What are the causes of elevated Red Cell Distribution Width (RDW)?

Causes of Elevated Red Cell Distribution Width (RDW)

Elevated RDW (>14.0%) reflects heterogeneous red blood cell volumes and most commonly indicates iron deficiency anemia, but also occurs with vitamin B12/folate deficiency, hemolysis, inflammatory conditions, and mixed anemia states. 1

Primary Hematologic Causes

Iron Deficiency Anemia

• Iron deficiency is the most common cause of elevated RDW, particularly when combined with microcytosis (low MCV). 1
• The elevated RDW reflects the wide variation in red cell sizes as iron-deficient erythropoiesis produces progressively smaller cells alongside older normal-sized cells. 2
• Diagnosis requires serum ferritin <30 μg/L in the absence of inflammation, or <100 μg/L when inflammation is present. 3, 1
• Transferrin saturation <16-20% and raised total iron-binding capacity support the diagnosis. 3

Vitamin Deficiencies

• Vitamin B12 and folate deficiency cause elevated RDW, though 31% of untreated pernicious anemia patients may have normal RDW values. 4
• These deficiencies produce macrocytic anemia with high RDW due to ineffective erythropoiesis creating variable cell sizes. 2
• Normal RDW does not exclude B12 deficiency, particularly in early stages, making it a less reliable marker than for iron deficiency. 4

Hemolytic Anemia

• Hemolysis elevates RDW due to the mixture of young reticulocytes (larger) and fragmented or damaged red cells. 2
• The shortened red cell lifespan and compensatory increased erythropoiesis create marked size heterogeneity. 5

Mixed Anemia States

• When microcytosis and macrocytosis coexist (producing normal MCV), elevated RDW is the key diagnostic clue. 1
• This occurs with combined iron and B12/folate deficiency, or iron deficiency in patients on thiopurine therapy. 3

Inflammatory and Chronic Disease Causes

Chronic Inflammation

• Inflammatory conditions elevate RDW through multiple mechanisms including impaired erythropoiesis, oxidative stress, and altered iron metabolism. 2, 5
• In inflammatory bowel disease, RDW helps distinguish iron deficiency from anemia of chronic disease or mixed patterns. 3
• Anemia of chronic disease typically shows ferritin >100 μg/L with transferrin saturation <20%. 3

Acute COVID-19 and Post-Viral Syndromes

• Substantial RDW increases occur during acute COVID-19 due to erythrocyte membrane injury, reduced deformability, and complement deposition on red cells. 3
• Inflammatory secretory phospholipase A₂ IIA metabolizes phospholipids in erythrocytes, contributing to membrane damage. 3
• Similar erythrocyte pathology occurs in other post-viral conditions like ME/CFS. 3

Metabolic and Systemic Causes

Oxidative Stress and Metabolic Derangements

• Elevated RDW reflects underlying metabolic imbalances including oxidative stress, inflammation, poor nutritional status, and dyslipidemia. 5
• These factors impair both erythropoiesis and red blood cell survival, creating anisocytosis. 5
• Shortened telomere length, altered erythropoietin function, and erythrocyte fragmentation contribute to RDW elevation. 5, 6

Cardiovascular and Chronic Organ Disease

• RDW elevation occurs in cardiovascular disease, liver failure, kidney failure, and diabetes through inflammation and oxidative stress pathways. 5
• In coronary artery disease, elevated RDW predicts poor outcomes due to decreased red cell deformability impairing microcirculation. 6

Cancer

• Lung cancer patients show elevated RDW associated with increased eryptosis (programmed red cell death) and accelerated red cell turnover. 3
• Cytostatic agents, particularly platinum-based drugs, induce eryptosis and worsen anemia with elevated RDW. 3

Diagnostic Approach

Initial Workup

• Minimum evaluation includes complete blood count with MCV, reticulocyte count, serum ferritin, transferrin saturation, and CRP. 1
• Peripheral blood smear assessment for red cell morphology, schistocytes, and hemolysis is essential. 7

Interpretation by MCV Pattern

• Microcytic anemia (low MCV) + high RDW = iron deficiency anemia until proven otherwise. 1
• Normocytic anemia + high RDW = early iron deficiency, vitamin deficiency, or hemolysis. 1
• Normal MCV + high RDW = mixed deficiency states (iron plus B12/folate). 1

Common Pitfalls

• Nearly half of thalassemia cases may show elevated RDW, limiting its specificity for distinguishing from iron deficiency. 8
• RDW values vary between laboratory instruments; always use the specific laboratory's reference range. 1
• Normal RDW does not exclude vitamin B12 deficiency, particularly in early stages. 4
• Do not empirically treat with iron based solely on elevated RDW without confirming iron deficiency with ferritin and transferrin saturation. 7