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      Choice of High-Dose Intravenous Iron Preparation Determines Hypophosphatemia Risk

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          Abstract

          Background

          Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM.

          Aim

          To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort.

          Methods

          Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included.

          Results

          The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM—OR = 20.8; 95% CI, 2.6–166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation.

          Conclusion

          Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

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          Most cited references18

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          European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases.

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            Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.

            Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.
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              A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial.

              Anemia is a common complication of inflammatory bowel diseases (IBD) This multicenter study tested the noninferiority and safety of a new intravenous iron preparation, ferric carboxymaltose (FeCarb), in comparison with oral ferrous sulfate (FeSulf) in reducing iron deficiency anemia (IDA) in IBD. Two hundred patients were randomized in a 2:1 ratio (137 FeCarb:63 FeSulf) to receive FeCarb (maximum 1,000 mg iron per infusion) at 1-wk intervals until the patients' calculated total iron deficit was reached or FeSulf (100 mg b.i.d.) for 12 wk. The primary end point was change in hemoglobin (Hb) from baseline to week 12. The median Hb improved from 8.7 to 12.3 g/dL in the FeCarb group and from 9.1 to 12.1 g/dL in the FeSulf group, demonstrating noninferiority (P= 0.6967). Response (defined as Hb increase of >2.0 g/dL) was higher for FeCarb at week 2 (P= 0.0051) and week 4 (P= 0.0346). Median ferritin increased from 5.0 to 323.5 mug/L at week 2, followed by a continuous decrease in the FeCarb group (43.5 mug/L at week 12). In the FeSulf group, a moderate increase from 6.5 to 28.5 mug/L at week 12 was observed. Treatment-related adverse events (AEs) occurred in 28.5% of the FeCarb and 22.2% of the FeSulf groups, with discontinuation of study medication due to AEs in 1.5% and 7.9%, respectively. FeCarb is effective and safe in IBD-associated anemia. It is noninferior to FeSulf in terms of Hb change over 12 wk, and provides a fast Hb increase and a sufficient refill of iron stores.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 December 2016
                2016
                : 11
                : 12
                : e0167146
                Affiliations
                [1 ]Medical University of Innsbruck, Department of Medicine II, Gastroenterology and Hepatology, Anichstr. Innsbruck, Austria
                [2 ]Central Institute for Medical and Chemical Laboratory Diagnosis, Innsbruck University Hospital, Anichstr. Innsbruck, Austria
                [3 ]Medical Research Council (MRC) Human Nutrition Research, Elsie Widdowson Laboratories, Fulbourn Road, Cambridge, United Kingdom
                [4 ]Medical University of Innsbruck, Department of Medicine I, Gastroenterology, Endocrinology and Metabolism, Anichstr. Innsbruck, Austria
                [5 ]Medical University of Vienna, Department of Pathology, Währingergürtel, Vienna, Austria
                Lady Davis Institute for Medical Research, CANADA
                Author notes

                Competing Interests: HZ & VB received honoraria for consulting from Pharmacosmos and AM received honoraria for lecturing from Vifor. All other authors have nothing to disclose in relation to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: BS HZ.

                • Data curation: BS PW AF VB AV ME IS AM AG HZ.

                • Formal analysis: BS HZ.

                • Funding acquisition: WV.

                • Investigation: BS HZ.

                • Methodology: BS HZ.

                • Project administration: BS HZ.

                • Resources: BS PW AF VB AV ME IS AM AG HZ.

                • Supervision: HZ.

                • Validation: BS HZ.

                • Visualization: BS HZ.

                • Writing – original draft: BS HZ.

                • Writing – review & editing: BS HZ VB HT.

                Article
                PONE-D-16-38551
                10.1371/journal.pone.0167146
                5131956
                27907058
                00baa43a-d14e-427e-b9ff-d1223d1cd3b1
                © 2016 Schaefer et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 September 2016
                : 9 November 2016
                Page count
                Figures: 3, Tables: 4, Pages: 11
                Funding
                Funded by: Medical University of Innsbruck
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award Recipient :
                The study was funded by the Medical University of Innsbruck and the Medical Research Council. Benedikt Schaefer received a grant from the “Verein zur Foerderung der Wissenschaft in Gastroenterologie & Hepatologie.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Phosphates
                Biology and Life Sciences
                Biochemistry
                Hormones
                Parathyroid Hormone
                Biology and Life Sciences
                Nutrition
                Nutritional Deficiencies
                Iron Deficiency
                Medicine and Health Sciences
                Nutrition
                Nutritional Deficiencies
                Iron Deficiency
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Adverse Events
                Medicine and Health Sciences
                Hematology
                Anemia
                Iron Deficiency Anemia
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Hematology
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Phosphatases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Phosphatases
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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