Phosphate is one of the most important molecular elements to normal cellular functions within the body. It acts as an integral component of nucleic acids and is used to replicate DNA and RNA. It is an energy source for molecular functions through its role in adenosine triphosphate (ATP) and adds and deletes phosphate groups to or from proteins functions as an on/off switch for the regulation of molecular activity. Given its widespread role in nearly every molecular, cellular function, aberrations in serum phosphate levels can be highly impactful.
Hypophosphatemia is defined as an adult serum phosphate level of less than 2.5 mg/dL. The normal level of serum phosphate in children is considerably higher and 7 mg/dL for infants. Hypophosphatemia is a relatively common laboratory abnormality and is often an incidental finding. 
In general, phosphate is upregulated through absorption in the intestines and decreased through renal excretion. Excesses are stored in the bones which act as a buffer to maintain a relatively stable total body content. A typical, nutritious diet provides 1000 to 2000 mg of phosphate daily. Of this 600 mg to 1200 mg is absorbed via the intestines. Normal serum levels of phosphate should be 4 to 7 mg/dL in children and 3 to 4.5 mg/dL in adults. Phosphate exists primarily in the crystallized extracellular matrix of bones within the body where it is relatively stable and inert. In the absence of pathology, homeostasis of bone phosphate is neutral with resorption and deposition of approximately 300 mg per day. Bone homeostasis of phosphate is regulated primarily by parathyroid hormone, vitamin D, and sex hormones. Free phosphate within the body is predominantly intracellular at a concentration of approximately 100 mmol/L. This intracellular concentration is maintained using sodium-coupled transport proteins where extracellular high sodium gradients are used to cotransport phosphate against its concentration gradient into the cellular space. Type 1 sodium phosphate cotransporters are expressed primarily in kidney cells but also are seen in brain and liver tissues. Type 2 sodium phosphate cotransporters function under parathyroid hormone, dopamine, vitamin D, and phosphate concentration regulation. The three types of type 2 transporters are Type 2a, Type 2b, and Type 2c. Type 2a transporters primarily function to modulate renal phosphate homeostasis. Type 2b transporters are expressed in the small intestine and control the dietary uptake of phosphate. Type 2c are thought to be growth-related phosphate transporters and primarily function in the kidneys. Type 3 sodium phosphate cotransporters are present in nearly all cells and function to regulate intracellular phosphate levels.
Hypophosphatemia is most commonly induced by one of three causes: (1) Inadequate phosphate intake, (2) increased phosphate excretion, and (3) shift from extracellular phosphate into the intracellular space.
Hypophosphatemia is typically asymptomatic and is present in up to 5% of patients. It is much more prevalent in alcoholism, diabetic ketoacidosis, or sepsis with a frequency of up to 80%. The morbidity of hypophosphatemia is highly dependent on its etiology and severity.
As previously stated, hypophosphatemia's most common causes are inadequate phosphate intake, increased phosphate excretion, and shift from extracellular phosphate into the intracellular space.
Hypophosphatemia secondary to inadequate intake of phosphate occurs in the setting of prolonged poor dietary sources of phosphate, intestinal malabsorption, and intestinal binding by exogenous agents. As stated above, almost all diet types contain a surplus of phosphate sufficient to maintain needs. Additionally, renal adaptations typically can compensate for the short-term deficiency. Intestinal malabsorption may be due to a variety of causes. Notably, chronic diarrhea has been shown to increase phosphate losses through the intestines. Certain medications are known to bind with phosphate, decreasing the available free ion to be absorbed via the small intestines into circulation. Aluminum and magnesium antacids are notoriously associated with a net loss of phosphate from the body by binding to both ingested and excreted phosphate. This chemical reaction creates aluminum- or magnesium-bound phosphate salts which are nonabsorbable by the body.
