In a 15‑year‑old female with an elevated red blood cell count, microcytic anemia (mean corpuscular volume ~67 fL, mean corpuscular hemoglobin ~21 pg) and increased red cell distribution width, what is the next step in evaluation and management?

Diagnostic Evaluation and Management of Microcytic Anemia in a 15-Year-Old Female

Order serum ferritin and transferrin saturation immediately to confirm iron deficiency anemia, which is the most likely diagnosis given the elevated RDW (16.7%) combined with severe microcytosis (MCV 66.8 fL). 1

Understanding the Laboratory Pattern

The combination of laboratory findings strongly points toward iron deficiency anemia:

• The elevated RBC count (6.02) with low MCV (66.8 fL) and low MCH (20.9 pg) indicates microcytic hypochromic anemia. 1
• The elevated RDW (16.7%) is the key discriminator: RDW > 14% with low MCV strongly suggests iron deficiency anemia rather than thalassemia trait, which typically shows RDW ≤ 14%. 1, 2
• This pattern reflects a mixed population of older normal-sized red cells and newer microcytic cells as iron stores become progressively depleted. 1

However, approximately 50% of thalassemia cases can show elevated RDW, so iron studies remain essential rather than relying on RDW alone. 3, 4

Required Initial Laboratory Tests

Order the following tests as first-line evaluation:

• Serum ferritin: A level < 30 µg/L confirms iron deficiency in the absence of inflammation; a cut-off of 45 µg/L provides optimal sensitivity and specificity in routine practice. 1
• Transferrin saturation (TSAT): A value < 16–20% confirms iron deficiency and is less affected by inflammation than ferritin. 1, 5
• C-reactive protein (CRP): Necessary because ferritin is an acute-phase reactant that can be falsely elevated by inflammation, infection, or other conditions. 1
• Reticulocyte count: A low or inappropriately normal count indicates inadequate bone marrow response to anemia. 5

Interpretation Algorithm

If ferritin < 30 µg/L and TSAT < 16–20%:

• Diagnosis of iron deficiency anemia is confirmed. 1
• Proceed to investigate the underlying cause (see below). 1

If ferritin is 30–100 µg/L with elevated CRP:

• Iron deficiency may still be present despite "normal" ferritin due to inflammatory elevation. 1
• TSAT < 16–20% confirms true iron deficiency in this context. 1

If ferritin > 30 µg/L, TSAT > 20%, and RDW remains elevated:

• Order hemoglobin electrophoresis to exclude thalassemia trait, particularly given the extreme microcytosis (MCV 66.8 fL). 1
• Hemoglobin electrophoresis should only be ordered after iron studies are normal or borderline, not as a first-line test. 1

Investigation of Underlying Cause

Once iron deficiency is confirmed, identify the source of iron loss:

• In a 15-year-old female, the most common cause is heavy menstrual bleeding. 1
• Assess dietary intake: vegetarian or vegan diets increase risk of iron deficiency in adolescents. 1
• Screen for celiac disease with tissue transglutaminase antibodies, as celiac disease accounts for 2–3% of iron deficiency anemia cases and may present with isolated anemia. 1
• Evaluate for gastrointestinal blood loss if menstrual history does not fully explain the severity of anemia. 1

Treatment Protocol

Initiate oral iron supplementation immediately while diagnostic workup proceeds:

• Ferrous sulfate 200 mg three times daily is first-line therapy. 1
• Alternative formulations (ferrous gluconate or ferrous fumarate) can be used if ferrous sulfate is not tolerated. 1
• Adding ascorbic acid (vitamin C) enhances iron absorption. 1
• A hemoglobin rise ≥ 10 g/L within 2 weeks confirms iron deficiency as the cause. 1
• Continue treatment for at least three months after hemoglobin normalizes to replenish iron stores. 1

Monitoring and Follow-Up

• Recheck hemoglobin concentration and red cell indices at three-monthly intervals for one year, then after a further year. 1
• Provide additional oral iron if hemoglobin or MCV falls below normal during follow-up. 1
• Monitor for treatment response: expect hemoglobin increase of at least 2 g/dL within 4 weeks. 1

Critical Pitfalls to Avoid

• Do not order hemoglobin electrophoresis before confirming iron status with ferritin and TSAT, as this is costly and unnecessary when iron deficiency is present. 1
• Do not rely on ferritin alone when inflammation may be present; always add TSAT and CRP to the workup. 1
• Do not assume all microcytic anemia is iron deficiency: if iron studies are normal, thalassemia trait must be excluded with hemoglobin electrophoresis. 1
• Do not overlook combined deficiencies: iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by elevated RDW. 1
• Do not attribute iron deficiency solely to dietary inadequacy in adolescents without investigating for celiac disease or other malabsorption disorders. 1

When to Consider Rare Genetic Causes

If the patient fails to respond to oral iron therapy within 2–4 weeks despite good compliance:

• Consider iron-refractory iron deficiency anemia (IRIDA), characterized by remarkably low TSAT with low-to-normal ferritin and failure to respond to oral iron but potential response to intravenous iron. 1
• Consider genetic testing for disorders such as SLC11A2, STEAP3, or ALAS2 defects if extreme microcytosis (MCV < 70 fL) or family history of refractory anemia is present. 1
• X-linked sideroblastic anemia (ALAS2 defects) may respond to pyridoxine (vitamin B6) 50–200 mg daily initially, then 10–100 mg daily lifelong if responsive. 1