Diagnostic Considerations

Because the symptoms of hypophosphatemia are nonspecific weakness, several alternatives are plausible from the history and include the following:

Hypokalemia
Hypomagnesemia
Hypothyroidism
Primary muscle disorders

Once hypophosphatemia has been diagnosed, establishing that the symptoms the patient is having are due to the hypophosphatemia may be challenging, especially if the hypophosphatemia is mild. Bone pain is a clue that hypophosphatemia may be exerting an important symptomatic effect. The differential diagnosis of hypophosphatemia then becomes a matter of determining whether the patient has any of the following features:

Very poor diet or evidence of malabsorption
A history suggestive of a renal phosphate wasting syndrome, either genetic or acquired
A clinical scenario consistent with shift of phosphate into cells, such as refeeding

Differential Diagnoses

Workup

Sharma S, Hashmi MF, Castro D. Hypophosphatemia. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].
Lapointe JY, Tessier J, Paquette Y, Wallendorff B, Coady MJ, Pichette V. NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int. 2006 Jun. 69(12):2261-7. [QxMD MEDLINE Link].
Prié D, Huart V, Bakouh N, Planelles G, Dellis O, Gérard B, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med. 2002. 347:983-991. [QxMD MEDLINE Link].
Jones A, Tzenova J, Frappier D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene. J Am Soc Nephrol. 2001 Mar. 12(3):507-14. [QxMD MEDLINE Link].
Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol. 2009. 20:104-113. [QxMD MEDLINE Link]. [Full Text].
Lederer E. Renal phosphate transporters. Curr Opin Nephrol Hypertens. 2014 Sep. 23 (5):502-6. [QxMD MEDLINE Link]. [Full Text].
Nowik M, Picard N, Stange G, Capuano P, Tenenhouse HS, Biber J, et al. Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased renal phosphate reabsorption. Pflugers Arch. 2008. 457:539-549. [QxMD MEDLINE Link].
Collins JF, Bal L, Ghishan FK. The SLC20 family of protiens: dual functions as sodium-phosphate cotransporters and viral receptors. Pflugers Arch. 2004. 447:647-652. [QxMD MEDLINE Link].
Virkki LV, Biber J, Murer H, Forster IC. Phosphate transporters: a tale of two solute carrier families. Am J Physiol Renal Physiol. 2007. 293:F643-654. [QxMD MEDLINE Link].
Shaikh A, Berndt T, Kumar R. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr Nephrol. 2008 Aug. 23(8):1203-10. [QxMD MEDLINE Link]. [Full Text].
Thomas L, Bettoni C, Knöpfel T, Hernando N, Biber J, Wagner CA. Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone. J Am Soc Nephrol. 2017 Mar. 28 (3):903-914. [QxMD MEDLINE Link].
Tenenhouse HS, Gauthier C, Martel J, Gesek FA, Coutermarsh BA, Friedman PA. Na+ -phosphate cotransport in mouse distal convoluted tubule cells: evidence for Glvr-1 and Ram-1 gene expression. J Bone Miner Res. 1998 Apr. 13 (4):590-7. [QxMD MEDLINE Link]. [Full Text].
Clinkenbeard EL, White KE. Systemic Control of Bone Homeostasis by FGF23 Signaling. Curr Mol Biol Rep. 2016 Mar 1. 2(1):62-71. [QxMD MEDLINE Link].
Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab. 2006 Jul. 291(1):E38-49. [QxMD MEDLINE Link].
Mirams M, Robinson BG, Mason RS, Nelson AE. Bone as a source of FGF23: regulation by phosphate?. Bone. 2004 Nov. 35(5):1192-9. [QxMD MEDLINE Link].
Razzaque MS. FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?. Am J Physiol Renal Physiol. 2009. 296:F70-476. [QxMD MEDLINE Link]. [Full Text].
Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev. 2015 Apr. 36 (2):174-93. [QxMD MEDLINE Link]. [Full Text].
Pande S, Ritter CS, Rothstein M, Wiesen K, Vassiliadis J, Kumar R. FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation. Nephron Physiol. 2006. 104(1):p23-32. [QxMD MEDLINE Link].
Nishida Y, Taketani Y, Yamanaka-Okumura H, Imamura F, Taniguchi A, Sato T. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. 2006 Dec. 70(12):2141-7. [QxMD MEDLINE Link].
Schaefer B, Tobiasch M, Wagner S, Glodny B, Tilg H, Wolf M, et al. Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management. Bone. 2022 Jan. 154:116202. [QxMD MEDLINE Link]. [Full Text].
Megapanou E, Florentin M, Milionis H, Elisaf M, Liamis G. Drug-Induced Hypophosphatemia: Current Insights. Drug Saf. 2020 Mar. 43 (3):197-210. [QxMD MEDLINE Link].
Bökenkamp A, Ludwig M. Disorders of the renal proximal tubule. Nephron Physiol. 2011. 118(1):p1-6. [QxMD MEDLINE Link].