Increased excretion of phosphate occurs primarily in the renal system. The proximal renal tubule reabsorbs up to 70% of filtered phosphate normally, and the distal tubule reabsorbs up to 15% of filtered phosphate. Resorption is regulated by serum phosphate concentration with mild phosphate depletion which directly triggers increased phosphate reabsorption via the sodium-phosphate cotransporters of the proximal tubule and increases expression and formation for new sodium-phosphate cotransporters. Conversely, parathyroid hormone functions to increase phosphate excretion by inhibiting the activity of sodium-phosphate cotransporters. Additionally, fibroblast growth factor 23, fibroblast growth factor 7, extracellular matrix phosphoglycoprotein, and secreted frizzled-related protein-4 decrease phosphate reabsorption by sodium-phosphate cotransporters. Therefore, any increase in parathyroid hormone has the potential for inducing hypophosphatemia.
Primary or secondary hyperparathyroidism are the most likely causes where primary hyperparathyroidism is due to hypercalcemia and secondary hyperparathyroidism is induced by any of the causes that lead to vitamin D deficiency. Primary renal phosphate-wasting syndromes also exist where there is a direct failure of the renal system without coexisting systemic failure. These include a wide variety of genetic malformations, leading to faulty sodium-phosphate cotransporters. One of the larger examples of this includes X-linked hypophosphatemic rickets where a mutation in the PHEX gene leads to increased levels of fibroblast growth factor 23 and directly decreases resorption of phosphate in the proximal renal-collecting tubules. Mutations in the sodium-phosphate cotransporter gene SLC34A3 causes type 2c sodium-phosphate cotransporter failure. The SLC34A1 gene is responsible for encoding the type 2a sodium-phosphate cotransporter and has been associated with mutations. The sodium-hydrogen exchanger regulatory factor 1 is responsible for creating the sodium gradient which powers most ion reabsorption. Mutations here lead to pan-ionic losses. Fanconi syndrome is another classic cause of renal losses. It is a generalized impairment in proximal tubular function leading to urinary wasting most often due to illnesses such as multiple myeloma where immunoglobulin light chains induce renal tubular damage and Wilson disease with copper accumulation in children. Anything that increases urine production also will lead to increased phosphate loss, including glucosuria, alcohol, lithium, and diuretics such as acetazolamide and thiazides, rapid fluid volume expansion from oral or intravenous fluids. In patients with renal failure, hypophosphatemia can be seen as a result of dialysis therapy removing phosphate in bulk.
Intracellular shifting of phosphate stores may occur in a variety of clinical scenarios. Refeeding syndrome occurs when a patient who has been starved of nutrition suddenly is replenished with carbohydrates, proteins, and lipids. Insulin and glucose assist in driving phosphate intracellularly. The net body stores of phosphate necessary to perform basic metabolism such as glycolysis are depleted. The body begins to process the newfound foods to produce ATP for energy. Cells uptake all available free phosphate, leading to profound hypophosphatemia. Hungry bone syndrome occurs after correction of hyperparathyroidism where osteopenic bones begin to reabsorb and store phosphate and calcium. This leads to increased bone demand for these ions and hypophosphatemia. Acute respiratory alkalosis induces hypophosphatemia via changes in cellular pH. Increased pH stimulates phosphofructokinase, thus stimulating glycolysis to produce ATP thus consuming phosphate from the cellular space. Serum phosphate is shifted intracellularly to meet this demand. While typically mild, extreme hyperventilation with subsequent PCO2 changes to less than 20 mmHg can lower phosphate concentrations to below 0.32 mmol/L. This is thought to be the most common cause of marked hypophosphatemia in hospitalized patients.
Most patients with hypophosphatemia are asymptomatic, and it is an incidental finding. Those with mild hypophosphatemia may complain of generalized mild to moderate weakness. The history of presenting illness will rarely indicate possible hypophosphatemia. For this reason, a clinician should have suspicion for phosphate abnormalities whenever an etiology is present that is associated with hypophosphatemia. Conditions to consider possible hypophosphatemia include poor nutritional status, symptoms or history of intestinal malabsorption, history of antacid use, frequent or recurrent bone pain, fractures, history of or suspicion for multiple myeloma, parenteral nutrition supplementation, medication use including chronic glucocorticoids, cisplatin, or pamidronate, current treatment for diabetic ketoacidosis, and any hospitalization requiring an Intensive care unit setting.
