In a patient with mild normocytic anemia (RBC 3.63 ×10⁶/µL, hemoglobin 11.0 g/dL, hematocrit 34.8%), markedly elevated ferritin (~1440 ng/mL), low total iron‑binding capacity (~205 µg/dL) and normal transferrin saturation, what is the most likely diagnosis and what is the appropriate management?

Anemia of Chronic Inflammation with Iron Sequestration

This patient has anemia of chronic disease (anemia of inflammation) characterized by iron sequestration in macrophages, not iron deficiency, and the primary management goal is to identify and treat the underlying inflammatory, infectious, or malignant condition driving the anemia. 1, 2, 3

Diagnostic Confirmation

The laboratory pattern is pathognomonic for anemia of chronic inflammation:

• Markedly elevated ferritin (~1440 ng/mL) indicates abundant iron stores trapped in the reticuloendothelial system 1, 2
• Low TIBC (~205 µg/dL) reflects suppressed transferrin synthesis due to inflammation 1, 3
• Normal transferrin saturation with low serum iron confirms functional iron deficiency—iron is present but sequestered and unavailable for erythropoiesis 2, 4
• Normocytic anemia (MCV typically 80-100 fL) is characteristic, as this is a hypoproliferative anemia with impaired erythropoietin response 1, 5

This pattern definitively excludes absolute iron deficiency, which would show ferritin <30 µg/L (or <100 µg/L even with inflammation) and elevated TIBC 1, 6.

Pathophysiology

The anemia results from inflammatory cytokines (especially IL-6) inducing hepatic hepcidin production, which blocks iron release from macrophages, hepatocytes, and enterocytes 2, 3. Additionally, inflammatory cytokines directly suppress erythropoietin production and inhibit erythroid progenitor cell responsiveness 3, 4. Iron supplementation will not correct this anemia because the problem is not iron availability but rather cytokine-mediated suppression of erythropoiesis and iron sequestration. 4

Mandatory Diagnostic Workup

Immediate investigations to identify the underlying cause:

Inflammatory/Infectious screening:

• C-reactive protein and erythrocyte sedimentation rate to document active inflammation 5
• Complete infectious workup if fever, weight loss, or localizing symptoms present 3

Malignancy evaluation (critical given markedly elevated ferritin):

• Peripheral blood smear to assess for dysplastic features, blasts, or abnormal morphology suggesting myelodysplastic syndrome or hematologic malignancy 5
• Age-appropriate cancer screening (colonoscopy, mammography, CT chest/abdomen/pelvis) as ferritin >1000 ng/mL raises suspicion for solid tumors or lymphoma 5
• Serum protein electrophoresis, free light chains, and quantitative immunoglobulins to exclude multiple myeloma (which causes normocytic anemia in 75% of cases at diagnosis) 5

Renal assessment:

• Serum creatinine and estimated GFR, as chronic kidney disease (GFR <30 mL/min/1.73 m²) produces an identical anemia pattern 5

Autoimmune/Rheumatologic screening:

• ANA, rheumatoid factor, anti-CCP if joint symptoms, rash, or other autoimmune features present 3

Reticulocyte count:

• Should be low (reticulocyte index <1.0-2.0), confirming hypoproliferative anemia rather than hemolysis or blood loss 1, 5

Indications for Bone Marrow Examination

Bone marrow aspiration and biopsy are indicated if: 5

• Peripheral smear shows dysplastic features, blasts, or unexplained abnormalities
• Unexplained pancytopenia or abnormalities in multiple cell lines
• Progressive anemia despite treatment of identified underlying condition
• Clinical suspicion for myelodysplastic syndrome or infiltrative marrow process
• Failure to identify a cause after comprehensive non-invasive workup

Management Algorithm

Primary treatment: Address the underlying disease

The anemia will not improve without controlling the inflammatory/infectious/malignant process. 3, 4

• Chronic inflammatory conditions (rheumatoid arthritis, inflammatory bowel disease): Optimize disease-modifying therapy and monitor hemoglobin every 6 months for stable disease, more frequently during flares 5
• Chronic infections: Treat with appropriate antimicrobials 3
• Malignancy: Oncologic treatment per tumor type 1
• Chronic kidney disease: See specific management below 5

Iron supplementation: DO NOT GIVE

Iron therapy (oral or intravenous) is contraindicated when ferritin is markedly elevated (>500-800 ng/mL) because hepcidin-mediated sequestration prevents utilization and may cause iron overload. 5, 4 Iron is only appropriate if ferritin falls below 100 µg/L during treatment of the underlying condition 5.

Erythropoiesis-stimulating agents (ESAs): Reserved for specific scenarios

Chronic kidney disease:

• Do not start ESAs until hemoglobin <10 g/dL in asymptomatic patients 5
• Use minimal dose to reduce transfusion needs, not to target specific hemoglobin 5
• Provide supplemental iron only if ferritin <100 µg/L or transferrin saturation <20% while on ESA therapy 5

Inflammatory conditions:

• Reserve ESAs for patients with hemoglobin <10 g/dL who remain symptomatic despite optimal control of underlying disease 5

Myelodysplastic syndrome (if diagnosed):

• Low-risk MDS with hemoglobin ≤10 g/dL and erythropoietin ≤500 mU/mL may receive ESAs 5
• High-risk MDS requires hypomethylating agents (azacitidine or decitabine) 5

Transfusion thresholds

Transfuse packed red blood cells only if: 1

• Hemoglobin <7-8 g/dL, OR
• Severe symptoms (chest pain, resting dyspnea, hemodynamic instability) regardless of hemoglobin level

Do not transfuse based solely on crossing an arbitrary hemoglobin threshold. 1

Monitoring and Follow-Up

• Repeat complete blood count 4-6 weeks after initiating treatment of underlying condition 5
• Serial reticulocyte counts can indicate therapeutic response; upward trend suggests effective disease control 5
• Monitor for recurrence: anemia recurs in >50% of patients within 1 year after initial improvement 5

Critical Pitfalls to Avoid

• Do not give iron supplementation when ferritin is >500 ng/mL—this will not improve anemia and risks iron overload 5, 4
• Do not assume anemia of chronic disease without measuring inflammatory markers and investigating for malignancy, especially with ferritin >1000 ng/mL 5
• Do not delay malignancy workup—markedly elevated ferritin in normocytic anemia mandates evaluation for hematologic and solid tumors 5
• Do not use ESAs as first-line therapy—treat the underlying disease first 5, 4
• Do not overlook combined deficiencies—check vitamin B12 and folate, as these can coexist and require separate treatment 5