Hypophosphatemia: Physiology, Symptoms, Diagnosis, and Treatment.

Introduction:

Hypophosphatemia is the reduced phosphate levels. Phosphates are essential for the normal cellular functioning of the human body. They play a vital role in the formation of bone and teeth by forming calcium phosphate crystals. It is an integral part of the nucleic acid that helps in the replication of DeoxyRiboNucleic Acid (DNA) and RiboNucleic Acid (RNA.). It acts as a building block and energy source for the cells to function by contributing to the formation of ADP (adenosine diphosphate). Foods like eggs, milk, and meat are rich in phosphate. A reduction in the phosphate level will have a serious effect on the body tissues causing disturbances in the normal homeostasis. Hence hypophosphatemia should be addressed early and treated promptly.

What Is the Normal Physiology of Phosphates?

Foods like eggs, milk, fish, liver, meat, and legumes are rich in phosphate. Around 20 % to 50 % of phosphate is absorbed from these food items, and a nutritious meal provides an average of 1000 mg to 2000 mg of phosphate daily. Phosphates are absorbed through the intestine from the digested food items. Phosphates are usually stored in the bone as hydroxyapatite crystals, and the free phosphates of around 300 mg are present within the cell to maintain and regulate cellular functions.

There are three types of transporters for phosphate in the body that are coupled with sodium called sodium phosphate cotransporter to mediate their function in the body.

Type1:

Sodium phosphate cotransporters are mainly present in the kidneys as well as in the liver and brain.

Type 2:

• Sodium phosphate cotransporters regulate the renal phosphate balance and function.

• Sodium phosphate cotransporters are present in the small intestine to regulate the absorption of phosphate from dietary substances.

• Sodium phosphate cotransporters are primarily found in the kidneys.

Type 3:

Sodium phosphate cotransporters are expressed in almost all the cells of the body and regulate the intracellular functions of the phosphate. The physiological function and deposition of phosphate in the bone are regulated by the parathyroid hormone, vitamin D, and sex hormones; any alterations in the levels of these factors would, in turn, affect the levels of phosphate.

What Is Hypophosphatemia?

Hypophosphatemia is characterized by the reduction in serum phosphate levels, and it is considered to be one of the electrolyte disorders. The normal serum phosphate level in adults ranges from 2.8 mg/dl to 4.5 mg/dl, and in children, it ranges between 4.0 mg/dl to 7.0 mg/dl. The levels less than 2.8 mg/dl will result in hypophosphatemia. In children, it mostly occurs due to familial or genetic causes.

What Is the Epidemiology of Hypophosphatemia?

Hypophosphatemia is reported to be one of the common electrolyte disorders. It is estimated to be seen among five percent of the general population. The prevalence of hypophosphatemia is reported to be high, that is around 80 % in patients with diabetic ketoacidosis, chronic alcoholics, etc.,

What Is the Etiology of Hypophosphatemia?

The causes of hypophosphatemia are categorized into three types,

1. Hypophosphatemia Due to Inadequate Phosphate Intake.

This may occur due to the causes such as:

• Dietary deficiency of phosphate.

• Malabsorption of phosphate in the intestine.

  • Due to chronic diarrhea.

  • Medications such as aluminum and magnesium antacids.

• Binding of phosphate by some exogenous agents.

2. Hypophosphatemia Due to Increased Excretion of Phosphate.

• Increased Parathyroid Hormone - This can cause inhibition of the sodium phosphate cotransporters and thereby increase the renal excretion of phosphates.

• X-linked Hypophosphatemic Rickets - Mutation of the PHEX gene would indirectly affect the reabsorption of phosphate from the kidneys, thereby causing hypophosphatemia.

• Fanconi Syndrome- It is characterized by the altered renal tubular function causing excessive renal loss of phosphates.

• Others - This includes the conditions which increase urine loss and will eventually end up in excessive excretion of phosphates, including chronic alcohol usage, glucosuria, chronic use of diuretics, etc.,

3. Hypophosphatemia Due to the Shift of Phosphate From Extracellular to Intracellular Space.

• Refeeding Syndrome - It occurs when a person who has been starving for a prolonged time is suddenly fed with a highly nutritious diet rich in carbohydrates, lipids, protein, etc. This, in turn, increases the demand for phosphate in the cell due to the enzyme hexokinase that binds phosphate to glucose to begin the glycolysis, and also phosphate is needed for the production of ADP, causing the shift of extracellular phosphate into the cells leading to decreased serum phosphate levels.

