We are going to discuss on another common type of hemolytic anemia which is thalassemia. Thalassemia is weirdly common at the the tropical place (especially place with malarial endemic) during the last few millenniums. Maybe, it has some kind of protective mechanism towards that infection. Ok, enough with malaria, now let us get down to business.
1) Thalassemia is heterogenous group of inherited disorders
2) Caused by mutations that decreased production of either alpha or beta chain
3) Leads to hemoglobin deficiency
4) With secondary red cells abnormalities due to the excessed unaffected globin chain
Thalassemia is further divided into 2 types which are Alpha Thalassemia and Beta Thalassemia even though both manifested same clinical symptoms.
So let us discuss on the subtypes Thalassemia individually.
Beta Thalassemia (Chromosome 11)
Let us again do some simple recap on Molecular Medicine.
1) Let us concentrate on the HBA1, since its the most prominent one. It consists of:
+ 2 alpha globins
– Encoded by 2 loci at chromosome 16
+ 2 beta globins
– Encoded by a single loci at chromosome 11
2) 2 categories of beta gene mutation
- No Beta chain production – B0
- Reduced Bata chain production but still detectable – B+
3) Let me try to simplify the molecular basis of beta thalassemia ( B only indicates normal Beta gene)
- B0/B0 or B+/B+ (Homozygous) – Major Beta Thalassemia
- B+/B0 (Compound Heterozygous) – Intermediate Beta Thalassemia
- B+/B or B0/B (Heterozygous) – Thalassemia trait
4) Both major and intermediate thalassemias manifest severe clinical symptom and only major thalassemia needs regular blood transfusion. Meanwhile, beta thalassemia trait doesn’t elicit any major clinical and most of the time its rather asymptomatic.
5) So what happens in both mutants? Let me try to simplify it then :-
- B+ – The mutant lies at the promoter region which leads to the reduction in beta chain synthesis
- B0 – There is either gene deletion (frameshift mutation) or single nucleotide substitution (point mutation) which leads to STOP codon. Stop codon automatically terminates beta chain synthesis.
Alpha thalassemia (chromosome 16)
a) –/– – Hydrops fetalis; fatal in utero
b) –/-a – moderately severe
c) –/aa – alpha thalassemia trait
d) –a/aa – silent carrier, asymptomatic
Alpha thalassemia is due to gene deletion, which eventually leads to complete termination of any 2 loci of the alpha gene.
Above is the molecular pathogenesis, below we will talk grossly about the pathogenesis and clinical course of beta thalassemia. But you just have to be clear that alpha thalassemia is having pretty much the same pathogenesis, clinical course and morphology like beta thalassemia. So, just replace what is beta to alpha in the below explanation, as simple as that.
We already agreed that beta thalassemia is having reduced production of beta chain. Therefore, there must be an increased concentration of alpha hemoglobin with regard to the reduced beta chain. Alpha globin is not soluble without the presence of beta globin, thus it will form precipitate.
Aggregation of alpha globin is then detected by the splenic macrophage of the spleen and Kupffer cells of the liver as abnormalities. These cells will then engulf the red cells, and lead to extravascular hemolysis. Due to the increased hemolysis, body tries to compensate the lost by increasing the rate of erythropoeisis. Constant increased in erythropoeisis will lead to erythroid tissue hyperplasia.
Hyperplasia of the erythroid tissue (bone marrow expansion) will somehow depress the bone structure and lead to bone deformity. But toward some extent, the expansion is stop and then erythropoeisis starts to happen outside the red marrow (extramedullary erythropoeisis). Extramedullary erythropoeisis usually happens at the reticuloendothelial system in which liver and the spleen are the main targets.
As we discussed, hemolysis happened at the liver and spleen will increase the production of hemolysis by products which are bilirubin and iron. Bilirubin level in serum will increase (hyperbilirubinemia) which will eventually lead to jaundice (prominently seen at the sclera).
Iron also starts to accumulate, but at this point it doesn’t lead to any tissue damage (hemosiderosis). Somehow, beta thalassemia major patient needs a regular blood transfusion. This procedure exacerbates the condition as blood tranfusion contains high iron. Further accumulation of iron the body will cause excessive tissue damage (hemochromatosis). The most severely affected organs due to iron overload are heart and pancreas.
Now, liver and spleen are doing extra works, so it needs to increase its workload. Liver and spleen start to enlarge (hepatosplenomegaly). Eventually, the liver and the spleen will fail.
- Reduced MCHC (Mean Cell Hemoglobin Concentration). Please refer previous post (Basic Pathology of Anemias) for better understanding.
- Hypochromic (pale) and microcytic (small in size)
- Marked poikilocytosis (abnormal shape of RBCs) and anisocytosis (unequal in size of RBCs. But overall, all RBCs are smaller in size compared to normal ones)
- Increased number of reticulocytes at the peripheral blood (reticulocytosis) due to increase erythropoeisis
- Skeletal deformity due to red marrow expansion
- Severe hemosiderosis and hemochromatosis due to iron overload
Thats all for Thalassemia. Thanks! =)