Determination of FGF23 levels for the diagnosis of FGF23-mediated hypophosphatemia

Hartley, Iris R.; Gafni, Rachel I.; Roszko, Kelly L.; Brown, Sydney M.; de Castro, Luis F.; Saikali, Amanda; Ferreira, Carlos R.; Gahl, William A.; Pacak, Karel; Blau, Jenny E.; Boyce, Alison M.; Salusky, Isidro B.; Collins, Michael T.; Florenzano, Pablo

Affiliations

¹Skeletal Disorders and Mineral Homeostasis Section, National Institutes of Dental and Craniofacial Research. National Institutes of Health, Bethesda, MD, USA

²Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

³Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

⁴Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

⁵National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

⁶Division of Nephrology, Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, CA, USA

⁷Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

⁸School of Medicine, Pontificia Universidad Catolica de Chile, Centro Traslacional en Endocrinología UC (CETREN-UC), Santiago, Chile

Abstract and keywords

Fibroblast growth factor-23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), in whom pathology-driving FGF23 levels can be in the “normal range.” To determine FGF23 levels that are diagnostic for the identification of patients with FGF23-mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23-mediated and FGF23-independent hypophosphatemia and defined cut-off levels for both intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) that can accurately distinguish between FGF23-mediated and FGF23-independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23-mediated from FGF23-independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23-independent hypophosphatemia. There was overlap in the cFGF23 range of 45–90 RU/mL between genetic forms of FGF23 excess and FGF23-independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23-mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23-mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFhttps://asbmr.onlinelibrary.wiley.com/GF23 and cFGF23 cut-off values to assist in the evaluation and diagnosis of hypophosphatemic conditions.

Keywords: PTH/VIT D/FGF23; OSTEOMALACIA AND RICKETS; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM

Links

DOI: 10.1002/jbmr.4702

PubMed: 36093861

WoS: 000868794100001

History

Received: 2022-06-01

Revised: 2022-08-22

Accepted: 2022-09-05

Cited Works (4)

Year	Entry
2021	Florenzano P, Hartley IR, Jimenez M, Roszko K, Gafni RI, Collins MT. Tumor-induced osteomalacia. Calcif Tiss Int. January 2021;108(1):128-142.
2021	Jan de Beur SM, Miller PD, Weber TJ, Peacock M, Insogna K, Kumar R, Rauch F, Luca D, Cimms T, Roberts MS, San Martin J, Carpenter TO. Burosumab for the treatment of tumor‐induced osteomalacia. J Bone Miner Res. April 2021;36(4):627-635.
2022	Ovejero D, Hartley IR, Diaz LFdC, Theng E, Li X, Gafni RI, Collins MT. PTH and FGF23 exert interdependent effects on renal phosphate handling: evidence from patients with hypoparathyroidism and hyperphosphatemic familial tumoral calcinosis treated with synthetic human PTH 1–34. J Bone Miner Res. February 2022;37(2):179-184.
2021	Roszko KL, Brown S, Pang Y, Huynh T, Zhuang Z, Pacak K, Collins MT. C‐terminal, but not intact, FGF23 and EPO are strongly correlatively elevated in patients with gain‐of‐function mutations in HIF2A: clinical evidence for EPO regulating FGF23. J Bone Miner Res. February 2021;36(2):315-321.