What effect does Hemoglobin (Hb) E have on Red Blood Cells (RBCs) that results in a low Mean Corpuscular Volume (MCV)?

Effect of Hemoglobin E on Red Blood Cells

Hemoglobin E causes microcytosis (low MCV) in affected individuals primarily due to cellular dehydration resulting from altered red blood cell membrane properties and selective potassium loss, leading to reduced cell volume despite normal hemoglobin content. 1, 2

Mechanism of Microcytosis in Hemoglobin E

Hemoglobin E is one of the world's most common hemoglobin variants, particularly prevalent in Southeast Asia. The effect on red blood cells includes:

1. Cellular Dehydration (Xerocytosis):

   • Hemoglobin E causes selective potassium loss from red blood cells without corresponding sodium changes 1
   • This leads to decreased cell water content and subsequent cell shrinkage
   • The result is microcytic (small) red blood cells with normal or even increased hemoglobin concentration

2. Laboratory Findings:

   • Marked microcytosis (MCV < 80 fL)
   • Normal or slightly elevated hemoglobin concentration
   • Normal RDW (red cell distribution width) in homozygous HbE, unlike the elevated RDW seen in iron deficiency 3, 4
   • Absence of anemia in homozygous HbE state 1

Differential Diagnosis of Microcytic Anemias

It's important to distinguish Hemoglobin E from other causes of microcytosis:

Parameter	Hemoglobin E	Iron Deficiency	Thalassemia	Anemia of Chronic Disease
MCV	Low	Low	Very low	Low or normal
RDW	Normal (≤14.45)	Elevated (>14.0%)	Normal	Normal or slightly elevated
Serum Ferritin	Normal	Low (<30 μg/L)	Normal	Normal or high
Hemoglobin	Normal or mild ↓	Decreased	Decreased	Decreased

3, 4

Clinical Presentations of Hemoglobin E Disorders

The clinical significance varies based on the genotype:

• Hemoglobin E trait (heterozygous): Clinically asymptomatic with mild microcytosis

• Homozygous Hemoglobin E (HbEE):

  • Presents with marked microcytosis and mild erythrocytosis
  • Normal hemoglobin levels (not anemic)
  • No hemolysis (normal red cell survival time of 28 days) 1
  • Clinically well without pallor, jaundice, or splenomegaly

• Compound heterozygous states:

  • HbE/β-thalassemia: Most severe form, ranging from mild anemia to transfusion-dependent thalassemia major 2
  • HbE/HbS (Sickle cell): Results in sickle cell disease syndrome similar to sickle β+ thalassemia 2

Diagnostic Considerations

When evaluating microcytosis in a patient with suspected hemoglobin E:

• Hemoglobin electrophoresis or high-pressure liquid chromatography (HPLC) is essential for diagnosis 2
• RDW can help distinguish HbE trait (normal RDW ≤14.45) from iron deficiency (elevated RDW >14.0%) 4, 3
• Consider genetic testing to confirm the diagnosis and rule out co-inherited conditions like alpha-thalassemia 5

Clinical Implications

• Homozygous HbE is a benign condition that mimics beta-thalassemia minor without causing anemia or hemolysis 1
• Patients with homozygous HbE should be reassured about its benign nature
• The finding of anemia in a patient with high proportions of HbE should prompt investigation for other causes 1
• Patients with compound heterozygous states (particularly HbE/β-thalassemia) require more intensive monitoring and management 2