What is the differential diagnosis and appropriate workup for microcytic hypochromic anemia with a normal ferritin level?

Microcytic Hypochromic Anemia with Normal Ferritin

When microcytic hypochromic anemia presents with normal ferritin (30-100 µg/L), you must immediately measure inflammatory markers (CRP/ESR) and transferrin saturation (TSAT) to distinguish between true iron deficiency with inflammation, anemia of chronic disease, or genetic disorders of iron metabolism. 1

Initial Diagnostic Workup

Measure Inflammatory Status First

• Check CRP and ESR immediately because ferritin 30-100 µg/L with elevated inflammatory markers indicates a mixed picture of true iron deficiency combined with anemia of chronic disease. 1, 2
• Calculate TSAT as (serum iron × 100) ÷ TIBC—a TSAT <20% confirms iron deficiency requiring treatment even when ferritin reaches 100 µg/L. 1, 2

Interpret Results Based on Inflammation

If inflammation is present (elevated CRP/ESR):

• Ferritin 30-100 µg/L with TSAT <20% = true iron deficiency coexisting with anemia of chronic disease; initiate iron therapy while treating the underlying inflammatory condition. 1, 2
• Ferritin >100 µg/L with TSAT <20% = primarily anemia of chronic disease with functional iron deficiency; focus on aggressive management of the underlying inflammatory disease. 1, 2

If no inflammation (normal CRP/ESR):

• Ferritin 30-100 µg/L with TSAT <20% = true iron deficiency; start oral iron supplementation. 1, 2
• Ferritin >100 µg/L without inflammation makes absolute iron deficiency unlikely; investigate alternative causes including vitamin B12/folate deficiency, hemolysis, or bone marrow disease. 2

Differential Diagnosis Beyond Common Causes

When Standard Iron Studies Are Discordant

If ferritin is normal but clinical suspicion for iron deficiency remains high:

• Measure soluble transferrin receptor (sTfR)—an elevated sTfR confirms true iron deficiency even in inflammation because sTfR is not an acute-phase reactant. 2, 3
• Check red cell distribution width (RDW)—increased RDW can reveal iron deficiency even when MCV is normal, reflecting coexistence of micro- and macrocytic cells. 2

Consider Genetic Disorders of Iron Metabolism

When anemia is refractory to iron supplementation despite normal ferritin:

• Iron-refractory iron deficiency anemia (IRIDA) due to TMPRSS6 mutations presents with very low TSAT, low-to-normal ferritin, and failure to respond to oral iron. 1
• Rule out autoimmune atrophic gastritis, H. pylori infection, and celiac disease before pursuing genetic testing, as these conditions also cause oral iron refractoriness. 1

If ferritin is normal-to-high with microcytic anemia:

• Sideroblastic anemias due to defects in SLC25A38, STEAP3, or ABCB7 present with microcytic hypochromic anemia, elevated TSAT, and increased ferritin even before transfusions. 1
• Bone marrow examination showing ring sideroblasts confirms sideroblastic anemia; genetic testing identifies the specific mutation. 1
• Hypotransferrinemia due to TF defects presents in early life with microcytic hypochromic anemia, low serum iron, high ferritin, and fully saturated transferrin (though transferrin levels are markedly reduced). 1

Additional Laboratory Tests

Measure free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZnPP):

• Elevated FEP occurs in iron deficiency, anemia of chronic disease, and lead toxicity but remains normal in thalassemias and hemoglobin E disorders. 4
• This test helps differentiate iron deficiency from thalassemia trait when ferritin is normal. 4

Obtain hemoglobin electrophoresis:

• Essential to exclude thalassemia trait and hemoglobin E disorders when ferritin is normal or elevated and TSAT is normal. 4, 5

Check reticulocyte count:

• Low or normal reticulocyte count suggests deficiency states or bone marrow failure; elevated reticulocytes point toward hemolysis. 2
• If reticulocytes are elevated, measure haptoglobin, LDH, and bilirubin to confirm hemolysis. 2

Common Pitfalls to Avoid

• Do not assume normal ferritin excludes iron deficiency in the presence of inflammation—ferritin up to 100 µg/L may still represent iron deficiency when inflammation is present. 1, 2
• Do not rely on ferritin alone; always calculate TSAT because functional iron deficiency can occur despite high ferritin when TSAT <20%. 1, 2
• Do not overlook genetic disorders when anemia is refractory to iron therapy—family history and early presentation suggest inherited conditions. 1
• Do not miss lead toxicity—elevated FEP with normal ferritin and microcytic anemia should prompt blood lead level testing. 4

Special Population Considerations

In inflammatory bowel disease:

• Ferritin <30 µg/L during remission reliably indicates iron deficiency, but during active inflammation ferritin up to 100 µg/L may still represent iron deficiency. 1, 2

In chronic kidney disease and heart failure:

• Use a ferritin threshold <100 µg/L (not <30 µg/L) to screen for iron deficiency in these populations. 2