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). It 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. [1][2][3][4][5]

Cellular

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.[6][7][8]

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 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 that 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.