fbpx

Hypophosphatemia

Updated : January 8, 2024





Background

Phosphate is a crucial element for various cellular functions in the body. It plays a critical role in the replication of DNA and RNA as essential components of nucleic acids. Additionally, it serves as an energy source for molecular functions by contributing to the production of ATP.

Furthermore, phosphate adds or removes phosphate groups to or from proteins, acting as an on/off switch to regulate molecular activity. Given its vital role in numerous cellular functions, disturbances in serum phosphate levels can significantly affect the body. Hypophosphatemia occurs when the adult serum phosphate level falls below 2.5 mg/dL.

A normal serum phosphate level in infants is significantly higher, approximately 7 mg/dL. Hypophosphatemia is a common laboratory abnormality often detected incidentally during routine blood tests. Low phosphate levels can lead to various symptoms, including muscle weakness, bone pain, and confusion.

Epidemiology

In most cases, patients with hypophosphatemia do not show any symptoms. However, the condition is prevalent among certain groups of people, such as those with alcoholism, diabetic ketoacidosis, or sepsis, with a frequency of up to 80%. The morbidity, or the diseased state, associated with hypophosphatemia varies greatly and depends on its underlying cause and severity.

For instance, individuals with severe hypophosphatemia may experience muscle weakness, respiratory failure, and cardiac dysfunction. On the other hand, those with milder forms of hypophosphatemia may experience symptoms such as bone pain, loss of appetite, and difficulty concentrating.

Anatomy

Pathophysiology

Hypophosphatemia can occur due to inadequate phosphate intake over a prolonged period, malabsorption in the intestines, or phosphate binding by certain medications. Most diets contain enough phosphate to meet the body’s needs, and renal adaptations can compensate for short-term deficiencies.

Intestinal malabsorption can be caused by various factors, including chronic diarrhea, which increases phosphate losses through the intestines. Certain medications, such as aluminum and magnesium antacids, can bind with phosphate, resulting in a net loss of phosphate from the body. This reaction creates non-absorbable aluminum or magnesium-bound phosphate salts.

The primary mechanism for increased phosphate excretion occurs in the renal system, where the proximal and distal tubules reabsorb up to 70% and 15% of filtered phosphate, respectively. The regulation of phosphate resorption depends on serum phosphate concentration, whereby mild phosphate depletion triggers increased reabsorption via sodium-phosphate cotransporters in the proximal tubule and increased formation of these transporters.

Conversely, parathyroid hormone inhibits the activity of sodium-phosphate cotransporters, thereby increasing phosphate excretion. In addition, several factors, such as 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, an increase in parathyroid hormone levels may lead to hypophosphatemia.

Etiology

Hypophosphatemia is typically caused by one of three factors insufficient intake of phosphate, excessive excretion of phosphate, or a shift of phosphate from the extracellular space into the intracellular space. Insufficient phosphate intake can occur due to inadequate dietary intake or malabsorption of phosphate in the gastrointestinal tract.

In some cases, patients with chronic alcoholism or anorexia nervosa may not consume enough phosphate in their diet to maintain normal levels in the blood. Excessive phosphate excretion can result from conditions such as renal tubular disorders, hyperparathyroidism, and certain medications such as diuretics. When the kidneys excrete too much phosphate, it can lead to hypophosphatemia.

The third cause of hypophosphatemia is the shift of phosphate from the extracellular space into the intracellular space. This can occur in various situations, including refeeding syndrome, diabetic ketoacidosis, and respiratory alkalosis. In these conditions, the body’s cells rapidly take up phosphate from the blood, decreasing phosphate concentration in the extracellular space.

Genetics

Prognostic Factors

Clinical History

Clinical History

When the body experiences prolonged hypophosphatemia, the result can be a variety of negative impacts on different systems in the body. One of the most significant effects is decreased bone mineralization, leading to osteoporosis, osteopenia, osteomalacia, and rickets. The central nervous system can also be affected, leading to metabolic encephalopathy due to ATP depletion.

