Introduction:
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. Any alteration in the physiological levels of phosphates would result in a disturbance in their normal function.
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 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. The kidneys play an important role in the reabsorption and excretion of phosphates. Almost 90 % of phosphates are excreted by the kidneys, with the rest ten percent by the gastrointestinal tract. 75 % of filtered phosphate reabsorption takes place in the proximal tubule of the kidney.
There are three types of transporters for phosphate in the body that are coupled with sodium called sodium phosphate cotransporters to mediate their function in the body.
Type 1 - 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 phosphate absorption 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 Hyperphosphatemia?
Hyperphosphatemia is characterized by an increase in serum phosphate levels. The normal biological value of phosphate in the human body ranges from 2.8 to 4.5 mg/dl in adults and 4.0 to 7.0 mg/dl in children. Hyperphosphatemia is when the levels go above 4.5 mg/dl in adults and above 7.0 mg/dl in children.
What Is Pseudohyperphosphatemia?
Pseudohyperphosphatemia is defined as a laboratory artifact with falsely elevated serum phosphate levels. Mainly occurring as a result of a monoclonal immunoglobulin interference (paraprotein) on the automated analyzer. This is commonly seen in multiple myeloma patients and also present in patients with hyperlipidemia and hyperbilirubinemia.
What Is the Epidemiology of Hyperphosphatemia?
Studies report that it is one of the most common electrolyte disorders among patients with renal disorders. It is estimated to be seen in around 50 to 74 % of patients with end-stage renal disease. 12 % of patients receiving tertiary care other than kidney diseases are reported to be positive for hyperphosphatemia. 45 % of children with tumor conditions receiving liposomal amphotericin are found to develop hyperphosphatemia.
What Is the Etiology of Hyperphosphatemia?
The causes of hyperphosphatemia can be due to two main reasons:
Decreased Excretion of Phosphates.
- Chronic Kidney Disease or Kidney Failure - This is one of the important causes of hyperphosphatemia as the reduced glomerular filtration rate due to renal failure may reduce the filtration of the inorganic phosphate, thereby increasing its level in the blood.
- Tumoral Calcinosis - This is a rare genetic condition characterized by the development of tumor-like masses in the extra-capsular soft tissues due to the deposition of calcium. It is associated with mutations of the gene involved in the formation of FGF23. This, in turn, causes the metabolic dysfunction of phosphates causing its decreased renal excretion and thereby increasing the serum phosphate levels.
Increased Intake of Phosphates or Increased Renal Reabsorption.
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Phosphate-Containing Laxatives - Increased usage of such medications for constipation would result in increased phosphate levels in the blood.
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Phosphate-Containing Enemas - This could also cause hyperphosphatemia.
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Hormonal Factors - Factors such as acromegaly (increase in growth hormone), thyrotoxicosis (toxicity of thyroid hormone), and hypoparathyroidism (decreased parathyroid hormone levels) would increase the renal reabsorption of phosphates.
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Vitamin D Intoxication - Intoxication due to vitamin D excess may increase the intestinal absorption of phosphates, thereby increasing serum phosphate levels.
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Pseudohypoparathyroidism - Is characterized by resistance to the parathyroid hormones, thereby decreasing the serum calcium and increasing serum phosphate levels.
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Heparin Therapy - Might increase serum phosphate levels.
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Muscle Damage or Crush Injuries - This may serve as one of the causes of hyperphosphatemia.
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Transcellular Shift - Conditions such as diabetic ketoacidosis and lactic acidosis cause the shift of phosphate from the cells into the extracellular space.
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Albright Hereditary Osteodystrophy (AHO)- This is a hereditary disorder caused due to mutation in the GNAS1 gene. Patients with this syndrome are characterized by a round face, short stature, obesity, dental hypoplasia, etc.
What Are the Symptoms of Hyperphosphatemia?
The symptoms include:
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Muscle cramps.
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Muscle spasms.
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Bone pain.
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Joint pain.
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Ectopic calcifications (formation of osseous tissues in the soft tissues, including eyes, lungs, arteries, and other organs, due to the deposition of calcium).
