In a 15‑year‑old female with microcytic, hypochromic anemia, mean corpuscular volume ≈66 fL, low serum iron, red‑cell distribution width ≈16.6 %, and red blood cell count ≈6.0 ×10⁶/µL, is the diagnosis iron‑deficiency anemia or thalassemia trait, and what is the appropriate next step in management?

Diagnosis: Iron-Deficiency Anemia

In this 15-year-old female with microcytic hypochromic anemia (MCV ≈66 fL), low serum iron, elevated RDW (≈16.6%), and RBC count ≈6.0 ×10⁶/µL, the diagnosis is iron-deficiency anemia, not thalassemia trait, and the appropriate next step is to order serum ferritin and transferrin saturation while simultaneously initiating empiric oral iron therapy (60–120 mg elemental iron daily). 1

Algorithmic Differentiation: Iron Deficiency vs. Thalassemia Trait

Primary Discriminating Features

• RDW > 14% combined with severe microcytosis (MCV ≈66 fL) strongly indicates iron-deficiency anemia, whereas thalassemia minor typically presents with RDW ≤14% because red cells are uniformly small rather than showing the mixed population of older normocytic and newer microcytic cells seen in iron deficiency. 1

• Low serum iron (≈45 µg/dL in context) further supports iron deficiency over thalassemia trait, as thalassemia typically shows normal iron studies. 1

• The elevated RBC count (≈6.0 ×10⁶/µL) might initially suggest thalassemia, but when combined with elevated RDW and low serum iron, iron deficiency remains the more likely diagnosis—approximately 50% of thalassemia cases can show elevated RDW, but the concurrent presence of high RDW, low serum iron, and elevated ESR makes iron deficiency far more probable. 1

Diagnostic Algorithm

Step 1: Evaluate RDW and MCV together:

• RDW > 14% + low MCV → proceed to iron studies (iron deficiency likely) 1
• RDW ≤ 14% + low MCV → consider thalassemia trait (requires hemoglobin electrophoresis) 1

Step 2: Confirm with iron studies:

• Serum ferritin < 30 µg/L confirms depleted iron stores when inflammation is absent 1, 2
• Transferrin saturation < 15–16% supports iron deficiency and is less affected by acute inflammation than ferritin 1, 2
• Measure C-reactive protein concurrently because ferritin rises as an acute-phase reactant; inflammation can falsely elevate ferritin up to 100 µg/L and still be consistent with true iron deficiency 1

Step 3: Reserve hemoglobin electrophoresis for specific scenarios:

• Order only when iron studies are normal or borderline 1
• When MCV is disproportionately low relative to anemia severity 1
• In high-risk ethnic groups (African, Mediterranean, Southeast Asian ancestry) 1
• Do not use electrophoresis as a first-line test—it is costly and unnecessary when iron studies are abnormal 1

Immediate Management Protocol

Empiric Iron Therapy

• Begin oral ferrous sulfate 60–120 mg elemental iron daily (one to two 60-mg tablets) taken between meals on an empty stomach to maximize absorption while awaiting confirmatory iron studies. 2

• A rise in hemoglobin of ≥1 g/dL (or hematocrit increase ≥3%) within 4 weeks confirms iron-deficiency anemia even if baseline iron studies were equivocal, validating the diagnosis and justifying continuation of therapy. 1, 2

Dietary Counseling

• Advise consumption of iron-rich foods (red meat, poultry, fish, fortified cereals, beans, lentils) and vitamin C-rich foods (citrus, tomatoes) to enhance absorption. 2

Follow-Up Assessment

• Re-measure hemoglobin/hematocrit at 4 weeks: if hemoglobin rises ≥1 g/dL, continue iron therapy for an additional 3 months (total 4-month course) to fully replenish iron stores. 2

• If no hematologic response after 4 weeks despite documented adherence, order hemoglobin electrophoresis to exclude thalassemia trait and screen for celiac disease (tissue transglutaminase antibodies) to identify malabsorption. 2

Investigation of Underlying Cause

Adolescent-Specific Considerations

• In premenopausal adolescent females, menstrual blood loss is the most common cause of iron deficiency, with prevalence exceeding 50% in some cohorts due to menstrual losses, rapid growth, and inadequate dietary iron intake (often below the recommended 15 mg/day). 2

• Assess menstrual history carefully: heavy menstrual bleeding may necessitate gynecologic referral if losses appear excessive. 2

• Evaluate dietary intake, particularly vegetarian or vegan eating patterns, which increase iron deficiency risk in adolescents. 1

When to Pursue Gastrointestinal Evaluation

• If menstrual losses seem inadequate to explain the severity of deficiency, consider gastrointestinal blood loss by taking a careful history of NSAID use, gastrointestinal symptoms, and occult bleeding. 2

• Screen for celiac disease (tissue transglutaminase antibodies) if malabsorption is suspected, as celiac disease accounts for approximately 2–5% of iron-deficiency anemia cases and is the most important cause of true IDA not responding to oral iron therapy. 1, 3

Critical Pitfalls to Avoid

• Do not rely on MCV alone to exclude iron deficiency—mean corpuscular hemoglobin (MCH) typically falls before MCV in early deficiency, and a normal MCV does not rule out iron deficiency. 1, 2

• Do not use ferritin alone without measuring CRP—inflammation can falsely elevate ferritin and mask true iron deficiency; in inflammatory states, ferritin up to 100 µg/L may still indicate iron deficiency. 1

• Do not assume dietary insufficiency is the sole cause—even when dietary history suggests inadequate intake, occult gastrointestinal blood loss must be excluded in adults, though in adolescent females menstrual loss is the primary concern. 4, 2

• Do not order hemoglobin electrophoresis as a first-line test—it should be reserved for cases with normal or borderline iron parameters, as it is costly and unnecessary when iron studies confirm deficiency. 1

• Do not overlook combined deficiencies—iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by elevated RDW; measure B12 and folate if clinical suspicion exists. 4, 1