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, chronic disease) and increased destruction or loss (hemolysis, hemorrhage). 1

Initial Laboratory Test: Reticulocyte Count

The reticulocyte count serves as the critical branch point in your diagnostic algorithm 1:

• Low or normal reticulocyte count indicates ineffective erythropoiesis from bone marrow disorders, chronic disease, or nutritional deficiencies 1
• Elevated reticulocyte count indicates hemolysis or recent hemorrhage with appropriate marrow response 1

Pathway for Elevated Reticulocyte Count

If the reticulocyte count is elevated, proceed with hemolysis evaluation 1:

• Order a peripheral blood smear to identify schistocytes and red cell morphology abnormalities 1
• Check haptoglobin (decreased in hemolysis), LDH (elevated), and indirect bilirubin (elevated) 1
• Look for clinical signs including jaundice and hepatosplenomegaly 2

Pathway for Low or Normal Reticulocyte Count

When reticulocyte count is low or normal, screen systematically for reversible causes 1:

Essential Initial Tests

• Iron studies (serum ferritin and transferrin saturation) - even with normocytic indices, as mixed deficiencies can mask microcytosis 1, 3
• Renal function tests (creatinine and GFR) - normocytic anemia develops when creatinine ≥2.0 mg/dL or GFR <30-35 mL/min/1.73m² due to erythropoietin deficiency 1, 4
• Vitamin B12 and folate levels - combined deficiency states may result in normal MCV 3
• Inflammatory markers (CRP and ESR) to assess for chronic inflammation 3

Additional Helpful Tests

• MCH alongside MCV - reduced MCH despite normal MCV indicates concurrent iron deficiency 1
• RDW (red cell distribution width) - elevated RDW suggests mixed nutrient deficiencies and warrants comprehensive iron, B12, and folate assessment 1, 3
• Methylmalonic acid and homocysteine levels to definitively assess vitamin B12 and folate deficiencies 1

Common Pitfalls to Avoid

• Don't assume normocytic anemia excludes iron deficiency - check iron studies regardless, as early deficiency or combined deficiencies can present with normal MCV 1, 3
• Don't overlook chronic kidney disease - when serum creatinine ≥2.0 mg/dL and normocytic anemia is present without other identified causes, EPO deficiency is the likely diagnosis 1
• Don't mistake anemia of chronic disease for iron deficiency - patients with chronic inflammation may have normocytic anemia with functional iron deficiency despite normal iron stores 3, 5

When to Consider Bone Marrow Examination

Bone marrow aspiration and biopsy should be considered when 3:

• Unexplained pancytopenia or other cytopenias are present
• The noninvasive workup fails to identify a cause
• However, bone marrow examination is only rarely contributive in idiopathic normocytic anemia and should not be routine 6

Special Population Considerations

• Chronic kidney disease patients: When creatinine ≥2.0 mg/dL with normocytic anemia and no other identified causes, EPO deficiency is likely 1
• Cancer patients: Evaluate for chemotherapy-induced anemia, which increases progressively with treatment cycles 1
• Inflammatory bowel disease patients: Require assessment for multiple potential nutritional deficiencies and medication effects 1
• Older adults: Normocytic anemia of unknown cause is encountered mainly in older patients and has excellent prognosis when correctable causes are excluded 6, 7