Thalassemia is a major cause of microcytic anemia, due to an imbalance in the production of alpha or beta globin. α-Thalassemia results from deficiency of α-chains. β-Thalassemia results from deficiency of β-chains. The treatment, if required, is with blood transfusion.

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Image: “Peripheral Blood film from a patient with Delta Beta Thalassemia.” by Prof. Osaro Erhabor. License: CC BY-SA 4.0

Image: “Peripheral Blood film from a patient with Delta Beta Thalassemia.” by Prof. Osaro Erhabor. License: CC BY-SA 4.0


Definition of Thalassemia

Thalassemia is a microcytic-hypochromic anemia. Its cause is a decreased synthesis of one or several globin chains. Since this globin synthesis is flawed, the disease is one of the so-called hemoglobinopathies. Depending on which globin chain is affected by the disorder, one speaks off ß- or α-thalassemia.

Thalassemias are caused by gene mutations leading to decreased production of globin protein. Deletions of α-globin genes cause α-thalassemia. There are two α-globin genes closely linked on chromosome 16. It is a total of 4 alleles.

thalassemia

Epidemiology of Thalassemia

Since thalassemia more frequently occurs in the Mediterranean area including Turkey, it is also referred to as ‘Mediterranean anemia’. However, it can be found worldwide. It is estimated that ca. 3% of the world population carry at least one ß-thalassemia-gene. In Germany, the most frequent form is heterozygous ß-thalassemia.

Etiology of Thalassemia

Thalassemia is inherited autosomal-codominantly. At heterozygosity, a milder form of the disease develops (minor thalassemia). At homozygosity, the severe form (major thalassemia) can be observed. Also, the so-called intermediate thalassemia exists as an intermediate form. The primary causes are genetic defects, which form the pathogenetic basis of the decreased synthesis of one of several polypeptide chains of the globin molecule.

In turn, this results in a decreased hemoglobinization of the erythroblasts. In the blood count, this condition can be observed as hypochromasia of the erythrocytes. Additionally, the globin chains which continue being produced aggregate and make for increased apoptosis of precursor cells via different pathophysiological mechanisms. Also, the erythrocytes in the peripheral blood have a decreased lifespan.

α-Thalassemia

thalassemia_alpha

The picture shows one example of how alpha thalassemia is inherited. The alpha globin genes are located on chromosome 16. A child inherits four alpha globin genes (two from each parent). In this example, the father is missing two alpha globin genes and the mother is missing one alpha globin gene. Each child has a 25 percent chance of inheriting two missing genes and two normal genes (thalassemia trait), three missing genes and one normal gene (hemoglobin H disease), four normal genes (no anemia), or one missing gene and three normal genes (silent carrier).

The characteristics and severity of the disease depend on the number of genes deleted:

Disease Genotype Clinical Manifestations
Silent Carrier -α/αα Asymptomatic
α-Thalassemia Trait –/αα

-α/-α

Asymptomatic, with mild anemia
HgH Disease –/-α Inermediate to severe chronic anemia
Hydrops Fetails –/– Pre- or neonatal lethal

Hemoglobin Electrophoresis

hemoglobin-electrophoresisNewborns: splenic macrophages phagocytose and destroy RBCs with HbF and replace with HbA and HbA2; takes a few months.

thalassemia2

Anemia, but no change in % of Hb A, A2, or F (all of them need α-globin chains for their synthesis).

β-Thalassemia

thalassemia_beta

The picture shows one example of how beta thalassemia is inherited. The beta globin gene is located on chromosome 11. A child inherits two beta globin genes (one from each parent). In this example, each parent has one altered beta globin gene. Each child has a 25 percent chance of inheriting two normal genes (no anemia), a 50 percent chance of inheriting one altered gene and one normal gene (beta thalassemia trait), or a 25 percent chance of inheriting two altered genes (beta thalassemia major).

splicing-patternThere is only one β-globin gene on chromosome 11, total of 2 alleles. β-Thalassemia is primarily caused by splicing mutations in β-globin genes.

There are two types of mutations in the β-globin gene: 

  • β+ mutations – variable decreased expression
  • β0 mutations – absent expression

This results in three different clinical syndromes:

Syndrome Genotype Clinical Features
Thalassemia minor β0/β or β+ Asymptomatic; mild anemia
Thalassemia intermedia β0/β or β++ Variable moderate anemia, requiring occasional transfusion
Thalassemia major a.k.a. Cooley´s anemia β00 or β++ Severe, transfusion-dependent anemia

Clinic of Thalassemia

Depending on the genetic defect, thalassemia shows a variable clinical picture.

