Management of Iron-Deficiency Anemia in Inflammatory Bowel Disease: A Systematic Review

Ole Haagen Nielsen, Mark Ainsworth, Mehmet Coskun, Günter Weiss, Ole Haagen Nielsen, Mark Ainsworth, Mehmet Coskun, Günter Weiss

Abstract

Anemia is the most frequent complication of inflammatory bowel disease (IBD), but anemia, mostly due to iron deficiency, has long been neglected in these patients. The aim was to briefly present the pathophysiology, followed by a balanced overview of the different forms of iron replacement available, and subsequently, to perform a systematic review of studies performed in the last decade on the treatment of iron-deficiency anemia in IBD. Given that intravenous therapies have been introduced in the last decade, a systematic review performed in PubMed, EMBASE, the Cochrane Library, and the websites of WHO, FDA, and EMA covered prospective trials investigating the management of iron-deficiency anemia in IBD published since 2004. A total of 632 articles were reviewed, and 13 articles (2906 patients) with unique content were included. In general, oral supplementation in iron-deficiency anemia should be administered with a target to restore/replenish the iron stores and the hemoglobin level in a suitable way. However, in patients with IBD flares and inadequate responses to or side effects with oral preparations, intravenous iron supplementation is the therapy of choice. Neither oral nor intravenous therapy seems to exacerbate the clinical course of IBD, and intravenous iron therapy can be administered even in active disease stages and concomitantly with biologics. In conclusion, because many physicians are in doubt as to how to manage anemia and iron deficiency in IBD, there is a clear need for the implementation of evidence-based recommendations on this matter. Based on the data presented, oral iron therapy should be preferred for patients with quiescent disease stages and trivial iron deficiency anemia unless such patients are intolerant or have an inadequate response, whereas intravenous iron supplementation may be of advantage in patients with aggravated anemia or flares of IBD because inflammation hampers intestinal absorption of iron.

Conflict of interest statement

OHN, MA, and MC have no conflicts of interest to disclose. GW has received lecture honoraria from Vifor Pharma and Pharmacosmos.

Figures

FIGURE 1
FIGURE 1
Regulation of systemic iron homeostasis by hepcidin. Enterocytes and monocytes release Fe2+ via the iron exporter ferroportin, which is then oxidized to Fe3+ and transported via the bloodstream. Liver-derived hepcidin inhibits iron efflux from these cells by binding to ferroportin, which promotes ferroportin internalization and degradation. The synthesis of hepcidin in the liver is induced by iron and inflammatory signals and suppressed by iron deficiency, anemia, or hypoxia.
FIGURE 2
FIGURE 2
Iron absorption from oral or intravenous iron supplementation. Oral preparations of iron supplements are given as tablets and result in a daily absorption of 10–20 mg elemental iron (predominantly in the duodenum and upper jejunum). The oral iron supplementation mainly consists of the Fe2+ (ferrous) form that can be absorbed directly by enterocytes. Dietary iron, mostly in the Fe3+ (ferric) form, contains 10–30% of heme-bound iron, whereas the majority consists of nonheme iron (Fe3+ form). These 2 dietary iron formulations are taken up by enterocytes via different pathways with subsequent yield of Fe2+ which is exported to the circulation by ferroportin. Here, Fe2+ becomes oxidized to Fe3+ and specifically recognized and bound by transferrin and transported via bloodstream to target cells in the liver, bone marrow, and other tissues and organs for use or storage. Intravenous iron supplementation can be administered as high doses of iron directly in the bloodstream in its trivalent Fe3+ form, which is taken up by circulating monocytes (leading to an increase in their iron content), which redeliver Fe3+ to the blood circulation, where it is bound by plasma transferrin and transported to target cells.
FIGURE 3
FIGURE 3
Flowchart of study screening process.
FIGURE 4
FIGURE 4
Algorithm for the treatment of anemia with iron deficiency in IBD. The decision tree provides a ready-to-use tool for clinicians to find the most appropriate therapy for patients with anemia/iron deficiency and IBD based on the data contained in this systematic review. Insufficient response is defined as a hemoglobin increase

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