HIS Case 1: Thalassaemia Flashcards
Haemoglobin study
Normal:
Hb A: α2β2
Hb A2: α2δ2 (adult haemoglobin apart from Hb A: α2β2)
Hb F: α2γ2 (fetal haemoglobin, still some during adulthood)
Abnormal:
Hb H: β4 (α-Thalassaemia)
Hb Bart: γ4 (α-Thalassaemia)
Classify and Investigate causes of anaemia
See lecture
Causes
- Production
- Destruction
- Sequestration
- Dilution
Investigations
- CBC
- Peripheral blood smear
Describe genetics of alpha and beta-thalassaemia
See lecture
Alpha thalassaemia
- 2 alpha gene loci on chromosome 16
- total 4 alpha genes in an individual
- ***Deletions of DNA
Phenotypes:
- Normal:
- 4 functional α alleles (1 mother, 1 father —> code for 1 α chain, total 2 α chains) - Carrier (asymptomatic):
- α-/αα - α-Thalassaemia Trait / Minor (mild / asymptomatic):
- α-/α- or –/αα
- mild anaemia, considered carriers
- ↑ RBC - HbH disease (symptomatic)
- HbH: ***β4; α-/–
- moderate to severe anaemia - Haemoglobin Bart’s hydrops fetalis
- α-Thalassaemia Major; hydrops fetalis with Hb Bart’s i.e. ***γ4; –/–
- could not survive and usually die before/shortly after birth
Beta thalassaemia
- 1 beta gene locus on chromosome 11 —> 3 alleles: B0, B+, B++
- ***Single nucleotide mutations
Phenotypes:
- β-Thalassaemia minor / trait (e.g. β++/βN; βsilent/βN):
- **βo / β+ heterozygous (i.e. βo/βN, β+/βN)
- **mild / no anaemia
- **↑ HbA2
- **↑ RBC - β-Thalassaemia intermedia (e.g. β++/β++):
- 2 β-globin genes carrying a thalassaemia mutation (at least 1 mild) OR
- 1 β-globin Thalassaemia mutation in combination with **excess α globin genes (less common)
- **mild to moderate anaemia - β-Thalassaemia major (e.g. βo/βo):
- **2 β-globin genes carrying a **severe thalassaemia mutation (βo / β+ **homozygous OR **compound heterozygous e.g. βo/β+)
- severe anaemia requiring **regular transfusion
- **HbF (98%) - Haemoglobin E Thalassaemia:
- 1 β-globin gene carrying a Thalassaemia mutation (mild/severe) in combination with 1 β-globin gene carrying point mutation encoding HbE
- mild to severe anaemia
Primary and secondary modifiers of β-Thalassaemia phenotype includes variable output from:
1. **β-globin gene
2. **α-globin gene
3. ***HbF response
—> determine degree of chain imbalance (α / non-α globin ratio) + severity of ineffective erythropoiesis
***Clinical and laboratory features of alpha thalassaemia syndromes (Trait, HbH disease, Hb Bart’s hydrops fetalis) with respect to the underlying genotypes
Trait (2 gene deletion):
- CBC
- ↓ Hb
- ↑ RBC - Peripheral blood smear
- HbH inclusions
- Hypochromic, Microcytic
- Reticulocytosis
- Anisocytosis
- Poikilocytosis
- Normoblasts
- Target cells - Hb F, Hb A2 quantitation by chromatography / electrophoresis
- HbH band —> fast running
- Hb Bart’s —> slower running - Detection of Hb H inclusions
- Genotyping for complex cases / Prenatal diagnosis
Clinical features:
- HbH disease (3 gene deletion: β4)
- Chronic anaemia
- Splenomegaly
- HbH inclusions
- Can be completely asymptomatic - Hb Bart’s hydrops fetalis (4 gene deletion: γ4)
- Hb Bart’s Hb: γ4
- Incompatible with life
- Heart failure
- Liver dysfunction
Take a clinical history and physical examination with the intent to help identify cause of anaemia
- History
- Chief complaint
- Travel history (Malaria)
- Food history (B12, Folate)
- Medical history (Gastrectomy, Liver disease)
- Drug history (Antifolates)
- Family history (Hereditary haematological disease: G6PD deficiency, Thalassaemia, Hereditary spherocytosis) - Physical examination
- Central pallor
- Jaundice
- Abdominal exam —> Liver, Spleen palpation
- LN palpation —> Haematological malignancy
- Neurological examination —> B12 neuropathy, TTP
- Other system examination for underlying cause
***Identify main changes observed in peripheral blood film of patients with anaemia due to thalassaemia
- Hypochromic, Microcytic
- Reticulocytosis
- Anisocytosis
- Poikilocytosis
- Target cells (Hb in centre)
- Normoblasts
Recognise typical diagnostic findings of HbH disease and be able to explain the results in light of the pathophysiology of the disease
Diagnostic findings:
- Hb study
—> HbH inclusion body
—> HbH band (on electrophoresis)
Pathophysiology of HbH disease - 3 gene deletion - Chronic anaemia - Splenomegaly - Exacerbation (SOB): —> Infection —> Oxidant drugs —> Pregnancy
Discuss screening for thalassaemia carriers in HK and how this is currently undertaken
- Antenatal screening
- silent carriers (1 alpha gene deletion) —> normal MCV —> not proceed further
- detect carriers of 2 alpha globin gene deletion with low MCV
—> may give birth to baby with hydrops fetalis
—> 1st trimester: Chorionic villi sampling + Molecular analysis
—> 2nd trimester: Fetal blood sampling + Molecular analysis + Globin chain synthesis
—> Couples can decide whether to continue pregnancy - Neonatal screening
- debatable
Ethical issues and limitations of thalassaemia screening as related to the present case
Prenatal screening:
For:
- parents can decide whether to continue pregnancy
Against:
- encourage abortion
- HbH not a fatal disease —> only moderate burden
Neonatal screening (at birth):
For:
- parents can be better informed of potential morbidity of child
- parents can be alert about exacerbation of anaemia during acute illness
Against:
- unnecessary to alarm parents since its not life-threatening
Treatment of HbH
- Folate supplement
- Blood transfusion
- Fe chelation - Follow-up
- aware of gallstones
- screen for G6PD deficiency since it is common in HK
