What are the causes of a moderate‑to‑severe normochromic, normocytic anemia with an elevated red‑cell distribution width?

Causes of Moderate-to-Severe Normochromic Normocytic Anemia with Elevated RDW

The most common causes of moderate-to-severe normochromic normocytic anemia with elevated RDW are early or evolving iron deficiency (before microcytosis develops), combined nutritional deficiencies (iron plus B12 or folate), hemolytic anemia, anemia of chronic disease with concurrent iron deficiency, and bone marrow failure syndromes such as aplastic anemia. 1

Understanding the Clinical Significance of Elevated RDW

• An elevated RDW (>14.0%) indicates increased heterogeneity in red blood cell size, reflecting a mixed population of cells or active erythropoiesis with variable cell production 1
• When RDW is elevated with normal MCV, this typically represents either early nutritional deficiency (before MCV changes), combined deficiencies that "cancel out" the MCV effect, or active hemolysis with reticulocytosis 1
• The combination of normocytic anemia with high RDW distinguishes these conditions from pure anemia of chronic disease or chronic kidney disease, which typically show normal RDW 2

Primary Differential Diagnosis

Iron Deficiency (Early or Evolving)

• Iron deficiency initially presents as normocytic anemia with elevated RDW before microcytosis develops, as iron stores become depleted but existing red cells remain normal-sized 1
• Confirm with serum ferritin <30 μg/L (or <100 μg/L if inflammation is present) and transferrin saturation <16-20% 3, 1
• All adult men and post-menopausal women require upper and lower gastrointestinal endoscopy to exclude malignancy as the source of blood loss 3, 1
• Pre-menopausal women require GI investigation unless heavy menstrual bleeding fully accounts for the severity of anemia 3

Combined Nutritional Deficiencies

• Iron deficiency coexisting with B12 or folate deficiency produces normocytic anemia because the macrocytic effect of B12/folate deficiency "masks" the microcytic effect of iron deficiency 4, 3
• This combination is specifically recognized by elevated RDW reflecting the mixed cell population 4, 1
• Check serum ferritin, transferrin saturation, vitamin B12, and folate levels simultaneously 3
• Do not overlook this possibility—it requires treatment of both deficiencies to achieve full correction 3

Hemolytic Anemia

• Hemolysis produces normocytic anemia with elevated RDW due to increased reticulocyte production (reticulocytes are larger and increase heterogeneity) 2
• Confirm with elevated reticulocyte count, unconjugated hyperbilirubinemia, decreased haptoglobin, and clinical signs such as jaundice or splenomegaly 2
• The elevated RDW reflects the mixture of mature red cells and larger reticulocytes 1

Anemia of Chronic Disease with Concurrent Iron Deficiency

• Pure anemia of chronic disease typically shows normal RDW, but when combined with true iron deficiency, RDW becomes elevated 3, 1
• Distinguish using ferritin >100 μg/L with transferrin saturation <20% (suggests anemia of chronic disease) versus ferritin <100 μg/L with low transferrin saturation (suggests concurrent iron deficiency) 3
• Inflammatory markers (CRP, ESR) will be elevated 3

Aplastic Anemia and Bone Marrow Failure

• In severe aplastic anemia, most patients exhibit normocytic-normochromic anemia with normal RDW (74.3% of cases), but 25.7% present with elevated RDW 5
• Patients with elevated RDW in aplastic anemia may have better residual bone marrow hematopoietic function but more severe anemia 5
• Diagnosis requires pancytopenia (low WBC, hemoglobin, and platelets) with low reticulocyte count and bone marrow biopsy showing hypocellularity 5, 2
• Non-severe aplastic anemia more commonly shows macrocytic anemia with elevated RDW (64% of cases) 5

Chronic Kidney Disease

• Renal anemia typically presents as normochromic normocytic anemia when GFR drops below 20-30 mL/min 6
• However, pure renal anemia usually has normal RDW—if RDW is elevated, investigate for concurrent iron deficiency from occult GI bleeding (common in CKD patients) 6, 2
• Check serum creatinine, BUN, and assess for uremic symptoms 6

Diagnostic Algorithm

Initial Laboratory Workup

• Complete blood count with MCV, RDW, and reticulocyte count 1
• Serum ferritin and transferrin saturation 3, 1
• C-reactive protein (to interpret ferritin in context of inflammation) 3, 1
• Peripheral blood smear to assess cell morphology 2
• Vitamin B12 and folate levels 3
• Renal function (creatinine, BUN) 6

Second-Line Testing Based on Initial Results

• If reticulocyte count is elevated: pursue hemolysis workup (LDH, indirect bilirubin, haptoglobin, direct antiglobulin test) 2
• If pancytopenia is present: consider bone marrow biopsy for aplastic anemia or myelodysplastic syndrome 5
• If iron deficiency is confirmed: mandatory GI investigation with upper endoscopy (including small bowel biopsies for celiac disease) and colonoscopy in adults 3, 1

Critical Pitfalls to Avoid

• Do not assume all normocytic anemia is anemia of chronic disease or renal disease—elevated RDW demands investigation for iron deficiency, combined deficiencies, or hemolysis 1
• Do not rely on ferritin alone when inflammation is present; ferritin up to 100 μg/L may still indicate iron deficiency in inflammatory states 3
• Do not attribute iron deficiency in adults to dietary insufficiency alone—occult GI malignancy must be excluded 3, 1
• Do not overlook combined nutritional deficiencies, which produce normal MCV despite severe deficiency states 4, 3
• In elderly patients on antiplatelet agents (aspirin, clopidogrel), occult GI bleeding is the most common cause and requires immediate endoscopic evaluation 3