What is the diagnosis and treatment for a patient with hypoferritinemia (low iron), low Total Iron-Binding Capacity (TIBC), and normal ferritin levels, suggestive of anemia of chronic disease?

Anemia of Chronic Disease (ACD)

This presentation of low serum iron, low TIBC, and normal ferritin is characteristic of anemia of chronic disease (ACD), not iron deficiency anemia, and the primary treatment is addressing the underlying inflammatory or chronic condition rather than iron supplementation. 1, 2

Understanding the Laboratory Pattern

The key to this diagnosis lies in interpreting the iron studies in context:

• Low serum iron with low TIBC (transferrin) distinguishes ACD from iron deficiency anemia 1
• Normal ferritin indicates adequate or increased iron stores, confirming this is NOT iron deficiency 1, 2, 3
• In true iron deficiency, TIBC would be elevated (not low) as the body attempts to capture more circulating iron 1
• The low TIBC reflects decreased transferrin synthesis due to chronic inflammation 1, 3

Critical distinction: Ferritin is an acute phase reactant and can be falsely elevated by inflammation, but when ferritin is truly normal (not elevated) alongside low iron and low TIBC, this pattern is most consistent with early or mild ACD rather than iron deficiency 1

Pathophysiology

ACD results from several mechanisms driven by inflammatory cytokines:

• Impaired erythropoietin production and response - the primary defect 2, 3
• Iron sequestration in reticuloendothelial cells, making it unavailable for erythropoiesis despite adequate stores 2, 3
• Reduced iron absorption from the gut 3
• Mild shortening of red cell lifespan 3

Importantly, iron delivery to bone marrow is NOT significantly impaired in ACD, which is why erythropoietin therapy can correct this anemia while it cannot correct true iron deficiency 3

Diagnostic Workup

Confirm the diagnosis:

• Check inflammatory markers (CRP, ESR) to document underlying inflammation 1
• Assess for chronic diseases: infectious, inflammatory, or neoplastic conditions 2, 3
• Rule out coexisting iron deficiency: If ferritin is 30-100 μg/L with inflammation present, iron deficiency may coexist 1
• Consider soluble transferrin receptor (sTfR) if diagnosis is unclear - this is elevated in iron deficiency but normal/low in pure ACD 1

Search for underlying cause:

• Complete history focusing on chronic infections, autoimmune diseases, malignancies, chronic kidney disease 1, 2
• Age-appropriate cancer screening if no obvious inflammatory condition is identified 2
• Assess renal function - chronic kidney disease commonly causes this pattern 1

Treatment Approach

Primary treatment:

Treat the underlying chronic disease - this is the definitive therapy for ACD 2, 3

• The anemia typically resolves when the underlying condition is successfully managed 2
• ACD itself seldom requires specific treatment if mild 2

When to consider iron supplementation:

Iron therapy is NOT recommended for pure ACD with normal ferritin 1, 4

• Iron supplementation in the presence of normal or high ferritin is potentially harmful 1, 4
• Exception: If ferritin is 30-100 μg/L with inflammation, consider a trial of IV iron (50-125 mg weekly for 8-10 doses) to distinguish functional iron deficiency from inflammatory block 1
• If no erythropoietic response occurs, stop iron - this confirms inflammatory block 1

When to consider erythropoiesis-stimulating agents (ESAs):

For chronic kidney disease patients with hemoglobin <10 g/dL:

• Initiate ESA therapy only when hemoglobin is <10 g/dL 5, 6
• Use the lowest dose to reduce transfusion need, NOT to normalize hemoglobin 5, 6
• Target hemoglobin should NOT exceed 11 g/dL due to increased cardiovascular risks and mortality 5, 6
• Ensure adequate iron stores: ferritin >100 μg/L and transferrin saturation >20% before and during ESA therapy 5, 6

For cancer patients on myelosuppressive chemotherapy:

• Use ESAs only for chemotherapy-induced anemia with planned chemotherapy ≥2 months 5, 6
• NOT indicated when cure is anticipated or for non-chemotherapy causes 5, 6
• Increased risks of tumor progression and thrombosis 5, 6

Common Pitfalls to Avoid

• Do NOT assume iron deficiency based solely on low serum iron - always interpret with TIBC and ferritin 1, 7
• Do NOT give iron supplementation when ferritin is normal or elevated - this is ineffective and potentially harmful 1, 4, 3
• Do NOT target normal hemoglobin levels with ESAs - this increases mortality and cardiovascular events 5, 6
• Do NOT overlook coexisting conditions - ACD frequently coexists with true iron deficiency or renal insufficiency 1, 2
• Do NOT forget to check inflammatory markers - ferritin interpretation requires knowing the inflammatory status 1

Monitoring

• Hemoglobin and iron studies should be rechecked after treating the underlying condition 2
• If ESA therapy is initiated, monitor hemoglobin weekly until stable, then monthly 5, 6
• Avoid frequent dose adjustments of ESAs - changes should not occur more than every 4 weeks 5, 6