Symptoms can include irritability, altered mental state, numbness, paresthesias, seizures, or even coma. The heart can also be impacted, with possible systolic heart failure and increased risk of arrhythmias due to less stable myocytes. Hypophosphatemia can also affect pulmonary function, leading to hypoventilation, particularly concerning ventilator-dependent patients.

Those with gastrointestinal issues may also experience dysphagia or ileus due to ATP deficiency. Additionally, generalized muscle weakness and rhabdomyolysis may occur, leading to renal injury and increased creatinine phosphokinases, particularly in acute or chronic hypophosphatemia cases, such as in individuals with alcohol use disorder.

While rare, hypophosphatemia can also impact the hematology systems, such as increased erythrocyte rigidity, predisposing individuals to hemolysis, reduced phagocytosis, and granulocyte chemotaxis by white blood cells, as well as thrombocytopenia.

Physical Examination

Physical Examination

Although most patients with mild hypophosphatemia do not experience symptoms, those with severe hypophosphatemia may present with various clinical manifestations. One of the most common symptoms of hypophosphatemia is generalized weakness, which can range from mild to moderate in severity.

In addition, patients with severe hypophosphatemia may experience altered mental status and focal neurologic findings such as numbness or reflexive weakness. Cardiac manifestations of hypophosphatemia may include heart failure, as phosphate is critical in maintaining normal cardiac function. Muscle pain and muscle weakness may also be present in severe cases of hypophosphatemia.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential Diagnoses

  • Delirium
  • Dilated cardiomyopathy
  • Hypothyroidism
  • Insulin overdose
  • Myopathies
  • Rhabdomyolysis
  • Uremic encephalopathy

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

 

potassium phosphate/sodium acid phosphate 

Take 1 to 2 tablets orally every 4 hours
One packet dissolved in 75 ml of water
Low urinary phosphate
Take 1 to 2 tablets orally every 6 hours
Dosage Modifications
Renal impairment: Be cautious while using it in patients with long-term kidney disease or impaired kidney function



ergocalciferol (vitamin D2) 

Take a dose of 300 to 12500 mcg orally daily



potassium phosphate 

The dose and intravenous infusion rate for potassium phosphates are determined by the patient's specific needs
below 0.5 mg/dL phosphorus serum level: 0.5 mmol/kg intravenous administered over 4-6 hours
0.5-1 mg/dL phosphorus serum level: 0.25 mmol/kg intravenous administered over 4-6 hours
Preventing hypophosphatemia (for example, in TPN): A normal dosage of 20-40 mmol/day intravenous admixed with TPN is used, but electrolyte levels were adjusted accordingly



 

calcitriol 

Indicated for Familial Hypophosphatemia:


Initial dose: 0.015-0.02mcg/kg orally everyday
Maintenance dose: 0.03-0.06 mcg/kg orally every day
Do not exceed 2mcg orally every day



potassium phosphate/sodium acid phosphate 

4 years: Safety and efficacy not determined
≥4 years: take 1 tablet orally every 6 hours
1 packet orally every 6 hours dissolved in 75 ml of water
Low urinary phosphate
<4 years: safety and efficacy not determined
≥4 years: take 1 to 2 tablets orally every 6 hour



ergocalciferol (vitamin D2) 

Take a dose of 300 to 12500 mcg orally daily



potassium phosphate 

Premature neonates should be treated with caution due to aluminium toxicity
The dose and intravenous infusion rate for potassium phosphates are determined by the patient's specific needs
below 0.5 mg/dL phosphorus serum level: 0.5 mmol/kg intravenous administered over 4-6 hours
0.5-1 mg/dL phosphorus serum level: 0.25 mmol/kg intravenous administered over 4-6 hours
Preventing hypophosphatemia (for example, in TPN)
Children and infants: 0.5-2 mmol/kg daily intravenous
Children weighing more than 50 kg or adolescents: 10-40 mmol daily intravenous
Dosage adjustments based on electrolyte levels are ongoing



 

Media Gallary

References

Hypophosphatemia

Updated : January 8, 2024




Phosphate is a crucial element for various cellular functions in the body. It plays a critical role in the replication of DNA and RNA as essential components of nucleic acids. Additionally, it serves as an energy source for molecular functions by contributing to the production of ATP.

