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Hypophosphatemia

Phosphate involved in a vast umber of cellular processes including DNA synthesis, energy generation and use, maintains the redox state of all body cells, aids in oxygen uptake and delivery to red blood cells.

The most abundant intracellular anion and is essential for membrane structure, energy storage, and transport in all cells.

Electrolyte disturbance in which there is an abnormally low level of phosphate in the blood.

Most commonly seen when malnourished patients,especially alcoholics, are given large amounts of carbohydrates creating a high phosphorus demand by cells.

Necessary to produce ATP, which provides energy for nearly all cell functions.

Phosphate is an essential component of DNA and RNA.

Serum phosphate is regulated by three hormones: parathyroid hormone, fibroblast growth factor 23 and calcitriol.
Fibroblast growth factor 23 is a peptide hormone produced by osteocytes and osteoblasts in response to high serum phosphate level and lowers the serum phosphate level by impairing resorption of phosphate in the proximal tubule of the kidney by down regulating sodium-phosphate cotransporters, and lowers serum calcitriol level by decreasing its synthesis, and promotes its catabolism.
 
Renal causes of hypophosphatemia are FGF-23 dependent or FGF-23 independent.

Phosphate is 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.

Most of the remaining phosphate is present in soft tissue.

Only 0.1% of phosphorus is present in extracellular fluid, and is measured with a serum phosphorus level.

May compromise any organ system.

Has a critical role in every cell, tissue, and organ which 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.

Clinical manifestations of hypophosphatemia rarely apparent until phosphate levels for below 1 mg/dL.

Manifests as muscle dysfunction and weakness occurring in major muscles, but also may manifest as: diplopia, low cardiac output, dysphagia, and respiratory depression due to respiratory muscle weakness.

Hypophosphatemia can cause rhabdomyolysis, heart failure, and respiratory failure, and chronic hypophosphatemia can be complicated by osteomalacia and fractures.

May be associated with mental status changes with confusion, irritability, delirium and even coma.

May be associated with proximal myopathy dysphasia ileus and impaired cardiac contractility.

May be associated with white cell dysfunction with increasing risk of infections.

Major clinical sequelae usually occur only in severe hypophosphatemia.

A decrease in the level of phosphate should be distinguished from a decrease in total body storage of phosphate.

Signs of phosphate depletion are nonspecific.

Findings may include respiratory insufficiency, congestive heart failure, comatose state, hypotension, weakness, fatigue and malaise.

Commonly occurs in the intensive care unit setting when nutrition is impaired and intravenous phosphate is less than optimal, patients receive diuretics and saline infusions which increase losses of phosphate via the kidney.

Hallmark of refeeding syndrome.

When a chronic process can lead to impaired skeletal mineralization such as rickets in children and osteomalacia in adults.

In adulthood widespread bone pain may occur with prolonged hypophosphatemia.

Gait abnormalities attributed to pain with ambulation is a common manifestation of osteomalacia in adulthood due to chronic hypophosphatemia.

Adult osteomalacia can manifest on skeletal imaging as pseudo-fractures, insufficiency fractures or hot spots on bone scans mimicking metastatic cancer.

Causes include:1-impaired intake disorders as in starvation, malabsorption, use of phosphate binding antacids, and alcoholism, 2-renal losses associated in hyperparathyroidism, hypercalcemia of malignancy associated with PTH like hormone, use of diuretics, use of calcitonin, rickets, osteomalacia, Fanconi’s syndrome and alcoholism, 3-excessive mineralization associated with hungry bone syndrome after parathyroidectomy, osteoblastic metastases, and healing in rickets and osteomalacia, 4-shifts of PO4 into extracellular fluid as seen in recovery of metabolic acidosis, respiratory alkalosis, use of intravenous glucose and refeeding after starvation.

Refeeding syndrome caused by a demand for phosphate in cells due to the action of phosphofructokinase, that attaches phosphate to glucose to begin metabolism of this, and by the production of ATP when cells are fed and recharged requiring phosphate.

Respiratory alkalosis, caused by hyperventilation causes carbon dioxide decreases in the extracellular space, causing intracellular CO2 to diffuse out of the cell, increasing cellular pH which stimulates glycolysis, requiring increased phosphate in metabolically active tissue so that moves phosphate out of the blood into cells.

Alcohol impairs phosphate absorption, is associated with refeeding, and the stress of alcohol withdrawal may create respiratory alkalosis, which exacerbates hypophosphatemia.

Alcoholics are usually also malnourished with regard to minerals.

With malabsorption failure to absorb phosphate due to lack of vitamin D, or chronic use of phosphate binders such as sucralfate, aluminum-containing antacids, and calcium-containing antacids.

Primary hypophosphatemia is the most common cause of nonnutritional rickets.

Rare causes of hypophosphatemia include: lymphoma or leukemia, hereditary causes, hepatic failure and tumor-induced osteomalacia.

All types of hyperparathyroidism associated with hypophosphatemia as long as renal function is normal, including primary hyperparathyroidism, and secondary hyperparathyroidism associated with malabsorption of vitamin D and calcium.

May be the only finding in vitamin D deficiency associated with malabsorption.

In the setting of low to normal serum calcium suggests the presence of secondary hyperparathyroidism due to calcium malabsorption and vitamin D deficiency.

Because almost all foods have rich phosphate content it is difficult to have phosphate depletion on the basis of poor intake of phosphorus.

Can occur in the presence of extreme caloric deprivation such as with anorexia nervosa, prisoner of war camps, malabsorption diseases or chronic alcoholism.

Hypophosphatemia is associated with cell membrane instability related to low ATP levels that may cause elevated CPK, rhabdomyolysis, and hemolytic anemia.

Standard intravenous preparations of potassium phosphate are available and are routinely used in malnourished patients and alcoholics.

Oral supplementation also is useful where no intravenous treatment is available.

Replacement generally by the oral route with divided doses of two to four times per day with 2-4000 mg per day.

Phosphate treatment above 1-2000 mg/day associated with diarrhea.

Intravenous doses of 500-800 mg per day may be needed.

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