HbSE disease

Hemoglobin SE (HbSE) Disease: A Comprehensive Medical Review

Introduction

Hemoglobin SE disease (also known as HbSE compound heterozygosity or sickle cell-hemoglobin E disease) is a rare genetic hemoglobinopathy characterized by the compound heterozygous inheritance of hemoglobin S (HbS) from one parent and hemoglobin E (HbE) from the other, resulting in a unique variant of sickle cell disease (SCD). HbSE disease has historically been classified as a benign form of SCD, particularly in comparison to homozygous HbSS disease; however, recent systematic reviews and case reports have documented severe complications including vaso-occlusive crises, acute chest syndrome, bone infarction, splenic complications, stroke, and even death, requiring reclassification as a moderate form of SCD.^[1]^[2]^[3]^[4]^[5]

According to comprehensive systematic reviews published in peer-reviewed journals, the National Institutes of Health (NIH), MSD Manual (Merck), American Society of Hematology (ASH), and scientific literature, HbSE disease is more common in Southeast Asia and the Mediterranean region, where both HbS and HbE alleles circulate at appreciable frequencies in the population. The compound heterozygous state produces variable clinical manifestations, with hemoglobin levels typically averaging 11.64 ± 1.73 g/dL, and HbS and HbE percentages averaging 61.1% ± 7.25% and 32.3% ± 5.06%, respectively.^[6]^[2]^[3]^[1]

Etiology and Genetics

Genetic Basis

HbSE disease results from the compound heterozygous inheritance of two abnormal hemoglobin genes, one causing sickle hemoglobin and one causing hemoglobin E:^[2]^[6]

Hemoglobin Gene Mutations:

Hemoglobin S (HbS):

β-Globin Gene Mutation: Point mutation at codon 6
Specific Change: Glutamic acid → Valine (Glu6Val)
Nucleotide Change: GAG → GTG (point mutation in position 2 of codon 6)
Consequence: Hydrophobic valine replaces hydrophilic glutamic acid
Result: HbS polymerizes under deoxygenated conditions ^[7]^[6]

Hemoglobin E (HbE):

β-Globin Gene Mutation: Point mutation at codon 26
Specific Change: Glutamic acid → Lysine (Glu26Lys)
Nucleotide Change: GAG → AAG
Consequence: Glutamic acid (negative charge) replaced by lysine (positive charge)
Result: HbE has mild effects on hemoglobin function; very common in Southeast Asia ^[6]^[2]

Inheritance Pattern:

Autosomal recessive: Requires two abnormal hemoglobin alleles
Parental genotypes:
- One parent with genotype AS (sickle cell trait) or SS (HbSS disease)
- Other parent with genotype AE (hemoglobin E trait) or EE (HbE disease)
Compound heterozygosity: Offspring inherits one S and one E allele
Frequency: Rare in most populations; higher in Southeast Asia where both HbS and HbE are prevalent ^[2]^[6]

Hemoglobin Structure and Function

Normal Hemoglobin A (HbA):

Structure: α₂β₂ tetramer (two alpha chains, two beta chains)
Function: Oxygen carrier, reversible oxygenation
Solubility: Remains soluble in both oxygenated and deoxygenated states ^[6]

Hemoglobin S Polymerization:
According to biochemical studies:^[6]

Polymerization: HbS polymerizes specifically under deoxygenated conditions
Mechanism: Hydrophobic interactions between HbS molecules
Consequence: Rigid, elongated red blood cells with characteristic sickle shape
Effect: Increased blood viscosity, vaso-occlusion, hemolysis ^[7]^[6]

Hemoglobin E Characteristics:

Effect on polymerization: HbE does not polymerize
Functional impairment: Mild, usually clinically insignificant in heterozygous state
In HbE trait (AE genotype): Mostly asymptomatic with mild microcytic anemia
In HbSE disease: HbE provides approximately 32% of hemoglobin ^[2]^[6]

HbSE Disease Hemoglobin Composition:

Hemoglobin S: 61.1% (can polymerize under hypoxia)
Hemoglobin E: 32.3% (non-polymerizing but present in significant amounts)
Hemoglobin F: 2.2% (fetal hemoglobin, protective)
Hemoglobin A: Absent (no normal beta-globin production)
Hemoglobin A₂: Normal or absent ^[3]^[8]^[1]

Pathophysiology

Red Cell Sickling:
The fundamental mechanism affecting HbSE patients:^[7]^[6]

Deoxygenation: In low-oxygen environments (tissues, high altitude, illness)
HbS polymerization: Forms rigid fibers within red cells
Cell deformation: Red cells take on characteristic sickle shape
Consequence: Increased blood viscosity, vessel occlusion, hemolysis ^[6]

Hemolytic Anemia Mechanisms:
Multiple factors contribute to anemia in HbSE disease:^[4]^[7]

Reduced RBC lifespan: 10-20 days vs. 120 days normal
Hemoglobin-mediated hemolysis: Polymerizing HbS damages red cell membrane
Splenic sequestration: Damaged cells removed from circulation
Intravascular hemolysis: Direct damage by polymerized HbS
Oxidative stress: Free hemoglobin generates reactive oxygen species ^[7]

Vaso-Occlusion:
Critical pathophysiological event triggering pain and organ damage:^[5]^[1]

Red cell rigidity: Sickled cells cannot deform through small vessels
Vessel occlusion: Blockade of blood flow to tissues
Ischemic injury: Tissue hypoxia and infarction
Inflammation: Activation of adhesion molecules and inflammatory cascade
Triggering factors: Hypoxia, dehydration, infection, acidosis, cold exposure ^[1]^[5]

Unique Aspects of HbSE Disease:
Compared to HbSS disease:^[3]^[1]

Lower HbF levels: 2.2% in HbSE vs. 5% in HbSS (HbF is protective)
Significant HbE presence: Approximately 32% of hemoglobin doesn’t polymerize
Variable clinical phenotype: Milder baseline anemia but similar polymerization potential
Delayed symptom onset: Mean age of presentation 20.9 years vs. younger in HbSS ^[1]

Clinical Presentation

Demographics and Epidemiology

According to the systematic review of 68 published cases and contemporary literature:^[3]^[1]^[2]

Geographic Distribution:

Turkey: Highest reported cases (n = 22, 32.4% of all published cases)
Southeast Asia: Common due to high prevalence of HbE trait
Mediterranean region: Some cases, particularly in areas with HbE
Other regions: Increasingly recognized worldwide ^[1]^[2]

Demographics:

Reported cases: 68 published cases in literature (as of 2021)
Gender: 32 (47%) males, 36 (53%) females
Mean age: 20.9 ± 18.26 years at presentation
Age range: From infancy to adulthood, with significant variability ^[3]^[1]

Prevalence:

Exact prevalence: Unknown but rare globally
Endemic areas: Higher frequency where both HbS and HbE alleles prevalent
United States: Uncommon, but increasing recognition
Clinical presentation variability: Suggests possible underdiagnosis ^[2]^[1]

Clinical Manifestations

Baseline Clinical Features:
Most patients with HbSE disease have relatively mild baseline findings compared to HbSS:^[4]^[1]^[3]

Hemoglobin and Laboratory Values:

Mean hemoglobin: 11.64 ± 1.73 g/dL (mild to moderate anemia)
Hemoglobin range: Typically 9-14 g/dL
MCV (Mean Corpuscular Volume): 70.9 fL (microcytic)
Reticulocyte count: Elevated, indicating ongoing hemolysis
Peripheral smear: Sickled cells visible, though may be less prominent than HbSS ^[8]^[1]

Splenomegaly:
Present in a minority of cases:^[4]^[1]^[3]

Frequency: Reported in 16.1% (11/68 cases)
Mechanism: Sequestration of sickled cells, chronic hemolysis
Degree: Mild to moderate, rarely massive
Functional consequence: Usually asymptomatic but can contribute to hemolysis ^[1]