Furthermore, phosphate adds or removes phosphate groups to or from proteins, acting as an on/off switch to regulate molecular activity. Given its vital role in numerous cellular functions, disturbances in serum phosphate levels can significantly affect the body. Hypophosphatemia occurs when the adult serum phosphate level falls below 2.5 mg/dL.

A normal serum phosphate level in infants is significantly higher, approximately 7 mg/dL. Hypophosphatemia is a common laboratory abnormality often detected incidentally during routine blood tests. Low phosphate levels can lead to various symptoms, including muscle weakness, bone pain, and confusion.

In most cases, patients with hypophosphatemia do not show any symptoms. However, the condition is prevalent among certain groups of people, such as those with alcoholism, diabetic ketoacidosis, or sepsis, with a frequency of up to 80%. The morbidity, or the diseased state, associated with hypophosphatemia varies greatly and depends on its underlying cause and severity.

For instance, individuals with severe hypophosphatemia may experience muscle weakness, respiratory failure, and cardiac dysfunction. On the other hand, those with milder forms of hypophosphatemia may experience symptoms such as bone pain, loss of appetite, and difficulty concentrating.

Hypophosphatemia can occur due to inadequate phosphate intake over a prolonged period, malabsorption in the intestines, or phosphate binding by certain medications. Most diets contain enough phosphate to meet the body’s needs, and renal adaptations can compensate for short-term deficiencies.

Intestinal malabsorption can be caused by various factors, including chronic diarrhea, which increases phosphate losses through the intestines. Certain medications, such as aluminum and magnesium antacids, can bind with phosphate, resulting in a net loss of phosphate from the body. This reaction creates non-absorbable aluminum or magnesium-bound phosphate salts.

The primary mechanism for increased phosphate excretion occurs in the renal system, where the proximal and distal tubules reabsorb up to 70% and 15% of filtered phosphate, respectively. The regulation of phosphate resorption depends on serum phosphate concentration, whereby mild phosphate depletion triggers increased reabsorption via sodium-phosphate cotransporters in the proximal tubule and increased formation of these transporters.

Conversely, parathyroid hormone inhibits the activity of sodium-phosphate cotransporters, thereby increasing phosphate excretion. In addition, several factors, such as 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, an increase in parathyroid hormone levels may lead to hypophosphatemia.

Hypophosphatemia is typically caused by one of three factors insufficient intake of phosphate, excessive excretion of phosphate, or a shift of phosphate from the extracellular space into the intracellular space. Insufficient phosphate intake can occur due to inadequate dietary intake or malabsorption of phosphate in the gastrointestinal tract.

In some cases, patients with chronic alcoholism or anorexia nervosa may not consume enough phosphate in their diet to maintain normal levels in the blood. Excessive phosphate excretion can result from conditions such as renal tubular disorders, hyperparathyroidism, and certain medications such as diuretics. When the kidneys excrete too much phosphate, it can lead to hypophosphatemia.

The third cause of hypophosphatemia is the shift of phosphate from the extracellular space into the intracellular space. This can occur in various situations, including refeeding syndrome, diabetic ketoacidosis, and respiratory alkalosis. In these conditions, the body’s cells rapidly take up phosphate from the blood, decreasing phosphate concentration in the extracellular space.

Clinical History

When the body experiences prolonged hypophosphatemia, the result can be a variety of negative impacts on different systems in the body. One of the most significant effects is decreased bone mineralization, leading to osteoporosis, osteopenia, osteomalacia, and rickets. The central nervous system can also be affected, leading to metabolic encephalopathy due to ATP depletion.

