Anemia of inflammation Original paper

What was reviewed?

This narrative review, Anemia of Inflammation, Hepcidin Iron Sequestration, synthesizes how chronic immune activation produces anemia through coordinated changes in iron handling and erythropoiesis. The authors outline anemia of inflammation (AI; also called anemia of chronic disease) as a highly prevalent anemia in hospitalized and chronically ill patients, occurring in settings such as infections, autoimmune disease, cancer, chronic kidney disease, heart failure, chronic lung disease, and obesity. Central to the review is the concept of “nutritional immunity,” where inflammatory signaling increases the liver hormone hepcidin, which in turn blocks the iron exporter ferroportin on enterocytes and macrophages, reducing dietary iron absorption and trapping recycled iron in the reticuloendothelial system. This creates iron-restricted erythropoiesis despite adequate or increased iron stores, producing the characteristic pattern of hypoferremia with hyperferritinemia.

Who was reviewed?

Rather than focusing on one cohort, the paper integrates evidence from human studies and animal models relevant to patients with prolonged inflammation. The clinical populations discussed span common inpatient and chronic disease contexts, including inflammatory bowel disease, rheumatoid arthritis and other immune-mediated disorders, malignancy-associated inflammation, critical illness/sepsis, chronic kidney disease (including dialysis), and congestive heart failure. The review also addresses special diagnostic subgroups where AI overlaps with true iron deficiency (AI/IDA), which is frequent due to bleeding, iatrogenic phlebotomy, or dialysis losses, and emphasizes that children and older adults may be particularly vulnerable to mixed etiologies. The authors frame these groups as the practical targets for improved diagnostic discrimination (eg, ferritin interpretation in inflammation, soluble transferrin receptor–based indices, and emerging hepcidin/erythroferrone testing) and for individualized therapy selection.

Most important findings

The most clinically actionable synthesis is that inflammatory cytokines—especially IL-6—drive hepcidin upregulation (via STAT3), and hepcidin then degrades/blocks ferroportin, leading to macrophage iron retention and reduced duodenal iron export, which together limit iron delivery to erythroid precursors. Additional inflammation-mediated mechanisms compound anemia: cytokines suppress renal erythropoietin (EPO) production and blunt EPO receptor signaling; interferon-γ and other mediators directly impair erythroid differentiation and can shorten erythrocyte lifespan via enhanced erythrophagocytosis and oxidative injury. Importantly for microbiome-aware clinicians, the review links microbial and microbe-derived signals (notably lipopolysaccharide [LPS]) to hepcidin induction and highlights how iron restriction is a host defense strategy against pathogens—meaning iron therapy decisions can theoretically influence infection risk. The paper also notes specific infection-related modifiers such as Helicobacter pylori (reduced dietary iron absorption) and viral/bacterial inflammatory pathways that intensify hypoferremia.

Key implications

For clinicians, AI should be approached as a biologically purposeful iron-withholding state rather than a simple iron deficiency. Diagnosis hinges on interpreting iron indices in inflammation (low transferrin saturation with normal/high ferritin) and actively considering mixed AI/IDA, where treatment and evaluation for bleeding sources differ. Therapeutically, addressing the underlying inflammatory driver is primary; iron (often IV when hepcidin is high) and erythropoiesis-stimulating agents may help selected patients but require caution given infection and malignancy contexts. Emerging strategies that target the hepcidin–ferroportin axis (hepcidin antagonists, IL-6 pathway inhibition, or hypoxia-inducible factor stabilizers) aim to mobilize sequestered endogenous iron, but the review underscores that the safest indications will depend on improved biomarkers and an explicit risk–benefit assessment tailored to the underlying disease.

Citation

Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40-50. doi:10.1182/blood-2018-06-856500