What is anemia of chronic disease?

Anemia of inflammation is a generally hypoproliferative anemia associated with persistent inflammatory, infectious or neoplastic disorders. Chronic kidney disease, endocrine disorders, liver disease and heart failure may cause anemia through additional mechanisms and are not synonymous with anemia of inflammation. It is characterized by reduced iron availability, an inadequate erythropoietin response, and decreased red blood cell production and survival.

Which diseases can cause anemia of chronic disease?

Classic conditions associated with inflammatory anemia include autoimmune and rheumatologic diseases, inflammatory bowel disease, chronic infections and malignancies. Chronic kidney disease, endocrine disorders, liver disease and heart failure require separate assessment because anemia is often multifactorial.

Why does chronic inflammation cause anemia?

Inflammatory cytokines increase hepatic hepcidin production, reduce erythropoietin synthesis and effectiveness, inhibit erythroid precursors in the bone marrow and shorten red blood cell survival.

What is functional iron deficiency?

Functional iron deficiency is a condition in which iron is present in the body's stores but is not adequately available for erythropoiesis. In anemia of chronic disease, this phenomenon is mainly caused by increased hepcidin.

What is the role of hepcidin in anemia of chronic disease?

Hepcidin binds to ferroportin and causes its internalization and degradation. It therefore reduces intestinal iron absorption and prevents iron release from macrophages and hepatocytes, limiting its availability to the bone marrow.

What type of anemia is anemia of chronic disease?

In most cases it is a normocytic, normochromic anemia with a reduced reticulocyte response. In prolonged forms or when true iron deficiency is also present, it may become microcytic.

What are the symptoms of anemia of chronic disease?

Symptoms include fatigue, pallor, easy fatigability, reduced exercise tolerance, dyspnea and palpitations. They often overlap with manifestations of the underlying chronic disease.

What is the blood test profile in anemia of chronic disease?

The typical profile includes reduced serum iron and transferrin saturation, normal or increased ferritin, normal or reduced transferrin, a low or inappropriately normal reticulocyte count, and elevated inflammatory markers.

Why can ferritin be elevated when iron is not available?

Ferritin is an iron storage protein but also an acute-phase protein. During inflammation it may rise even when the iron available for red blood cell production is insufficient.

How is anemia of chronic disease distinguished from iron deficiency anemia?

In iron deficiency anemia, iron stores are truly depleted and ferritin is generally low. In anemia of chronic disease, ferritin is often normal or elevated, transferrin tends to be normal or reduced, and iron is sequestered in storage sites.

Can iron deficiency anemia and anemia of chronic disease coexist?

Yes. Mixed forms are common in older patients, people with cancer, inflammatory bowel disease and chronic disorders associated with bleeding or malnutrition. Diagnosis requires integrated interpretation of iron and inflammatory indices.

Which tests help identify associated iron deficiency?

In addition to ferritin and transferrin saturation, the soluble transferrin receptor and the sTfR/log(ferritin) index may be useful. Hepcidin can provide additional information, but it is not a routine test.

Does a lack of response to oral iron prove the presence of anemia of chronic disease?

No. An inadequate response may also result from poor adherence, malabsorption, persistent blood loss, an inadequate dose or an incorrect diagnosis. Increased hepcidin may nevertheless reduce the effectiveness of oral iron in inflammatory anemia.

How is anemia of chronic disease treated?

The main treatment is control of the underlying disorder, such as inflammation, infection, cancer, kidney disease or endocrine dysfunction. Any associated nutritional or iron deficiencies must also be identified and corrected.

When can intravenous iron be used?

Intravenous iron may be considered when absolute or functional iron deficiency is documented, especially if oral therapy is ineffective, not tolerated or poorly absorbed. The indication must be individualized.

When are erythropoiesis-stimulating agents used?

Erythropoiesis-stimulating agents may be used in selected settings, particularly in chronic kidney disease and in some patients with cancer. Their use requires assessment of cardiovascular and thromboembolic risk.

What complications can anemia of chronic disease cause?

It can reduce physical capacity and quality of life, worsen heart disease and other comorbidities, increase the risk of hospitalization and impair tolerance of treatments for the underlying disease.

What is the prognosis of anemia of chronic disease?

Prognosis mainly depends on the severity and control of the underlying disease. Reducing inflammation or treating the cause may improve erythropoiesis, whereas persistence of the disorder promotes chronic anemia.

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Anemia of Chronic Disease: General Overview

Article written and reviewed by Dr Luca Moretti

Anemia of chronic disease (ACD), also known as anemia of inflammation, is the second most common form of anemia after iron deficiency anemia and is typically associated with chronic inflammatory, infectious, neoplastic or systemic conditions. It is a multifactorial condition characterized by reduced iron availability for erythropoiesis, altered production or action of erythropoietin, direct inhibition of erythroid proliferation and reduced red blood cell survival, despite iron stores that are often normal or increased.

ACD differs substantially from pure iron deficiency anemia in both its pathogenetic mechanisms and its laboratory and clinical profile, although the two conditions may coexist in the same patient in some situations.

Epidemiology

The frequency of anemia associated with chronic disease varies widely according to the population, diagnostic definition, severity and underlying disorder; it is not appropriate to apply a single percentage to hospitalized patients, older adults, cancer, kidney disease and rheumatologic conditions. The likelihood increases with age and disease burden.

