What is the appropriate diagnostic and treatment approach for a patient with normocytic or macrocytic anemia, elevated ferritin, normal iron and TIBC, and normal RDW, without evidence of iron, vitamin B12, or folate deficiency?

Diagnostic Approach for Normocytic/Macrocytic Anemia with Elevated Ferritin

This presentation most likely represents anemia of chronic disease (ACD), and your primary focus should be identifying and treating the underlying inflammatory or chronic condition causing the anemia, while simultaneously evaluating for bone marrow pathology if the patient is elderly or has other cytopenias. 1

Understanding the Clinical Pattern

The combination of elevated ferritin with normal iron/TIBC in the context of anemia strongly suggests ACD rather than iron deficiency:

• Elevated ferritin (>100 μg/L) with transferrin saturation <20% is diagnostic of ACD in the presence of inflammation 1
• In ACD, inflammatory cytokines upregulate hepcidin production in the liver, which traps iron in macrophages and reduces iron availability for erythropoiesis despite adequate total body iron stores 1
• Normal RDW argues against iron deficiency, as high RDW is a specific indicator of iron deficiency reflecting heterogeneous red cell populations 1, 2
• The normocytic or macrocytic pattern with normal iron studies excludes absolute iron deficiency 1

Essential Diagnostic Workup

Inflammatory and Chronic Disease Markers

• Measure CRP and ESR to document inflammation, as these are essential to interpret ferritin correctly and confirm ACD 1
• Obtain reticulocyte count to classify the anemia—low/normal reticulocytes with normocytic anemia points to ACD, renal disease, or primary bone marrow disorders 1
• Check renal function (creatinine, eGFR) as renal anemia presents identically with inappropriately low endogenous erythropoietin levels 1

Exclude Myelodysplastic Syndrome (MDS)

If the patient is elderly or has other cytopenias:

• Review peripheral blood smear for dysplastic features including abnormal cell morphology 3
• Consider bone marrow examination if cytopenias persist or if the smear shows dysplastic features, as almost all MDS patients have macrocytic anemia with or without other cytopenias 3
• MDS is a critical diagnosis not to miss in elderly patients with unexplained normocytic or macrocytic anemia 3

Screen for Underlying Chronic Conditions

The most common causes of ACD include:

• Malignancy: Obtain age-appropriate cancer screening, particularly if unexplained weight loss or constitutional symptoms are present 1, 4
• Chronic infection: Consider HIV, hepatitis C, tuberculosis, or chronic bacterial infections 4
• Inflammatory bowel disease: Even without GI symptoms, IBD can present with ACD—up to 45% of IBD patients have iron deficiency and one-third have anemia during active disease 3
• Autoimmune disorders: Check ANA, rheumatoid factor if clinically indicated 4
• Chronic kidney disease: Already mentioned above but bears emphasis as a common cause 1

Critical Diagnostic Pitfall to Avoid

Do not assume this is simply "anemia of chronic disease" without actively searching for the underlying cause—the chronic disease itself may be occult malignancy, undiagnosed IBD, or another serious condition requiring specific treatment 3, 4. The anemia is a manifestation, not the primary problem.

Treatment Approach

Address the Underlying Disease First

• Treatment of ACD primarily involves treating the underlying chronic condition, as the anemia will often improve when inflammation is controlled 4
• Cytokines and acute-phase proteins drive the pathogenesis through hepcidin-mediated iron sequestration, so anti-inflammatory treatment is key 4

Consider Erythropoiesis-Stimulating Agents

• Erythropoiesis-stimulating agents (ESAs) may be indicated in specific contexts such as chronic kidney disease or when the underlying disease cannot be fully controlled 4
• ESAs are particularly useful when endogenous erythropoietin production is inappropriately low for the degree of anemia 1

Iron Supplementation Has Limited Role

• Iron supplementation is generally not effective in ACD because the problem is functional iron sequestration, not absolute deficiency 4
• However, if ferritin is between 30-100 μg/L, a combination of true iron deficiency and ACD may coexist, and iron supplementation could be considered 1

Transfusion for Severe Symptomatic Anemia

• Blood transfusion should be reserved for severe symptomatic anemia affecting quality of life or causing hemodynamic compromise 4

When to Pursue Aggressive Workup

If no underlying chronic disease is identified after initial evaluation, or if the patient has additional cytopenias or is elderly, proceed directly to hematology referral for bone marrow examination to exclude MDS, leukemia, or other primary bone marrow disorders 1, 3. Do not delay this evaluation with empiric trials of therapy.