Published on

1 Comment
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide


  1. 1. ThalassemiaGerald A. Soff, M.D.
  2. 2. Case: CC• C.C./HPI: – 27 year old woman, immigrant from Taiwan, with mild, chronic anemia since childhood. – Asymptomatic, very active, runs 3-5 miles, several times per week.• Fam Hx: – Father and several paternal relative with thalassemia.• PMHx, PSHx: Negative• Social History: Recently married, contemplating children.• Physical exam: Normal
  3. 3. Case CC: (2) Test Results NormalWBC 5.2 X 103/ul 4-11Hgb 11.5 g/dl 11.5-16Platelet 249 X 103/ul 160-400RBC 5.29 X 106/ul 4.0-5.2MCV 67 fl 82-98Ferritin 55 ng/ml 6-200Iron, Total 93 mcg/dl 34-165TIBC 355 mcg/dl 235-425LDH 139 U/L 12-246
  4. 4. CC (3) Hemoglobin Electrophoresis Hgb Results Normal Hgb A1 97.2% 96.3-98.7% Hgb A2 2.8% 1.9-3.5% Hgb F None detected 0-2%
  5. 5. CC (4)• Diagnostic Molecular: (Performed at Mayo)• HBA: “Two alpha globin genes are deleted in the cis, i.e., on the same chromosome (Southeast Asia type).”• HBB: “Beta-Globin DNA Mutations: Negative”
  6. 6. CC (5)Issues/Interventions?
  7. 7. Hemoglobin;Globin Tetramer • Hemoglobin can consist of two alpha chains and 2 beta class chains of globin. • 2 2; Hgb A • 2 2; Hgb A2 • 2 2; Hgb F
  8. 8. Globin Chain Switching During Development
  9. 9. Hemoglobins in Development
  10. 10. Thalassemia• -Thalassemia; Decreased Production of -globin chains• -Thalassemia; Decreased Production of -globin chains.• Results in decreased Hemoglobin synthesis and a microcytic/hypochromic anemia• Severity of disease is depending upon the number of mutant genes.
  11. 11. Thalassemia Syndromes• Depending on genetic severity;• Chronic anemia, high out-put cardiac states• Hepatosplenomegaly due to extramedullary hematopoiesis.• Transfusion-Dependent (Thalassemia major) – Need for iron chelation.• Due to increased marrow turnover, need for folic acid replacement.
  12. 12. Severe Thalassemia (Major)
  13. 13. Pathophysiology of Thalassemia Major
  14. 14. Thalassemia Major; Expansion of Marrow Disrupts Bone CortexPrior To Transfusion After Transfusion Skull, From Therapy Therapy Autopsy
  15. 15. Pigment Gall Stones in Thalasemia;(Common in all chronic Hemolytic Anemias)
  16. 16. Iron Overload in Thalassemia(Don’t give iron for all microcytic anemias!)
  17. 17. Geographic Distribution ofThalassemia/Hemoglobinopathies
  18. 18. Hemoglobinopathies and Thalassemia; Role in Malaria • The malarial parasite (Plasmodium) has an essential intra- erythrocyte stage. • Sickle trait (as well as G6PD deficiency) causes red cell lysis prior to successful replication of parasite.
  19. 19. Alpha Thalassemia• Most frequently due to absence of one or more of the normal complement of 4 alpha genes• The fewer the alpha genes present the more severe the clinical syndrome• Absence of 1 or 2 genes produces only hypochromia and microcytosis – alpha thal trait• African-Americans – 30 % lack 1 alpha gene. Frequently mistaken for Fe deficiency.• No increase in HbA2
  20. 20. -THALASSAEMIA• Particularly common in South East Asia and the Far East. Also frequent in Africa and the Mediterranean but is rare in northern Europe.
  21. 21. -Thalassemia Syndromes• Normally four genes for -Globin, two on each of chromosome 16. – +; One normal/one mutant on chromosome. – 0; Both mutant genes on one chromosome. (Mostly in Asians)• If two genes mutant, Thalassemia minor – Hemoglobin electrophoresis normal.• If three genes mutant; Hemoglobin H Disease – Hgb H; 4 Tetramer• If all four genes mutant; Hydrops Fetalis; – Hgb Barts; 4 Tetramer
  22. 22. Gene Deletions in Alpha Thalassemia
  23. 23. MOLECULAR CLASSIFICATION OF -THAL• Gene mapping allows deletions to be identified.• Loss of 1 of 2 genes on a single chromosome (- α/) – α+ thal. haplotype.• Loss of both genes on a single chromosome (- -/) – α° thal. haplotype.
  24. 24. “Golf ball” appearance of Hb H ( 4) stained supravitally with brilliant cresyl blue (Reticulocyte Stain).