• Hungry Bone Syndrome - This is the condition that occurs after the treatment of hyperparathyroidism, where the damaged (osteopenic) bones require more phosphate for their repair. Hence all the free phosphate is absorbed, causing phosphate deficiency.

• Respiratory Alkalosis - In which the cellular pH increases, thereby stimulating glycolysis which uses phosphate from the extracellular space because of the increased demand. This, in turn, causes hypophosphatemia.

What Are the Symptoms of Hypophosphatemia?

In cases with mild hypophosphatemia, it usually does not produce any symptoms. Symptoms start to appear when the phosphate levels decrease to a low extent.

• Fatigue.

• Weakness.

• Irritability.

• Bone pain.

• Muscle weakness.

• Bone fractures.

• Confusion.

• Delirium.

• Numbness.

• Diplopia (double vision).

• Rhabdomyolysis (damaged skeletal muscles).

How Is Hypophosphatemia Diagnosed?

1. History: A thorough history of the associated symptoms will provide a major clue in diagnosing the condition. Drug and medical histories, such as the use of Antacids, Diuretics, and any offending drugs, and underlying diseases like diabetic ketoacidosis and genetic syndromes, are important to diagnose the causative factor of hypophosphatemia. Habit history in the case of patients with the habit of chronic alcohol usage will serve as an important factor in managing the condition.

2. Physical Examination: Physical examination of the patient would reveal the signs of muscle weakness, tremors, eye problems, fractured bones, etc. All this will help in diagnosis and treatment planning.

3. Blood Test:

• Serum Phosphate Levels - A blood test would reveal a reduction in phosphate levels; levels less than 2.5 mg/dl indicate hypophosphatemia.

• Hyperparathyroidism - To determine the parathyroid hormone levels, as hyperparathyroidism is one of the causative factors of hypophosphatemia.

4. Urine Test: A 24-hour urine test is indicated to check for renal phosphate excretion or to calculate the fractional excretion of filtered phosphate excretion (FEPO4).

Interpretation:

• 24-hour urine phosphate excretion less than 100 mg or FEPO4 less than five percent- Indicates decreased intestinal absorption.

• 24-hour urine phosphate excretion of more than 100 mg or FEPO4 more than five percent- Indicates renal loss of phosphates.

How Is Hypophosphatemia Treated?

The steps in management include,

• Stop the Offending Drug: If the patient gives a history of taking the above-discussed drugs that are the causative factors of hypophosphatemia, it should be stopped immediately to prevent further progression of hypophosphatemia.

• Treat the Underlying Disease: The underlying systemic or genetic conditions causing this condition should be addressed and treated as quickly as possible The conditions include hyperparathyroidism, diabetic ketoacidosis, genetic syndromes, etc.,

• Dietary Intake of Phosphate: Patients with mild hypophosphatemia are advised to take phosphate-rich foods in their diet, such as eggs, meat, fish, milk, nuts, whole grains, etc.,

• Oral Phosphate Supplements: Oral phosphate supplements are given to patients with mild to moderate phosphate deficiency in the form of tablets with a dosage of 30 to 80 mmol/day.

• Parenteral Administration of Phosphates: In patients with severe hypophosphatemia, phosphate should be administered intravenously to compensate for the reduced levels and to promote normal physiological functions.

What Are the Complications of Hypophosphatemia?

The complications include,

• Bone Fracture - Bones may fracture easily as the phosphate deficiency (osteopenia and osteoporosis) would weaken the hydroxyapatite crystals that make up the bone strength.

• Respiratory Failure - It may develop as a result of worsening alkalosis.

• Rhabdomyolysis - Damage to the skeletal muscle tissue and loss of function.

• Arrhythmia - An irregular heartbeat.

• Metabolic Encephalopathy - It may develop as a consequence of ATP depletion.

• Increased Chances of Infection - Increased depletion of ATP would eventually affect the chemotactic mechanisms of the white blood cells and decrease phagocytic activity, thereby increasing the chances of infection.

Conclusion:

Hypophosphatemia is one of the common electrolyte disorders. Phosphates play a vital role in maintaining the normal homeostasis of the human body. Their deficiency has a severe impact on the body's cellular and metabolic functions. Hypophosphatemia though it is asymptomatic in mild cases, it leads to a lot of complications in severe conditions. Hence addressing it early and timely treatment is necessary to prevent further complications.