Hypophosphatemia: Signs, Symptoms, Causes, Pathophysiology, Diagnosis, Treatment, Complications and Associated Conditions

It is an abnormally low level of phosphate in the blood.

Phosphate is an electrolyte that helps your body with energy production and nerve function. Phosphate also helps build strong bones and teeth.

You get phosphate from foods like milk, eggs, and meat. Most of the phosphate in your body is stored in your bones.

Because a decrease in phosphate in the blood is sometimes associated with an increase in phosphate in the urine, the terms hypophosphatemia and “phosphaturia” are occasionally used interchangeably.

However, this is incorrect as there are many causes of hypophosphatemia in addition to overexcretion and phosphaturia, and in fact the most common causes of hypophosphatemia are not associated with phosphaturia. There are two types of hypophosphatemia:

  • Acute hypophosphatemia, which appears quickly.
  • Chronic hypophosphatemia, which develops over time.

Familial hypophosphatemia is a rare form of the disease that is transmitted from parents to children. This form of the disease can also lead to the rickets of bone disease and a softening of the bones called osteomalacia.

Most people with the familial form have familial X-linked hypophosphatemia (XLH). A smaller number have autosomal dominant familial hypophosphatemia (ADHR).

Another rare genetic form of this disease is hereditary hypophosphatemic rickets with hypercalciuria (HHRH). In addition to hypophosphatemia, this condition is characterized by high levels of calcium in the urine (hypercalciuria).

In general, hypophosphatemia is rare. It is more common in people who are hospitalized or admitted to intensive care units (ICU). Between 2% and 3% of people admitted to the hospital and up to 34% of those who are in the intensive care unit have this condition.

Signs and symptoms of hypophosphatemia

Many people with mild hypophosphatemia have no symptoms. Symptoms may not appear until phosphate levels drop very low. When symptoms do occur, they can include:

  • Muscular weakness.
  • Fatigue.
  • Bone-ache.
  • Bone fractures
  • Loss of appetite
  • Irritability.
  • Numbness.
  • Confusion.
  • Slow growth and shorter than normal height in children.
  • Caries or late milk teeth (in familial hypophosphatemia).

Muscle dysfunction and weakness : This occurs in the major muscles, but can also manifest as diplopia, low cardiac output, dysphagia, and respiratory depression due to weakness of the respiratory muscles.

Changes in mental status can range from irritability to general confusion, delirium and coma, and white blood cell dysfunction, which makes infections worse.

Instability of cell membranes due to low levels of adenosine triphosphate (ATP), this can cause rhabdomyolysis with increased creatine phosphokinase (CPK) and also hemolytic anemia.

Increased affinity for oxygen in the blood caused by decreased production of 2,3-bisphosphoglyceric acid (2,3-BPG).

Causes

Because phosphate is found in many foods, it is rare for you to be deficient, unless you are malnourished. Certain medical conditions can cause hypophosphatemia by:

  • Decrease the amount of phosphate your intestines absorb.
  • Increase the amount of phosphate that your kidneys get rid of in your urine.
  • Move phosphate from inside the cells to the area outside the cells.

Causes of hypophosphatemia include:

  • Severe malnutrition, such as anorexia or starvation.
  • Alcoholism.
  • Severe burns
  • A complication of diabetes called diabetic ketoacidosis.
  • Kidney disorder, Fanconi syndrome.
  • Too much parathyroid hormone ( hyperparathyroidism ).
  • Chronic diarrhea.
  • Vitamin D deficiency (in children).
  • Hereditary conditions such as ax-linked familial hypophosphatemia (XLH) or hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Low phosphate levels can also be due to prolonged or excessive use of certain medications, such as:

  • Diuretics
  • Antacids that bind to phosphate.
  • Theophylline , bronchodilators, and other asthma medications.
  • Corticosteroids
  • Mannitol (osmitrol).
  • Hormones like insulin, glucagon, and androgens.
  • Nutrients such as glucose, fructose, glycerol, lactate, and amino acids.
  • Bisphosphonates.
  • Aciclovir (zovirax).
  • Acetaminofeno (tylenol).

Familial hypophosphatemia is caused by genetic changes (mutations) that are passed from parents to children. These genetic changes cause the kidneys to excrete more phosphate than normal from the blood into the urine.

Overheating syndrome : This causes a demand for phosphate in cells due to the action of hexokinase, an enzyme that binds phosphate to glucose to start glucose metabolism.

Furthermore, the production of adenosine triphosphate when cells feed and recharge their energy supplies requires phosphate.

Respiratory alkalosis : Any alkaloid condition moves phosphate from the blood into the cells. This includes the more common respiratory alkalemia (a higher than normal blood pH from low levels of carbon dioxide in the blood).

Which in turn is caused by any hyperventilation (such as sepsis, fever, pain, anxiety, drug withdrawal and many other causes).

This phenomenon is observed because in respiratory alkalosis, carbon dioxide (CO2) decreases in the extracellular space, which causes intracellular carbon dioxide (CO2) to freely diffuse outside the cell.

This drop in intracellular carbon dioxide (CO2) causes an increase in cellular pH that has a stimulating effect on glycolysis.

Since the process of glycolysis requires phosphate (the end product is adenosine triphosphate), the result is a massive absorption of phosphate into the metabolically active tissue (such as muscle) of the serum.

However, it is interesting to note that this effect is not observed in metabolic alkalosis, since in these cases the cause of alkalosis is an increase in bicarbonate rather than a decrease in carbon dioxide (CO2).

Bicarbonate, unlike carbon dioxide (CO2), diffuses poorly across the cell membrane and therefore there is little change in intracellular pH.

Alcohol abuse : Alcohol impairs the absorption of phosphate. Alcoholics are also generally malnourished with regard to minerals.