Chronic Hemolysis Markers:

Jaundice: Mild, from chronic unconjugated hyperbilirubinemia
Dark urine: From urobilinuria
Gallstones: Chronic hemolysis increases bilirubin load (4.4% of cases)
Growth: Usually normal, though some growth retardation possible ^[3]^[1]

Acute Clinical Manifestations

Recent evidence demonstrates that HbSE disease can have severe acute complications, contrary to historical classification as benign:^[5]^[1]^[3]

Vaso-Occlusive Crisis (Most Common Severe Manifestation):
Present in 32.3% (22/68) of reported cases:^[1]

Clinical Features:

Pain severity: Acute, severe pain in affected areas
Location:
- Extremities (hands, feet, arms, legs) most common
- Chest, back, abdomen also reported
- Bone pain particularly characteristic
Onset: Sudden, often without obvious precipitant
Duration: Hours to days
Associated symptoms: Swelling, fever, tenderness
Triggers: Infections, hypoxia, dehydration, high-altitude travel, stress ^[5]^[1]

Age at Presentation:

Earlier than HbSS: Mean 20.9 years vs. variable in HbSS
Pediatric cases: Some cases presenting in childhood
Delayed presentation: Some cases may not manifest until adulthood ^[1]

Bone Infarction:
Documented in 5.8% (4/68) of reported cases:^[3]^[1]

Aseptic necrosis: Particularly femoral head, femoral condyle, humeral head
Mechanism: Vaso-occlusion within bone marrow
Clinical presentation: Severe pain, functional limitation
Radiological findings: Bone infarction on imaging
Long-term consequences: Chronic pain, joint dysfunction ^[1]

Acute Chest Syndrome:
Documented in several cases, potentially life-threatening:^[5]^[1]

Clinical presentation: Chest pain, cough, fever, dyspnea
Mechanism: Pulmonary infarction, infection, or fat embolism
Severity: Can progress rapidly
Mortality: Potential for fatal outcome if untreated
Frequency: Rare in HbSE compared to HbSS, but well-documented ^[1]

Infections:
Documented in 11.7% (8/68) of reported cases:^[1]

Types: Bacterial infections, sepsis
Mechanism: Functional asplenia, impaired immunity
Severity: Can be serious, leading to septic shock
Risk: Increased with splenic involvement or splenic infarction ^[1]

Hemolytic Anemia Crisis:
Acute worsening of anemia:^[3]^[1]

Etiology: Accelerated hemolysis during infection or stress
Presentation: Severe fatigue, dyspnea, tachycardia, hypotension
Laboratory findings: Significant hemoglobin drop, elevated reticulocytes
Requirement: Possible transfusion support ^[1]

Other Reported Complications

Stroke:
Documented in 2.9% (2/68) of cases:^[1]

Mechanism: Vaso-occlusion in cerebral vessels
Risk factors: Young age, possibly lower hemoglobin F levels
Prevention: Transcranial Doppler screening recommended
Management: Acute intervention required ^[1]

Venous Thromboembolism:
Documented in 2.9% (2/68) of cases:^[1]

Mechanism: Hypercoagulable state in SCD
Presentation: Deep vein thrombosis or pulmonary embolism
Risk factors: Prolonged immobility, infection, dehydration
Management: Anticoagulation therapy ^[1]

Hematuria:
Documented in 2.9% (2/68) of cases:^[1]

Mechanism: Sickling in renal microvasculature
Types: Gross or microscopic hematuria
Clinical course: Usually self-limited but can be severe ^[1]

Mortality:
Documented in 4.4% (3/68) of cases:^[1]

Causes of death: Complications including acute chest syndrome, sepsis
Timing: Cases described across different age groups
Implications: HbSE disease can be life-threatening despite historical classification as benign ^[3]^[1]

Severity Spectrum

Asymptomatic Patients:
Some individuals remain largely asymptomatic:^[2]^[1]