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Renal osteodystrophy (includes the biochemical and skeletal changes in patients with renal failure).
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Numbness.
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Tingling.
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Weak bones.
How Is Hyperphosphatemia Diagnosed?
The steps in diagnosis include:
1. History - A thorough medical and drug history would provide a major clue in diagnosing the condition as well as knowing the underlying systemic diseases if any.
2. Physical Examination - A careful physical examination of the patient is necessary to check for the signs of calcification and to understand the symptoms of the condition.
3. Blood Test -
- Serum Phosphate Levels - This would reveal the increase in serum phosphate levels to a level of more than 4.5 mg/dl. Repeated blood tests are necessary to confirm hyperphosphatemia as phosphate levels are influenced by many factors, especially in patients under hemodialysis as phosphates are removed during dialysis. Proper intervals should be followed between the sample collection and the dialysis.
- Parathyroid Hormone Levels - Decreased parathyroid hormone levels indicate hypoparathyroidism.
- Kidney Function Tests - The functional status of the kidneys should be evaluated to understand the presence of underlying kidney damage.
- Serum Blood Urea Nitrogen and Creatinine - Increased BUN and creatinine levels indicate kidney dysfunction.
- Vitamin D Levels - Increased vitamin D levels along with hypercalcemia and hyperphosphatemia indicate vitamin D intoxication.
- Tumor lysis Syndrome - This can be diagnosed by the evidence of hyperphosphatemia with hypocalcemia, hyperkalemia, and hyperuricemia.
- Tumoral Calcinosis - Can be diagnosed with the evidence of hyperphosphatemia with normal serum calcium, parathyroid hormone, alkaline phosphatase, and normal or elevated vitamin D levels.
4. Urine Test
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Urinary Phosphate Assessment - Is carried out to differentiate between the renal and the extrarenal cause of hyperphosphatemia in patients with normal renal functions.
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X-ray Imaging - This may demonstrate the presence of calcified masses in the extra-capsular soft tissues (metastatic calcifications).
How Is Hyperphosphatemia Managed?
The steps in management include:
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Dietary Restriction of Phosphates - The phosphate-containing foods should be restricted; the kidney disease improving global outcomes (KDIGO) recommends a daily intake of 800 to 1000 mg of phosphate with 1.2 g/kg body weight of protein. The phosphate-containing drugs should also be stopped and replaced with alternative drugs.
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Treating the Underlying Diseases - The underlying systemic diseases or the genetic conditions causing hyperphosphatemia, such as hypoparathyroidism, vitamin D intoxication, etc., should be treated to prevent the progression of the condition.
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Using Phosphate Binders - Phosphate binding drugs can be used to remove the excess phosphate from the blood. Aluminum hydroxide was used as a binder initially, but now it is stopped due to the risk of aluminum toxicity. Recently used phosphate binders include magnesium carbonate, sevelamer, ferric citrate, and sucroferric oxyhydroxide.
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Saline Diuresis - Saline diuresis can be tried in patients with good renal function to remove excess phosphate.
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Reducing Intestinal Phosphate Absorption - Certain drugs such as Nicotinic acid, Nicotinamide, and Tenapanor are involved in targeting the phosphate transporters in the intestine, thereby reducing its absorption from the intestine.
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Hemodialysis - It is indicated in patients with end-stage renal disease, as hemodialysis would remove the excess phosphate in the blood.
What Are the Complications of Hyperphosphatemia?
The complications include:
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Tetany (caused due to hypocalcemia).
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Metastatic calcifications (calcifications of the soft tissues).
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Acute phosphate nephropathy (kidney injury due to the increased phosphate levels).
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Death (most common in dialysis patients with end-stage renal disease).
Conclusion:
Hyperphosphatemia is a common electrolyte disturbance among patients with renal failure. It is one of the causes of increased mortality in patients under dialysis. Hence frequent monitoring of their levels is mandatory to improve survival rates. Hyperphosphatemia due to other causes should be treated cautiously to prevent further complications.
