Differential Diagnosis of Low Mentzer Index with Normal HPLC
Direct Answer
Iron deficiency is the most likely cause of your patient's low Mentzer index (10) with microcytosis and elevated RBC count, despite normal hemoglobin, and this should be confirmed with serum ferritin and transferrin saturation before considering other etiologies. 1, 2
Understanding the Mentzer Index
- The Mentzer index (MCV/RBC count) is calculated to distinguish beta-thalassemia trait from iron deficiency anemia, with values <13 suggesting thalassemia trait and values >13 suggesting iron deficiency 2
- Your patient's Mentzer index of 10 strongly suggests thalassemia trait by traditional interpretation, but the normal HPLC electrophoresis excludes beta-thalassemia trait 2
- The Mentzer index has 98.7% sensitivity and 82.3% specificity for detecting beta-thalassemia trait, making it highly reliable but not infallible 2
Most Likely Alternative Causes
Iron Deficiency Without Anemia
- Iron deficiency can present with microcytosis and low Mentzer index even when hemoglobin remains normal, particularly in early stages 1, 3
- In a study of healthy apheresis donors with low MCV (<80 fL) and normal hemoglobin (≥12.5 g/dL), 64% had iron deficiency 3
- Mean corpuscular hemoglobin (MCH) is more reliable than MCV for detecting iron deficiency because it identifies both absolute and functional iron deficiency 1
- Serum ferritin <30 μg/L confirms iron deficiency in the absence of inflammation, while transferrin saturation <15-16% provides additional confirmation 1
Alpha-Thalassemia Trait
- Alpha-thalassemia trait produces microcytosis with elevated RBC count and normal hemoglobin, but is not detected by standard HPLC electrophoresis 3
- Alpha-thalassemia should be presumed when RBC count is elevated, no variant hemoglobins are detected on electrophoresis, and iron studies are normal 3
- This diagnosis requires specialized genetic testing for alpha-globin gene deletions, as HPLC only detects beta-chain variants 3
Combined Iron Deficiency and Hemoglobinopathy
- Iron deficiency may mask underlying hemoglobinopathy on HPLC electrophoresis 3
- In the apheresis donor study, 15% of those with low MCV had both iron deficiency and hemoglobinopathy 3
- If iron deficiency is confirmed and treated, repeat HPLC electrophoresis after 16 weeks of iron therapy to unmask any underlying hemoglobinopathy 2
Recommended Diagnostic Workup
Essential First-Line Tests
- Obtain serum ferritin and transferrin saturation immediately to confirm or exclude iron deficiency 1
- Measure reticulocyte count to assess bone marrow response 1
- Calculate MCH (mean corpuscular hemoglobin), which is more sensitive than MCV for iron deficiency 1
- Check C-reactive protein to assess for inflammation that might falsely elevate ferritin 4, 1
Interpretation of Iron Studies
- Ferritin <30 μg/L confirms iron deficiency without inflammation 4, 1
- In the presence of inflammation (elevated CRP), ferritin <100 μg/L may still indicate iron deficiency 4
- Transferrin saturation <15-16% supports iron deficiency and is less affected by inflammation than ferritin 1
If Iron Studies Are Normal
- Consider alpha-thalassemia trait as the primary diagnosis, which requires genetic testing for alpha-globin gene deletions 3
- Evaluate for other causes of microcytosis including anemia of chronic disease, sideroblastic anemia, or lead toxicity 4
- Consider referral to hematology if the diagnosis remains unclear after comprehensive workup 4
Clinical Pitfalls to Avoid
- Do not assume normal HPLC excludes all hemoglobinopathies—alpha-thalassemia trait is not detected by standard electrophoresis 3
- Normal hemoglobin does not exclude iron deficiency; microcytosis often precedes anemia in iron depletion 1, 3
- Ferritin can be falsely elevated by inflammation, chronic disease, malignancy, or liver disease, requiring clinical context for interpretation 1
- If treating for iron deficiency, repeat HPLC after iron repletion to unmask any underlying beta-thalassemia trait that was obscured 2, 3