Incidence: Approximately 32% without documented complications in literature
Discovery: Often identified through screening or family studies
Monitoring: Still require regular follow-up, as complications can develop ^[1]

Mild Symptomatic:
Most commonly described presentation:^[3]^[1]

Symptoms: Chronic fatigue, mild jaundice, occasional pain episodes
Hemoglobin: Relatively stable, typically 10-13 g/dL
Frequency: Majority of reported cases
Quality of life: Generally preserved with appropriate management ^[1]

Moderate to Severe Symptomatic:
Increasingly recognized manifestations:^[5]^[1]

Complications: Regular pain crises, acute chest syndrome, other acute events
Frequency: 68% of literature cases had sickling-related complications
Hemoglobin: Lower baseline, episodic drops during crises
Management burden: Significant, requiring close follow-up ^[1]

Diagnosis

Clinical Diagnostic Approach

Diagnosis of HbSE disease requires a combination of clinical suspicion, laboratory findings, and molecular confirmation:^[8]^[4]^[7]^[2]

Clinical Suspicion:
Should consider HbSE disease in patients with:^[4]^[2]

Geographic or ethnic background from high-prevalence areas (Southeast Asia, Mediterranean)
Family history of hemoglobinopathy or anemia
Hemolytic anemia with microcytosis
Unexplained vaso-occlusive episodes or acute chest syndrome
Complications atypical for simple anemia ^[2]

Laboratory Investigation

Complete Blood Count:
Initial laboratory assessment:^[8]^[1]

Hemoglobin: 9-14 g/dL (mean 11.64 g/dL)
MCV: Microcytic, typically 65-75 fL (mean 70.9 fL)
MCH: 19-23 pg (reduced)
RBC count: Normal or elevated despite anemia
Reticulocyte count: 5-15% (elevated, indicating hemolysis)
WBC: Often elevated, particularly during pain crisis or infection
Platelets: Usually normal or elevated ^[8]^[1]

Peripheral Blood Smear:
Characteristic findings:^[8]^[5]

Sickled cells: Crescent or comma-shaped cells visible
Target cells: “Bull’s eye” appearance (more prominent with HbE)
Polychromasia: Increased young RBCs (reticulocytes)
Nucleated RBCs: May be present
Fragmented cells: Schistocytes indicating hemolysis ^[8]

Hemolysis Markers:
Indicating active hemolysis:^[7]^[5]

Bilirubin: Elevated unconjugated bilirubin (typically 1-3 mg/dL)
LDH: Markedly elevated (>600 U/L)
Haptoglobin: Low or absent (consumed binding free hemoglobin)
Reticulocyte count: Elevated (>5%)
Urobilinogen: Present in urine ^[8]

Sickle Cell Solubility Test:
Screening test:^[7]^[8]

Principle: HbS precipitates in presence of reducing agents
Positive result: Turbidity in sample
Limitation: Does not differentiate between HbSS, HbSC, HbSβ-thalassemia, HbSE, and trait
Follow-up: Requires hemoglobin electrophoresis for definitive diagnosis ^[7]^[8]

Hemoglobin Electrophoresis or HPLC

The Definitive Diagnostic Test:
Essential for establishing diagnosis of HbSE disease:^[8]^[1]

Hemoglobin Electrophoresis (Cellulose Acetate):

HbS band: Major band, representing ~61% of hemoglobin
HbE band: Distinct band at different migration point, representing ~32%
HbA: Absent
HbF: Normal or slightly elevated (~2.2%)
HbA₂: Normal or absent
Pattern: Unique pattern distinguishing HbSE from other SCD variants ^[8]^[1]

High-Performance Liquid Chromatography (HPLC):

Accuracy: More precise quantification of hemoglobin fractions
Current standard: Increasingly used in modern laboratories
Advantages: Automated, objective measurements
Results: Exact percentages of each hemoglobin type ^[8]

Acid-Citrate Agar Electrophoresis:

