Hyperphosphatemia
Hyperphosphatemia is a medical condition characterized by elevated serum phosphate levels, exceeding 5 mg/dL in adults and 7 mg/dL in children or adolescents. It can result from various factors, including kidney failure, high dietary intake of phosphate-rich foods, certain medications, and genetic predispositions. The body typically maintains a balance of phosphate through gastrointestinal absorption and renal elimination, regulated by hormones like parathyroid hormone (PTH) and vitamin D. When this balance is disrupted, excess phosphate can accumulate in the bloodstream, leading to symptoms such as muscle cramping, confusion, and irregular heart rhythms.
Two rare genetic disorders, hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperostosis-hyperphosphatemia syndrome (HHS), are associated with hyperphosphatemia and stem from mutations in specific genes. Diagnosis often includes blood tests to measure phosphate levels and may require genetic testing for HFTC or HHS. Treatment primarily focuses on normalizing serum phosphate levels through medications like phosphate binders or diuretics. Preventative measures include dietary restrictions and careful management of phosphate-containing medications. Understanding hyperphosphatemia is essential for those at risk, particularly individuals with kidney issues or genetic conditions.
Hyperphosphatemia
ALSO KNOWN AS: Elevated serum phosphate; hyperphosphatemic familial tumoral calcinosis (HFTC); hyperostosis-hyperphosphatemia syndrome (HHS)
DEFINITION Hyperphosphatemia is defined as a serum phosphate concentration greater than 5 milligrams per deciliter (mg/dL) in adults or 7 mg/dL in children or adolescents. Phosphate is consumed in the diet, eliminated by the kidneys, and stored in bone.
Risk Factors
Characteristics that put persons at risk for developing hyperphosphatemia include kidney failure, high consumption of phosphate-containing foods (carbonated beverages, processed foods, meat, eggs, milk, chocolate, and many others), taking medications that contain high amounts of phosphate (laxatives and dietary supplements), and genetic predisposition to the disorder.
Etiology and Genetics
A balance of phosphorus in the body is usually maintained by matched gastrointestinal absorption and elimination by the kidney. The release of phosphorus during cellular processes is balanced by uptake into other tissues. Parathyroid hormone (PTH) regulates the elimination of phosphate and vitamin D controls phosphate release from bone. Hyperphosphatemia occurs when the amount of phosphorus in the blood exceeds kidney elimination and tissue uptake. The reference range for serum phosphate is 2.5 to 4.5 mg/dL for adults and 3 to 6 mg/dL for children and adolescents.
Hyperphosphatemic familial tumoral calcinosis (HFTC) can be caused by a mutation in the GALNT3, FGF23, or KLOTHO genes. The gene map locus for FHTC is 13q12, 12p13.3, 2q24-q31. HFTC is a rare autosomal recessive disease that has been observed in Druze and African American families. Biallelic mutations alter FGF23 metabolism. Hyperostosis-hyperphosphatemia syndrome (HHS) is also a rare allelic disorder with elevated phosphorus and abnormal bone formation that is caused by a mutation in the GALNT3 gene. Mutations in GALNT3 can lead to low bioactive circulating levels of FGF23. The gene map locus for HHS is 2q24-q31. HHS has been reported in less than twenty persons, both males and females, and in children of Arab, Black, Saudi Arabian and Druze families. HFTC and HHS are similar diseases, however, the lack of skin involvement (deposits of calcium-phosphate crystals) differentiates HHS from HFTC.
Persons with kidney failure cannot eliminate phosphate in the urine, continue to absorb phosphate from the gut, and thus accumulate it in the blood. Persons with HFTC or HHS, because of genetic mutations in GALNT3, FGF23, or KLOTHO genes, do not eliminate phosphate in the urine and continue to absorb phosphate from the gut. FGF23 appears to act as a counter-regulatory hormone to vitamin D and likely coordinates phosphate elimination from the kidney and release from the bone.
Symptoms
Persons with hyperphosphatemia may have muscle cramping, numbness or paralysis, confusion, seizures, irregular heartbeat or rhythm, or low blood pressure. Persons with HFTC or HHS may have pain, heat, and swelling in the bone and joints that comes and goes, tooth and bone abnormalities, thyroid problems, and calcifications (bony formations) in soft tissues. Laboratory measurements of blood often reveal increased phosphate and increased or decreased calcium, magnesium, vitamin D, and PTH levels.
Screening and Diagnosis
Screening for hyperphosphatemia is done with a routine laboratory blood test that will show if the phosphate level is elevated. Some patients may have elevated creatinine and blood urea nitrogen concentrations (measures of renal function). Additional blood tests may be done to assess vitamin D and PTH levels. Diagnosis of HFTC or HHS requires genetic testing. A physical exam may reveal swelling of joints, enlarged thyroid, or bony calcifications. Tooth abnormalities or calcifications in salivary glands may be discovered during a routine dental exam. Persons with HFTC and HHS are often misdiagnosed with arthritis or bone disorders.
Treatment and Therapy
Normalization of serum phosphate levels is the goal of treatment. In some patients, the primary reason for hyperphosphatemia may be reversible; if possible, this should also be resolved. HFTC and HHS is not a reversible disease. Hyperphosphatemia is usually treated with phosphate binders such as calcium or aluminum salts (like calcium acetate or calcium chloride), iron or bile acid sequestrantes (sevelamer or lanthanum), or medications that promote the elimination of phosphate in the urine (diuretics like acetazolamide). In 2024, Alebund Pharmaceuticals announced that development of AP306, the first pan-inhibitor of sodium-dependent phosphate transporters. If further testing concludes that AP306 is both safe and effective, it could become an effective method of serum phosphate control for patients with hyperphosphatemia.
Prevention and Outcomes
Hyperphosphatemia can be prevented or minimized by restricting foods high in phosphate and avoiding medications that contain phosphate. Persons with HFTC and HHS may develop symptoms as children.
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