Etiology and associated conditions

ACD develops in the setting of multiple chronic diseases that share persistent inflammation or systemic dysfunction affecting erythropoietic physiology. The main categories are:

Chronic inflammatory diseases: rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, spondyloarthritis, vasculitis and connective tissue diseases.
Chronic infectious diseases: tuberculosis, HIV infection, endocarditis, osteomyelitis and chronic viral hepatitis.
Cancer: solid tumors, such as lung, colon, breast and prostate cancer, and hematologic malignancies, including lymphomas, leukemias and multiple myeloma.
Chronic kidney disease: chronic kidney failure of any cause.
Endocrine disorders: hypothyroidism, hypopituitarism, hypogonadism and adrenal insufficiency; in diabetes, anemia is often mediated by nephropathy, inflammation or other comorbidities.
Other associated conditions: chronic heart failure, chronic liver disease and obesity with persistent inflammation.

In many of these settings, anemia develops gradually and insidiously, often overlapping with other hematologic and nutritional abnormalities.

Pathogenesis and pathophysiology

Anemia of chronic disease is a complex condition involving numerous mechanisms that are often synergistic and interdependent:

Iron sequestration: chronic inflammation induces hepatic production of hepcidin, the main regulator of iron homeostasis, which blocks iron export from enterocytes and macrophages, preventing the release of iron from stores and reducing intestinal absorption. This results in “functional iron deficiency”: iron is present in storage sites but is not accessible for erythropoiesis.
Reduced response to erythropoietin: proinflammatory cytokines, particularly IL-6, TNF-α and IFN-γ, reduce renal erythropoietin synthesis and inhibit its effect on bone marrow erythroid precursors.
Direct inhibition of erythropoiesis: inflammatory cytokines induce apoptosis and reduce proliferation of erythroid precursors, decreasing red blood cell production.
Reduced red blood cell survival: chronic inflammation shortens red blood cell lifespan by increasing splenic and bone marrow clearance.

Together, these mechanisms generally produce normocytic, normochromic anemia with normal or increased ferritin, low serum iron, reduced transferrin saturation and a suboptimal response to oral iron therapy.

Clinical presentation and laboratory findings

Anemia of chronic disease usually presents insidiously and progressively, with anemia-related symptoms, including fatigue, pallor, reduced exercise tolerance and exertional dyspnea, overlapping with those of the underlying disease. In severe cases, signs of cardiovascular compensation or worsening quality of life may occur.

From a laboratory perspective, ACD is typically characterized by:

Normocytic, normochromic anemia, although it may become microcytic in more prolonged forms
Normal or increased ferritin, which is a marker of inflammation as well as iron stores
Reduced serum iron and transferrin saturation
Normal or reduced total transferrin
Elevated inflammatory markers, including ESR, CRP, fibrinogen and alpha-1 and alpha-2 globulins

Ferritin must be interpreted together with transferrin saturation, inflammatory markers and the clinical context because, as an acute-phase protein, it may be normal or elevated and cannot by itself distinguish coexisting iron deficiency.

Differential diagnosis

Distinguishing ACD from iron deficiency anemia is crucial for treatment planning and is based on:

Clinical context, including a known chronic disease or signs of persistent inflammation
Laboratory profile, including normal or elevated ferritin, low transferrin and normocytic, normochromic anemia
Response to iron therapy considered only as contextual information, because an insufficient response is not diagnostic and may depend on adherence, dose, absorption, persistent losses or an alternative diagnosis
Hepcidin measurement only in research or highly specialized settings: methods are not fully standardized and there is no universal clinical cutoff
Assessment of the soluble transferrin receptor (sTfR), which is generally normal or only slightly elevated in ACD and increased in pure iron deficiency

Coexistence of the two forms, referred to as mixed anemia, is common in advanced chronic disease or older adults and requires an integrated assessment.

Management and treatment principles

Treatment of anemia of chronic disease is based primarily on management of the underlying disease, including control of inflammation, cancer, kidney dysfunction or endocrine dysfunction. Iron is indicated when absolute or functional deficiency is documented, and the choice between oral and intravenous administration depends on absorption, tolerance, urgency and the clinical context. In patients with chronic kidney disease or certain cancers, recombinant erythropoietin may be appropriate.

The indication for treatment must always be individualized, weighing the risk of complications, such as iron overload, thrombosis or disease progression, and the impact on quality of life.

Links to specific in-depth articles

For details on the main clinical settings of anemia of chronic disease, see the dedicated monographs:

References

Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40-50.
Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832-1843.
Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425-4433.
World Health Organization. Guideline on haemoglobin cutoffs to define anaemia in individuals and populations. Geneva: WHO; 2024.
Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease. Kidney Int. 2026;109(1S):S1-S99.
Roy CN, Andrews NC. Anemia of inflammation: the hepcidin link. Curr Opin Hematol. 2005;12(2):107-111.
Cascio MJ, DeLoughery TG. Anemia: Evaluation and Diagnostic Tests. Med Clin North Am. 2017;101(2):263-284.
Powell DJ, Achebe MO. Anemia for the Primary Care Physician. Prim Care. 2016;43(4):527-542.
Singh AK, Szczech L, Tang KL, et al.; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.
Aapro M, Beguin Y, Bokemeyer C, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(Suppl 4):iv96–iv110.

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