Oral iron therapy: Current concepts and future prospects for improving efficacy and outcomes

Abstract

Iron deficiency (ID) and iron-deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iron supplementation, typically using iron salts (e.g. FeSO₄ ); however, dosing at several-fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental forms of iron are transported across the intestinal epithelium and whether these transport pathways are subject to regulation by the iron-regulatory hormone hepcidin.

Keywords: DMT1; FPN; anaemia; hepcidin; intestinal iron absorption; iron supplementation.

Figure 1:. Oral Iron Supplements and Pathways of Absorption.

Ferrous iron salts (A) ionize within the intestinal lumen and iron is then absorbed via the DMT1/FPN pathway. Some ferrous iron may be oxidized and require reduction prior to absorption. The iron-polysaccharide complex (IPC) slowly dissolves in the gut lumen (B), thus releasing ferric iron, which is then reduced and absorbed by the DMT1/FPN pathway. Absorption may be less efficient as some iron is liberated from the carbohydrate shell in more distal gut segments. Heme-iron polypeptide (HIP) may be absorbed like dietary heme (C). This process likely involves a BBM heme transporter/receptor, possibly HRG1, intracellular HO1, a reductase and possibly a BLM heme exporter. Details of this process, for heme, or for HIP, remain to be clarified. Amino acids and peptides are known to enhance iron absorption (D). Iron-AA complexation may increase iron bioavailability by delivering iron to the surface of enterocytes where free iron is absorbed via DMT1. Iron-AA chelates (e.g., Fe-Gly) may be absorbed intact via AA/peptide transporters (e.g., PEPT1), and then hydrolyzed within enterocytes, thus liberating free iron. Sucrosomial iron (SI) and nanoparticle iron (NPI) are likely absorbed via endocytosis, followed by dissociation within lysosomes and iron transport into the cytosol, possibly via DMT1 (E). The lipophilic iron chelate ferric maltol may also be absorbed by this pathway, followed by breakdown in enterocytes, or it could traverse cells intact and be taken up by resident tissue macrophages (not shown). There is also evidence that some of these forms of iron can be absorbed via intestinal M cells, and then taken up by macrophages of the reticuloendothelial system (RES). Hinokitiol probably allows iron to simply diffuse across membranes, followed by iron release to other iron-binding ligands within enterocytes (E).