Beta Thalassemia Major

Beta Thalassemia Major

Article
Kidney & Bladder Health
Diseases & Conditions
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Contributed byKrish Tangella MD, MBAJul 17, 2018

What are the other Names for this Condition? (Also known as/Synonyms)

  • Cooley’s Anemia
  • Thalassemia Major

What is Beta Thalassemia Major? (Definition/Background Information)

  • Beta Thalassemia Major (or Thalassemia Major) is a genetic disease affecting the production of components of hemoglobin (a protein that carries oxygen to the tissues)
  • A normal hemoglobin molecule consists of two identical alpha and two identical beta chains. The alpha and beta chains differ between each other
  • In Beta Thalassemia Major, there is very little production of the beta chains (beta thalassemia plus) or there is total absence of the beta chains (beta thalassemia zero). This is caused by mutation in the chromosome 11. In Thalassemia Major, both copies of the genes involved in beta chain production are affected
  • Beta Thalassemia Major causes severe transfusion-dependent anemia. The severe imbalance of globin chain synthesis (alpha >> beta) results in ineffective erythropoiesis (formation of red blood cells) and severe microcytic hypochromic anemia (resulting in the ineffective formation of pale and small red cells). The excess alpha chains clump together inside the RBCs (Red Blood Cells) and form precipitates, which affects the red cell membrane, causing destruction of RBCs in the blood vessels
  • Manifestation of the disease occurs after 6 months in a newborn child, because until the first 6 months, the type of hemoglobin predominantly present in the child is the ‘fetal hemoglobin’
  • Fetal hemoglobin has two alpha chains and two gamma chains. Once the child completes 6 months, the fetal hemoglobin decreases in quantity and the ‘adult’ hemoglobin containing the beta protein chains begins to increase. This is the reason why Beta Thalassemia is difficult to be diagnosed before the age of 6 months

Who gets Beta Thalassemia Major? (Age and Sex Distribution)

  • Beta Thalassemia Major occurs in individuals with a defective production of beta protein of hemoglobin. The disease is identified at about 6 months of life
  • Both male and female sexes are equally affected; there is no sexual predilection
  • This disorder is more prevalent among populations of the African, Mediterranean, and South East Asian countries

Note: The prevalence of Beta Thalassemia Major in these populations seems to be adaptive association to endemic malaria. It has been found that individuals with Beta Thalassemia Major have an inherent ability to defend better against malarial infections. As a result, in areas where malaria is prevalent, these individuals have a better chance of survival. Due to this survival advantage, the proportion of population with individuals affected by Thalassemia Major increased in areas where malaria is very common. Superior detection methods and treatment for malaria has decreased the survival advantage of such individuals in these endemic areas.

What are the Risk Factors for Beta Thalassemia Major? (Predisposing Factors)

Following are the risk factors for Beta Thalassemia Major:

  • People belonging to the African, Mediterranean and Asian races
  • Family history of Thalassemia

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Beta Thalassemia Major? (Etiology)

Beta Thalassemia Major is caused by genetic mutation of the beta-globin gene on chromosome 11 and both copies of the gene are affected. The clinical manifestation and disease severity varies with certain other factors (mentioned below), even though the mutation in the beta-globin gene is common in all affected patients:

  • Effect of fetal hemoglobin: Children with high concentration of fetal hemoglobin have a less severe form of the disorder. This is because fetal hemoglobin does not have beta chains in the hemoglobin
  • Co-existing alpha thalassemia: Individuals with co-existing alpha thalassemia have a less severe disease, due to lesser alpha-beta chain imbalance. This results in lesser freely floating alpha chains in the red blood cells, causing less damage to them
  • Co-existing sickle cell trait: Individuals with co-existing sickle cell trait have a severe disease, due to severe hemolysis. This is because both thalassemia and sickle cell disease/trait cause combined damage to the red blood cells, though acting through different mechanisms

What are the Signs and Symptoms of Beta Thalassemia Major?

The signs and symptoms in individuals with Beta Thalassemia Major are related to severe anemia, ineffective red blood cells formation (erythropoiesis), extra-medullary hematopoiesis (formation of RBCs in locations other than the bone marrow), and iron overload due to blood transfusions, and increased absorption of iron.