Alternative method: Complements cellulose acetate
Specific separation: Particularly useful for separating HbE from HbA₂
Clinical utility: Helps confirm HbE diagnosis ^[8]

Molecular Genetic Testing

DNA Sequencing:
Confirmatory testing for research and genetic counseling:^[2]

β-Globin sequencing: Identifies specific mutations
Codon 6 mutation: Confirms HbS (GAG→GTG)
Codon 26 mutation: Confirms HbE (GAG→AAG)
Genetic counseling: Enables accurate family assessment and carrier identification ^[2]

Newborn Screening

Newborn Screening Tests:
Essential for early identification:^[7]

Hemoglobin electrophoresis: Performed on newborn screening cards
Timing: 24-48 hours after birth
Hemoglobin pattern: Shows HbSE pattern in affected newborns
Follow-up: Confirmatory testing at 3-6 months when HbF levels fall ^[7]

Neonatal Hemoglobin Findings:

Hemoglobin Bart’s: Typically <3% (alpha-thalassemia exclusion)
Hemoglobin F: Elevated in all neonates (normal finding)
Hemoglobin A: Absent
HbS and HbE: Present in neonatal screening ^[7]

Differential Diagnosis

HbSE disease must be differentiated from other sickle cell genotypes and hemoglobinopathies:^[6]^[2]^[8]

Primary Differential Diagnoses:

1. Hemoglobin SS Disease (HbSS):

Similarities: Vaso-occlusive crises, hemolytic anemia
Key differences:
- HbSS has >80% HbS on electrophoresis
- HbSE has ~60% HbS and ~32% HbE
- HbSS typically more severe, earlier onset
- HbSS has no HbE band
Clinical differences: HbSS generally has lower hemoglobin, more complications ^[8]

2. Hemoglobin SC Disease (HbSC):

Similarities: Compound heterozygous SCD
Key differences:
- HbSC has ~50% HbS and ~50% HbC on electrophoresis
- HbE band absent in HbSC
- HbSC often has slightly higher hemoglobin than HbSE
- Clinical severity spectrum similar to HbSE ^[8]

3. Sickle-Beta Thalassemia (HbSβ±):

Similarities: Hemolytic anemia, vaso-occlusive disease possible
Key differences:
- Elevated HbA₂ (>3.5%) in beta-thalassemia
- HbE absent
- Different electrophoresis pattern
Severity: HbSβ⁰ comparable to HbSS; HbSβ⁺ milder ^[8]

4. Hemoglobin E Trait (AE):

Similarities: HbE present on electrophoresis
Key differences:
- HbE trait has ~30-40% HbE with ~60% normal HbA
- No HbS present
- Mild microcytic anemia only, no sickling
- Benign condition ^[6]

5. Sickle Cell Trait (AS):

Similarities: HbS present
Key differences:
- Trait has ~40% HbS with ~60% normal HbA
- No HbE present
- Generally asymptomatic unless severe hypoxia/altitude
- Benign condition ^[6]

Management and Treatment

Treatment Philosophy

Management of HbSE disease has evolved significantly with recent recognition that many cases are more severe than historically believed:^[5]^[2]^[1]

Treatment Goals:

Prevent complications: Minimize vaso-occlusive crises and acute events
Manage acute episodes: Prompt recognition and treatment
Monitor for complications: Early detection of end-organ damage
Optimize quality of life: Balance treatment burden with benefit
Genetic counseling: Family planning and carrier identification ^[4]^[2]

Conservative Management

Folic Acid Supplementation:
Universal recommendation:^[4]^[2]

Dosage: 0.5-1.0 mg daily
Rationale: Chronic hemolysis increases folate requirements, supporting erythropoiesis
Benefits: Prevents megaloblastic anemia, supports red cell production
Lifelong: Continue indefinitely ^[4]

Vaccination:
Important preventive measure:^[2]

Pneumococcal vaccines: PCV13 and PPSV23
Meningococcal vaccines: Conjugate (MenACWY) and serogroup B (MenB)
Haemophilus influenzae type b: Hib vaccine
Influenza: Annual vaccination
COVID-19: As recommended
Rationale: Functional asplenia risk, splenic sequestration ^[2]

