphate is a rare cause of hypophosphatemia because of the ubiquity of phosphate in foods. Dietary sources of phosphate include fruits, vegetables, meats, and dairy products. Vitamin D enhances the absorption of both phosphate and calcium. Certain conditions such as anorexia nervosa or chronic alcoholism may lead to hypophosphatemia in part due to this mechanism, as well as increased renal excretion.

Manifestations of phosphate deficiency

In general, hypophosphatemia often does not show any clinical manifestations, even in very low concentrations.[16] However, despite this condition being often silent, phosphate depletion overall leads to two main consequences: depletion of ATP and increased affinity for oxygen to hemoglobin, thus decreasing oxygen delivery to tissues.[17]

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. However, a paradoxical consequence occurs; with muscle breakdown in rhabdomyolysis, the damaged cells release phosphate into the extracellular space, masking the clinical effects of hypophosphatemia. Plasma levels of hypophosphatemia may not accurately demonstrate the true plasma concentration during the peak level of rhabdomyolysis and may need to be repeated after peak muscle breakdown.[18] 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 referred 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. In fact, patients with concomitant heart failure and hypophosphatemia have shown improved cardiac function after supplementation.[19] Also, 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.[20] Extrapontine myelinolysis has also been reported.

Hematologic function may also 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. As mentioned previously, 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.

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Epidemiology

Frequency

United States

Hypophosphatemia may occur in as many as 2-3% of hospitalized patients and in 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

No predilection is known.

Age

Hypophosphatemia can affect people of all ages.

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Contributor Information and Disclosures
Author

Luda Khait, MD, MS Resident Physician, Department of Emergency Medicine, Detroit Medical Center, Detroit Receiving Hospital

Luda Khait, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Michigan State Medical Society, Emergency Medicine Residents' Association

Disclosure: Nothing to disclose.

Coauthor(s)

Adam J Rosh, MD Assistant Professor, Program Director, Emergency Medicine Residency, Department of Emergency Medicine, Detroit Receiving Hospital, Wayne State University School of Medicine

Adam J Rosh, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Chief Editor

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Disclosure: Nothing to disclose.

Additional Contributors

Robin R Hemphill, MD, MPH Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University School of Medicine

Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Devon J Moore, MD Resident Physician, Department of Emergency Medicine, Wayne State University Detroit Medical Center, Detroit Receiving Hospital

Devon J Moore, MD is a member of the following medical societies: American Medical Student Association/Foundation, Emergency Medicine Residents Association, and Wayne State School of Medicine Black Medical Association

Disclosure: Nothing to disclose.

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