Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: Another form of FGF23-related hypophosphatemia

doi:10.1016/j.bone.2009.06.017

Bone

Volume 45, Issue 4, October 2009, Pages 814-816

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Abstract

Fibroblast growth factor 23 (FGF23) is a humoral factor that is produced by osteocytes and regulates phosphate and vitamin D metabolism. Several hypophosphatemic diseases including X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia and tumor-induced rickets/osteomalacia are caused by excess actions of FGF23. These diseases are characterized by hypophosphatemia associated with impaired proximal tubular phosphate reabsorption and inappropriately low serum 1,25-dihydroxyvitamin D [1,25(OH)₂D] levels for hypophosphatemia. Saccharated ferric oxide is widely used in Japan for iron-deficiency anemia. While it has been shown that saccharated ferric oxide induces hypophosphatemic osteomalacia, the mechanism of this hypophosphatemia remains to be clarified. We here describe three hypophosphatemic patients caused by intravenous administration of saccharated ferric oxide. Hypophosphatemia in these patients were associated with impaired renal tubular phosphate reabsorption, rather low serum 1,25(OH)₂D and high FGF23 levels. All these biochemical features improved by the cessation of saccharated ferric oxide. These results indicate that hypophosphatemia caused by saccharated ferric oxide is another form of FGF23-related hypophosphatemia.

Introduction

Fibroblast growth factor 23 (FGF23) plays important roles both in physiological regulation of serum phosphate and 1,25-dihydroxyviamin D [1,25(OH)₂D] levels and in the development of several disorders of phosphate metabolism. FGF23 reduces serum 1,25(OH)₂D level by suppressing the synthesis and at the same time enhancing the degradation of 1,25(OH)₂D [1], [2], [3]. FGF23 also decreases serum phosphate level by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption through lowering 1,25(OH)₂D level [1], [4]. Previous studies indicated that excess actions of FGF23 are responsible for several hypophosphatemic diseases including X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia (XLH, ADHR, and ARHR) [5], [6], [7], [8], [9], [10], tumor-induced rickets/osteomalacia (TIO) [1] and hypophosphatemic disease associated with McCune–Albright syndrome/fibrous dysplasia of bone [11]. These diseases are characterized by hypophosphatemia associated with impaired proximal tubular phosphate reabsorption and inappropriately low serum 1,25(OH)₂D levels for hypophosphatemia. In contrast, deficient actions of FGF23 cause familial hyperphosphatemic tumoral calcinosis characterized by hyperphosphatemia with enhanced proximal tubular phosphate reabsorption and high 1,25(OH)₂D level [12], [13], [14], [15], [16].

Intravenous administration of saccharated ferric oxide is widely used for iron-deficiency anemia in Japan. Saccharated ferric oxide is a colloidal preparation of iron with maltose [Fe(OH)₃m(C₁₂H₂₂O₁₁)n]. While hypophosphatemic osteomalacia has been reported to be caused by saccharated ferric oxide [17], it has been unclear how this drug induces hypophosphatemia. Here we report three hypophosphatemic patients caused by saccharated ferric oxide with emphasis on the relationship between this drug and FGF23.

Section snippets

Case 1

Case 1 is a 43-year-old woman. She visited a hospital because of bone pain and muscle weakness and was found to be hypophosphatemic (1.2 mg/dl). She had been suffering from severe menorrhagia from myoma uteri since the age of 32. Marked iron-deficiency anemia developed and the administration of intravenous saccharated ferric oxide started at the age of 32. Oral medications containing iron could not be tolerable because of gastrointestinal side effects. Anemia did not improve even by myomectomy

Methods

FGF23 was measured by ELISA which detects only full-length FGF23 (Kainos, Tokyo, Japan) [5]. Tubular maximum transport of phosphate corrected for glomerular filtration rate (TmP/GFR) was obtained by using a nomogram [18]. This study was approved by the institutional review board in the University of Tokyo Hospital and written informed consent was obtained from all patients.

