How should I evaluate a patient with normocytic anemia (mean corpuscular volume 80–100 fL) and low hemoglobin?

Evaluation of Normocytic Anemia

Begin with a complete blood count including reticulocyte count, serum ferritin, transferrin saturation, C-reactive protein, and differential blood cell count to systematically determine whether the bone marrow is responding appropriately and to identify the underlying cause. 1, 2

Initial Laboratory Panel

The minimum workup for normocytic anemia (MCV 80–100 fL) must include: 1, 2

• Complete blood count with red cell indices (MCV, MCH, RDW) and differential white blood cell count
• Absolute reticulocyte count or reticulocyte index (corrected for degree of anemia)
• Serum ferritin and transferrin saturation to assess iron availability
• C-reactive protein to detect inflammation
• Renal function tests (creatinine and urea) to screen for chronic kidney disease

Algorithmic Approach Based on Reticulocyte Response

Low or Normal Reticulocyte Count (Inadequate Marrow Response)

This pattern indicates the bone marrow cannot respond appropriately to anemia. 1, 2, 3

Step 1: Assess Iron Status

• Check ferritin and transferrin saturation for functional iron deficiency, which can occur even with normocytic indices 1, 2
• Without inflammation (normal CRP): ferritin <30 µg/L indicates iron deficiency 1, 2
• With inflammation (elevated CRP): ferritin up to 100 µg/L may still represent iron deficiency because ferritin is an acute-phase reactant 1, 2
• Transferrin saturation <20% supports iron deficiency 2

Step 2: Evaluate for Chronic Kidney Disease

• Assess creatinine and urea, as CKD commonly causes normocytic anemia through erythropoietin deficiency 1, 2, 4
• The anemia of CKD is characteristically normocytic and normochromic 1

Step 3: Consider Anemia of Chronic Disease

• Suspect when CRP is elevated with normal or high ferritin 2, 4
• Characteristic findings include low serum iron, low or normal transferrin, low transferrin saturation, and normal or elevated ferritin 4
• The most common reason for inadequate reticulocyte response in CKD patients with adequate iron, folate, and B12 is insufficient erythropoietin production or inflammation 1, 2

Step 4: Assess Other Cell Lines

• Abnormalities in white blood cells and/or platelets suggest primary bone marrow pathology such as malignancy, vasculitis, or aplastic anemia 1, 2
• This warrants hematology consultation and possible bone marrow examination 1, 2

Elevated Reticulocyte Count (Appropriate Response)

An elevated reticulocyte count indicates increased red cell formation and suggests either hemolysis or acute blood loss. 1, 2

Hemolysis Workup:

• Order haptoglobin (decreased in hemolysis), lactate dehydrogenase (elevated), and indirect bilirubin (elevated) 1, 2
• Consider direct Coombs test and peripheral blood smear examination 2, 3
• Clinical signs may include jaundice and hepatosplenomegaly 3

Acute Blood Loss:

• Focus on identifying and stopping the source of bleeding 3
• Initial management of hypovolemia should use crystalloid fluids 3

Extended Diagnostic Tests When Initial Evaluation Is Inconclusive

If the cause remains unclear after the minimum workup: 1, 2

• Soluble transferrin receptor: Differentiates iron deficiency from anemia of chronic disease
• Percentage of hypochromic red cells or reticulocyte hemoglobin content: Detects functional iron deficiency
• Vitamin B12 and folate: Rule out nutritional deficiencies that may present with normal MCV when combined with microcytosis
• Bone marrow examination: Indicated for unexplained cytopenias across multiple lineages or suspected primary marrow disorder
• Hematology consultation: Advised if etiology remains unclear after extended workup

Critical Pitfalls to Avoid

Ferritin Interpretation in Inflammation: Ferritin can be falsely elevated during inflammation, making iron deficiency difficult to diagnose. Use a higher cutoff (≤100 µg/L) when CRP is elevated rather than the standard <30 µg/L threshold. 1, 2, 4

Mixed Deficiencies: Co-existing microcytosis and macrocytosis may normalize the MCV, masking the true picture. A markedly increased red cell distribution width (RDW) helps uncover this mixed pattern. 1, 2

Hemoglobin vs. Hematocrit: Use hemoglobin rather than hematocrit for diagnosis and monitoring, as hemoglobin has lower coefficients of variation and is not affected by sample storage time or plasma glucose levels. 1, 2

Population-Specific Thresholds: Standard anemia definitions may not apply to pregnant women, elderly patients (≥70 years in men), high-altitude residents, smokers, non-Caucasian populations, or those with chronic lung disease or hemoglobinopathies. 1, 2