Abstract
Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation.
Highlights
Iron has a crucial role in all living organisms
While iron retention in the mononuclear phagocyte system (MPS) appears to be beneficial for host responses during infections, as it withholds this metal from invading extracellular pathogens, anemia is an undesired, ultimate consequence of iron restriction in patients suffering from chronic diseases [17,18,19]
Anemia of inflammation (AI) or anemia of chronic disease (ACD) represents the most common disease-related complication in patients suffering from rheumatoid arthritis (RA) inflammatory bowel diseases (IBD), cancer, infectious diseases, and chronic kidney disease (CKD) [1,20,21,22,23,24,25,26]
Summary
Iron has a crucial role in all living organisms. In humans, iron is essential for many biochemical processes, including electron transfer reactions in mitochondria, the citric acid cycle, gene expression, binding and transport of oxygen, regulation of cell growth and differentiation as well as the cellular immune response [1]. Local and systemic iron availability determines microbial growth, and the efficacy of anti-microbial immune effector pathways It appears that the alterations of systemic and macrophage-responsible iron fluxes are regulated depending on the nature and localization of the pathogen [19,32,33,39,47]. We have several established and novel iron therapies at hand, there are still many unresolved questions and unmet needs when treating imbalances of iron homeostasis in patients with inflammatory diseases This includes lack of gold-standard tests to properly distinguish between absolute versus functional ID, lack of knowledge regarding safe and efficient therapeutic start and end points as well as complications of iron redistribution and supplementation strategies towards the course of the diseases underlying AI
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