Persistent Microcytic Anemia Despite Iron Supplementation in a 14-Year-Old Boy
This patient requires immediate evaluation for thalassemia trait and genetic disorders of iron metabolism, as failure to respond to iron supplementation in a child with severe microcytosis (MCV 62.6) strongly suggests a diagnosis other than simple iron deficiency anemia.
Diagnostic Approach
The laboratory findings reveal severe microcytic anemia with:
- Hemoglobin 10.6 g/dL (low for age)
- MCV 62.6 fL (markedly low, normal ~80-100)
- MCH 19.7 pg (low)
- MCHC 31.5 g/dL (low-normal)
Key Differential Diagnoses to Consider
Thalassemia trait is the most likely diagnosis given the profound microcytosis and lack of response to iron therapy. 1, 2 The Mentzer index (MCV/RBC count) should be calculated—if <13, this strongly suggests thalassemia rather than iron deficiency. 3 A low MCV with RDW ≤14.0% suggests thalassemia minor, while RDW >14.0% suggests iron deficiency. 1, 2
Iron-refractory iron-deficiency anemia (IRIDA) must be considered in children with microcytic anemia unresponsive to oral iron. 2 This genetic disorder presents with remarkably low transferrin saturation and low-to-normal ferritin, with complete failure to respond to oral iron supplementation. 2
Combined iron deficiency and thalassemia trait occurs in approximately 7% of children with microcytic anemia in regions where both conditions are prevalent. 3
Essential Laboratory Testing
Immediate next steps:
Serum ferritin: The most powerful single test for iron deficiency, with <12-15 μg/L diagnostic of iron deficiency. 1, 2 However, ferritin 15-45 μg/L may still indicate low iron stores. 1
Transferrin saturation (TSAT): More sensitive than hemoglobin alone for detecting iron deficiency. 1 TSAT <30% suggests iron deficiency, while markedly low TSAT (<10%) with low-normal ferritin suggests IRIDA. 2
Red cell distribution width (RDW): Helps differentiate iron deficiency (RDW >14%) from thalassemia (RDW ≤14%). 1, 2
Hemoglobin electrophoresis: Essential if iron studies are normal or near-normal. 1 Hemoglobin A2 >3.5% is diagnostic for β-thalassemia trait. 4
Complete blood count with RBC count: Thalassemia typically shows elevated or high-normal RBC count despite low hemoglobin, while iron deficiency shows low RBC count. 3
Clinical Decision Algorithm
If ferritin <15 μg/L and TSAT <30%:
- True iron deficiency exists
- Investigate cause of iron deficiency (dietary inadequacy, occult GI blood loss, malabsorption)
- Consider celiac disease screening if malabsorption suspected 1
- Continue oral iron therapy with ferrous sulfate 200 mg three times daily for at least 3 months after hemoglobin correction 1
- Expect hemoglobin rise ≥10 g/L within 2 weeks if truly iron deficient 1
If ferritin >30 μg/L or normal iron studies:
- Proceed immediately to hemoglobin electrophoresis to evaluate for thalassemia 1, 2
- Consider genetic testing for IRIDA (TMPRSS6 mutations) if TSAT is markedly low despite normal/elevated ferritin 2
- Bone marrow examination may be needed if sideroblastic anemia suspected (would show ring sideroblasts) 2
If ferritin 15-30 μg/L (equivocal range):
- This represents borderline iron stores 1
- Check TSAT and RDW to guide further evaluation
- Consider therapeutic trial of IV iron if malabsorption suspected, expecting hemoglobin increase ≥2 g/dL within 4 weeks 1
- If no response to IV iron, pursue hemoglobin electrophoresis 1
Critical Pitfalls to Avoid
Do not continue empiric oral iron indefinitely without confirming iron deficiency. 1 Repeated unnecessary iron therapy in thalassemia patients can lead to iron overload. 5
Do not assume all microcytic anemia is iron deficiency. 1 The profound microcytosis (MCV 62.6) in this patient is more consistent with thalassemia trait than typical iron deficiency. 2, 3
Do not overlook genetic disorders of iron metabolism. 1 IRIDA, DMT1 deficiency, and sideroblastic anemias can present with refractory microcytic anemia and require specialized treatment including IV iron, erythropoietin, or even stem cell transplantation. 6, 1, 2
Special Considerations for Genetic Disorders
If IRIDA is confirmed (TMPRSS6 mutations), treatment requires intravenous iron supplementation as oral iron is completely ineffective. 1, 2 Iron sacarose or ferric gluconate administered repeatedly can increase hemoglobin and ferritin, though complete normalization is rarely achieved. 1
For sideroblastic anemias (if ring sideroblasts found on bone marrow), initial treatment with pyridoxine (vitamin B6) 50-200 mg daily should be attempted, with lifelong maintenance at 10-100 mg daily if responsive. 6, 1 These patients require monitoring for iron overload even without transfusions. 6, 2
The low creatinine (0.44) is normal for a 14-year-old and does not contribute to the anemia evaluation. 6