Hypophosphatemia

Background
Phosphate is the most abundant intracellular anion and is essential for
- membrane structure,
- transport in all cells.
- production of ATP, which provides energy for nearly all cell functions.
- as an essential component of DNA and RNA.
- production of 2,3-diphosphoglycerate (2,3-DPG) in RBC’s, 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.
Normal Serum phosphate or phosphorus levels are 0.81-1.45 mmol/L.

Hypophosphatemia is defined as
mild: 0.65-0.81 mmol/L,
moderate: 0.32-0.65 mmol/L,
severe: < 0.32 mmol/L. Mild to moderately severe hypophosphatemia is usually asymptomatic. Major clinical sequelae usually occur only in severe hypophosphatemia.  

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 & growth hormone act to increase renal reabsorption of phosphate.
- Phosphatonins -Factors responsible for inhibition of renal phosphate reabsorption.

Major causes of hypophosphatemia
Internal redistribution
Increased insulin secretion, particularly during refeeding
Acute respiratory alkalosis
Hungry bone syndrome
Decreased intestinal absorption
Inadequate intake
Antacids containing aluminum or magnesium
Steatorrhea and chronic diarrhea
Vitamin D deficiency or resistance
Increased urinary excretion
Primary and secondary hyperparathyroidism
Vitamin D deficiency or resistance
Hereditary hypophosphatemic rickets
Oncogenic osteomalacia
Fanconi syndrome
Other – osmotic diuresis, acetazolamide, acute volume expansion

Internal re-distribution
1) Respiratory alkalosis moves phosphate into cells leading to activation of
phosphofructokinase which stimulates intracellular glycolysis leading 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.
2) Administering carbohydrate lowers serum phosphate by stimulating the release of insulin which moves phosphate and glucose into cells.
The 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) Catecholamines and beta-receptor agonists also stimulate phosphate uptake into cells.
4) Certain rapidly growing malignancies (eg, acute leukemia, lymphomas) may consume phosphate preferentially, leading to hypophosphatemia.
5) Hungry bone syndrome — Parathyroidectomy (for hyperparathyroidism) or rarely thyroidectomy (for hyperthyroidism) in patients with preexisting osteopenia can rarely result in marked deposition of calcium and phosphate in bone in the immediate postoperative period.
In most cases of intracellular phosphate shift, serum phosphate normalizes once the precipitating cause is removed.

Increased urinary excretion
1) Parathyroid hormone stimulates the kidneys to excrete phosphate,hypophosphatemia is a common sequela of primary and secondary hyperparathyroidism.
2) Urinary loss of phosphate occurs with acute volume expansion due to a dilution of serum calcium, which in turn triggers an increase in the release of parathyroid hormone.
3) 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.
4) 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.

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).

Decreased dietary intake
This is a rare cause of hypophosphatemia because of the ubiquity of phosphate in foods. Certain conditions such as anorexia nervosa or chronic alcoholism may lead to hypophosphatemia in part via this mechanism.

Manifestations of phosphate deficiency
1) Muscular weakness
2) 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.
3) Respiratory insufficiency
4) Myocardial depression, reduced threshold for ventricular arrhythmias.
5) Impaired neurologic function, manifested by confusion, seizures, and coma. Peripheral neuropathy and ascending motor paralysis, similar to Guillain-Barré syndrome. Extrapontine myelinolysis has also been reported.
6) The hemolytic anemia ,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.
7) Compromised oxygen delivery to the tissues due to decreases in erythrocyte 2,3-DPG
8) Leukocyte function is affected, which results in impaired chemotaxis and phagocytosis.

Treatment
Treatment of hypophosphatemia is twofold.
o Correct any precipitating causes of hypophosphatemia.
o Replace total body phosphates.

Depending on the clinical situation, replacement options include dietary phosphate, oral phosphate preparations, and IV phosphate.The most important consideration in choosing replacement therapy is whether the patient has signs or symptoms of phosphate depletion.

Mild to moderately severe, asymptomatic hypophosphatemia may require oral phosphate replacement; however, correcting factors that led to the hypophosphatemia usually is sufficient.
Severe/symptomatic Hypophosphatemia -Patients with symptoms of hypophosphatemia or with serum phosphate levels less than 0.32 mmol/L require IV phosphate replacement.

The intracellular nature of phosphate makes interpreting a low serum phosphate level difficult and predicting the amount required to replenish cellular stores nearly impossible.

Phosphate salt
IV preparations are available as sodium phosphate (Na2HPO4 and NAH2PO4)or potassium phosphate (K2HPO4 and KH2PO4).
Response to IV phosphorus supplementation varies widely and may be associated with hyperphosphatemia and hypocalcemia. Rate of infusion and choice of initial dosage should be based on severity of hypophosphatemia and presence of symptoms.

Thanks to Dr Harjit Mahay for contributing this wonderful article.