The signs and symptoms of Beta Thalassemia Major include:

  • Pallor (pale skin color) and anemia
  • Jaundice due to RBC destruction
  • Deformity of the skull and other bones, due to compensatory expansion of the bone marrow
  • Skin ulceration on the extremities
  • Cardiac failure and arrhythmias, due to either anemia or excess iron overload from repeated blood transfusions
  • Liver enlargement due to extra-medullary hematopoiesis, or hepatitis from iron overload
  • Splenomegaly, either due to extra-medullary hematopoiesis or extravascular hemolysis
  • Pigmented gall stones due to lifelong hemolytic state, resulting in potential gall bladder problems
  • Iron overload can also cause endocrine dysfunction; especially affecting the pancreas, testes, and thyroid glands
  • Increased need for blood transfusion occurs during a severe anemic state. Blood transfusions increase the risk of viral hepatitis. Thus, transfusion-associated viral hepatitis resulting in cirrhosis or portal hypertension may be also seen

How is Beta Thalassemia Major Diagnosed?

The following diagnostic studies are used to detect Beta Thalassemia Major genetic disorder:

  • Hemoglobin electrophoresis showing increased HbA2 and complete absence of normal adult hemoglobin HbA
  • Iron studies (serum iron, ferritin, total iron binding capacity) are used to rule out iron-deficiency anemia
  • Imaging studies are used to confirm skull and other bone deformities. Typical ‘hair-on-end’ appearance can be observed in skull x-ray, due to bone marrow expansion
  • Bone marrow examinations are undertaken to rule out other causes of microcytic anemia
  • The above shall be correlated with physical examination and thorough family medical history evaluation
  • Prenatal diagnosis is possible through analysis of DNA obtained via chorionic villi (placental tissue) sampling at 8-10 weeks gestation, or by amniocentesis (amniotic fluid analysis) between the 14th -20th week gestation period

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Beta Thalassemia Major?

The complications associated with Beta Thalassemia Major include:

  • Extra-medullary hematopoiesis resulting in large spleen and liver conditions
  • As the spleen gets bigger, the chances of its rupture increase. Hence, occasionally the spleen is removed. The medical term in an individual with no spleen, or when the spleen is removed, is known as asplenia. There is an increased risk for infections resulting from asplenia, such as increased infections with encapsulated organisms like pneumococcus
  • Individuals suffering from iron overload condition are greater prone to certain types of infections, such as those caused by the yersinia species bacteria
  • Medical complications from long-term transfusional therapy; iron overload and transfusion-associated infections (such as hepatitis)
  • Pigmented gall stones are formed due to lifelong hemolytic state, resulting in potential gall bladder problems. There is a formation of specific type of gall stones (or cholelithiasis) called bilirubin stones

How is Beta Thalassemia Major Treated?

The treatment methods for Beta Thalassemia Major may include:

  • Chronic transfusion therapy in order to maintain the hemoglobin level at 9-10 g/dl. This can also help suppress RBC formation in the marrow, thus preventing any bony deformities
  • Iron chelation therapy is used to absorb excessive iron from the body
  • As the spleen gets bigger, there is a higher chance of its rupture. Hence, in some cases, the spleen is removed (termed splenectomy)
  • In severe cases, bone marrow transplantations are performed

When the bone marrow is procured from a bone marrow donor, it is called allogeneic hematopoietic transplantation (bone marrow transplantation). This results in a very high and long-term survival rate in patients with favorable characteristics, such as young age, less HLA mismatch, and no organ dysfunction.

How can Beta Thalassemia Major be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Beta Thalassemia Major genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Thalassemia Major is a rare genetic disorder and it cannot be prevented. However, the incidence in children can be decreased through genetic and premarital counseling:

  • Mass screening of high risk communities for Thalassemia Major (patients with only one beta gene mutation)
  • Population education
  • Prenatal diagnosis

What is the Prognosis of Beta Thalassemia Major? (Outcomes/Resolutions)

  • The prognosis of patients with Beta Thalassemia Major is highly dependent on the patient's adherence to long-term treatment, such as chronic blood transfusions and life-long iron chelation
  • Allogeneic bone marrow transplantation may be curative
  • Major morbidities are caused due to anemia and iron overload
  • If complications arise, then the prognosis may not be favorable

Additional and Relevant Useful Information for Beta Thalassemia Major:

  • Beta Thalassemia Minor, a rare genetic blood disorder, is a defect in the synthesis of beta chains of hemoglobin
  • Beta Thalassemia Major is also known as Cooley’s Anemia, named after the American Pediatrician Thomas Cooley, who first identified this disease in 1925
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Krish Tangella MD, MBA

Pathology, Medical Editorial Board, DoveMed Team

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