Penicillin Prophylaxis:
Particularly important if splenic dysfunction present:^[2]

Dosage: 125-250 mg twice daily in children; 250 mg twice daily in adults
Indication: Documented or presumed functional asplenia
Duration: Lifelong or until demonstrated splenic function
Alternative: Amoxicillin if penicillin allergy ^[2]

Infection Prevention:
Critical component of care:^[4]^[2]

Avoid infections: Prompt treatment of fever, infections
Hygiene: Hand hygiene, infection avoidance strategies
Exposure management: Minimize contact with ill individuals
Fever protocol: Any fever >38.5°C requires evaluation ^[2]

Pain Management

Vaso-Occlusive Crisis Management:
Standard SCD protocols:^[5]^[4]^[7]

Analgesic Therapy:

Non-opioid analgesics: Acetaminophen, NSAIDs for mild pain
Opioid medications:
- Morphine (first-line IV opioid)
- Hydromorphone (alternative IV)
- Codeine or acetaminophen with codeine (oral)
Dosing: Weight-based, titrated to effect
Tolerance: Manage chronic pain and pseudoaddiction versus true addiction ^[4]^[7]

Supportive Care During Crisis:

Hydration: Aggressive IV or oral hydration
Oxygen therapy: If hypoxia present (SpO₂ <95%)
Warming: Avoid cold exposure
Rest: Reduce physical activity
Heat application: Local heat for pain control ^[5]^[4]

Monitoring During Crisis:

Vital signs: Frequent monitoring
Pain assessment: Regular reassessment
Complication screening: Chest pain, dyspnea suggest acute chest syndrome
Length of stay: Typically 1-7 days depending on severity ^[5]

Acute Chest Syndrome Management

Immediate Recognition and Management:
Critical for survival:^[5]^[1]

Clinical suspicion: Any patient with chest pain, dyspnea, fever
Diagnostic tests: Chest X-ray, CBC, reticulocyte count, blood gas
Oxygen therapy: Maintain SpO₂ >95%
Antibiotics: Broad-spectrum (cephalosporin) if infection suspected
Transfusion: May be necessary, particularly if hemoglobin drops significantly ^[5]^[1]

Complication Management:

Respiratory support: Supplemental oxygen, BiPAP if hypoxic
ICU care: If severe, multi-organ involvement
Exchange transfusion: Consider if severe hypoxia despite standard measures ^[5]

Transfusion Therapy

Indications for Transfusion:
Similar to other SCD genotypes but individualized:^[4]^[2]

Indications Include:

Acute severe anemia: Hemoglobin drop during crisis
Acute chest syndrome: To increase oxygen-carrying capacity
Stroke/TIA: To reduce HbS percentage
Splenic sequestration: Acute severe hemolysis
Pre-operative transfusion: For major surgery
Chronic transfusion: Rarely needed in HbSE compared to HbSS, but considered for severe complications ^[4]

Transfusion Protocol:

Type: Packed red blood cells, leukoreduced
Goal hemoglobin: Typically 10-11 g/dL for acute crisis
Simple transfusion: Most common approach
Exchange transfusion: Consider if severe and frequent crises
Target HbS: Typically maintain <30% HbS during chronic transfusion ^[2]

Disease-Modifying Therapy

Hydroxyurea (Hydroxycarbamide):
Important therapeutic option, though underutilized in HbSE:^[4]^[1]

Mechanism: Increases HbF production, inhibits HbS polymerization
Efficacy: Reduces pain crisis frequency by approximately 50% in HbSS
Current use in HbSE: Only 4.4% of published cases received HU
Dosage: 15-35 mg/kg/day
Monitoring: Complete blood count every 2-4 weeks during induction and periodically during maintenance
Side effects: Myelosuppression, potential teratogenicity
Benefits: May improve outcomes in symptomatic HbSE patients ^[4]^[1]

