eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Hypophosphatemia

Author: Devon J Moore, MD, Resident Physician, Department of Emergency Medicine, Wayne State University Detroit Medical Center, Detroit Receiving Hospital
Coauthor(s): Adam J Rosh, MD, MS, Assistant Professor, Department of Emergency Medicine, Wayne State University/Detroit Receiving Hospital
Contributor Information and Disclosures

Updated: Sep 22, 2009

Introduction

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.

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).

Pathophysiology

Phosphorus 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, such as oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia, and tumoral calcinosis.¹

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, when clinically appropriate.²

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.³  

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.⁴  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.

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.⁵  

There is also evidence that shows estrogen to be a downregulator of a renal sodium phosphate cotransporter, causing significant hypophosphatemia in patients.⁶     

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.⁷

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

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.⁸ 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.

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.

Clinical

History

• Weakness is the most common symptom suggesting hypophosphatemia and may involve any muscular system to any extent.
  • Diplopia
  • Dysarthria
  • Dysphagia
  • Weakness of trunk or extremities, particularly the large muscle groups
• Symptoms of respiratory insufficiency or myocardial depression may indicate hypophosphatemia.
• Neurologic symptoms may vary, ranging from simple paresthesias to profound alterations in mental status.

Physical

• Muscle weakness is the most common physical finding; careful assessment of motor strength on neurologic examination is critical. Weakness may be subtle or profound and may involve any muscle group.
• Diminished respiratory rate and tidal volume may reflect respiratory impairment due to hypophosphatemia; however, tachypnea may be present, an important clue to one of the most common etiologies of hypophosphatemia (respiratory alkalosis).²
• Hypotension and cardiac compromise due to severe hypophosphatemia is rare.
• The skin and conjunctivae may be pale secondary to the hemolytic anemia that may complicate hypophosphatemia.
• Signs of rhabdomyolysis may be present on extremities.
• Mental status abnormalities may occur with severe hypophosphatemia, ranging from simple irritability or confusion to florid altered mental status and coma.

Causes

• The ED physician is most likely to encounter hypophosphatemia in patients withdrawing from alcohol and in patients undergoing treatment for DKA.
• Other risk factors
  • Chronic alcoholism
  • Chronic ingestion of phosphate-binding antacids
  • Patients on total parenteral nutrition (TPN) with inadequate phosphate supplementation
  • Refeeding after prolonged starvation (eg, anorexia nervosa)
• Hypophosphatemia may also occur in the setting of thyrotoxic periodic paralysis (TPP). If considering this diagnosis, the presence of hypophosphatemia suggests TPP rather than spontaneous periodic paralysis, in which phosphorus levels are likely to be normal.

• Search for CME/CE on This Topic »

• Hypophosphatemia (Nephrology)
• Parathyroid Adenoma (Radiology)
• Urinary Obstruction (Emergency Medicine)
• Hydrocarbon Inhalation Injury (Pediatrics: General Medicine)

• Higher-Intensity Continuous Renal Replacement May Not Reduce Mortality Risk From Acute Kidney Injury

• Motexafin Gadolinium for the Treatment of Metastatic Renal Cell Carcinoma: Phase II Study Results
• Factitious Biochemical Measurements Resulting From Hematologic Conditions
• Pharmacokinetics and Pharmacodynamics of Six Epoetin Alfa Dosing Regimens in Anemic Critically Ill Patients without Acute Blood Loss