Anemia of chronic disease (anemia of inflammation)

Definition

Anemia of chronic disease (ACD), now increasingly called anemia of inflammation, is a multifactorial, usually mild to moderate anemia occurring in chronic infections, autoimmune disorders, malignancy, heart failure or kidney disease. Its hallmark is functional iron deficiency: iron stores are adequate, but iron is retained in macrophages and enterocytes and is unavailable to erythropoiesis.

Not every anemia in a chronic illness is ACD – the term applies only to anemias caused by a cytokine- and hepcidin-mediated disturbance of iron utilisation.

Occurrence & epidemiology

Worldwide, ACD is the second most common form of anemia after iron deficiency anemia. Common underlying conditions are chronic infections, rheumatoid arthritis and other autoimmune disorders, cancer, chronic kidney disease and heart failure. The same mechanism also starts acutely in virtually any infection or inflammation, for example in trauma, critical illness or after surgery.

Aetiopathogenesis

Three mechanisms act together:

• Disturbed iron metabolism: inflammatory cytokines, especially interleukin-6, increase hepatic production of hepcidin. Hepcidin causes degradation of the iron exporter ferroportin; less iron is absorbed from the gut and iron from senescent red cells is retained in macrophages. Transferrin saturation falls and erythropoiesis becomes iron-deficient.
• Restricted erythropoiesis: erythropoietin production and the marrow response to it are reduced; cytokines (e.g. interleukin-1β, TNF-α, interferon-γ) additionally impair proliferation and maturation of red cell precursors via radical formation and apoptosis.
• Slightly shortened red cell lifespan due to increased hemophagocytosis by macrophages, especially in acute inflammatory phases.

Sequestering iron is essentially a non-specific defence reaction: it deprives pathogens and tumor cells of iron – but equally deprives blood formation.

Clinical features

The clinical picture is usually dominated by the underlying disease (infection, inflammation, tumor). The anemia develops after a course of at least 6–8 weeks, is usually mild to moderate and causes the usual signs of anemia such as fatigue, reduced performance and exertional dyspnea. Hemoglobin is usually above 8 g/dl; lower values suggest an additional mechanism, such as coexisting true iron deficiency or frequent blood sampling.

Diagnosis

• Blood count: initially normochromic-normocytic, with a longer course hypochromic-microcytic; reticulocytes low; RDW normal or only slightly raised.
• Serum iron and transferrin saturation low, transferrin (total iron-binding capacity) normal or low.
• Ferritin normal or raised (acute-phase protein), typically above 100 ng/ml.
• Soluble transferrin receptor normal; a rise points to coexisting true iron deficiency. Zinc protoporphyrin is raised, hepcidin raised (assay not yet standardised).
• Coexisting iron deficiency: likely with ferritin below 100 ng/ml despite inflammation (below 200 ng/ml in chronic kidney disease); the ferritin index and a low reticulocyte hemoglobin content are also helpful.
• CRP and ESR as non-specific markers of inflammation; search for the underlying disease.
• Bone marrow (rarely needed): storage iron present.

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Further reading (open access)

1. MSD Manual Professional: Anemia of Chronic Disease
2. Onkopedia-Leitlinie (DGHO): Eisenmangel und Eisenmangelanämie (Kapitel Funktioneller Eisenmangel)
3. MSD Manual Professional: Iron Deficiency Anemia

Cross-references