Results

Laboratory data and clinical course of these three cases are shown in Table 1 and Fig. 1. All cases showed hypophosphatemia with low TmP/GFR, rather low 1,25(OH)₂D levels in the presence of hypophosphatemia, and high alkaline phosphatase mimicking several hypophosphatemic diseases caused by excess actions of FGF23. Therefore, we measured FGF23 levels in these patients. FGF23 levels in these cases were clearly elevated when they were hypophosphatemic. Because saccharated ferric oxide has been

Discussion

We have previously shown that measurement of serum FGF23 level is useful for the differential diagnosis of hypophosphatemic diseases [19]. While FGF23 is high in FGF23-related hypophosphatemia such as TIO and XLH, it is rather low in hypophosphatemic patients from other causes including Fanconi's syndrome, vitamin D deficiency and Cushing's syndrome from ectopic production of ACTH. These results imply that FGF23 production is suppressed in chronic hypophosphatemic diseases which do not derive

Acknowledgments

This study was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

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Cited by (123)

The pathophysiology of hypophosphatemia
2024, Best Practice and Research: Clinical Endocrinology and Metabolism
After identification of fibroblast growth factor (FGF) 23 as the pivotal regulator of chronic serum inorganic phosphate (Pi) levels, the etiology of disorders causing hypophosphatemic rickets/osteomalacia has been clarified, and measurement of intact FGF23 serves as a potent tool for differential diagnosis of chronic hypophosphatemia. Additionally, measurement of bone-specific alkaline phosphatase (BAP) is recommended to differentiate acute and subacute hypophosphatemia from chronic hypophosphatemia. This article divides the etiology of chronic hypophosphatemia into 4 groups: A. FGF23 related, B. primary tubular dysfunction, C. disturbance of vitamin D metabolism, and D. parathyroid hormone 1 receptor (PTH1R) mediated. Each group is further divided into its inherited form and acquired form. Topics for each group are described, including “ectopic FGF23 syndrome,” “alcohol consumption-induced FGF23-related hypophosphatemia,” “anti-mitochondrial antibody associated hypophosphatemia,” and “vitamin D-dependent rickets type 3.” Finally, a flowchart for differential diagnosis of chronic hypophosphatemia is introduced.
Prevalence of FGF23 elevation in patients with hypophosphatemia
2024, Clinica Chimica Acta
To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders.
We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer.
Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0–14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1).
In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia.
Clinical performance of a new intact FGF23 immunoassay in healthy individuals and patients with chronic hypophosphatemia
2023, Bone Reports
While the positive association between automated intact fibroblast growth factor (FGF) 23 measurement kit (Determinar CL FGF23 [CL]) and the former assay (Kainos [KI]), and clinical utility of CL was well established, the clinical performance of Medfrontier FGF23 (MED), which was the manual intact FGF23 measurement kit with same antibody set as CL, has not yet been validated. Therefore, this study aims to compare MED FGF23 levels to KI FGF23 levels. A total of 380 samples were collected from healthy individuals, and 200 samples were collected from 20 patients with chronic hypophosphatemia. The intact FGF23 level of each sample was measured by KI and MED. Among the healthy individuals, the reference range of MED FGF23 levels was 18.6–59.8 pg/mL when calculated as the average ± 2 standard deviations. When compared with KI FGF23 levels, MED FGF23 levels were lower than KI levels both among samples from healthy individuals (KI FGF23, 40.9 [interquartile (IQR), 31.1–50.6]; MED FGF23, 38.0 [IQR, 31.5–45.7]; p value = 0.02) and among samples from patients with chronic hypophosphatemia (KI FGF23, 172.5 [IQR, 115.8–290.7]; MED FGF23, 130.2 [IQR, 93.6–247.0]; p value = 0.003). The linear regression analysis showed that the correlation between KI FGF23 and MED FGF23 was interpreted as a slope of 0.83 with a y-intercept of 0.53, revealing good linearity (R² = 0.99). This study showed that the discrepancy between KI and MED was very similar to the previously reported data between KI and CL.
Regulators impeding erythropoiesis following iron supplementation in a clinically relevant rat model of iron deficiency anemia with inflammation
2022, Life Sciences
While elevated hepcidin levels with inflammation have been postulated as a putative mechanism hindering effective erythropoiesis after intravenous (IV) iron therapy in anemic patients undergoing surgery, little is known about the concomitant changes in other major regulators affecting erythropoiesis. This study investigated the activities of relevant regulators after iron replenishment in a rat model of iron deficiency anemia with inflammation.
Inflammation was induced by administration of complete Freund's adjuvant (CFA) in male Sprague-Dawley rats. After 2 weeks of CFA treatment, the rats received IV iron (CFA‑iron) or saline (CFA-saline). The control group received saline instead of CFA and iron (saline-saline). At 1, 3, and 10 days after iron or saline treatment, inflammatory cytokines, oxidative markers, iron profiles, hepcidin, erythropoietin (EPO), erythroferrone (ERFE), fibroblast growth factor 23 (FGF 23), and expression of mRNA and proteins in the liver involved in hepcidin signaling pathways were measured.
CFA treatment and iron restriction decreased hemoglobin and serum iron levels, significantly increasing inflammatory and oxidative markers. Iron supplementation did not restore hemoglobin levels despite improved iron profiles. CFA injections increased hepcidin and FGF 23 levels and decreased EPO and ERFE levels, which further intensified after iron supplementation with concomitantly elevated levels of oxidative stress and inflammatory markers.
Under inflammatory conditions, IV iron administration exacerbated inflammatory and oxidative stress and did not resolve anemia, even under iron deficiency conditions. Iron therapy exerted adverse influences on the changes in key regulators toward impeding erythropoiesis that was already impeded by inflammation.
Induction of FGF23-related hypophosphatemic osteomalacia by alcohol consumption
2021, Bone Reports
Citation Excerpt :
