Why is the red cell distribution width (RDW) elevated in a patient with anemia?

Why RDW is Elevated in Anemia

High RDW in anemia indicates heterogeneous red blood cell sizes (anisocytosis), which most commonly signals iron deficiency anemia, but can also reflect vitamin B12/folate deficiency, hemolysis, or mixed deficiency states where microcytosis and macrocytosis coexist. 1, 2

Primary Mechanism: Iron Deficiency

Iron deficiency anemia is the most common cause of elevated RDW with anemia, presenting with RDW >14.0% combined with low MCV. 2 This occurs because:

• Iron-restricted erythropoiesis produces red blood cells of varying sizes as iron stores become progressively depleted 1
• The bone marrow releases both small iron-deficient cells and residual normal-sized cells simultaneously, creating marked size heterogeneity 3
• RDW elevation (mean 20.7 ± 3.2%) in iron deficiency is significantly higher than in other microcytic anemias 3

Diagnostic confirmation requires serum ferritin <30 μg/L without inflammation, or <100 μg/L with inflammation present, plus transferrin saturation <16-20%. 1, 2

Vitamin Deficiency States

Vitamin B12 or folate deficiency causes elevated RDW through impaired DNA synthesis, leading to macrocytic anemia with variable cell sizes. 1 However:

• 31% of untreated pernicious anemia patients have normal RDW despite active disease 4
• Over half of B12-deficient patients with normal RDW also have normal MCV, making RDW less reliable than in iron deficiency 4
• Macrocytosis may also result from thiopurine medications (azathioprine, 6-mercaptopurine), alcohol, or hypothyroidism 1

Mixed Deficiency and Masked Anemia

When microcytosis and macrocytosis coexist, they neutralize each other producing normal MCV, but high RDW reveals the underlying dual pathology. 1, 2 This critical scenario requires:

• Complete blood count with reticulocyte count 1
• Serum ferritin, transferrin saturation, and CRP 1, 2
• Vitamin B12 and folate levels 1

Hemolytic Anemia

Elevated reticulocyte count with high RDW indicates hemolysis, where the bone marrow responds appropriately by releasing young, larger reticulocytes alongside remaining mature cells. 1 Confirm with:

• Haptoglobin (decreased) 1
• Lactate dehydrogenase (elevated) 1
• Indirect bilirubin (elevated) 1

Anemia of Chronic Disease vs. Iron Deficiency

Distinguishing these overlapping conditions is critical for treatment selection:

• Anemia of chronic disease: RDW elevated in only 32% of cases, ferritin >100 μg/L, transferrin saturation <20% 5, 1
• Iron deficiency: RDW elevated in 90% of cases, ferritin <30-100 μg/L depending on inflammation 5, 1
• Functional iron deficiency: Elevated ferritin but inadequate iron availability for erythropoiesis, RDW typically elevated 1

Thalassemia Trait: The Key Exception

Thalassemia trait presents with low MCV but normal or only mildly elevated RDW (mean 15.4 ± 1.4%), distinguishing it from iron deficiency. 2, 3 Specifically:

• Beta-thalassemia trait: RDW elevated in 66% but significantly lower than iron deficiency 5
• Alpha-thalassemia trait: RDW elevated in 53% of men, 34% of women 5
• Confirm with hemoglobin electrophoresis; avoid empiric iron supplementation 6

Inflammatory and Chronic Disease States

RDW elevation reflects broader metabolic derangement beyond simple anemia:

• Inflammatory conditions cause erythrocyte membrane injury and reduced deformability 2, 7
• Chronic kidney disease impairs erythropoietin production, leading to hypoproliferative anemia with variable RDW 1
• Cancer patients show elevated RDW from accelerated red cell turnover and eryptosis (programmed red cell death) 2

Medication-Induced RDW Elevation

Platinum-based chemotherapy directly induces eryptosis and accelerates red cell turnover, elevating RDW in cancer patients. 8 Other culprits include:

• Cytostatic agents worsen anemia heterogeneity through impaired erythropoiesis 8
• Long-term antibiotics (nafcillin, rifampin) may affect red cell parameters through CYP450 enzyme induction, though effects take 2-4 weeks to manifest 8

Critical Diagnostic Algorithm

When encountering anemia with elevated RDW, follow this sequence:

1. Check MCV first:

   • Low MCV + High RDW → Iron deficiency anemia (confirm with ferritin, transferrin saturation) 2
   • Low MCV + Normal RDW → Thalassemia trait (confirm with hemoglobin electrophoresis) 2
   • High MCV + High RDW → Vitamin B12/folate deficiency 1
   • Normal MCV + High RDW → Early iron deficiency, hemolysis, or mixed deficiency 2

2. Check reticulocyte count:

   • Low/normal reticulocytes → Deficiency states or bone marrow failure 1
   • Elevated reticulocytes → Hemolysis or acute blood loss 1

3. Assess inflammation:

   • CRP, ESR, clinical/endoscopic evidence guides ferritin interpretation 1
   • Without inflammation: ferritin <30 μg/L confirms iron deficiency 1
   • With inflammation: ferritin up to 100 μg/L may still indicate iron deficiency 1

Common Pitfalls to Avoid

Never diagnose iron deficiency by RDW alone—10% of iron-deficient patients have normal RDW, and 32% of chronic disease patients have elevated RDW. 5 Always confirm with ferritin and transferrin saturation before initiating iron therapy 1, 2.

Do not assume elevated RDW always indicates nutritional deficiency—it may reflect underlying inflammation, malignancy, or medication effects requiring different management. 2, 7