How can I distinguish iron deficiency anemia from thalassemia and what are the appropriate diagnostic steps and management for each?

Distinguishing Iron Deficiency Anemia from Thalassemia

Use a combination of red blood cell count, RDW, and serum ferritin to distinguish iron deficiency anemia from thalassemia, as these parameters provide the most reliable differentiation in clinical practice.

Initial Laboratory Approach

Start with a complete blood count including MCV, red blood cell count, RDW, and serum ferritin to establish the diagnosis 1.

Key Distinguishing Features

Red Blood Cell Count:

• Thalassemia typically shows an elevated or high-normal RBC count despite microcytosis 1
• Iron deficiency anemia presents with a low or low-normal RBC count 2

Red Cell Distribution Width (RDW):

• RDW >14.0% strongly suggests iron deficiency anemia 1, 3
• Thalassemia typically shows RDW ≤14.0% with more uniform cell sizes 3, 2
• High RDW reflects heterogeneous red cell populations as iron stores deplete 3

Serum Ferritin:

• Ferritin <15 μg/L is diagnostic of iron deficiency 4, 3
• Ferritin <30 μg/L indicates low body iron stores 1, 4
• Normal or elevated ferritin effectively excludes iron deficiency (unless inflammation is present) 1

Confirmatory Testing Algorithm

When Iron Deficiency is Suspected (Low Ferritin + High RDW):

• Obtain transferrin saturation (<30% supports iron deficiency) 1, 3
• Check CRP to interpret ferritin correctly, as inflammation can falsely elevate ferritin and mask true iron deficiency 3
• In inflammatory states, ferritin up to 100 μg/L may still indicate iron deficiency 1

When Thalassemia is Suspected (Normal Ferritin + Low RDW + Elevated RBC):

• Order hemoglobin electrophoresis to confirm thalassemia trait 1
• This definitively identifies beta-thalassemia variants and hemoglobin E 5
• Molecular testing may be needed for alpha-thalassemia diagnosis 6

Additional Discriminating Parameters

Mean Corpuscular Hemoglobin Concentration (MCHC):

• Low MCHC with high RDW strongly favors iron deficiency over thalassemia 3
• Thalassemia shows low MCV but typically maintains better MCHC 3

Mentzer Index (MCV/RBC):

• Values <13 suggest thalassemia 6
• Values >13 suggest iron deficiency 6

Green & King Index and Ehsani Index:

• These discriminant indices show excellent performance but lack sufficient sensitivity/specificity to establish diagnosis alone 6
• They serve as additional screening tools, not definitive diagnostic tests 6

Critical Pitfalls to Avoid

Never assume thalassemia based on ethnicity alone without laboratory confirmation 1. Haemoglobinopathies frequently cause microcytosis in certain ethnic groups but must be confirmed by testing 1.

Do not start empiric iron therapy without confirming iron deficiency, as this causes harm in thalassemia patients and delays proper diagnosis 3.

Recognize that combined deficiencies can occur, where iron deficiency and thalassemia coexist, potentially normalizing MCV while showing elevated RDW 1.

Ferritin is an acute phase reactant—it can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency 1, 3. If ferritin is >100 μg/L, iron deficiency is almost certainly not present 1.

Management Based on Diagnosis

For Confirmed Iron Deficiency:

• Initiate oral iron supplementation once confirmed by ferritin testing 3
• All adult men and post-menopausal women require gastrointestinal evaluation to identify the source of blood loss, including upper endoscopy with small bowel biopsies and colonoscopy 1, 4, 3
• Continue iron for 3-6 months after hemoglobin normalizes to fully replete stores 3
• Therapeutic response to 3 weeks of oral iron (hemoglobin rise ≥10 g/L within 2 weeks) confirms the diagnosis when other tests are equivocal 1, 4, 3

For Confirmed Thalassemia:

• Do not give iron supplementation unless concurrent iron deficiency is documented 3
• Provide genetic counseling 6
• Monitor for complications if more severe forms are identified 5