Introduction

Phosphate is an essential electrolyte in the human body as it constitutes about 1% of the total body weight. In an adult, the normal serum phosphate level ranges between 2.5 to 4.5 mg/d L. The normal serum levels of phosphate tend to decrease with age and its highest levels i.e., 4.5 to 8.3 mg/dL are seen in infants, about 50% higher than adults; this is because infants and children need more phosphate for their growth and development.

Phosphate is readily available in our diet as it is present in almost all-natural foods. Important dietary sources of phosphate are milk, cereal grains, fish, poultry, eggs, meat, and peanuts.

Of the total phosphate in the body, 85% is n the bones and teeth,1% in the extracellular fluid and the remaining 14% is distributed in other tissues where it is an important constituent of cell membranes, nucleic acids, high energy phosphate esters (ATP) and intracellular signaling proteins.

 In the skeleton, the majority of the phosphate is in combination with calcium in the form of hydroxyapatite crystals, and the rest is present in the form of amorphous calcium phosphate. There are two forms of phosphate present in the serum, dihydrogen phosphate( H2PO4) and mono hydrogen phosphate (HPO4); the balance between these two forms depends on the acid-base status of the body.[1][2]

Development

Phosphate deficiency is a non-nutritional cause of rickets. It occurs due to renal phosphate wasting, the cause of which can be any of the following:

1. Renal tubular disorder i.e., Fanconi syndrome or dent disease[3]
2. X- linked hypophosphatemic rickets: it results from a mutation in the phosphate regulating endopeptidase homolog (PHEX gene)  that leads to unregulated FGF23 production.[4]
3. Autosomal dominant hypophosphatemic rickets.
4. Autosomal recessive hypophosphatemic rickets with hypercalciuria: Clinical features: In children, it presents with delayed closure of fontanelle, craniotabes (soft skull bones), rachitic rosary (enlargement of the costochondral junction), leg bowing, growth delay, and tooth decay. In adults, it presents as osteomalacia. Diagnosis: Clinical features and radiographic imaging indicative of rickets in the presence of normal serum calcium and PTH levels and decreased serum phosphate levels suggest phosphopenic rickets. The different causes of phosphopenic rickets can be differentiated by checking urinary levels of calcium, glucose, bicarbonate, and amino acids.[5]. X linked hypophosphatemic rickets is diagnosed by measuring renal tubular reabsorption of phosphate (TRP), the formula for its calculation is following

                              Phosphate clearance (CPi) / creatinine clearance ) x 100

          The formula for CPi calculation is as following

                              urine phosphate( mg/dL) x Volume (mL/ min ) / Plasma phosphate( mg/dL)

Normal TRP is greater than 90%. A TRP of 60% is diagnostic for X-linked hypophosphatemic rickets.[6]

Organ Systems Involved

Serum phosphate levels depend upon dietary intake, mobilization of phosphate from bone, and renal excretion of the phosphate. Levels of phosphate are tightly regulated since hyperphosphatemia, as seen in chronic kidney disease, is associated with significant cardiovascular morbidity, while hypophosphatemia can lead to rickets and osteomalacia. There are three regulatory hormones which are responsible for the phosphate homeostasis.

• Vitamin D in its active form calcitriol, also known as 1,25-dihydroxycholecalieferol
• Parathyroid hormone
• FGF-23 in association with its membrane-bound protein klotho

In the gastrointestinal tract, most of the dietary phosphate is absorbed in the jejunum. At the subcellular levels, this absorption occurs through two pathways

      1-Paracellular, Na+ independent pathway

      2-Transcellular, Na+ dependent pathway via sodium phosphate cotransporter (NaPi-IIb)

In the gut, 1-25 dihydroxy vitamin D increases phosphate absorption increasing the expression of sodium phosphate cotransporter ( NaPi-IIb). Conversely, FGF-23, which is released from osteoblasts and osteocytes of the bone in response to increased serum phosphate levels, causes decreased intestinal phosphate absorption by inhibiting the synthesis of the active form of vitamin D. 

In the kidneys, nearly all of the plasma phosphate is filtered. The main site of phosphate reabsorption in kidneys is the proximal convoluted tubule. At the subcellular level, this reabsorption occurs through 3 different transport proteins. Most of the reabsorption occurs through Sodium phosphate cotransporters NaPi- IIa, and NaPi-IIc while some of it occurs through PiT-2 transporter.

In the kidneys, PTH released from the parathyroid gland in response to high serum phosphate levels, exerts its phosphaturic effect by causing internalization of  NaPi-IIa and NaPi-IIC cotransporters. FGF-23 inhibits proximal tubular reabsorption of phosphate by inhibiting the expression of NaPi-IIa at the translational level.

Note that  PTH has dual effects in phosphate homeostasis as it also increases GI phosphate absorption indirectly by increasing activation of vitamin D, but contrary to that, FGF-23 decreases serum phosphate level by inhibiting its GI absorption and increasing its renal excretion.[7][8][9][10]

Function

Phosphate is responsible for several functions in the human body. Its role in different parts of the body are as follows:

Bone mineralization: phosphate is responsible for mineralization of the bony matrix. This process begins in the matrix vesicle, which are extracellular structures derived from the cell membrane of the osteoblast and chondrocytes. Matrix vesicles acquire phosphate by two pathways:

1. Tissue nonspecific Alkaline phosphatase present within matrix vesicles hydrolyzes phosphoric esters to inorganic phosphate.
2. Matrix vesicles uptake extracellular phosphate via Type II Na/Pi cotransporter.

Matrix vesicles form hydroxyapatite crystals from calcium and phosphate; these crystals mineralize the extracellular matrix of the bone.

