What is the best course of action for a patient presenting with hypochromic anemia (low hemoglobin) and an elevated Red Cell Distribution Width-Coefficient of Variation (RDW-CV)?

Diagnostic Approach to Low Hemoglobin with Elevated RDW-CV

Order iron studies immediately (serum ferritin, transferrin saturation, TIBC) as elevated RDW with low hemoglobin strongly suggests iron deficiency anemia, which requires confirmation before treatment and investigation for underlying blood loss. 1, 2

Understanding the Laboratory Pattern

The combination of low hemoglobin with elevated RDW-CV (>14.0%) creates a highly specific diagnostic signature:

• Elevated RDW reflects heterogeneous red cell populations, indicating active but disordered erythropoiesis where both normal-sized older cells and smaller, hypochromic newer cells coexist in circulation 1, 2
• This pattern is the hallmark of iron deficiency anemia, where progressive iron depletion causes the bone marrow to produce red blood cells with decreasing hemoglobin content 1, 3
• RDW elevation often precedes changes in MCV, making it an early and sensitive indicator of iron deficiency 2, 4
• The degree of RDW elevation correlates inversely with hemoglobin level and transferrin saturation, reflecting the severity of iron deficiency 3

Essential Diagnostic Workup

First-Line Laboratory Tests

• Serum ferritin is the single most powerful test: <30 μg/L confirms iron deficiency in the absence of inflammation; <100 μg/L with concurrent inflammation still suggests iron deficiency 1, 2
• Transferrin saturation <15-16% supports iron deficiency and is less affected by inflammation than ferritin 1
• Complete blood count with red cell indices (MCV, MCH, MCHC) to characterize the anemia pattern 1
• Reticulocyte count to evaluate bone marrow response to anemia 1, 2
• C-reactive protein (CRP) to identify inflammation that may falsely elevate ferritin and mask iron deficiency 2

Critical Interpretation Considerations

• Ferritin can be falsely elevated in inflammatory conditions, chronic disease, malignancy, or liver disease, potentially masking true iron deficiency 1, 2
• MCH is more reliable than MCHC for detecting iron deficiency as it is less dependent on storage conditions and laboratory equipment 1
• Low MCH with elevated RDW has 72% sensitivity for detecting iron deficiency even before frank anemia develops 1

Differential Diagnosis Based on RDW Pattern

When RDW is Elevated (>14.0%)

Primary consideration: Iron deficiency anemia 1, 2, 3, 4

Alternative diagnoses to consider:

• Mixed nutritional deficiencies (combined iron, folate, or B12 deficiency can produce elevated RDW with variable MCV) 1
• Early vitamin B12 deficiency (though 31% of pernicious anemia patients have normal RDW, most have elevated RDW) 5
• Hemoglobinopathies with active hemolysis (sickle cell disease, sickle-thalassemia) 4
• Anemia of chronic disease with concurrent iron deficiency 1

Distinguishing Iron Deficiency from Thalassemia Trait

• Iron deficiency: markedly elevated RDW (mean 18-21%) with progressive microcytosis 3, 4
• Thalassemia trait: normal or mildly elevated RDW (mean 15.4%) with stable microcytosis and elevated red blood cell count 2, 3, 4
• However, almost half of thalassemia cases can have elevated RDW, so iron studies and hemoglobin electrophoresis remain essential for definitive diagnosis 6

Investigation for Underlying Cause

Mandatory Evaluation for Blood Loss

All adult men and postmenopausal women with confirmed iron deficiency require endoscopic evaluation (both upper and lower endoscopy) to exclude gastrointestinal malignancy, regardless of anemia severity 7, 1, 2

Premenopausal women: Assess menstrual blood loss patterns, but do not assume menstruation is the sole cause without excluding other sources 1

Additional sources to investigate:

• Occult gastrointestinal bleeding (even without obvious symptoms) 2
• Genitourinary blood loss 1
• Chronic intravascular hemolysis 1

Treatment Algorithm

If Iron Deficiency is Confirmed

• Initiate iron supplementation (oral ferrous sulfate 325 mg daily or intravenous iron if oral not tolerated or rapid repletion needed) 1
• Monitor iron status during treatment to assess response and detect potential iron overload 8
• Investigate and address the underlying cause of iron loss simultaneously with iron replacement 1, 2

If Iron Studies are Normal Despite Elevated RDW

• Measure vitamin B12 and folate levels to evaluate for megaloblastic anemia 1
• Consider hemoglobin electrophoresis if patient has appropriate ethnic background for hemoglobinopathies 1
• Assess for hemolysis with haptoglobin, LDH, and bilirubin 1
• Evaluate for chronic kidney disease with creatinine and estimated GFR 1, 9

Critical Pitfalls to Avoid

• Never assume iron deficiency without laboratory confirmation, as empiric iron treatment in thalassemia patients can cause dangerous iron overload 7
• Do not overlook combined deficiencies (iron plus B12 or folate), which may result in normal MCV despite severe anemia and elevated RDW 1
• Do not attribute elevated RDW solely to inflammation or chronic disease without first excluding iron deficiency with ferritin and transferrin saturation 1, 9
• Never dismiss mild anemia as clinically insignificant, as severity does not correlate with likelihood of serious underlying disease such as malignancy 7
• Do not rely on RDW alone for distinguishing iron deficiency from thalassemia trait, as there is significant overlap requiring iron studies and hemoglobin electrophoresis 6