FGF23-related hypophosphatemia in the present cases was strongly suggested to be induced by chronic heavy drinking according to the time course of the serum phosphate and FGF23 levels, which changed in parallel with alcohol consumption. Our cases were, in some ways, similar to iron infusion-induced FGF23-related hypophosphatemia, which was reported by our laboratory and others approximately a decade ago, indicating that an exogenous factor led to FGF23-related hypophosphatemia (Schouten et al., 2009; Shimizu et al., 2009; Wolf et al., 2013). Subsequent randomized controlled trials have revealed that the diverse reactions of serum FGF23 and phosphate are highly dependent on the forms of intravenous iron preparation utilized; the administration of ferric carboxymaltose led to FGF23-related hypophosphatemia in approximately 70% of the participants; whereas fermoxytol and ferric derisomaltose led its development in less than 10% of the participants (Emrich et al., 2020; Wolf et al., 2020, 2018).
Fibroblast growth factor (FGF) 23 is a hormone that regulates serum phosphate levels, the excess action of which causes chronic hypophosphatemic rickets/osteomalacia. To date, there are only two identified causes of acquired FGF23-related hypophosphatemic osteomalacia: tumor-induced osteomalacia (TIO) and osteomalacia induced by the intravenous infusion of some forms of iron preparations. In the current study, two cases of FGF23-related hypophosphatemia probably induced by chronic alcohol consumption were first introduced.
Case 1 and case 2 had been drinking high amounts of alcohol for more than twenty years until they were admitted to the hospital. Case 1 was a 43-year-old man with progressive worsening multiple pains and muscle weakness who exhibited chronic hypophosphatemia with increased intact FGF23 levels. A week after admission, the serum phosphate level recovered to the reference range, and the intact FGF23 level declined. Case 1 resumed drinking after discharge, and hypophosphatemia concomitant with high intact FGF23 levels recurred. The alleviation of FGF23-related hypophosphatemia was observed each time he temporarily abstained from drinking for a short period. Case 2 was a 60-year-old man with recurrent fractures and exacerbation of pain in multiple joints who also exhibited hypophosphatemia with increased intact FGF23 levels. After admission, the serum phosphate level gradually increased to the lower limit of the normal range. The intact FGF23 level decreased, but it was still higher than 30 pg/ml, and causative FGF23-producing tumors were not identified even with thorough examinations, including somatostatin receptor scintigraphy, fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) and systemic venous FGF23 sampling. He completely abstained from alcohol after discharge. Along with the serum phosphate level, intact FGF23 was subsequently decreased and had been normalized for 5 months. Both patients had no genetic mutation related to hereditary FGF23-related hypophosphatemic rickets/osteomalacia, including autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR).
Two cases of FGF23-related hypophosphatemia probably induced by alcohol were first introduced in this study. Identifying this reversible condition among acquired FGF23-related hypophosphatemic osteomalacia is critical to obtain better patient outcomes and save medical resources. This condition is similar to iron infusion-induced FGF23-related hypophosphatemia in terms of the dysregulation of FGF23 due to exogenous factors. Future research to elucidate the precise mechanism of these conditions is warranted.
Hypophosphatemia following the administration of intravenous iron formulations: A case report and literature review
2021, Therapies
Iron deficiency and iron-deficiency anemia are common medical conditions. Management of the etiology and iron supplementation are both necessary to treat this condition. Use of intravenous iron preparations is increasing due to its advantages over oral iron. Indeed, the total dose required can be provided in a single infusion, and it is more effective and increases hemoglobin levels more quickly than oral iron. Hypophosphatemia, sometimes severe, following intravenous iron administration, has been described in literature these past years, in particular with ferric carboxymaltose. We report here a case of severe hypophosphatemia with ferric carboxymaltose and carry out a literature review to determine the incidence of hypophosphatemia and to precise its clinical presentation, its pathophysiological mechanisms and its treatment. We found that hypophosphatemia is frequent with ferric carboxymaltose. Most of the time, there are no clinical manifestations, but cases of symptomatic osteomalacia have been described. Duration of hypophosphatemia is variable, from a few weeks to several months in case of prolonged administration. Hypophosphatemia owing to renal phosphate wasting is caused by an increase in intact fibroblast growth factor 23 (FGF-23) levels. However, the mechanism of ferric carboxymaltose- induced increase in intact FGF-23 is still unknown.
La carence martiale et l’anémie sont fréquentes dans la population générale. Leur traitement repose sur la prise en charge de l’étiologie de la carence et sur la supplémentation en fer. Le recours à une supplémentation par voie intraveineuse est de plus en plus fréquent, cette voie d’administration permettant de délivrer des doses de fer plus importantes en une seule injection et de corriger ainsi la carence martiale et l’anémie plus efficacement et plus rapidement. La survenue d’une hypophosphatémie, parfois sévère, après administration de fer injectable a été rapportée à plusieurs reprises dans la littérature ces dernières années, en particulier avec le carboxymaltose ferrique. Nous rapportons ici un cas clinique illustrant cet effet indésirable mal connu, puis analysons les données de la littérature concernant la fréquence, la présentation clinique, la physiopathologie et le traitement de l’hypophosphatémie induite par le fer intraveineux. Ces données montrent que l’hypophosphatémie est fréquente après carboxymaltose ferrique. Elle est le plus souvent asymptomatique, mais peut être compliquée d’ostéomalacie. Elle peut être résolutive spontanément en quelques semaines ou persister dans le temps en cas d’injections répétées. Cette hypophosphatémie est secondaire à une fuite urinaire de phosphate induite par une augmentation de la concentration plasmatique de fibroblast growth factor 23 (FGF-23) intact. Toutefois, les mécanismes physiopathologiques à l’origine de cette élévation du FGF-23 sont encore mal connus.