Symptoms can include irritability, altered mental state, numbness, paresthesias, seizures, or even coma. The heart can also be impacted, with possible systolic heart failure and increased risk of arrhythmias due to less stable myocytes. Hypophosphatemia can also affect pulmonary function, leading to hypoventilation, particularly concerning ventilator-dependent patients.

Those with gastrointestinal issues may also experience dysphagia or ileus due to ATP deficiency. Additionally, generalized muscle weakness and rhabdomyolysis may occur, leading to renal injury and increased creatinine phosphokinases, particularly in acute or chronic hypophosphatemia cases, such as in individuals with alcohol use disorder.

While rare, hypophosphatemia can also impact the hematology systems, such as increased erythrocyte rigidity, predisposing individuals to hemolysis, reduced phagocytosis, and granulocyte chemotaxis by white blood cells, as well as thrombocytopenia.

Physical Examination

Although most patients with mild hypophosphatemia do not experience symptoms, those with severe hypophosphatemia may present with various clinical manifestations. One of the most common symptoms of hypophosphatemia is generalized weakness, which can range from mild to moderate in severity.

In addition, patients with severe hypophosphatemia may experience altered mental status and focal neurologic findings such as numbness or reflexive weakness. Cardiac manifestations of hypophosphatemia may include heart failure, as phosphate is critical in maintaining normal cardiac function. Muscle pain and muscle weakness may also be present in severe cases of hypophosphatemia.

Differential Diagnoses

  • Delirium
  • Dilated cardiomyopathy
  • Hypothyroidism
  • Insulin overdose
  • Myopathies
  • Rhabdomyolysis
  • Uremic encephalopathy

potassium phosphate/sodium acid phosphate 

Take 1 to 2 tablets orally every 4 hours
One packet dissolved in 75 ml of water
Low urinary phosphate
Take 1 to 2 tablets orally every 6 hours
Dosage Modifications
Renal impairment: Be cautious while using it in patients with long-term kidney disease or impaired kidney function



ergocalciferol (vitamin D2) 

Take a dose of 300 to 12500 mcg orally daily



potassium phosphate 

The dose and intravenous infusion rate for potassium phosphates are determined by the patient's specific needs
below 0.5 mg/dL phosphorus serum level: 0.5 mmol/kg intravenous administered over 4-6 hours
0.5-1 mg/dL phosphorus serum level: 0.25 mmol/kg intravenous administered over 4-6 hours
Preventing hypophosphatemia (for example, in TPN): A normal dosage of 20-40 mmol/day intravenous admixed with TPN is used, but electrolyte levels were adjusted accordingly



calcitriol 

Indicated for Familial Hypophosphatemia:


Initial dose: 0.015-0.02mcg/kg orally everyday
Maintenance dose: 0.03-0.06 mcg/kg orally every day
Do not exceed 2mcg orally every day



potassium phosphate/sodium acid phosphate 

4 years: Safety and efficacy not determined
≥4 years: take 1 tablet orally every 6 hours
1 packet orally every 6 hours dissolved in 75 ml of water
Low urinary phosphate
<4 years: safety and efficacy not determined
≥4 years: take 1 to 2 tablets orally every 6 hour



ergocalciferol (vitamin D2) 

Take a dose of 300 to 12500 mcg orally daily



potassium phosphate 

Premature neonates should be treated with caution due to aluminium toxicity
The dose and intravenous infusion rate for potassium phosphates are determined by the patient's specific needs
below 0.5 mg/dL phosphorus serum level: 0.5 mmol/kg intravenous administered over 4-6 hours
0.5-1 mg/dL phosphorus serum level: 0.25 mmol/kg intravenous administered over 4-6 hours
Preventing hypophosphatemia (for example, in TPN)
Children and infants: 0.5-2 mmol/kg daily intravenous
Children weighing more than 50 kg or adolescents: 10-40 mmol daily intravenous
Dosage adjustments based on electrolyte levels are ongoing