In a primary‑care patient with low mean corpuscular hemoglobin and low mean corpuscular volume (microcytic, hypochromic anemia), what is the next step in the work‑up?

Next Step: Order Iron Studies Immediately

In a primary‑care patient with low MCH and low MCV (microcytic, hypochromic anemia), the next step is to obtain serum ferritin, transferrin saturation (TSAT), and C‑reactive protein (CRP) together as first‑line tests to confirm iron deficiency and distinguish it from other causes of microcytosis. 1, 2

Initial Laboratory Panel

Order the following tests simultaneously:

• Serum ferritin – the single most powerful test for diagnosing iron deficiency, with ferritin <30 µg/L confirming depleted iron stores and <15 µg/L providing 99% specificity for absent iron stores 1, 2
• Transferrin saturation (TSAT) – values <16–20% confirm iron deficiency and are less affected by inflammation than ferritin alone 1, 2
• C‑reactive protein (CRP) – essential because ferritin is an acute‑phase reactant that can be falsely elevated by inflammation, infection, malignancy, or liver disease 1, 2
• Reticulocyte count – a low or inappropriately normal count indicates inadequate bone marrow response and helps differentiate impaired erythropoiesis from hemolysis or acute blood loss 1

Interpretation Algorithm

If Ferritin <30 µg/L and TSAT <20%:

• Iron deficiency is confirmed – proceed immediately to investigate the underlying source of iron loss rather than simply treating with iron supplementation 1, 2
• In adult men and non‑menstruating women, gastrointestinal evaluation (upper endoscopy with duodenal biopsies and colonoscopy) is mandatory to exclude malignancy, even at mild anemia levels 1, 2
• In premenopausal women, assess menstrual blood loss but still consider GI evaluation if menstrual losses do not fully explain the severity of anemia 2

If Ferritin 30–100 µg/L (Borderline Range):

• Check CRP to assess for inflammation – if CRP is elevated, ferritin may be falsely normal despite true iron deficiency 1, 2
• TSAT <16–20% confirms iron deficiency even when ferritin appears borderline 1, 2
• A ferritin cut‑off of 45 µg/L provides optimal sensitivity and specificity in routine practice 2

If Ferritin >100 µg/L and TSAT >20%:

• Iron deficiency is unlikely – consider alternative diagnoses 1, 2:
  • Thalassemia trait – order hemoglobin electrophoresis, especially if the patient has African, Mediterranean, or Southeast Asian ancestry, or if MCV is disproportionately low relative to the degree of anemia 1, 2
  • Anemia of chronic disease – characterized by ferritin >100 µg/L with TSAT <20% in the presence of elevated inflammatory markers 1, 2
  • Sideroblastic anemia – rare; consider if iron studies show elevated ferritin with microcytosis 1

Red‑Cell Distribution Width (RDW) as a Discriminator

• RDW >14% with low MCV strongly favors iron deficiency over thalassemia trait, which typically shows RDW ≤14% because red cells are uniformly small 1, 2
• Elevated RDW reflects a mixed population of older normal‑sized cells and newer microcytic cells produced during progressive iron depletion 1
• Approximately 50% of thalassemia cases can show elevated RDW, so RDW alone cannot definitively exclude thalassemia, but the combination of high RDW + low ferritin + low TSAT makes iron deficiency far more likely 2

Mean Corpuscular Hemoglobin (MCH) Considerations

• MCH is more reliable than MCV for detecting iron deficiency because it is less dependent on specimen storage conditions and counting machine variability 1, 2
• Low MCH occurs in both absolute and functional iron deficiency, making it a sensitive early marker 1

Critical Pitfalls to Avoid

• Do not rely on ferritin alone when inflammation is present – always add TSAT and CRP to the workup 1, 2
• Do not assume all microcytic anemia is iron deficiency – anemia of chronic disease, thalassemia, and sideroblastic anemia require different management 1, 2
• Do not order hemoglobin electrophoresis as a first‑line test – it should be reserved for cases with normal or borderline iron studies 1, 2
• Do not attribute iron deficiency solely to dietary inadequacy in adults – occult gastrointestinal bleeding, especially from malignancy, must be excluded 1, 2
• Do not overlook combined deficiencies – iron deficiency can coexist with vitamin B12 or folate deficiency, suggested by an elevated RDW 1, 2

When to Order Hemoglobin Electrophoresis

Reserve electrophoresis for patients who meet any of these criteria:

• Iron studies are normal (ferritin >30 µg/L and TSAT >20%) 1, 2
• MCV is disproportionately low relative to the degree of anemia 1, 2
• Patient belongs to a high‑risk ethnic group (African, Mediterranean, Southeast Asian ancestry) 2
• Failure of anemia to improve after 4 weeks of adequate oral iron therapy despite good compliance 2

Practical Summary

1. Order serum ferritin, TSAT, CRP, and reticulocyte count as the initial panel 1, 2
2. Interpret ferritin in the context of CRP – if CRP is elevated, ferritin up to 100 µg/L may still indicate iron deficiency 1, 2
3. Use TSAT <16–20% to confirm iron deficiency when ferritin is equivocal 1, 2
4. If iron deficiency is confirmed, investigate the source of iron loss before or concurrent with iron replacement 1, 2
5. If iron studies are normal, proceed to hemoglobin electrophoresis to evaluate for thalassemia trait 1, 2