What to do if a patient has microcytosis with normal Hemoglobin (Hb) and ferritin levels?

Microcytosis with Normal Hemoglobin and Ferritin: Diagnostic Approach

In a patient with microcytosis but normal hemoglobin and ferritin, the most likely diagnoses are thalassemia trait (especially alpha-thalassemia), early iron deficiency not yet reflected in ferritin levels, or hemoglobinopathies—and the next step is to obtain hemoglobin electrophoresis and assess red cell distribution width (RDW). 1, 2

Initial Laboratory Assessment

The key is to distinguish between the major causes of isolated microcytosis:

• Check RDW first: An elevated RDW (>14%) suggests iron deficiency even when ferritin appears normal, as RDW is an early indicator of iron deficiency that precedes changes in ferritin 1, 3
• Verify the ferritin threshold: In the presence of any inflammation (even subclinical), ferritin up to 100 μg/L may still be consistent with iron deficiency, so a "normal" ferritin of 30-100 μg/L does not exclude iron deficiency 1
• Assess transferrin saturation: A transferrin saturation <30% supports iron deficiency even when ferritin is in the normal range 1, 3

Differential Diagnosis Priority

Thalassemia Trait (Most Likely)

• Obtain hemoglobin electrophoresis to identify beta-thalassemia trait, which typically shows elevated HbA2 >3.5% 4, 2
• Thalassemia trait is characterized by microcytosis that is disproportionate to the degree of anemia (MCV typically reduced out of proportion to hemoglobin level) 1
• Alpha-thalassemia is the second most common cause of microcytosis (31.1% in one series) and may require gene mapping for definitive diagnosis, as HbA2 is normal 5
• Consider ethnic background: Thalassemia is more common in Mediterranean, African, Middle Eastern, and Southeast Asian populations 1

Functional or Early Iron Deficiency

• Even with "normal" ferritin, iron deficiency may be present if ferritin is <45 μg/L, which provides optimal sensitivity-specificity trade-off 1
• Order additional iron studies: serum iron (low in iron deficiency), total iron-binding capacity (increased in iron deficiency), and transferrin saturation 2, 6
• A low transferrin saturation with low-normal ferritin suggests iron-restricted erythropoiesis 1, 3

Hemoglobinopathies

• Hemoglobin E disease and other hemoglobinopathies can cause microcytosis with minimal or no anemia 1, 5
• Hemoglobin electrophoresis will identify these conditions 2

Recommended Diagnostic Algorithm

1. Measure RDW and review red cell indices:

   • High RDW + microcytosis → likely iron deficiency 3
   • Normal RDW + microcytosis → likely thalassemia trait 2

2. Obtain complete iron panel (serum iron, TIBC, transferrin saturation) even if ferritin is "normal":

   • If transferrin saturation <30% → functional iron deficiency 1, 3
   • If all iron studies truly normal → proceed to step 3

3. Order hemoglobin electrophoresis:

   • HbA2 >3.5% → beta-thalassemia trait 4, 2
   • Normal HbA2 with appropriate ethnic background → consider alpha-thalassemia gene studies 5

4. Consider trial of oral iron therapy: A therapeutic response to three weeks of oral iron confirms iron deficiency even when initial ferritin was "normal" 3

Important Caveats

• Normal hemoglobin does not exclude iron deficiency: Compensatory mechanisms (elevated RBC count) may maintain hemoglobin despite depleted iron stores 3
• Ferritin is an acute phase reactant: Any concurrent inflammation, infection, or chronic disease can falsely elevate ferritin, masking iron deficiency 1
• Combined deficiencies can coexist: Iron deficiency and thalassemia trait may occur together, particularly in at-risk populations 3
• Anemia of chronic disease can present with microcytosis and normal ferritin, suggested by low iron with decreased TIBC 2, 7

When to Investigate Further

• If hemoglobin electrophoresis and complete iron studies are normal, consider:
  • Rare causes: Sideroblastic anemia, lead toxicity (check free erythrocyte protoporphyrin), or hereditary disorders 4, 7
  • Non-deletional alpha-thalassemia: Requires specialized genetic testing if family history or ethnic background is suggestive 5
  • IRIDA (iron-refractory iron deficiency anemia): Consider if patient has low transferrin saturation with low-normal ferritin and does not respond to oral iron; measure serum hepcidin and consider TMPRSS6 mutation analysis 1