Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications
Abstract
The anemia of chronic disease (ACD) is characterized by macrophage iron retention induced by cytokines and the master regulator hepcidin. Hepcidin controls cellular iron efflux on binding to the iron export protein ferroportin. Many patients, however, present with both ACD and iron deficiency anemia (ACD/IDA), the latter resulting from chronic blood loss. We used a rat model of ACD resulting from chronic arthritis and mimicked ACD/IDA by additional phlebotomy to define differing iron-regulatory pathways. Iron retention during inflammation occurs in macrophages and the spleen, but not in the liver. In rats and humans with ACD, serum hepcidin concentrations are elevated, which is paralleled by reduced duodenal and macrophage expression of ferroportin. Individuals with ACD/IDA have significantly lower hepcidin levels than ACD subjects, and ACD/IDA persons, in contrast to ACD subjects, were able to absorb dietary iron from the gut and to mobilize iron from macrophages. Circulating hepcidin levels affect iron traffic in ACD and ACD/IDA and are more responsive to the erythropoietic demands for iron than to inflammation. Hepcidin determination may aid to differentiate between ACD and ACD/IDA and in selecting appropriate therapy for these patients.
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A serious consequence of infection or inflammation is the development of anemia of inflammation (AI), also known as anemia of chronic disease (ACD).
“A serious consequence of any infection, or indeed inflammation, is the development of anemia of inflammation (AI) also known as anemia of chronic disease (ACD) (Theurl et al., 2009).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Theurl et al., 2009
Hepcidin overexpression leads to low plasma iron levels (hypoferremia) and anemia.
“Hepcidin overexpression leads to low plasma iron levels (hypoferremia) and anemia (Weinstein et al., 2002; Roy et al., 2007; Theurl et al., 2009; Altamura et al., 2014).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Theurl et al., 2009
The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators.
“The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators [171, 229].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [229]
Inflammation leads to typical alterations of iron homeostasis hallmarked by increased iron acquisition and retention within macrophages along with reduced intestinal iron absorption.
“Inflammation leads to typical alterations of iron homeostasis hallmarked by increased iron acquisition and retention within macrophages along with reduced intestinal iron absorption [9].”
From Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection (2020) · cites this paper as [9]
Hepcidin regulates cellular iron efflux via degradation of ferroportin 1, which induces cellular iron retention in macrophages and reduces duodenal iron absorption.
“Hepcidin regulates cellular iron efflux via degradation of the sole cellular iron exporter ferroportin 1 (FPN1), which induces cellular iron retention in macrophages and reduces duodenal iron absorption [5, 6].”
Inflammation-driven dysregulation of iron homeostasis is well established.
“It has been suggested that the COVID-19 related inflammation may be the main cause of COVID-19 associated iron disorders, as an inflammation-driven dysregulation of iron homeostasis is well established [4, 6, 7].”
Hepcidin is suppressed in iron deficiency anemia, in the normal range in combined iron deficiency anemia and anemia of inflammation, and elevated in anemia of inflammation.
“For instance, HAMP is suppressed in IDA, in the normal range in IDA/AI, and elevated in AI [112, 118].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [112]
Soluble transferrin receptor is increased in iron deficiency, hemolytic anemias, thalassemia, and some hematologic malignancies, while its levels tend to be normal in anemia of inflammation.
“sTFR is increased in ID, hemolytic anemias, thalassemia, and some hematologic malignancies, while its levels tend to be normal in AI [112].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [112]
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Serum Hepcidin in Inflammatory Bowel Diseases: Biological and Clinical Significance
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Self-citationClassical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytes
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- Authors
- Theurl, I., Aigner, E., Theurl, M., Nairz, M., Seifert, M., Schroll, A., Sonnweber, T., Eberwein, L., Witcher, D. R., Murphy, A. T., Wroblewski, V. J., Wurz, E., Datz, C., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- Krankenhaus Oberndorf (AT)
- Eli Lilly (United States) (US)
- Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Innsbruck, Austria;
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-05-21
- Volume
- 113
- Issue
- 21
- Pages
- 5277-5286
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2121871264
- Cited by
- 421
- References
- 54
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 15 · 2023: 16 · 2022: 20 · 2021: 21 · 2020: 26 · 2019: 25 · 2018: 18 · 2017: 21 · 2016: 22 · 2015: 25 · 2014: 36 · 2013: 29 · 2012: 35
- FWCI
- 26.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- iron homeostasis, anemia of chronic disease, iron deficiency anemia, hepcidin, ferroportin, inflammation, dietary iron absorption, iron mobilization, phlebotomy, chronic arthritis, erythropoiesis, differential diagnosis
- MeSH terms
- Ferroportin, Anemia, Animals, Chronic Disease, Disease Models, Animal, Duodenum, Homeostasis, Humans, Inflammation, Iron, Macrophages, Rats, Inbred Lew, Spleen, Case-Control Studies, Anemia, Iron-Deficiency, Antimicrobial Cationic Peptides, Cation Transport Proteins, Rats, Hepcidins
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