1. Diseases affecting the structure, function or production of Hb.
Hemoglobinopathies
Diseases affecting the structure, function or production of Hb.

2. Types 1- Structural Hemoglobinopathies
A- Abnormal Hb polymerization --- Sickle cell anemia
B- Altered O2 affinity --- High affinity – polycythemia
--- Low affinity – Cyanosis, pseudo anemia
C- Hb that oxidize readily
--- Unstable Hb (HA, jaundice)
--- MetHb (cyanosis)

3. 2- Thalassemia (defective biosynthesis of globin chains)
A- α-thalassemia
B- β-thalassemia
C- δβ, γδβ, αβ thalassemias

4. 3- Thalassemic Hb variants
(structurally abnormal Hb associated with co-inherited thalassemic phenotype)
A- Hb-E
B- Hb - Constant spring
C- Hb- Lepore

5. 4- Hereditary persistence of fetal Hb (HPHF)
(Hb F in adults)

6. 5- Acquired Hemoglobinopathies
A- Met-Hb due to toxic exposure.
B- Sulf-Hb due to toxic exposure.
C- CarboxyHb due to CO.
D- Hb-H in erythroleukemia.
E- Elevated Hb-F in states of erythroid stress & BM dysplasia.

7. Thalassemia
This is an inherited disorder of α or β globin chain biosynthesis.
Causes reduced production of Hb tetramers causing hypochromia &microcytosis. The latter is leading to ineffective erythropoiesis & hemolytic anemia.
Normal Hb consists of 2α and 2β chains.
Two clusters of genes encode for globin synthesis (β genes on chromosome 11 & α genes on chromosome 16).
An unbalanced accumulation of α or β chains results

8. α- Thalassemia
Decreased α-chain production relative to β-chain production forming β4 (Hb-H inclusion bodies).
RBCs bearing inclusion bodies are rapidly removed from the circulation by RES cells thus shortening RBC survival.

9. S & S
Deletion of 1 gene (-α/αα) & 2 genes (-/αα; -α/-α) are virtually asymptomatic.
Deletion of 3 genes (--/-α) producing Hb H disease (Hb Barts).
Moderate hypochromic microcytic anemia & splenomegaly.
Hb= 8-10 g/dL, special stain shows Hb H inclusions.
Hb electrophoresis shows Hb H. Hb H tends to precipitate during oxidative stress & under increased temperature as in infections causing hemolysis.

10. Deletion of 4 genes (--/--) is the most severe form that is incompatible with life leading to intrauterine death of the fetus (hydrops fetalis).

11. β- Thalassemia
Decrease in β-chain production relative to α-chain production.
Common in Mediterranean, Asian & African populations (areas endemic with malaria).
Trait --- asymptomatic.
Clinical anemia ---- is seen in homozygous or compound heterozygous e.g. β thalassemia/Hb E.

12. Reduced β globin chain synthesis leads to accumulation of free α globin chains that precipitate in early erythroblast development since they are insoluble.
These lead to ineffective erythropoiesis in BM & enhanced destruction in circulation.

13. Anemia, splenomegaly ± hypersplenism, osteoporosis, skeletal & soft tissue changes due to BM expansion, iron overload ( ↑GIT absorption & blood transfusion) deposit in liver, heart, pancreas, pituitary & other endocrine organs.

14. Lab. Dx Microcytic hypochromic anemia, MCV ↓.
Hb- electrophoresis --- Hb A2 ↑ > 4-6%, Hb F ↑ 5-20%.
PCR, DNA probes.
Antenatal Dx --- Amniotic fluid analysis & chorionic villous sampling.

15. ℞
α-thalassemia gene or 2 genes deletion may be asymptomatic and require no treatment.
Hb H disease- Folic acid 1mg/day orally
Splenectomy for progressive anemia.

16. β thalassemia
Improved outcome recently due to the use of aggressive blood transfusion support & effective iron chelation therapy.
The only curative ttt by BM transplantation.

17. Blood transfusion
– non-transfused pt survives only 2 y in homozygous state.
-- Aim to maintain Hb at 11-13g/dL
-- Pre-transfusion level>10g/dL
-- extend life to 2nd decade, minimize bony abnormalities, and improve sexual development.
-- Leukocyte-poor RBCs given to minimize allosenstization & not to prejudice future BMT.
-- HB vaccine given for pt with –ve Ab test

18. Splenectomy
if transfusion requirement > 1.5 normal (>200ml/kg/year)
-- preceded by polyvalent pneumococcal vaccine (pediatric pt also given H influenza & N meningitides vaccine)

19. Iron chelation --- if not given pts will die of iron overload.
--- Subcutaneous desferrioxamine g/d
--- Oral defroperone, deferasirox
--- S.C desferral h infusion 5-6x/w --- S/E visual disturbances, tinnitus, azotemia, proteinuria.
Annual ophth & audiol exam needed.

20. --- Periodic estimation of iron burden (S Fe, TIBC & S Ferritin)
--- Estimate of liver iron concentration
--- Annual cardiac evaluation to detect early dis
--- GTT, thyroid function test, cortisol determination
--- Hormone replacement therapy

21. Stem cell transplant
Allogeneic BMT for homozygous β thalassemia

22. Manipulation of globin chain gene expression with
5-azacytidine, hydroxyurea, erythropoietin,
butyrate analogues to stimulate Hb F synthesis by γ globin chain augmentation

23. Experimental ttt --- gene therapy * For β globin alleles
* Still investigational