Emerging Therapies:

Voxelotor:

Mechanism: Allosteric hemoglobin modifier increasing oxygen affinity, reducing sickling
FDA approval: 2019, approved for SCD
Dosage: 1500 mg daily
Clinical data: Increases hemoglobin, decreases hemolysis markers
Potential: May benefit HbSE patients, though clinical experience limited ^[1]

Crizanlizumab:

Mechanism: P-selectin antagonist reducing adhesion events
FDA approval: 2019, approved for SCD
Dosage: 5 mg/kg IV infusion every 4 weeks
Clinical data: Reduced pain crisis frequency in clinical trials
Potential: Early data suggests potential benefit in various SCD genotypes ^[1]

Luspatercept:

Mechanism: Erythroid maturation agent
Status: Under investigation for SCD
Potential: May improve hemoglobin levels and reduce transfusion need ^[1]

Special Considerations

Splenic Function:
Important for risk stratification:^[4]^[2]

Assessment: Functional asplenia testing, imaging if indicated
Sequestration risk: Increased with poor splenic function
Prophylaxis: Penicillin and aggressive infection management
Monitoring: Regular blood counts, fever response ^[2]

Pregnancy Management:
Special considerations for affected women:^[4]^[2]

High-risk pregnancy: Increased risks of preeclampsia, pain crises
Fetal risks: Intrauterine growth restriction, preterm birth
Close monitoring: Frequent obstetric and hematology evaluation
Transfusion threshold: Lower threshold for transfusion during pregnancy
Genetic counseling: Essential for reproductive planning
Delivery planning: Coordinate with obstetrics and hematology ^[2]

Prognosis and Long-term Outcomes

Overall Prognosis

The prognosis for HbSE disease has been substantially revised based on recent literature:^[3]^[2]^[1]

Historical Classification:

Previously considered: Mild, benign form of SCD
Current understanding: Moderate form of SCD with variable phenotype
Mortality: Documented deaths from SCD-related complications ^[1]

Life Expectancy:

With appropriate management: Near-normal life expectancy possible
Variable outcomes: Depends on individual severity and complication development
Long-term survival: Most reach adulthood, many survive well into later life ^[2]^[1]

Manifestation Frequency and Severity

According to the systematic review of 68 cases:^[1]

Complications Documented:

No complications: 32% (21/68 patients)
Vaso-occlusive crisis: 32.3% (22/68 patients)
Splenomegaly: 16.1% (11/68 patients)
Hemolytic anemia: 14.7% (10/68 patients)
Infections: 11.7% (8/68 patients)
Bone infarction: 5.8% (4/68 patients)
Gallstones: 4.4% (3/68 patients)
Venous thromboembolism: 2.9% (2/68 patients)
Stroke: 2.9% (2/68 patients)
Deaths: 4.4% (3/68 patients)^[1]

Implications:

Reclassification needed: 68% had sickling-related complications, supporting moderate classification
Enhanced management: Recognition of severity should lead to increased disease-modifying therapy use (currently only 4.4% on hydroxyurea)^[1]
Vigilance required: Any HbSE patient can develop serious complications ^[1]

Quality of Life

Factors Affecting Quality of Life:

Baseline anemia: Chronic fatigue in many patients
Pain episodes: Unpredictable, debilitating when occur
Medical management burden: Monitoring, medications, preventive care
Psychosocial impact: Living with chronic, potentially serious disease
Educational and employment: Most achieve normal achievements ^[2]^[1]

Positive Factors:

Milder baseline: Lower baseline hemolysis than HbSS
Normal life expectancy: Possible with appropriate management
Fertility: Usually preserved, enabling family planning
Cognitive function: Preserved ^[2]^[1]

Research Directions and Future Perspectives

Clinical Research Needs

Gaps in Knowledge:

Natural history studies: Better understanding disease progression
Predictive biomarkers: Identify which patients will develop severe manifestations
Therapeutic trials: Specific studies of HbSE patients with disease-modifying agents
Outcome registries: International databases tracking HbSE patients ^[5]^[1]

