What are the initial steps in diagnosing and managing microcytosis (small red blood cell condition) based on lab results, including complete blood count (CBC) and serum iron studies?

Initial Laboratory Workup for Microcytosis

Order serum ferritin as the first-line test when microcytosis (MCV <80 fL) is detected, as it is the most specific marker for iron deficiency in the absence of inflammation. 1

Step 1: Confirm Microcytosis and Assess Red Cell Distribution Width (RDW)

• Low MCV with elevated RDW (>14.0%) strongly suggests iron deficiency anemia 1
• Low MCV with normal RDW (≤14.0%) points toward thalassemia trait 1
• Note that RDW has limitations—nearly half of thalassemia cases may show elevated RDW, so this cannot be used as the sole discriminator 2

Step 2: Serum Ferritin Interpretation

• Ferritin <30 μg/L confirms iron deficiency in patients without inflammation 1
• Ferritin <100 μg/L may still indicate iron deficiency when inflammation is present (inflammatory conditions can falsely elevate ferritin) 1
• If ferritin is not low, proceed to comprehensive iron studies 3

Step 3: Complete Iron Panel (If Ferritin Not Diagnostic)

Order the following tests simultaneously 3:

• Serum iron level
• Total iron-binding capacity (TIBC)
• Transferrin saturation
• Hemoglobin electrophoresis

Interpretation patterns:

• Iron deficiency anemia: Low iron, high TIBC, low transferrin saturation, low ferritin 3, 4
• Anemia of chronic disease: Low iron, low TIBC, normal or high ferritin 1, 3
• Beta-thalassemia trait: Elevated hemoglobin A2 levels on electrophoresis, normal or elevated ferritin 3

Step 4: Identify Underlying Cause of Iron Deficiency

Once iron deficiency is confirmed, investigate the source 1:

• Men and post-menopausal women: Presume gastrointestinal blood loss until proven otherwise; gastrointestinal malignancy must be excluded 1, 3
• Pre-menopausal women: Consider menstrual blood loss, but still evaluate for GI sources if history suggests 1
• All patients: Assess for malabsorption, poor dietary intake, previous gastrectomy, NSAID use 1

Step 5: Consider Genetic Disorders in Refractory Cases

If microcytosis persists despite adequate iron supplementation or if transferrin saturation is paradoxically elevated 5:

• Test for genetic disorders including SLC11A2 defects, STEAP3 defects, SLC25A38 defects, ABCB7 defects, or ALAS2 defects 5
• Family screening may be warranted once genetic diagnosis is confirmed 5

Common Pitfalls to Avoid

• Don't rely solely on RDW to differentiate iron deficiency from thalassemia—significant overlap exists between these conditions 2
• Don't miss concurrent iron deficiency in patients with inflammatory conditions where ferritin may be falsely reassuring; use the higher threshold of <100 μg/L in these cases 1
• Don't forget to investigate the source of iron deficiency—simply treating with iron without identifying blood loss (especially GI malignancy) is inadequate 1, 3
• Don't overlook medication-induced causes including chronic NSAID use 1
• Don't proceed to bone marrow biopsy until completing the above non-invasive workup, unless additional cytopenias are present 5

Special Population Considerations

• Multi-ethnic populations: Microcytosis is present in 35% of males and 45% of females from ethnic minorities, with only a minority being iron-deficient; most have probable alpha thalassemia 6
• Patients with genetic iron metabolism disorders: Monitor iron status regularly to detect toxic iron loading early, as these patients may paradoxically develop iron overload despite microcytosis 5