What is the approach to evaluating normocytic anemia?

Evaluation of Normocytic Anemia

The evaluation of normocytic anemia (MCV 80-100 fL) begins with a reticulocyte count to distinguish between decreased RBC production (low reticulocyte index) and increased destruction or blood loss (high reticulocyte index), which then directs all subsequent testing. 1, 2

Initial Diagnostic Steps

Step 1: Confirm Normocytic Anemia and Assess Bone Marrow Response

• Obtain a complete blood count (CBC) with indices to verify MCV is 80-100 fL and identify any additional cytopenias (thrombocytopenia, leukopenia) 3, 2
• Perform peripheral blood smear review to assess RBC morphology, identify abnormal cells, and look for evidence of hemolysis, renal disease, or liver disease 3, 4
• Calculate the reticulocyte index (RI) corrected for the degree of anemia—this is the critical branching point in your evaluation 1, 2, 4

Step 2: Branch Based on Reticulocyte Index

The reticulocyte index divides normocytic anemia into two mechanistic categories that require completely different workups 1, 2:

Low Reticulocyte Index (<1.0): Decreased RBC Production

This is the most common presentation of normocytic anemia and indicates bone marrow failure to compensate. 2 The differential includes anemia of chronic disease/inflammation, chronic kidney disease, endocrine disorders, early nutritional deficiencies, bone marrow infiltration, and aplastic anemia 1, 2, 5.

Essential Laboratory Tests for Low RI:

• Iron studies: serum ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) 1, 2

  • Anemia of chronic disease typically shows: low iron, low TIBC, normal or elevated ferritin, low TSAT 2
  • Early iron deficiency may present as normocytic before becoming microcytic 1

• Renal function tests: serum creatinine and BUN to calculate GFR 1, 2

  • Normocytic anemia develops when GFR falls below 20-30 mL/min due to erythropoietin deficiency 1, 2

• Inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1, 2

  • Elevated markers suggest anemia of chronic inflammation 2

• Endocrine evaluation: thyroid function tests (TSH, free T4) 2

  • Hypothyroidism commonly causes normocytic anemia 2

• Nutritional assessment: vitamin B12 and folate levels 1, 2

  • Early deficiencies may present as normocytic before MCV rises 1
  • Combined deficiency states (iron + B12/folate) can result in normal MCV 1
  • Riboflavin deficiency can cause normochromic, normocytic anemia with marrow aplasia 1

When to Consider Bone Marrow Examination:

• Unexplained pancytopenia or multiple cytopenias warrant bone marrow aspiration and biopsy 1
• Older patients with unexplained normocytic anemia should be evaluated for myelodysplastic syndromes 2
• Suspected bone marrow infiltration from malignancy 2
• However, bone marrow examination is rarely contributive in isolated normocytic anemia without other cytopenias or concerning features 6

High Reticulocyte Index (>2.0): Increased Destruction or Blood Loss

An elevated reticulocyte count indicates the bone marrow is responding appropriately, pointing to either hemolysis or acute blood loss. 1, 2

Hemolysis Workup:

• Lactate dehydrogenase (LDH): elevated in hemolysis 2, 5
• Haptoglobin: decreased in intravascular hemolysis 2, 5
• Indirect (unconjugated) bilirubin: elevated in hemolysis 2, 5
• Direct antiglobulin test (Coombs' test): distinguishes immune from non-immune hemolysis 7
• Look for clinical signs: jaundice, hepatosplenomegaly, dark urine 3, 5

Blood Loss Assessment:

• Stool guaiac test for occult gastrointestinal bleeding 2
• Detailed menstrual history in women of reproductive age 2
• Assess for signs of bleeding: blood in stool, petechiae, recent trauma or surgery 3, 2
• Acute blood loss may present with normocytic anemia before iron stores are depleted 5

Critical Pitfalls to Avoid

• Mixed anemias can mask each other: Combined iron deficiency and B12/folate deficiency may neutralize MCV changes, appearing normocytic 1, 8

  • Check red cell distribution width (RDW): elevated RDW (>14%) in normocytic anemia suggests underlying iron deficiency or mixed deficiency 1

• Functional iron deficiency in chronic inflammation: Patients may have normal or elevated ferritin but low transferrin saturation, indicating iron is sequestered and unavailable for erythropoiesis 1, 2

• Early nutritional deficiencies: Iron, B12, and folate deficiencies may initially present as normocytic before morphological RBC changes become apparent 1

• Anemia of chronic disease is often mistaken for iron deficiency: Do not empirically treat with iron without confirming true iron deficiency through appropriate studies 9

Special Clinical Contexts

Cancer-Related Anemia:

• May result from bone marrow infiltration, chronic inflammation, chemotherapy effects, or radiation 3, 2
• Hemoglobin ≤11 g/dL or a decrease of ≥2 g/dL from baseline should prompt evaluation 3
• Consider imaging (PET/CT) if malignancy is suspected 2

Chronic Kidney Disease:

• Normocytic anemia typically develops when GFR <20-30 mL/min 1, 2
• Primarily due to erythropoietin deficiency 1, 2
• Erythropoiesis-stimulating agents should not be initiated in asymptomatic patients until hemoglobin <10 g/dL 5

Idiopathic Normocytic Anemia in Elderly:

• After thorough noninvasive evaluation, some elderly patients have unexplained mild normocytic anemia 6
• Bone marrow examination is rarely contributive in this setting 6
• Prognosis is generally excellent with marginal improvement over time 6