Mineral Biomarkers: Phosphorus

Optimal Takeaways

Phosphorus is essential in the diet and the body, where it is associated with bone structure, energy and oxygen metabolism, cellular activity, acid-base balance, and B vitamin activation. Low levels are associated with compromised nutritional status, while higher levels are associated with kidney disease, liver disease, CVD, and dementia. A diet high in processed foods and soft drinks may promote excess consumption of dietary phosphorus.

Standard Range: 2.50 - 4.50 mg/dL (0.81 - 1.45 mmol/L)

The ODX Range: 2.6 – 3.5 mg/dL (0.81 – 1.13 mmol/L)

Low phosphorus levels are associated with inadequate intake, hyperparathyroidism, hypercalcemia, vitamin D deficiency, rickets, osteomalacia, malnutrition, alcoholism, diabetic ketoacidosis, hyperinsulinemia, chronic antacid ingestion, alkalosis, sepsis, a shift from extracellular to intracellular concentration, wasting via the kidney, GI losses, or a substantial dose of carbohydrates including IV glucose. Drugs that decrease phosphorus include antacids, albuterol, anesthesia, estrogen, insulin, mannitol, and oral contraceptives (Pagana 2021). Both low and high phosphorus have been associated with anemia (Tran 2016).

High phosphorus is associated with excess intake, reduced excretion by the kidneys, renal failure, hypoparathyroidism, hypocalcemia, metabolic acidosis, acromegaly, liver disease, rhabdomyolysis, hemolytic anemia, sarcoidosis, bone metastasis, and advanced lymphoma or myeloma. Drugs that can increase phosphorus include excess vitamin D, methicillin, and sodium phosphate enemas or laxatives (Pagana 2021). Elevated serum phosphorus may be associated with atherosclerosis, vascular calcification (Foley 2009), and dementia (Li 2017).

Overview

Phosphorus is an essential mineral in the diet and the second most abundant mineral in the body, with 85% found in the bone. It is also found in every cell and cell membrane; is a component of DNA, RNA, ATP, and cAMP; is a buffering anion that participates in acid-base balance; participates in the release of oxygen from hemoglobin; regulates cell and enzyme activities; and is required for the active form of B vitamins including thiamin diphosphate and pyridoxal phosphate. Phosphorus is abundant in protein-rich foods though significant amounts are also found in food additives, processed foods, and cola-type soft drinks (Gropper 2021).

Phosphorus levels in the blood are regulated by intestinal absorption, renal excretion (Pagana 2021), parathyroid hormone, 1,25-OH vitamin D, and fibroblast growth factor (Park 2011). Low serum phosphorus may be corrected at the expense of tissue breakdown, concealing the initial hypophosphatemia (Gropper 2021).

Elevated phosphorus is associated with atherosclerosis and CVD risk in individuals with chronic kidney disease, though the risk in healthy individuals is less well-defined. In the CARDIA study, a community-based cohort of 3,015 healthy young adults with normal kidney function, phosphorus above 3.9 mg/dL (1.26 mmol/L) was associated with an increased risk of coronary artery atherosclerosis. However, the association was only evident in multivariant models and needed to be more definitive. Researchers note that a similar association was observed in the Framingham Offspring Study and warrants further investigation (Foley 2009).

Research also supports the link between higher serum phosphorus and risk in those with existing CVD. A post hoc analysis of The CARE study of 4,127 MI patients comparing pravastatin versus control looked at phosphorus levels and all-cause mortality. Researchers found that a phosphorus of 3.5 mg/dL (1.13 mmol/L) or above was a significant and independent risk factor for mortality compared to a level below 3.5 mg/dL. They also observed that higher phosphorus was associated with an increased risk of new heart failure and cardiovascular events (Tonelli 2005).

Cardiovascular risk also increased with increasing phosphorus in individuals without a CVD diagnosis. One retrospective study of 402 healthy Korean adults with normal renal function found that phosphorus above 3.6 mg/dL (1.16 mmol/L) appeared to be a significant factor in those with an Agatston coronary artery calcium score above 100. A lower phosphorus of 3.3 (1.07 mmol/L) or below was associated with a lower Agatston score in this study. Another study of healthy individuals (no CVD or renal disease) observed an increased risk of CVD events with phosphorus above 3.5 mg/dL (1.13 mmol/L) versus below 2.8 mg/dL (0.90 mmol/L) (Park 2011).

A cross-sectional study evaluating serum phosphorus and Agatston scores in 2,509 healthy Koreans found that the risk of coronary calcification increased by 18% when Agatston scores were 100 or below and increased by 50% when Agatston was above 100 (Park 2016).

A phosphorus of 3.5 mg/dL (1.13 mmol/L) or above was also associated with mild and moderate anemia in a large study of 155,974 individuals, whether or not they had renal insufficiency. Anemia was also related to low phosphorus below 2.0 mg/dL (0.65 mmol/L) (Tran 2016).

Phosphorus status may also affect the risk of dementia. An observational cohort study of 744,235 Veterans Affairs Healthcare System users found that dementia risk increased with a phosphorus level above 3.5 mg/dL (1.13 mmol/L), especially in those younger than 60. Types of dementia include Alzheimer’s disease, vascular dementia, and Lewy body dementia. For subjects older than 60, a lower phosphorus of 2.9 mg/dL (0.94 mmol/L) and below was associated with a slightly increased risk of dementia. However, this connection was thought to be associated with a greater risk of malnutrition in older subjects (Li 2017).

References

Foley, Robert N et al. “Serum phosphorus levels associate with coronary atherosclerosis in young adults.” Journal of the American Society of Nephrology : JASN vol. 20,2 (2009): 397-404. doi:10.1681/ASN.2008020141

Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8th edition. Wadsworth Publishing Co Inc. 2021.

Li, Tingting et al. “Serum phosphorus levels and risk of incident dementia.” PloS one vol. 12,2 e0171377. 2 Feb. 2017, doi:10.1371/journal.pone.0171377

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Park, Kyung Sun et al. “Lower concentrations of serum phosphorus within the normal range could be associated with less calcification of the coronary artery in Koreans with normal renal function.” The American journal of clinical nutrition vol. 94,6 (2011): 1465-70. doi:10.3945/ajcn.110.001974

Park, Kyung Sun et al. “Serum Phosphorus Concentration and Coronary Artery Calcification in Subjects without Renal Dysfunction.” PloS one vol. 11,3 e0151007. 18 Mar. 2016, doi:10.1371/journal.pone.0151007

Tonelli, Marcello et al. “Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.” Circulation vol. 112,17 (2005): 2627-33. doi:10.1161/CIRCULATIONAHA.105.553198

Tran, Lac et al. “Serum phosphorus and association with anemia among a large diverse population with and without chronic kidney disease.” Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association vol. 31,4 (2016): 636-45. doi:10.1093/ndt/gfv297