Mild hypophosphatemia will not be clinically apparent. Severe hypophosphatemia may have the clinical presence of altered mental status, neurological instability including seizures and focal neurologic findings such as numbness or reflexive weakness, a cardiac manifestation of possible heart failure, muscle pain, and muscular weakness.
Hypophosphatemia is diagnosed with a simple serum measurement. Etiology is typically evident from the history. However, if unknown it is essential to determine renal phosphate excretion. Renal phosphate excretion can be measured either from a 24-hour urine collection or by calculation of the fractional excretion of filtered phosphate (FEPO4) from a random urine specimen. EPO4 is calculated as follows where U is urine values and P is plasma values of phosphate (PO4) and creatinine (Cr):
A 24-hour urine phosphate excretion less than 100 mg or FEPO4 less than 5% shows decreased phosphate excretion, indicating hypophosphatemia is from a redistribution within the body or decreased intestinal absorption. A 24-hour urine phosphate excretion greater than 100 mg or FEPO4 greater than 5% indicates renal phosphate wasting. Hypophosphatemia in this scenario is likely due to by hyperparathyroidism or vitamin D deficiency.
The effects of hypophosphatemia are broad and impact nearly every system. Symptoms of this deficiency become apparent below 0.32 mmol/L. Effects primarily are due to intracellular depletion; however, chronic effects can be seen in the bone structures. Prolonged hypophosphatemia leads to osteopenia, osteoporosis, rickets, or osteomalacia due to decreased bone mineralization. The central nervous system may manifest with metabolic encephalopathy as a result of ATP depletion and may include altered mental state, irritability, paresthesias, numbness, seizures, or coma. Cardiac function is impacted by ATP depletion. In addition to possible systolic heart failure, the myocytes become less stable, and arrhythmias are possible. The decreased diaphragmatic function impacts pulmonary function with subsequent hypoventilation. Ventilator dependent patients have been shown to have longer hospital courses and worse outcomes when hypophosphatemia is present. Gastrointestinal dysfunction occurs as a result of ATP deficiency also with dysphagia or ileus possible. Generalized muscular weakness can occur. Rhabdomyolysis may occur resulting in renal injury and increased creatinine phosphokinases; however, this is typically only seen in acute or chronic hypophosphatemia such as in acutely ill persons with alcoholism. The hematology systems are rarely impacted, but depletion of ATP may result in increased erythrocyte rigidity, predisposing to hemolysis, reduced phagocytosis and granulocyte chemotaxis by white blood cells, and thrombocytopenia. 
While symptoms are not clinically present in mild cases, it is important to address and replace phosphate whenever abnormalities are noted. The appropriate regimen for replacement is determined depending on clinical symptoms. Mild, asymptomatic cases with a serum phosphate less than 0.64 mmol/L should receive oral phosphate therapy of 30 to 80 mmol of phosphate per day, depending on the severity of deficiency. Severe, symptomatic cases are appropriate for intravenous phosphate if the serum phosphate is less than 0.32 mmol/L and should be changed to oral replacement when the serum phosphate exceeds 0.48 mmol/L and there are no contraindicating reasons for oral replacement.
The most common manifestation is a generalized weakness. As such, any other electrolyte aberrations should also be suspected, including hypokalemia and hypomagnesemia.
Additionally, consider the following:
Because of the diverse presentation of hypophosphatemia, the condition is best managed by a multidisciplinary team that consists of an internist, endocrinologist, intensivist, general surgeon and a nurse practitioner. The effects of hypophosphatemia are broad and impact nearly every system. Symptoms of this deficiency become apparent below 0.32 mmol/L. In general, all symptomatic patients need treatment with phosphate; asymptomatic patients may be observed and monitored. The outlook for patients depends on the primary condition causing the hypophosphatemia. If the cause is benign, then treatment outcomes are excellent. (Level V)
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