  25. 25. Alpha Thalassemia Hb Bart’s-Hydrops Fetalis• Fetus inherits 2 chromosomes 16, both lacking any alpha genes.• No HbF can be made.• Hb Bart’s – γ4 tetramer - high O2 affinity, hyperbolic oxyhemoglobin dissociation curve• Fetus suffers from anoxia, develops intrauterine congestive heart failure, total body edema.• Death in utero or shortly after delivery.
  26. 26. Hydrops Fetalis
  27. 27. -Thalassemia• Two types of mutant alleles;• 0; Absence of expression. Typically a mutation in coding region of gene (On chromosome 11)• +; reduced expression of globin gene. Typically promoter mutation.
  28. 28. β-Thalassaemia Geographic Distribution• Mediterranean area• Northern Italy• Greece• Algeria• Saudi Arabia• Southeast Asia
  29. 29. -Thalassemia SyndromesType Heterozygous Homozygous0 Thalassemia Minor; Thalassemia Major; Hgb A2 >3.5%, MCV Absent Hgb A <75 Hgb A + F = 100%+; Thalassemia Minor; Thalassemia Major or Hgb A2 >3.5%, MCV intermediate; <75 Hgb F; 70 - 80% Hgb A2; >3.5 - 5% (variable) Hgb A; 10 - 20%
  30. 30. Beta Thalassemia Major: Cooley’s Anemia• Beta thalassemia gene present on both chromosomes 11 (βº/βº, βº/β+, β+/β+)• Cooley’s Anemia – Homozygous βº/βº thalassemia• May not be the same mutation on both chromosomes 11• Complete or very severe absence of beta globin• Preserved expression and relative increase of HbF and A2, but insufficient to support life (ie. does not fully replace HbA)• Life-long severe transfusion-dependent anemia
  31. 31. Beta Thalassemia Major• Hypochromia• Microcytosis• Anisocytosis• Poikilocytosis• Nucleated RBC’s• Hepato-splenomegaly• Growth defects• Bone defects• Transfusion dependence
  32. 32. - vs. -Thalassemia• Since only the -chain is synthesized of the -class of globin chains, the ratio of Hgb. A, A2, and F is not altered in -Thalassemia.• In -Thalassemia, Hgb A2 ( 2 2 ) and HgB F ( 2 2) levels as % of total Hgb are increased due to selective loss of - globin.• Hemoglobin electrophoresis can distinguish between - and -Thalassemia. (best for quantitation by column chromatography).
  33. 33. DNA Analysis For Thalassemia• Reference Laboratories now have standard assays available to screen for common globin gene mutations or sequence full DNA.
  34. 34. Differentiation of Microcytic Anemia• Iron deficiency vs. Thalassemia• In iron deficiency, red cell number, Hemoglobin, and MCV are all proportionally reduced.• In Thalassemia, the MCV is disproportionately low, and red cell number is “spared.”
  35. 35. Prevention Of Cooley’s Anemia Prenatal Diagnosis And Genetic Counseling• Cyprus: Thalassemia first identified in 1944• 1970 – prediction that in 40 years 78000 units/yr would be needed to treat all affected children• 40% of population would need to be donors• Total cost of transfusions would exceed health budget• Prevention program yielded 90% reduction in thalassemia births
  36. 36. Reduction In β-Thalassemia Births In Sardinia After Prenatal Screening
  37. 37. DELTA-BETA THALASSAEMIAS• Deletions of δ and β genes (δβ- thalassaemia).• Hb A2 is normal and Hb F is unusually high in the heterozygote. Hb A and Hb A2 are absent in the homozygote.
  38. 38. Hemoglobinopathies That Mimic Thalassemia
  39. 39. Hemoglobin Constant Spring• A mutation in the alpha globin gene produces an product that is abnormally long, (Loss of normal stop codon.• The messenger RNA for hemoglobin Constant Spring is unstable, reduced peptide translation.• The Constant Spring alpha chain protein is itself unstable.• The result is a thalassemic phenotype.• Distinct “slow moving hemoglobin” on electrophoresis.
  40. 40. Hemoglobin Lepore • Uneven cross-over of genes for beta and delta chains. • Results in decreased production of Lepore. • “no phenotypic evidence of thalassemia in persons with hemoglobin anti-Lepore, because no beta chain deficiency accompanies the latter condition.”
  41. 41. Treatment Of Transfusion- Dependent Thalassemia• Transfuse 3-4 units blood every 3-4 weeks• Maintain hemoglobin at 11-12 g/dL• Iron chelation – daily s.c. infusions of Desferal via syringe pump over 6-8 hrs• Oral chelating agents in development• Exjade – has recent FDA approval for oral administration