Hemoglobinopathies

Diseases affecting the structure, function or

production of Hb.

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)

2 -Thalassemia)defective biosynthesis of globin chains (

A- α-thalassemia

B- β-thalassemia

C- δβ, γδβ, αβ thalassemias

3 -Thalassemic Hb variants )structurally abnormal Hb associated with co-

inherited thalassemic phenotype (

A- Hb-E

B- Hb - Constant spring

C- Hb- Lepore

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

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.

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

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.

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.

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

fetalis).

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.

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.

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.

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.

℞

α-thalassemia ---- 1 gene or 2 genes deletion may be asymptomatic and

require no treatment .

Hb H disease- Folic acid 1mg/day orally

Splenectomy for progressive anemia.

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.

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

Splenectomy if transfusion requirement > 1.5 normal (>200ml/kg/year)

-- preceded by polyvalent pneumococcal vaccine (pediatric pt also given H influenza & N meningitides vaccine)

Iron chelation ---if not given pts will die of iron overload .

--- Subcutaneous desferrioxamine 1.5-2.5 g/d

--- Oral defroperone, deferasirox

--- S.C desferral 12-24 h infusion 5-6x/w --- S/E visual disturbances, tinnitus, azotemia,

proteinuria .

Annual ophth & audiol exam needed.

---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

Stem cell transplant

Allogeneic BMT for homozygous β thalassemia

Manipulation of globin chain gene expression with

5-azacytidine, hydroxyurea, erythropoietin ,

butyrate analogues to stimulate Hb F synthesis by γ globin chain augmentation

Experimental ttt

---gene therapy

* For β globin alleles

* Still investigational