What is Phosphate?
Phosphate, or PO43–, is an essential inorganic compound and is involved in a number of biochemical reactions and signaling pathways. The negative charge of phosphate ions allows them to participate in ionic and polar covalent bonds with other molecules and transfer large sums of energy between substrates.
Why is Phosphate Important?
Several key organic compounds contain phosphate. Nucleic acids such as DNA and RNA contain phosphate ions and are linked into polymeric chains by a type of chemical bond called phosphodiester bonds. Phosphate ions are also involved in the synthesis of essential lipids in the cell membrane [1], which serves as an essential barrier against the external environment and regulates the processes of cellular signaling and transport.
Energy-rich molecules like ATP and GTP also contain phosphate ions [1], which allows them to readily release energy by transferring phosphate groups.
Lastly, the transfer of phosphate molecules is a key process in various signaling pathways. The function of many proteins is regulated via phosphorylation and dephosphorylation, which is catalyzed by enzymes called kinases and phosphatases, respectively [1].
What Causes Low Phosphate Levels?
As various biochemical reactions occur within the body, serum phosphate levels fluctuate accordingly. Overall, phosphate levels tend to remain fairly stable thanks to mechanisms of homeostatic regulation. However, certain conditions may disrupt such homeostatic mechanisms and lead to abnormally low phosphate levels in the blood, or hypophosphatemia [2].
Low phosphatase levels in the body can be caused by several factors. Hypophosphatasia, a disorder due to pathogenic variants of the ALPL gene, is a common genetic cause of low serum alkaline phosphatase (ALP) levels [2,1]. Other causes can include severe acute injuries, diseases, drug therapy, malnutrition, vitamin and mineral deficiencies, and endocrine disorders [2]. Some patients may have unidentified mutations in regulatory regions of ALPL or abnormalities in other genes [2,3].
Main causes of low phosphate [2]:
- Inadequate phosphate intake. Inadequate phosphate intake may result from a prolonged phosphate-poor diet, poor intestinal absorption, or intestinal binding by exogenous agents such as medications.
- Excessive phosphate excretion. Excessive phosphate excretion may occur due to changes in renal function, such as those mediated by parathyroid hormone (PTH).
- Transfer of extracellular phosphate into the intracellular space. Intracellular shifting of phosphate can occur for several reasons. For example, refeeding syndrome can cause a rapid shift of extracellular phosphate into the intracellular space. Correction of hyperparathyroidism can also lead to such a shift, wherein phosphorous-deprived osteopenic bones begin to reabsorb phosphate from the extracellular space. Lastly, acute respiratory alkalosis may induce hypophosphatemia by raising pH, which increases the activity of an enzyme called phosphofructokinase and shuttles more phosphate ions into the production of ATP molecules.
Can Cancer Cause Low Phosphate Levels?
Certain cancers may cause excessive phosphate excretion, leading to low levels of phosphate in the blood. When this occurs, the condition is known as tumor-induced hypophosphatemia. However, low phosphate levels more frequently result from factors related to the cancer and cancer treatment, such as changes in weight or nutritional status, GI disturbances, and/or certain anticancer medications.
Low Phosphate in Cancer Patients
Cancer patients frequently present with low phosphate levels due to changes in nutritional status, use of certain anticancer medications, and/or particular types of malignancies, such as bone metastases and phosphaturic mesenchymal tumors [3, 4]. When hypophosphatemia is caused by the cancer itself, this is called tumor-induced hypophosphatemia [5]. Prolonged hypophosphatemia can result in symptoms such as bone pain, fractures, and musculoskeletal weakness [5]. The tumors underlying tumor-induced hypophosphatemia are typically small and difficult to detect, which makes phosphate levels a useful incidental marker which can prompt further diagnostic testing.
Key Clarification
While low phosphate levels commonly occur in cancer patients, there are many other causes of hypophosphatemia that are unrelated to cancer. Low phosphate levels should not be taken as a sign that an individual has cancer, and differential diagnoses which might more readily account for hypophosphatemia should be ruled out. Always consult your physician for help interpreting your own laboratory results.
Effects of Low Phosphate in Cancer Patients
Depending on severity of hypophosphatemia, patients may experience complications including [3]:
- Impaired tissue oxygenation
- Hemolysis
- Dysfunction of leukocytes and platelets
- Cardiac arrhythmias
- Encephalopathy
- Cardiomyopathy
- Seizures
- Coma
Management of Low Phosphate Levels in Cancer Patients
The most effective way to manage hypophosphatemia is to identify and address the underlying cause. Many cases of hypophosphatemia in cancer patients are caused not by the cancer itself, but by factors related to cancer treatment. For example, some cancer patients may take aluminum- or magnesium-based antacids to alleviate treatment-related gastrointestinal distress. Such medications can bind intestinal phosphate and prevent its absorption [3]. In simple cases like this, hypophosphatemia can be mitigated by discontinuing the use of such medications. Similarly, if inadequate caloric and/or dietary phosphorus intake is the culprit, dietary management and oral supplements may be sufficient to remedy the issue. In cases where the cancer itself is the cause of low phosphate levels, surgical resection of the tumor is typically considered the best course of action. However, because phosphaturic tumors are typically small and difficult to detect, it can be difficult to eradicate them completely using surgery. Tumors often recur, which necessitates careful monitoring of phosphate levels and consistent follow-ups to prevent relapse [3].
Conclusion
Phosphate is an essential inorganic compound which plays vital physiological roles in the body. Certain conditions can disrupt homeostatic regulation of phosphate levels and lead to hypophosphatemia, or low phosphate in the blood. Cancer patients often experience hypophosphatemia due to factors related to their disease and treatment: changes in nutritional status, GI disturbances, certain anticancer medications, and bone metastases can all result in low phosphate levels. In rarer cases, patients may suffer tumor-induced hypophosphatemia, wherein small, phosphaturic mesenchymal tumors trigger excessive phosphate excretion. Overall, hypophosphatemia occurs commonly in cancer patients and, in rarer cases, may be caused by the cancer itself.