What is Hemoglobin E (HbE)?

What is Hemoglobin E?

Hemoglobin E (HbE) is an extremely common structural beta-globin variant caused by a point mutation (β26 Glu→Lys) that produces a mildly unstable hemoglobin and activates a cryptic splice site, resulting in reduced beta-chain production and a mild beta-thalassemia phenotype. 1, 2

Molecular Basis and Prevalence

• HbE results from a G→A mutation at codon 26 of the beta-globin gene, substituting glutamic acid with lysine 3
• This mutation creates functional but unstable hemoglobin and simultaneously activates an abnormal RNA splicing site, causing the variant to be produced at reduced rates 1, 3
• HbE is the most common hemoglobin variant in Southeast Asia and the second most prevalent worldwide, reaching carrier frequencies of 60-80% in some Southeast Asian populations 4, 3
• While highly prevalent in Bengal and northeastern India, it remains relatively rare in other parts of the Indian subcontinent 4

Clinical Manifestations by Genotype

HbE Trait (Heterozygous)

• Clinically asymptomatic with no significant anemia 4, 2
• Mild microcytosis may be present on laboratory testing 4

HbE Disease (Homozygous)

• Clinically benign condition with no transfusion requirements and no hepatosplenomegaly 5, 2
• Patients exhibit mild microcytic anemia but remain asymptomatic 5
• Some individuals may have elevated HbF levels (up to 12% of cases), which can lead to misdiagnosis as HbE/beta-thalassemia 5
• Co-inheritance with alpha-thalassemia or G6PD deficiency does not significantly alter the benign clinical phenotype 5

HbE/Beta-Thalassemia (Compound Heterozygous)

• This represents the most clinically significant form and is the most common severe beta-thalassemia disorder globally, comprising approximately 50% of all severe beta-thalassemia cases 1, 2
• Affects approximately one million people worldwide with increasing prevalence in North America 2
• Clinical phenotype ranges from mild anemia to severe transfusion-dependent thalassemia major, similar to homozygous beta-thalassemia 4, 1, 2
• Patients may become symptomatic and transfusion-dependent at an early age 4
• Phenotypic severity is modified by the specific beta-thalassemia mutation type, HbF levels, and co-inheritance of alpha-thalassemia 2

HbE/HbS (Compound Heterozygous)

• Results in a sickle cell disease syndrome clinically similar to sickle beta-plus thalassemia 2

Diagnostic Approach

Laboratory Findings

• High-performance liquid chromatography (HPLC) is the primary diagnostic method for identifying HbE 4
• Red blood cell indices show microcytosis (low MCV) and hypochromia (low MCH) 4
• A negative correlation exists between HbA2 levels and RBC indices (MCV, MCH) 4
• Hemoglobin electrophoresis at alkaline pH can identify HbE, though it may co-migrate with other variants 2

Critical Diagnostic Considerations

• Distinguishing between homozygous HbE and HbE/beta-thalassemia is essential due to vastly different clinical implications 4, 2
• Elevated HbF in homozygous HbE cases can mimic HbE/beta-thalassemia, necessitating comprehensive DNA analysis 5
• When a partner is suspected of carrying alpha-thalassemia 1, comprehensive DNA analysis for alpha-thalassemia is necessary in homozygous HbE cases to assess reproductive risk 5

Clinical Significance and Complications

Reproductive and Genetic Counseling Implications

• Identification of HbE is critical for prenatal diagnosis and genetic counseling, particularly given that HbE/beta-thalassemia presents as thalassemia major 4
• Homozygous HbE carries hidden reproductive risk when combined with partner's thalassemia mutations 5

Complications in HbE/Beta-Thalassemia

• High risk for thromboembolism due to hypercoagulable state, particularly increased after splenectomy 2
• Iron overload occurs even in non-transfused patients secondary to increased gastrointestinal iron absorption 2
• Cardiopulmonary disease including pulmonary hypertension from iron overload, thromboembolism, and hemolysis-induced nitric oxide deficiency 2
• Acute and chronic complications cause significant morbidity and mortality requiring ongoing monitoring 2

Management Considerations

• HbE/beta-thalassemia patients are excellent candidates for HbF-modulating agents (such as hydroxyurea), as moderate increases in hemoglobin can result in marked phenotypic improvement 2
• Approximately 40% of patients show clinical improvement with hydroxyurea therapy 2
• Iron deficiency may coexist with homozygous HbE and should be evaluated and corrected with supplementation 5