Sirac C, Bridoux F, Essig M, Devuyst O, Touchard G, Cogné M. Toward understanding renal Fanconi syndrome: step by step advances through experimental models. Contrib Nephrol. 2011. 169:247-61. [QxMD MEDLINE Link].
Thongprayoon C, Cheungpasitporn W, Chewcharat A, Petnak T, Mao MA, Srivali N, et al. Hospital-acquired serum phosphate derangements and their associated in-hospital mortality. Postgrad Med J. 2022 Jan. 98 (1155):43-47. [QxMD MEDLINE Link].
Burak KW, Rosen CB, Fidler JL, Hesley GK, Nagorney D, Charlton MR, et al. Hypophosphatemia after right hepatectomy for living donor liver transplantation. Can J Gastroenterol. 2004 Dec. 18 (12):729-33. [QxMD MEDLINE Link].
Lee JH, Choi SJ, Lee JH, et al. Severe metabolic abnormalities after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 35:63-69. [QxMD MEDLINE Link].
Kalaitzidis R, Tsimihodimos V, Bairaktari E, et al. Disturbances of phosphate metabolism: another feature of metabolic syndrome. Am J Kidney Dis. 45:851-8. [QxMD MEDLINE Link].
Schwartz A, Brotfain E, Koyfman L, Kutz R, Gruenbaum SE, Klein M, et al. Association between Hypophosphatemia and Cardiac Arrhythmias in the Early Stage of Sepsis: Could Phosphorus Replacement Treatment Reduce the Incidence of Arrhythmias?. Electrolyte Blood Press. 2014 Jun. 12(1):19-25. [QxMD MEDLINE Link]. [Full Text].
Saito Y, Aoki Y, Takeshita E, Saito T, Sugai K, Komaki H, et al. Hypophosphatemia is a common complication in severely disabled individuals with neurological disorders and is caused by infection, refeeding and Fanconi syndrome. Brain Dev. 2013 Dec 18. [QxMD MEDLINE Link].
Kagansky N, Levy S, Koren-Morag N, Berger D, Knobler H. Hypophosphataemia in old patients is associated with the refeeding syndrome and reduced survival. J Intern Med. 2005 May. 257 (5):461-8. [QxMD MEDLINE Link].
Cohen J, Kogan A, Sahar G, Lev S, Vidne B, Singer P. Hypophosphatemia following open heart surgery: incidence and consequences. Eur J Cardiothorac Surg. 2004 Aug. 26 (2):306-10. [QxMD MEDLINE Link].
Assadi F. Hypophosphatemia: an evidence-based problem-solving approach to clinical cases. Iran J Kidney Dis. 2010 Jul. 4(3):195-201. [QxMD MEDLINE Link].
O'Connor G, Nicholls D. Refeeding hypophosphatemia in adolescents with anorexia nervosa: a systematic review. Nutr Clin Pract. 2013 Jun. 28 (3):358-64. [QxMD MEDLINE Link].
Friedli N, Stanga Z, Sobotka L, Culkin A, Kondrup J, Laviano A, et al. Revisiting the refeeding syndrome: Results of a systematic review. Nutrition. 2017 Mar. 35:151-160. [QxMD MEDLINE Link].
Cadman PE. Hypophosphatemia in Users of Cannabis. Am J Kidney Dis. 2017 Jan. 69 (1):152-155. [QxMD MEDLINE Link].
Schubert L, DeLuca HF. Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency. Arch Biochem Biophys. 2010 Aug 15. 500(2):157-61. [QxMD MEDLINE Link].
Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens. 2017 Jul. 26 (4):266-275. [QxMD MEDLINE Link].
Anand G, Schmid C. Severe hypophosphataemia after intravenous iron administration. BMJ Case Rep. 2017 Mar 13. 2017:468675. [QxMD MEDLINE Link]. [Full Text].
O'Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. N Engl J Med. 1977 Oct 27. 297(17):901-3. [QxMD MEDLINE Link].
Ruppe MD, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, et al. X-Linked Hypophosphatemia. 2017 Apr 13. [QxMD MEDLINE Link]. [Full Text].
Jaureguiberry G, Carpenter TO, Forman S, Jüppner H, Bergwitz C. A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am J Physiol Renal Physiol. 2008. 295:F371-379. [QxMD MEDLINE Link]. [Full Text].
Drezner MK. PHEX gene and hypophosphatemia. Kidney Int. 2000 Jan. 57(1):9-18. [QxMD MEDLINE Link].
Quarles LD, Drezner MK. Pathophysiology of X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemia: a perPHEXing problem. J Clin Endocrinol Metab. 2001 Feb. 86(2):494-6. [QxMD MEDLINE Link].
Clarke BL, Wynne AG, Wilson DM, Fitzpatrick LA. Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features. Clin Endocrinol (Oxf). 1995 Oct. 43(4):479-90. [QxMD MEDLINE Link].
Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003 Sep. 112(5):683-92. [QxMD MEDLINE Link].
Kaur U, Chakrabarti SS, Gambhir IS. Zoledronate Induced Hypocalcemia and Hypophosphatemia in Osteoporosis: A Cause of Concern. Curr Drug Saf. 2016 Apr 26. [QxMD MEDLINE Link].