Emerging Therapies

Gene Therapy:
Promising approaches under development:^[2]

Lentiviral vectors: Delivering functional β-globin genes
CRISPR/Cas9: Correcting HbS mutation
Status: Early-stage trials, eventual potential for cure
Timeline: Years away from clinical application ^[2]

Novel Therapeutic Targets:

Cell adhesion molecules: Reducing vaso-occlusive events
Hemoglobin polymerization inhibitors: Direct targeting of HbS polymerization
Erythroid maturation agents: Improving red cell production quality
Anti-inflammatory agents: Reducing inflammatory cascade activation ^[1]

Diagnostic Advances

Improved Screening:

Expanded newborn screening: Earlier identification enabling intervention
Point-of-care testing: Portable hemoglobin electrophoresis
Biomarker development: Non-invasive tests predicting severity ^[1]

Conclusion

Hemoglobin SE disease represents a rare but important variant of sickle cell disease that has been historically underappreciated in terms of disease severity and clinical significance. The compound heterozygous inheritance of hemoglobin S and hemoglobin E produces a unique hemoglobinopathy with variable clinical manifestations, ranging from asymptomatic individuals to patients with severe, life-threatening complications. The systematic review documenting 68 published cases has revealed that approximately 68% of HbSE patients have developed sickling-related complications, including vaso-occlusive crises, acute chest syndrome, bone infarction, and even death, warranting reclassification from historically “benign” to “moderate” form of sickle cell disease.

The geographic distribution of HbSE disease, concentrated in Southeast Asia and the Mediterranean region where both HbS and HbE circulate, combined with historical underrecognition and limited clinical experience, has likely resulted in significant underdiagnosis and undertreatment. The mean age at presentation of 20.9 years, substantially older than in HbSS disease, suggests delayed recognition of complications in many patients, with some disease manifestations potentially subclinical until triggering events such as infection or hypoxia precipitate acute decompensation.

The clinical presentation of HbSE disease, characterized by baseline hemoglobin averaging 11.64 g/dL and distinctive hemoglobin fractions of 61.1% HbS and 32.3% HbE, creates a unique biochemical environment. The moderate hemolytic anemia, despite potential for HbS polymerization, combined with lower hemoglobin F levels than in HbSS disease, may create a situation where patients appear relatively stable until encountering stressors that precipitate sickling and vaso-occlusive episodes.

The underutilization of disease-modifying therapies in HbSE disease—with only 4.4% of reported patients receiving hydroxyurea compared to 39% of HbSS patients—represents a significant gap in management. The emerging availability of newer agents such as voxelotor and crizanlizumab offers potential opportunities to improve outcomes, though clinical experience in HbSE disease remains limited. The recognition that HbSE disease may be more severe than historically believed supports more aggressive therapeutic approaches in symptomatic patients.

Healthcare providers should maintain awareness of HbSE disease when evaluating patients with unexplained hemolytic anemia, particularly those of Southeast Asian or Mediterranean ancestry. The recognition that vaso-occlusive crises, acute chest syndrome, stroke, and other serious complications can occur in HbSE disease, despite its historically benign classification, necessitates a higher index of suspicion and more aggressive management when complications develop. Early diagnosis through newborn screening, combined with appropriate genetic counseling and preventive measures, can optimize outcomes for affected individuals and their families.

The study of HbSE disease illustrates the importance of systematic review and meta-analysis in identifying previously underrecognized aspects of genetic diseases. As healthcare providers and researchers continue to document and study HbSE cases, our understanding will undoubtedly continue to evolve, potentially revealing additional insights into disease mechanisms, prognostic factors, and optimal therapeutic strategies. The hope that emerges from this growing body of literature is that improved recognition and more aggressive management of HbSE disease will eventually translate into better clinical outcomes for affected patients.

Sources

HbSE disease

Hemoglobin SE (HbSE) Disease: A Comprehensive Medical Review

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