Hemoglobinopathies & Globin Gene Variants
1. Normal Hemoglobins & Developmental Switching
- Embryonic
Hb: Gower I (ζ2ε2), Gower II (α2ε2), Portland (ζ2γ2) → ช่วงแรกของการตั้งครรภ์
- Fetal
Hb (Hb F): α2γ2 → เริ่มสัปดาห์ที่ 14 ของการตั้งครรภ์ → มี O2 affinity สูง
- Adult
Hb:
- Hb A
(α2β2): 95–98%
- Hb
A2 (α2δ2): 2–3%
- Hb
F: < 2%
การเปลี่ยนจาก Hb F → Hb A หลังคลอดเป็นช่วงเวลาสำคัญที่ทำให้
β-thalassemia และ SCD เริ่มมีอาการหลังอายุ 4–6 เดือน
2. Classification of Hemoglobin Variants
แบ่งตามลักษณะทางคลินิกและกลไก
1.
Quantitative Defects → การสร้าง globin
chain ลดลง เช่น
o α-thalassemia
o β-thalassemia
2.
Qualitative Defects → การเปลี่ยนโครงสร้าง
Hb เช่น
o Hb
S (Sickle cell) →
polymerization
o Hb
C → crystal formation
o Hb
E → splice site mutation +
mild β-thal effect
o Hb
D, Hb O-Arab → บางชนิดทำให้ sickling เมื่อเจอกับ Hb S
3.
Oxygen Affinity Variants
o High
O2 affinity →
Erythrocytosis
o Low
O2 affinity / Hb M →
Cyanosis
4.
Unstable Hemoglobins → Aggregation → Hemolytic anemia (เช่น Hb Köln)
3. Epidemiology & Evolutionary Factors
- Malaria
Protection: Hb S, Hb C, Hb E, α-thal,
β-thal → Heterozygous states ป้องกัน severe malaria
- Geographic
Prevalence:
- Hb
S → Africa, India,
Middle East
- Hb
C → West Africa
- Hb
E → SE Asia, India,
Bangladesh
- α-thal → SE Asia, Mediterranean,
Africa
- β-thal → Mediterranean, Middle
East, Asia
4. Clinical Presentations
|
Variant / Condition |
Onset |
Key Features / Severity |
|
SCD (Hb SS, Hb S/β⁰-thal) |
> 6 เดือน |
Hemolytic anemia, VOC, splenic
sequestration |
|
Hb SC Disease |
เด็กเล็ก–ผู้ใหญ่ |
Milder than Hb SS, retinopathy ↑ |
|
Hb SE Disease |
ผู้ใหญ่ |
Mild SCD phenotype |
|
α-thal
(--/-- = Hb Barts) |
ทารกแรกเกิด |
Hydrops fetalis, severe anemia |
|
β-thal
major (β⁰/β⁰) |
> 6 เดือน |
Transfusion-dependent anemia |
|
Hb C Disease (CC) |
เด็กเล็ก–ผู้ใหญ่ |
Mild hemolytic anemia,
splenomegaly |
|
Hb D-Punjab + Hb S |
> 6 เดือน |
Severe SCD phenotype |
|
Hb E homozygous (EE) |
ผู้ใหญ่ |
Mild microcytosis, anemia minimal |
|
Hb E/β-thal |
เด็กเล็ก–ผู้ใหญ่ |
Phenotype: Mild → Severe (TDT or NTDT) |
5. Diagnostic Approach
Stepwise Evaluation
1.
CBC + RBC indices:
o Microcytosis
→ Thalassemia, Hb E, Hb C
o Hemolysis
+ Reticulocytosis → SCD,
unstable Hb
o Sickle
form → sickle syndrome (Hb
SS, Hb S/β⁰-thal)
o Target
cell → Hb E, Hb C,
thalassemia
2.
Hemoglobin Analysis
o Electrophoresis/HPLC/Capillary
electrophoresis
o Hb
A2 ↑ → β-thal
o Hb
F ↑ → β-thal
major, HPFH, SCD
3.
Iron Studies → Rule out Iron Deficiency
4.
DNA Analysis →
o α-thal (deletions)
o Complex
genotypes, prenatal diagnosis
5.
Special Tests → Hb stability test, p50 for O2 affinity
variants
6. Key Hemoglobin Variants: Clinical Pearls
Hb S (Sickle Cell)
- Mutation:
β6 Glu→Val
- Phenotype:
SCD when homozygous or combined with β-thal/Hb
C/Hb D-Punjab
- Complications:
VOC, ACS, stroke, splenic infarction
- Mgmt:
Hydroxyurea ↑HbF,
transfusion, HSCT in selected cases
Hb C
- Mutation:
β6 Glu→Lys
- Homozygous
(CC): Mild hemolysis, splenomegaly, VTE risk ↑
- Hb
SC: Retinopathy ↑,
SCD-like complications
- Trait:
Asymptomatic
Hb D-Punjab
- Benign
unless with Hb S →
Sickle-Hb D Disease
Hb E
- Mutation:
β26 Glu→Lys + splice defect → Mild β-thal phenotype
- EE:
Mild microcytosis, minimal anemia
- E/β⁰-thal: Severity
variable → TDT/NTDT
Hb O-Arab
- Benign
unless with Hb S →
Severe SCD
Unstable Hb (Hb Köln, Hb Zurich)
- Hemolysis,
Heinz bodies, gallstones, splenomegaly
High O2 Affinity (Hb Chesapeake) → Erythrocytosis
Low O2 Affinity / Hb M → Cyanosis, methemoglobinemia
7. Management Principles
|
Condition |
Management Highlights |
|
SCD |
Hydroxyurea, Vaccines, Penicillin
prophylaxis, Transfusion, HSCT |
|
β-thal
Major |
Regular transfusion, Iron
chelation, HSCT, Gene therapy |
|
Hb E/β-thal |
Transfusion if severe,
Hydroxyurea in NTDT |
|
Hb C/SC Disease |
Monitor VTE, retinopathy, manage
as mild SCD if symptomatic |
|
High/Low O2 Affinity |
Genetic counseling, symptomatic
care |
|
Unstable Hb |
Splenectomy if severe, folate
supplementation |
8. Key Diagnostic Tables
- Hb
Electrophoresis Patterns: Distinguishes Hb S, C, D, E, O-Arab
- Hb
A2/Hb F Levels: β-thal
→ Hb A2↑, α-thal →
Hb A2↓
- Microcytosis
Differential: Iron deficiency vs Thalassemia vs Hb E/C
|
Practical Clinical Tips
|
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