Kreisl TN, Kimn L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent Bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurent glioblastoma. J Clin Oncol. 2009. 27:740-745. [QxMD MEDLINE Link]. [Full Text].
Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Effricacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008. 26:4311-4318. [QxMD MEDLINE Link]. [Full Text].
Berman E, Nicolaides M, Maki RG, Fleisher M, Chanel S, Scheu K. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006 May 11. 354(19):2006-13. [QxMD MEDLINE Link].
Joensuu H, Reichardt P. Imatinib and altered bone and mineral metabolism. N Engl J Med. 2006 Aug 10. 355(6):628; author reply 628-9. [QxMD MEDLINE Link].
Gollob JA, Rathmell WK, Richmond TM, Marino CB, Miller EK, Grigson G, et al. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients wtih metastatic renal cell cancer. J Clin Oncol. 2007. 25:3288-3295. [QxMD MEDLINE Link].
Micetich KC, Futscher B, Koch D, Fisher RI, Erickson LC. Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer. J Natl Cancer Inst. 1992. 84:256-260. [QxMD MEDLINE Link].
Stöhr W, Paulides M, Bielack S, Jürgens H, Treuner J, Rossi R, et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer. 2007. 48:447-452. [QxMD MEDLINE Link].
Kintzel PE. Anticancer drug-induced kidney disorders. Drug Saf. 2001. 24:19-38. [QxMD MEDLINE Link].
Florenzano P, Gafni RI, Collins MT. Tumor-induced osteomalacia. Bone Rep. 2017 Dec. 7:90-97. [QxMD MEDLINE Link]. [Full Text].
Laaban JP, Waked M, Laromiguiere M, Vuong TK, Rochemaure J. Hypophosphatemia complicating management of acute severe asthma. Ann Intern Med. 1990 Jan 1. 112(10:68-9. [QxMD MEDLINE Link].
Paleologos M, Stone E, Braude S. Persistent, progressive hypophosphataemia after voluntary hyperventilation. Clin Sci (Lond). 2000 May. 98(5):619-25. [QxMD MEDLINE Link].
Jain N, Reilly RF. Hungry bone syndrome. Curr Opin Nephrol Hypertens. 2017 Jul. 26 (4):250-255. [QxMD MEDLINE Link].
van Londen M, Aarts BM, Deetman PE, van der Weijden J, Eisenga MF, Navis G, et al. Post-Transplant Hypophosphatemia and the Risk of Death-Censored Graft Failure and Mortality after Kidney Transplantation. Clin J Am Soc Nephrol. 2017 Aug 7. 12 (8):1301-1310. [QxMD MEDLINE Link].
Baia LC, Heilberg IP, Navis G, de Borst MH; NIGRAM investigators. Phosphate and FGF-23 homeostasis after kidney transplantation. Nat Rev Nephrol. 2015 Nov. 11(11):656-66. [QxMD MEDLINE Link].
Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, et al. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab. 2015 Jul. 100 (7):2565-73. [QxMD MEDLINE Link]. [Full Text].
Crysvita (burosumab) [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc. June, 2020. Available at [Full Text].
Basquerizo A, Anselmo D, Shackleton C, et al. Phosphorus as an early predictive factor in patients with acute liver failure. Transplantation. 75:2007-2014. [QxMD MEDLINE Link].
Chung PY, Sitrin MD, Te HS. Serum phosphorus levels predict clinical outcome in fulminant hepatic failure. Liver Transplantation. 2003. 9:248-253. [QxMD MEDLINE Link].

Media Gallery

of 0

Author

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Coauthor(s)

Rosemary Ouseph, MD Professor of Medicine, Director of Kidney Transplant, University of Louisville School of Medicine

Rosemary Ouseph, MD is a member of the following medical societies: American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplant Surgeons

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Royal College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

James W Lohr, MD Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

James W Lohr, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Central Society for Clinical and Translational Research

Disclosure: Received research grant from: GSK<br/>Partner received salary from Alexion for employment.

Acknowledgements

Datinder Deo, MD Chief Fellow, Department of Nephrology, University of Louisville Hospitals

Disclosure: Nothing to disclose.

Deepak Mittal, MD Fellow, Department of Nephrology, University of Louisville School of Medicine

Disclosure: Nothing to disclose.

Snehal Patel, MD Fellow, Department of Nephrology, University of Louisville School of Medicine

Snehal Patel, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology, Kentucky Medical Association, and Renal Physicians Association

Disclosure: Nothing to disclose.