What is the best course of action for a patient with microcytic anemia and normal ferritin (iron storage) levels?

Microcytic Anemia with Normal Ferritin: Diagnostic and Management Approach

Primary Recommendation

When microcytic anemia presents with normal ferritin levels, the most likely diagnoses are thalassemia trait or early anemia of chronic disease, and you should immediately order hemoglobin electrophoresis and inflammatory markers (CRP, ESR) to differentiate between these conditions. 1

Algorithmic Diagnostic Approach

Step 1: Evaluate the Red Cell Distribution Width (RDW)

• RDW >14.0% with low MCV: Suggests iron deficiency anemia despite the normal ferritin, particularly if ferritin is in the low-normal range (30-45 μg/L) 1, 2
• RDW ≤14.0% with low MCV: Strongly suggests thalassemia minor and warrants immediate hemoglobin electrophoresis 1, 2, 3

Step 2: Refine Ferritin Interpretation

Normal ferritin does not always exclude iron deficiency. 1, 2

• Ferritin <45 μg/L confirms iron deficiency even if technically "normal" by lab reference ranges, as this cut-off provides optimal sensitivity and specificity 1, 2, 3
• Ferritin can be falsely elevated by inflammation, making transferrin saturation (TSAT) essential in these cases 2
• Check TSAT: Low TSAT (<20%) with normal ferritin suggests functional iron deficiency or early iron deficiency 1, 2

Step 3: Order Hemoglobin Electrophoresis

Hemoglobin electrophoresis is mandatory when: 2

• MCV is disproportionately low relative to the degree of anemia 2
• Patient has appropriate ethnic background (Mediterranean, African, Southeast Asian descent) 2
• RDW is normal or near-normal with microcytosis 2

This test definitively diagnoses β-thalassemia trait, which requires no iron supplementation unless coexistent iron deficiency is proven (ferritin <45 μg/L) 1

Step 4: Check Inflammatory Markers

• Elevated CRP or ESR with normal-to-high ferritin suggests anemia of chronic disease 1
• In anemia of chronic disease, treat the underlying inflammatory condition rather than giving iron 1

Treatment Algorithm

If Iron Deficiency is Confirmed (Ferritin <45 μg/L or Low TSAT)

Start ferrous sulfate 324 mg (65 mg elemental iron) one to three times daily for at least 3 months after hemoglobin normalizes. 1, 2

• Add ascorbic acid (vitamin C) to enhance absorption 1, 2
• Expect hemoglobin rise ≥10 g/L (≥1 g/dL) within 2 weeks, confirming the diagnosis 1, 2
• If no response within 2-4 weeks, consider intravenous iron for malabsorption or investigate for rare genetic disorders 2, 3

If Thalassemia Trait is Diagnosed

• No iron supplementation is needed unless coexistent iron deficiency is proven (ferritin <45 μg/L) 1
• Provide genetic counseling and family screening 1

If Anemia of Chronic Disease is Diagnosed

• Treat the underlying inflammatory condition 1
• Iron supplementation is generally ineffective and potentially harmful 1

Rare Genetic Disorders to Consider

When microcytic anemia persists with normal ferritin and normal hemoglobin electrophoresis, consider these rare conditions:

IRIDA (Iron-Refractory Iron Deficiency Anemia)

• Presents with low TSAT, low-normal ferritin, and poor response to oral iron but partial response to IV iron 4, 2
• Check serum hepcidin: elevated hepcidin:TSAT ratio suggests IRIDA 4
• Requires TMPRSS6 gene mutation analysis for confirmation 4
• Treatment: IV iron supplementation (iron sucrose or gluconate), monitoring ferritin to keep <500 μg/L 4, 2

SLC11A2 (DMT1) Defects

• Typically presents in childhood with high TSAT (not normal), making this unlikely with normal TSAT 4, 1
• Requires genotyping if suspected 4
• Treatment: oral iron, EPO, or transfusions based on individual needs 4, 2

Aceruloplasminemia

• Rare but important: presents with microcytic anemia, high ferritin (not normal), diabetes, and neurological symptoms 4, 5
• Check serum ceruloplasmin if high ferritin with diabetes 4, 5

Monitoring Protocol

• Check hemoglobin, MCV, and iron studies at 2 weeks, 4 weeks, 3 months, and every 3 months for the first year 1, 2
• Provide additional oral iron if hemoglobin or MCV falls below normal during follow-up 1, 2

Critical Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency: 20-30% will have another diagnosis, particularly thalassemia or anemia of chronic disease 6
• Do not rely solely on lab "normal" ranges for ferritin: Use the 45 μg/L cut-off for clinical decision-making 1, 2, 3
• Do not give iron to thalassemia patients without proven iron deficiency: This causes harmful iron overload 1
• Do not overlook combined deficiencies: Iron deficiency can coexist with B12 or folate deficiency 2, 3
• Always investigate the source of iron loss in adults: Men with Hb <110 g/L or non-menstruating women with Hb <100 g/L warrant fast-track GI referral 2