Academy of Diagnostics & Laboratory Medicine - Scientific Short

What is the clinical utility of FGF23?

Annemieke C. Heijboer and Giovanni Lombardi

This post is part of a series on bone markers standardization from the Committee on Bone Metabolism of the International Federation of Clinical Chemistry.

Introduction

Beside the classical functions (support and locomotion, calcium and phosphorous storage and haematopoiesis), a new endocrine role has emerged for bone tissue. This function implies a multilevel cooperation of factors whose expression depends upon the loading status of a bone segment and has effects on the regulation of energy metabolism, immune function, and phosphorous metabolism, among others. Fibroblast growth factor (FGF)-23 is a bone-derived hormone that acts as a phosphatonin at the kidney tubule level. Besides loading, FGF23 expression is regulated by several factors: calcium and inorganic phosphate levels, parathyroid hormone (PTH), vitamin D, cytokines (IL-1, IL-6, TNFα), growth factors (TGFβ, insulin), pathogen-associated molecular patterns (PAMPs, e.g., lipopolysaccharide), G protein-coupled receptor signalling. 1,25(OH)2D is the main physiological inducer of its expression while hypocalcaemia is the main inhibitor. Dietary phosphate loading induces FGF23 in osteoblasts and osteocytes, leading to increased renal disposal and reduced intestinal uptake. Through these mechanisms, serum phosphate levels are kept within a narrow range (1).

Diagnostic significance

In tumour-induced osteomalacia (TIO) or oncogenic osteomalacia an often benign and sometimes malign tumour produces phosphatonins such as FGF23. When a TIO is suspected FGF23 measurement can support the diagnosis and, later on, the post-surgery follow-up (2).

Hypophosphatemic rickets (HR) include several hereditary diseases such as X-linked hypophosphatemia (XLH) and autosomal dominant hypophosphatemic rickets (ADHR), genetic diseases associated with hypophosphatemia due to increased FGF23 concentrations. FGF23 measurements can be used in the early phase of diagnosis before mutation analyses is performed (2, 3).

Impaired kidney function associates with perturbed phosphate homeostasis; increased FGF23 early signals a deregulated mineral metabolism in chronic kidney disease (CKD) and correlates with the renal function decline. Elevated FGF23 suppresses calcidiol hydroxylation that, in turn, stimulates the release of PTH possibly determining secondary hyperparathyroidism. The combination of hyperparathyroidism, high FGF23, and hypovitaminosis D aims at reducing serum phosphorous levels (low intestinal absorption and high urinary excretion) but culminates into vascular calcification and bone disease. In CKD, FGF23 is a prognostic marker to clinical outcome and mortality independent of the estimated glomerular filtration rate (eGFR). FGF23 is, thereby, a promising marker in CKD to early detect deregulated mineral metabolism and to identify patients at risk for adverse outcomes, such as left ventricular hypertrophy and early mortality. More studies are needed to understand the real clinical utility of FGF23 in CKD (4).

Furthermore, FGF23 levels seems to be related to ageing, dyslipidaemia, insulin resistance, inflammation, myocardial infraction, stroke (5).

FGF23 assays

FGF23 can be measured with currently available methods as solely biologically active intact FGF23 or as the sum of intact and C-terminal fragments of FGF23 (6). Both methods may provide different information depending on the type of patient and pathology. Moreover, the various assays show standardisation differences (7) and are expressed in different units. Noteworthy, borosumab, a FGF23-blocking antibody used in the treatment of XLH, interferes in FGF23 measurements (8).

Summary

The clinical utility of FGF23 measurements is currently seen in the diagnosis and follow-up of patients suspected for TIO and HR and might be a valuable prognostic markers in CKD.

REFERENCES

1. Ho BB, Bergwitz C. FGF23 signalling and physiology. J Mol Endocrinol 2020 doi: 10.1530/JME-20-0178

2. Vlot MC, den Heijer M, de Jongh RT, Vervloet MG, Lems WF, de Jonge R, et al. Clinical utility of bone markers in various diseases. Bone 2018;114:215-25. doi: 10.1016/j.bone.2018.06.011.

3. Haffner D, Emma F, Eastwood DM, Biosse Duplan M, Bacchetta J, Schnabel D. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019;15(7):435-55. doi: 10.1038/s41581-019-0152-5.

4. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 2013;75:503-33. doi: 10.1146/annurev-physiol-030212-183727.

5. Hanks LJ, Casazza K, Judd SE, Jenny NS, Gutierrez OM. Associations of fibroblast growth factor-23 with markers of inflammation, insulin resistance and obesity in adults. PloS One 2015;10(3):e0122885. doi: 10.1371/journal.pone.0122885

6. Lombardi G, Barbaro M, Locatelli M, Banfi G. Novel bone metabolism-associated hormones: the importance of the pre-analytical phase to for understanding their physiological roles. Endocrine 2017;56(3):460-84. doi: 10.1007/s12020-017-1239-z.

7. Smith ER, McMahon LP, Holt SG. Method-specific differences in plasma fibroblast growth factor 23 measurement using four commercial ELISAs. Clin Chem Lab Med 2013;51(10):1971-81. doi: 10.1515/cclm-2013-0208.

8. Piketty ML, Brabant S, Souberbielle JC, Maruani G, Audrain C, Rothenbuhler A, et al. FGF23 measurement in burosumab-treated patients: an emerging treatment may induce a new analytical interference. Clin Chem Lab Med 2020;58(11):e267-e9. doi: 10.1515/cclm-2020-0460.

 

Academy of Diagnostics & Laboratory Medicine Designation

Fellows of the Academy use the designation of FADLM. This designation is equivalent to FACB and FAACC, the previous designations used by fellows of the National Academy of Clinical Biochemistry and AACC Academy. Those groups were rebranded as Academy of Diagnostics & Laboratory Medicine in 2023.