Endochondral Ossification: Phosphate is responsible for endochondral ossification of the bone as increased intracellular phosphate levels induce apoptosis of the terminally differentiated chondrocytes.

Teeth: Phosphate is important for mineralization of all the structural components of the teeth i.e., it is an integral component of enamel, dentin, cementum, and alveolar bone.[11][12]

Cellular functions: In the cells, phosphate is an important component of the lipid bilayer of cell membranes, DNA, RNA, and proteins. It is responsible for several enzymatic reactions within the cells, e.g., glycolysis and ammoniagenesis. It modifies the actions of different molecules by getting attached or detached from them in response to kinases and phosphates. It also carries out oxidative phosphorylation, which is the reaction that converts adenosine diphosphate to adenosine triphosphate, the energy currency of the cell.

Phosphate has a role in the oxygen-carrying capacity of hemoglobin by regulating the synthesis of 2,3-bisphosphoglycerate.

Urinary Buffer: Inorganic phosphate ( HPO42-)  is an important urinary buffer, as it can bind reversibly bind with free hydrogen ions, and its PKA, which is 6.8, is also very close to plasma pH. Also, the concentration of phosphate increases as the fluid is resorbed within the tubule, thus making it an excellent buffer.[13]

Clinical Significance

Hypophosphatemia:

Hypophosphatemia is defined as serum phosphate levels of less than 2.5 mg/dL. It can be due to any of the following mechanisms.

      .    Decreased dietary intake e.g., intestinal malabsorption, chronic alcoholism, malnutrition, and vitamin D deficiency.

      .    Increased excretion e.g., hyperparathyroidism, forced saline diuresis, genetic causes that involve proximal renal tubule i.e., Fanconi syndrome.

•  The transcellular shift from extracellular fluid to intracellular fluid e.g., treatment of diabetic ketoacidosis by insulin, refeeding syndrome

 Clinical presentation: Mild hypophosphatemia (2 to 2.5 mg/Dl) is usually asymptomatic. Some patients present with non-specific symptoms of fatigue, weakness, and bone pain depending upon the severity and underlying disorder.

In the context of hypophosphatemia, a condition called refeeding syndrome is especially important. It develops when a chronically malnourished patient suddenly receives parenteral nutrition, which causes the release of insulin that shifts phosphate ion from extracellular fluid to intracellular fluid leading to the development of acute hypophosphatemia, the consequences of which include electrolyte imbalance, arrhythmias, muscle weakness, seizure, and encephalopathy.

Management: It involves the treatment of underlying cause and phosphate replacement.[14][15][16]

Hyperphosphatemia:

Hyperphosphatemia, which is abnormally elevated levels of serum phosphate i.e.,> 4.5 mg/dL, is an important laboratory finding as it can have several underlying causes. 

Acute phosphate load: it can develop by any of the following mechanism:

• Exogenous e.g., intake of phosphate-containing laxatives and vitamin D toxicity
• Endogenous e.g., tumor lysis syndrome, rhabdomyolysis

 Decreased phosphate excretion: it can be due to,

• Decreased filtered load e.g., kidney failure
• Abnormal tubular handing e.g., hypoparathyroidism, pseudohypoparathyroidism

  Transcellular shift from intracellular to extracellular fluid: diabetic ketoacidosis, lactic acidosis.

Clinical presentation: Most of the patients are asymptomatic, or they have symptoms of the underlying cause of hyperphosphatemia. Hyperphosphatemia in CKD patients can lead to an increased risk of vascular calcification that increases the risk of cardiovascular events.

Acute hyperphosphatemia can present with hypocalcemia symptoms because of the binding of excessive phosphate ions with calcium, thus lowering serum calcium levels. This condition leads to the development of symptoms such as muscle cramps, tetany, perioral numbness, and tingling.

Diagnosis: To diagnose the cause of hyperphosphatemia, it is important to do a complete blood chemistry profile, including serum calcium levels, PTH, BUN, creatinine, and vitamin D levels.

Hyperphosphatemia in the setting of abnormal BUN and creatinine values indicate chronic renal failure, which is the most common cause of hyperphosphatemia.

Low serum calcium levels indicate renal failure, hypoparathyroidism, and pseudohypoparathyroidism as the cause of hyperphosphatemia, while high calcium levels with high phosphate levels indicate vitamin D toxicity and milk-alkali syndrome.

Elevated PTH would present in renal failure or pseudohypoparathyroidism, but low PTH levels in the setting of normal renal function test indicate primary or acquired hypoparathyroidism as the cause of hyperphosphatemia.

Rarely, if the cause of hyperphosphatemia cannot be established, then a 24-hour measure of urinary phosphate is helpful in diagnosis.

 Fractional renal excretion >15% indicates massive phosphate ingestion (laxative abuse) or tissue lysis. While fractional renal excretion of <15% shows impaired renal excretion of phosphate, it can happen due to impaired renal function or hypoparathyroidism.

Management: It involves the diagnosis and treatment of the underlying cause.

•  Limit phosphate intake: in patients of chronic renal failure, phosphate binders are used to decrease gastrointestinal absorption of phosphate.
• Increased renal excretion: in patients with normal renal function, phosphate excretion can be increased by giving saline along with forced diuresis using loop diuretic such as furosemide.[17][15]

Pharmacologic use: Phosphate ion, as a combination of sodium phosphate is used as a laxative to relieve constipation and also as a purgative for bowel preparation before colonoscopy or colon surgery. Sodium and potassium phosphate salts are used as supplements in hypophosphatemia in both intravenous and oral forms.