How should I evaluate a patient with an elevated red blood cell (RBC) count, low‑normal hemoglobin and hematocrit, and low mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC)?

Evaluation of Elevated RBC Count with Microcytic Hypochromic Indices

This presentation most strongly suggests iron deficiency anemia, and you should immediately check serum ferritin and transferrin saturation to confirm the diagnosis. 1

Understanding the Paradox

The combination of elevated RBC count with low-normal hemoglobin/hematocrit and reduced MCV, MCH, and MCHC creates a characteristic pattern where the bone marrow is producing more red cells, but each cell is smaller and contains less hemoglobin than normal. This is the hallmark of microcytic hypochromic anemia. 1

Why Iron Deficiency is Most Likely

• Iron deficiency is the most common cause of reduced MCH and MCHC, occurring when insufficient iron is available for hemoglobin synthesis in developing red blood cells. 1
• MCH is actually more reliable than MCV for detecting iron deficiency because it is less dependent on storage conditions and counting equipment, and it decreases in both absolute and functional iron deficiency. 1
• The elevated RBC count represents a compensatory response where the marrow produces more cells to maintain oxygen-carrying capacity, even though each individual cell is deficient in hemoglobin. 1

Immediate Diagnostic Workup

First-Line Testing

Order serum ferritin as your single most powerful diagnostic test:

• Ferritin <15 μg/L confirms absent iron stores 1
• Ferritin <30 μg/L indicates low body iron stores 1
• Add transferrin saturation; values <16-20% indicate insufficient circulating iron for erythropoiesis 1

Critical Pitfall to Avoid

Ferritin is an acute phase reactant and can be falsely normal or elevated during inflammation, infection, malignancy, or liver disease despite true iron deficiency. 1 However, ferritin >150 μg/L essentially excludes absolute iron deficiency even with concurrent inflammation. 1

• In inflammatory conditions, ferritin values up to 100 μg/L may still indicate iron deficiency. 1
• Ferritin between 30-100 μg/L suggests combined iron deficiency and anemia of chronic disease. 1

Alternative Diagnoses to Consider

Thalassemia Trait

If iron studies are normal, strongly consider thalassemia (particularly alpha or beta thalassemia trait):

• In thalassemia, MCV is typically reduced out of proportion to the level of anemia, helping distinguish it from iron deficiency. 1
• Thalassemia causes microcytosis and hypochromia with low MCH and MCHC but typically has normal or elevated RBC count. 1
• Low MCV with RDW ≤14.0% suggests thalassemia minor, while RDW >14.0% suggests iron deficiency. 1
• Order hemoglobin electrophoresis if iron studies are normal, particularly in patients of Mediterranean, African, Middle Eastern, or Southeast Asian descent. 1

Combined Deficiencies

Consider combined iron and vitamin B12/folate deficiency if the clinical picture is atypical:

• In patients with combined deficiencies, MCV may appear normal while MCH and MCHC remain low. 1
• A platelet count/MCH ratio >12.00 has 74.6% sensitivity for detecting combined iron and B12 deficiency. 2

Diagnostic Algorithm

Step 1: Check serum ferritin and transferrin saturation 1

Step 2 - If ferritin <30 μg/L (or <100 μg/L with inflammation) AND transferrin saturation <20%:

• Diagnose iron deficiency anemia 1
• Initiate oral iron supplementation 1
• In adult men and post-menopausal women, gastrointestinal evaluation is mandatory as GI blood loss is the most common cause 1

Step 3 - If ferritin >100 μg/L AND transferrin saturation <20%:

• Diagnose anemia of chronic disease 1
• Focus treatment on underlying inflammatory condition 1

Step 4 - If ferritin 30-100 μg/L:

• Suspect combined iron deficiency and anemia of chronic disease 1
• Consider therapeutic trial of iron while managing inflammatory disease 1

Step 5 - If iron studies are normal:

• Order hemoglobin electrophoresis to evaluate for thalassemia 1
• Check RDW: ≤14.0% favors thalassemia, >14.0% reconsider iron deficiency 1

Additional Considerations

Small bowel biopsies should be obtained during upper endoscopy as 2-3% of patients with iron deficiency anemia have celiac disease. 1

Therapeutic response to 3 weeks of oral iron supplementation confirms iron deficiency diagnosis when other tests are equivocal. 1