Additionally, alcohol treatment is associated with refeeding, and the stress of alcohol withdrawal can create respiratory alkalosis, exacerbating hypophosphatemia.

Malabsorption : This includes gastrointestinal (GI) damage and also lack of phosphate absorption due to lack of vitamin D or chronic use of phosphate binders such as sucralfate, aluminum-containing antacids, and (more rarely) calcium-containing antacids.

Primary hypophosphatemia is the most common cause of non-nutritional rickets. Laboratory findings include low-normal serum calcium, moderately low serum phosphate, elevated serum alkaline phosphatase, and low serum 1,25-dihydroxy-vitamin D levels, hyperphosphaturia, and no evidence of hyperparathyroidism.

Other rarer causes include:

  • Certain blood cancers, such as lymphoma or leukemia.
  • Hereditary causes.
  • Liver failure.
  • Tumor-induced osteomalacia.

Pathophysiology of hypophosphatemia

Hypophosphatemia is caused by the following three mechanisms:

  1. Inadequate intake (often unmasked in feedback after long-term low phosphate intake).
  2. Increased excretion (eg, in hyperparathyroidism, hypophosphatemic rickets).
  3. It changes from the extracellular to the intracellular space. This can be seen in the treatment of diabetic ketoacidosis, refeeding, short-term increases in cell demand (eg, hungry bone syndrome), and acute respiratory alkalosis.

Diagnosis

Hypophosphatemia is diagnosed by measuring the level of phosphate in the blood. Phosphate levels less than 0.81mmol / L (2.5mg / dL) are considered diagnostic of hypophosphatemia, although additional tests may be needed to identify the underlying cause of the disorder.

You are more likely to have hypophosphatemia if:

  • Having a parent or other close relative with the condition.
  • Having the blood infection, sepsis.
  • Having hyperparathyroidism .
  • They are severely malnourished due to starvation or anorexia.
  • He is an alcoholic.
  • Taking medications such as steroids, diuretics, or antacids in excess or for long periods of time.

Treatment for hypophosphatemia

Oral treatment

Treatment of the underlying disorder and oral phosphate replacement are often adequate in asymptomatic patients, even when the serum concentration is very low.

Phosphate can be administered in doses of up to 1g three times a day in tablets containing sodium phosphate or potassium phosphate. Oral sodium phosphate or potassium phosphate may be poorly tolerated due to diarrhea.

Ingesting 1L of skim milk provides 1g of phosphate and may be more acceptable. Eliminating the cause of hypophosphatemia may include stopping phosphate-binding antacids or diuretics or correcting hypomagnesemia.

You can correct mild symptoms and avoid low phosphate in the future by adding more phosphate to your diet. Milk and other dairy products are good sources of phosphate. Or, you can take a phosphate supplement.

Historically, one of the first demonstrations of this was in concentration camp victims who died shortly after being resupplied: those who received milk (rich in phosphate) were observed to have a higher survival rate than those who did not. drank.

If your hypophosphatemia is severe, you may need to receive high doses of phosphate through a vein. People with the familial form will need to take phosphate and vitamin D supplements to protect their bones. They may also need dental sealants to protect their teeth from cavities.

Standard intravenous potassium phosphate preparations are available and are used routinely in malnourished and alcoholic patients. Oral supplementation is also helpful when intravenous treatment is not available.

Parenteral treatment

Parenteral phosphate is generally administered intravenously. It should be administered in any of the following circumstances:

  • When serum phosphate is <1mg / dL (<0.32mmol / L).
  • Rhabdomyolysis , hemolysis, or central nervous system symptoms are present.
  • Oral replacement is not feasible due to an underlying disorder.

Intravenous administration of potassium phosphate (as a buffered mixture of K2HPO4 and KH2PO4) is relatively safe when renal function is well preserved. Parenteral potassium phosphate contains 93mg (3mmol) of phosphorus and 170mg (4.4mEq) of potassium per ml.

The usual dose is 0.5mmol phosphorus / kg (0.17mL / kg) intravenously over 6 hours. Patients with alcoholism may require ≥1g / day during total parenteral nutrition; supplemental phosphate stops when oral intake is resumed.

If patients have impaired kidney function or serum potassium> 4mEq / L, sodium phosphate preparations should generally be used; these preparations also contain 3mmol / ml phosphorus and are therefore administered at the same dose.

Serum calcium and phosphate concentrations should be monitored during treatment, particularly when phosphate is administered intravenously or to patients with renal impairment.

In most cases, no more than 7mg / kg (approximately 500mg for a 70kg adult) of phosphate should be given over 6 hours.

Close monitoring is done and faster rates of phosphate administration should be avoided to prevent hypocalcemia, hyperphosphatemia, and metastatic calcification due to excess calcium phosphate product.

Phosphorous levels should be checked after 2 to 4 hours after each dose, as well as serum potassium, calcium and magnesium. Cardiac monitoring is also recommended.

If a drug caused this condition, you will need to stop taking the drug. If your vitamin D levels are low, you will also need to increase your intake of this vitamin.

Complications and associated conditions

You need phosphate to maintain healthy bones. Lack of this can lead to bone weakness, fractures, and muscle damage. Very severe hypophosphatemia that is not treated can affect your breathing and heart function, and can be life threatening.

Complications of hypophosphatemia include:

  • Death of muscle tissue (rhabdomyolysis).
  • Respiratory failure.
  • Destruction of red blood cells ( hemolytic anemia ).
  • An irregular heartbeat ( arrhythmia ).

A mild case of hypophosphatemia usually improves if you add more phosphate to your diet or take a supplement. Severe cases will require intravenous phosphate treatment. Your outlook depends on whether the condition that caused your low phosphate levels is treated. Once it has been treated, the hypophosphatemia should not return.