Differential Diagnosis of Anemia
Algorithmic Classification by MCV and Reticulocyte Count
The most effective approach to anemia diagnosis uses a two-step classification: first by mean corpuscular volume (MCV) to categorize as microcytic, normocytic, or macrocytic, then by reticulocyte count to distinguish production defects from destruction or loss. 1
Initial Diagnostic Workup
The minimum essential laboratory evaluation includes: 1
- Complete blood count with MCV and red cell distribution width (RDW) 1
- Reticulocyte count (corrected) 1
- Serum ferritin and transferrin saturation 1
- C-reactive protein (CRP) to assess inflammation 1
Additional testing based on initial results: 1
- Vitamin B12 and folate levels (if macrocytic) 1
- Haptoglobin, lactate dehydrogenase, bilirubin (if elevated reticulocytes suggest hemolysis) 1
- Creatinine and estimated glomerular filtration rate (if normocytic) 1
Microcytic Anemia (Low MCV)
With Normal or Low Reticulocytes:
Iron deficiency anemia 1
- Diagnostic criteria without inflammation: serum ferritin <30 μg/L 1
- With inflammation present: ferritin up to 100 μg/L may still indicate iron deficiency 1
- High RDW is a sensitive indicator even when MCV is normal 1
Anemia of chronic disease 1
- Associated with cancer, infection, inflammatory conditions 1
- Caused by hepcidin upregulation reducing iron availability for erythropoiesis 1
- Typically shows low iron, low transferrin saturation, but elevated or normal ferritin 1
Lead poisoning (very rare) 1
Hereditary microcytic anemias (rare) 1
With Elevated Reticulocytes:
Hemoglobinopathies (thalassemia, sickle cell trait) 1
- Requires hemoglobin electrophoresis for diagnosis 1
Normocytic Anemia (Normal MCV)
With Normal or Low Reticulocytes:
Acute hemorrhage (may initially show elevated reticulocytes) 1
Renal anemia 1
- Inappropriately low endogenous erythropoietin levels 1
- Assess creatinine and GFR in all normocytic anemia 1
Anemia of chronic disease 1
- Can be normocytic in 50-70% of cases 2
- Associated with malignancy, chronic infection, autoimmune disease 1
Primary bone marrow diseases 1
- Severe aplastic anemia, pure red cell aplasia 1
- Leukemias, myelodysplastic syndromes 1
- May require bone marrow biopsy for definitive diagnosis 1
Medication-induced 1
- Azathioprine causes macrocytosis and may cause mild anemia, pancytopenia, or pure red cell aplasia 1
With Elevated Reticulocytes:
Hemolysis 1
- Confirm with haptoglobin (decreased), LDH (elevated), indirect bilirubin (elevated) 1
- Autoimmune hemolytic anemia (seen in chronic lymphocytic leukemia) 1
- Microangiopathic processes 1
Hypersplenism 1
- Common in myeloproliferative neoplasms, lymphoid malignancies 1
Macrocytic Anemia (High MCV)
With Normal or Low Reticulocytes:
Vitamin B12 deficiency 1
- Measure serum B12; if equivocal, check methylmalonic acid (specific for B12 deficiency) 1
- Homocysteine elevation indicates B12 or folate deficiency (less specific) 1
- Treatment: 100 mcg intramuscular B12 daily for 6-7 days, then alternate days for 7 doses, then every 3-4 days for 2-3 weeks, followed by 100 mcg monthly for life 3
- Oral B12 is not dependable for pernicious anemia 3
Folate deficiency 1
- Now rare in developed countries due to food fortification (prevalence <1%) 1
- Treatment: folic acid supplementation for megaloblastic anemia 4
- Critical warning: Never give folic acid alone without excluding B12 deficiency, as it may correct anemia while allowing irreversible neurologic damage to progress 3
Myelodysplastic syndromes 1
Medication-induced 1
- Azathioprine, hydroxyurea, antiretroviral drugs 1
With Elevated Reticulocytes:
Hemolysis with MDS 1
Combined deficiencies 1
Critical Diagnostic Pitfalls to Avoid
Masked deficiencies: When microcytosis and macrocytosis coexist (e.g., combined iron and B12 deficiency), they may neutralize each other resulting in falsely normal MCV—use RDW to detect this, as it will be elevated 1
Folate masking B12 deficiency: Doses of folic acid >0.1 mg daily may produce hematologic remission in B12 deficiency while neurologic damage progresses irreversibly 3
Inflammation affecting iron studies: In the presence of inflammation, ferritin up to 100 μg/L may still represent iron deficiency, not just anemia of chronic disease 1
Overlooking functional iron deficiency: Patients with chronic disease may have adequate iron stores (normal ferritin) but functional deficiency due to hepcidin-mediated sequestration 1
Assuming nutritional deficiency in cancer patients: Folate deficiency is essentially absent (0%) and B12 deficiency occurs in only 3.9% of cancer patients—reserve testing for high clinical suspicion (elevated MCV, neurologic symptoms) 1
Treatment Principles by Etiology
Iron Deficiency Anemia:
- Oral or intravenous iron supplementation 1
- Investigate source of blood loss (60-70% have GI source on endoscopy) 5
- Proactive iron replacement prevents anemia recurrence and reduces healthcare costs 1
Anemia of Chronic Disease:
- Optimize treatment of underlying disease first 1
- Intravenous iron if insufficient response 1
- Erythropoiesis-stimulating agents only after optimizing disease therapy and iron, with target hemoglobin ≤12 g/dL 1
Vitamin Deficiencies:
- B12 deficiency requires lifelong monthly injections for pernicious anemia 3
- Folate supplementation for documented deficiency 4
- Always supplement both if needed, never folate alone 3