What is the initial step in the workup of a patient with normocytic anemia?

Workup of Normocytic Anemia

The initial step in evaluating normocytic anemia is obtaining a reticulocyte count to distinguish between decreased red blood cell production (bone marrow failure) and increased destruction or loss (hemolysis or hemorrhage). 1, 2

Initial Laboratory Assessment

The reticulocyte count serves as the critical branch point in your diagnostic algorithm 2:

• Low or normal reticulocyte count suggests ineffective erythropoiesis from bone marrow disorders, chronic disease, or nutritional deficiencies 2
• Elevated reticulocyte count indicates hemolysis or recent hemorrhage with appropriate marrow response 2

Systematic Evaluation Based on Reticulocyte Count

If Reticulocyte Count is Elevated (Hemolysis or Blood Loss)

Proceed with hemolysis evaluation 2:

• Peripheral blood smear to identify schistocytes and red cell morphology abnormalities 2
• Haptoglobin (decreased in hemolysis) 2
• LDH (elevated in hemolysis) 2
• Indirect bilirubin (elevated in hemolysis) 2
• Direct assessment for acute blood loss including stool guaiac testing 1

If Reticulocyte Count is Low or Normal (Production Defect)

Screen for common reversible causes first 1:

1. Iron studies (serum ferritin, transferrin saturation, iron) - even with normocytic indices, as mixed deficiencies can mask microcytosis 2

   • Check MCH (mean corpuscular hemoglobin) specifically, as it is more sensitive than MCV for detecting iron deficiency that may be masked by concurrent macrocytosis 2
   • In inflammatory conditions, ferritin up to 100 μg/L may still represent iron deficiency 2

2. Renal function (serum creatinine, BUN) - normocytic anemia develops when creatinine ≥2.0 mg/dL or GFR <30-35 mL/min/1.73m² due to erythropoietin deficiency 1, 3

3. Thyroid function (TSH) - hypothyroidism causes normochromic, normocytic anemia mimicking EPO deficiency 1

4. Vitamin B12 and folate levels - despite classically causing macrocytosis, deficiencies can present with normocytic anemia in 9.2% of cases 4

   • Consider methylmalonic acid (specific for B12 deficiency with better sensitivity than serum B12) 2
   • Consider homocysteine (elevated in tissue deficiency despite normal serum levels) 2

5. Medication review - identify myelosuppressive drugs (azathioprine, 6-mercaptopurine, chemotherapy agents) 1, 2

6. Markers of chronic inflammation - anemia of chronic disease is a common cause of normocytic anemia 5, 6

Red Cell Distribution Width (RDW) Consideration

An elevated RDW suggests mixed nutrient deficiencies (e.g., concurrent iron deficiency with macrocytosis producing falsely normal MCV) and warrants comprehensive iron, B12, and folate assessment 2

When to Consider Bone Marrow Evaluation

Bone marrow aspiration and biopsy should be considered when 7:

• The cause remains unexplained after completing the above workup
• Other cytopenias are present (significantly increases diagnostic yield for bone marrow disorders) 2
• Progressive or severe anemia develops
• Elderly patients with persistent unexplained normocytic anemia 2

Important caveat: In "idiopathic" normocytic anemia without other cytopenias, bone marrow examination is rarely contributive (abnormal in only 2 of 31 patients in one series) 7

Special Population Considerations

Chronic kidney disease patients: When serum creatinine ≥2.0 mg/dL and normocytic anemia is present without other identified causes, EPO deficiency is the likely diagnosis 1. Measuring serum EPO levels is not indicated as they are rarely elevated in this setting and do not guide management 1.

Cancer patients: Evaluate for chemotherapy-induced anemia, which increases progressively with treatment cycles (19.5% in cycle 1 to 46.7% by cycle 5) 1

Inflammatory bowel disease patients: Require special attention for multiple potential nutritional deficiencies and medication effects 2

Critical Pitfall to Avoid

Do not assume normocytic anemia excludes nutritional deficiencies. Mixed deficiencies (iron + B12/folate) can produce a falsely normal MCV, identifiable only through elevated RDW and comprehensive nutritional assessment 2. Always check MCH alongside MCV, as reduced MCH despite normal MCV indicates concurrent iron deficiency 2.