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Bone

Abstract

Introduction

Section snippets

Case 1

Methods

Results

Discussion

Acknowledgments

References (22)

Nomogram for derivation of renal threshold phosphate concentration

Lancet

Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement

Bone

Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia

Proc. Natl. Acad. Sci. U. S. A.

Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

J. Clin. Invest.

FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis

J. Bone Miner. Res.

Role of the vitamin D receptor in FGF23 action on phosphate metabolism

Biochem. J.

Increased circulatory level of biologically active full length FGF-23 in patients with hypophosphatemic rickets/osteomalacia

J. Clin. Endocrinol. Metab.

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia

N. Engl. J. Med.

Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23

Nat. Genet.

Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23

Kidney Int.

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Nat. Genet.

Cited by (123)

The pathophysiology of hypophosphatemia

Prevalence of FGF23 elevation in patients with hypophosphatemia

Clinical performance of a new intact FGF23 immunoassay in healthy individuals and patients with chronic hypophosphatemia

Regulators impeding erythropoiesis following iron supplementation in a clinically relevant rat model of iron deficiency anemia with inflammation

Induction of FGF23-related hypophosphatemic osteomalacia by alcohol consumption

Hypophosphatemia following the administration of intravenous iron formulations: A case report and literature review

Technical NoteHypophosphatemia induced by intravenous administration of saccharated ferric oxide: Another form of FGF23-related hypophosphatemia

Abstract

Introduction

Section snippets

Case 1

Methods

Results

Discussion

Acknowledgments

Lancet

Bone

Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia

Proc. Natl. Acad. Sci. U. S. A.

Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

J. Clin. Invest.

FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis

J. Bone Miner. Res.

Role of the vitamin D receptor in FGF23 action on phosphate metabolism

Biochem. J.

Increased circulatory level of biologically active full length FGF-23 in patients with hypophosphatemic rickets/osteomalacia

J. Clin. Endocrinol. Metab.

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia

N. Engl. J. Med.

Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23

Nat. Genet.

Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23

Kidney Int.

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Nat. Genet.

Technical Note
Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: Another form of FGF23-related hypophosphatemia