Minor thalassemia usually does not show severe symptoms. Slight hepatosplenomegaly and possibly a recurrent jaundice in a mild form can be present. Also, target cells can be observed in the blood count.

Target-Cells

Image: “Target-Cells” by Osaretin. License: CC BY-SA 4.0

In its more distinct form, that is major thalassemia, thalassemia can lead to bone deformations, and even fractures, due to the reactive expansion of erythropoiesis in the bone marrow. Because of the decreased and often pathological erythrocytes, hypoxia becomes clinically relevant, as growth disturbances and trophic skin changes in child age show.

α-Thalassemia

There are two consequences of decreased α-globin production:

  • Decreased hemoglobin synthesis, causing microcytic, hypochromic anemia
  • Quantitative imbalance between α- and β-globin proteins resulting in the formation of insoluble β-globin (HbH) or γ-globin (Hb Barts) aggregates in the RBC. These RBCs are often cleared in the spleen and liver, worsening the anemia.

It is most common in the patients of Southern Asian (–allele) and African (-α allele) descent.

alpha-thalassemia

α-Globin chain gene deletions
2 deletions (trait)
3deletions (HbH; 4 β chains)
4 deletions (Hb Bart´s; 4 γ chains)

HbH disease

  • Signs and symptoms of anemia
  • Chronic hemolysis with variable jaundice and cholelithiasis (bilirubin stones)
  • Extramedullary hematopoiesis with frontal bossing and hepatosplenomegaly

Hydrops fetalis

  • Anasarca (generalized edema) from high-output heart failure
  • Hepatosplenomegaly
  • Causes death in the prenatal period

β-Thalassemia

Similar to α-Thalassemia.

  • AR disorder; Africans; Italian, Greeks
  • → RBC count: splicing defect for minor; nonsense mutation for major (stop codon)

β = normal
β+ = some
β0 = none

beta-thal-minor Microcytic 

β/β+

β-Thal minor

Note that HbA is decreased, because β-globin chain synthesis is decreased. There is a corresponding increase in HbA2 and HbF.

beta-thal-major Microcytic 

β/β0

β-Thal major

Note that there is no synthesis of HbA.

β-Thalassemia major (Cooley´s anemia)

Laboratory findings:

  • Decreased Hgb, Hct, and MCV
  • Variable RBC count
  • Hemoglobin electrophoresis varies depending on the severity of the disease with decreased HbA, increased HbF (α2γ2), and increased HbA22δ2)

It causes severe transfusion dependant anemia that develops at a few months of age (as HbF declines). Id adequately transfused, children will develop normally, but will develop secondary hemochromatosis and die of heart disease in their 20s. If not transfused, there is a stunted growth, bony changes, and high-output heart failure with death in infancy.

Diagnosis of Thalassemia

The blood count of minor thalassemia shows microcytic, hypochromic erythrocytes. Since this is also the case with iron deficiency and this condition is more frequent in practice, one should consider minor thalassemia when confronted with a non-confirmed iron deficiency anemia. A blood smear with target cells and poikilocytosis provides additional certainty.

  • Laboratory studies: decreased Hgb, Hct, MCV; increased RBC count, RDW; HbH on hemoglobin electrophoresis; iron studies normal

At major thalassemia and intermediate thalassemia, hypochromasia and poikilocytosis are more distinct. Reticulocytes, LDH and bilirubin are increased; haptoglobin is decreased.

Further criteria confirming the suspicion are a positive family history, disturbed hemoglobinization in bone marrow aspirate, and genome analysis.

Therapy of Thalassemia

The ideal therapy is allogenic stem cell transplantation. Since the minor form does usually not require treatment, this primarily applies to major thalassemia.

Course and Prognosis of Thalassemia

If the anemia is not treated adequately, there is a massive expansion of haemopoiesis within the bone marrow. This can lead to a “hair on end” appearance on skull X-ray. If regular transfusions are given, iron chelation must be started.

While minor thalassemia and intermediate thalassemia mostly progress without complications, major thalassemia leads to death at infant age without treatment. Another life-shortening factor is increased iron residue in the organism (hemosiderosis). This is why therapeutic iron substitution of any kind is contraindicated.

Note: Thalassemia is a microcytic-hypochromic anemia. Its cause is a genetically based decreased synthesis of one or several globin chains. One distinguishes 3 forms: minor thalassemia, major thalassemia and intermediate thalassemia. In blood smear, target cells can be seen. Concerning differential diagnoses, thalassemia must not be confused with iron deficiency anemia since iron substitution in the case of thalassemia falsely diagnosed as iron deficiency anemia leads to increased hemosiderosis.
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