Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2021; 27(17): 2039-2053
Published online May 7, 2021. doi: 10.3748/wjg.v27.i17.2039
Hypophosphatemia after high-dose intravenous iron treatment in patients with inflammatory bowel disease: Mechanisms and possible clinical impact
Trond Espen Detlie, Jonas Christoffer Lindstrøm, Marte Eide Jahnsen, Elisabeth Finnes, Heinz Zoller, Bjørn Moum, Jørgen Jahnsen
Trond Espen Detlie, Marte Eide Jahnsen, Jørgen Jahnsen, Department of Gastroenterology, Akershus University Hospital, Lørenskog 1478, Norway
Trond Espen Detlie, Jonas Christoffer Lindstrøm, Bjørn Moum, Jørgen Jahnsen, Institute of Clinical Medicine, University of Oslo, Oslo 0316, Norway
Jonas Christoffer Lindstrøm, Health Services Research Unit, Akershus University Hospital, Lørenskog 1478, Norway
Elisabeth Finnes, Bjørn Moum, Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo 0424, Norway
Heinz Zoller, Department of Medicine II, Gastroenterology and Hepatology, Medical University of Innsbruck, Innsbruck A-6020, Austria
Author contributions: Detlie TE, Moum B and Jahnsen J contributed responsible for the concept and design of the study, acquisition of data, analysis and interpretation of data, and drafting the article and revising it critically for important intellectual content; Lindstrøm JC and Zoller H performed analysis and interpretation of data, and contributed critical revision of the manuscript for important intellectual content; Jahnsen ME and Finnes E contributed acquisition of data and critical revision of the manuscript for important intellectual content; Moum B and Jahnsen J contributed equally as senior authors; all the authors read and approved the final version of the manuscript.
Institutional review board statement: The study was reviewed and approved by the Regionale Komiteer for Medisinsk og Helsefaglig Forskningsetikk (REK) in Helse Sør-Øst, Norway/Regional Ethics Committee from the South-East Health Region of Norway.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Detlie TE has served as a speaker, consultant or advisory board member for AbbVie, Ferring, Pfizer, Pharmacosmos, Tillotts, and Vifor Pharma. He has received unrestricted research grants from AbbVie, and Pharmacosmos. Jahnsen ME has received lecture fees from Pharmacosmos. Zoller H has served as a speaker, consultant or advisory board member for AbbVie, BMS, Gilead, MSD, Merck, Merz, Novartis, Pharmacosmos, and Vifor Pharma. Moum B has served as a speaker, consultant or advisory board member for AbbVie, Ferring, Janssen, Roche, and Takeda. Jahnsen J has served as a speaker, consultant or advisory board member for AbbVie, Astro Pharma, Boehringer Ingelheim, BMS, Celltrion, Ferring, Hikma, Janssen, Meda, MSD, Napp Pharma, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts, and Sandoz. The other authors have no disclosures.
Data sharing statement: The data underlying this article were provided by Akershus University Hospital and Oslo University Hospital Ullevål by permission. Data will be shared on request to the corresponding author with permission of Akershus University Hospital and Oslo University Hospital Ullevål.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Trond Espen Detlie, MD, Academic Fellow, Academic Research, Consultant Physician-Scientist, Doctor, Department of Gastroenterology, Akershus University Hospital, Sykehusveien 25, Lørenskog 1478, Norway. t.e.detlie@medisin.uio.no
Received: January 28, 2021
Peer-review started: January 28, 2021
First decision: March 6, 2021
Revised: March 19, 2021
Accepted: April 21, 2021
Article in press: April 21, 2021
Published online: May 7, 2021
Abstract
BACKGROUND

High-dose intravenous iron is an effective treatment option for iron deficiency (ID) or ID anaemia (IDA) in inflammatory bowel disease (IBD). However, treatment with ferric carboxymaltose (FCM) has been associated with the development of hypophosphatemia.

AIM

To investigate mechanisms behind the development of hypophosphatemia after intravenous iron treatment, and disclose symptoms and clinical manifestations related to hypophosphatemia short-term.

METHODS

A prospective observational study of adult IBD patients with ID or IDA was conducted between February 1, 2017 and July 1, 2018 at two separate university hospitals in the southeast region of Norway. Patients received one dose of 1000 mg of either FCM or ferric derisomaltose (FDI) and were followed for an observation period of at least 7 wk. Blood and urine samples were collected for relevant analyses at baseline, week 2 and at week 6. Clinical symptoms were assessed at the same timepoints using a respiratory function test, a visual analogue scale, and a health-related quality of life questionnaire.

RESULTS

A total of 106 patients was available for analysis in this study. The FCM treatment group consisted of 52 patients and hypophosphatemia was present in 72.5% of the patients at week 2, and in 21.6% at week 6. In comparison, the FDI treatment group consisted of 54 patients and 11.3% of the patients had hypophosphatemia at week 2, and 3.7% at week 6. The difference in incidence was highly significant at both week 2 and 6 (P < 0.001 and P < 0.013, respectively). We observed a significantly higher mean concentration of intact fibroblast growth factor 23 (P < 0.001), a significant rise in mean urine fractional excretion of phosphate (P = 0.004), a significant decrease of 1,25-dihydroxyvitamin D (P < 0.001) and of ionised calcium levels (P < 0.012) in the FCM-treated patients compared with patients who received FDI. No clinical symptoms could with certainty be related to hypophosphatemia, since neither the respiratory function test, SF-36 (36-item short form health survey) or the visual analogue scale scores resulted in significant differences between patients who developed hypophosphatemia or not.

CONCLUSION

Fibroblast growth factor 23 has a key role in FCM induced hypophosphatemia, probably by inducing loss of phosphate in the urine. Short-term clinical impact of hypophosphatemia was not demonstrated.

Keywords: Iron deficiency, Hypophosphatemia, Inflammatory bowel disease, Ferric carboxymaltose, Ferric derisomaltose

Core Tip: High-dose intravenous iron is an effective treatment for iron deficiency anaemia (IDA) in inflammatory bowel disease (IBD). However, ferric carboxymaltose (FCM) is associated with development of hypophosphatemia. This study of adult IBD patients with IDA investigated the mechanisms and clinical manifestations related to hypophosphatemia after treatment of either FCM or ferric derisomaltose (FDI). The incidence of hypophosphatemia was significantly higher after FCM than FDI, and fibroblast growth factor 23 had a key role, inducing loss of phosphate in the urine along with a significant lowering of 1,25-dihydroxyvitamin D and ionised calcium levels. Short-term clinical impact was not demonstrated.