Thalassemia

Thalassemia
Specialty	Hematology

Thalassemia (American English) (or Thalassaemia in British English) is an inherited disease of the red blood cells, classified as a hemoglobinopathy. The genetic defect results in synthesis of an abnormal hemoglobin molecule. The blood cells are vulnerable to mechanical injury and die easily. To survive, many people with thalassaemia need blood transfusions at regular intervals.

The disease's geographical association with the Mediterranean sea was responsible for its naming: Thalassa is Greek for the sea. Thalassemia occurs in all populations and ethnic groups, however the prevalence differs among different populations.

Classification

The thalassemias are classified according to which chain of the globin molecule is affected: in α thalassemia, the production of α globin is deficient, while in β thalassemia the production of β globin is defective. Thalassemia produces a deficiency of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.

Prevalence

The estimated prevalence is 16% in people from Cyprus, 3-14 % in Thailand, and 3-8 % in populations from India, Pakistan, Bangla Desh, and China. A lower prevalence has been reproted from black people in Africa (0.9%) and northern Europe (0.1%).(4)

Alpha (α) thalassemias

The alpha thalassemias involve the genes HBA1 (Online Mendelian Inheritance in Man (OMIM): 141800) and HBA2 (Online Mendelian Inheritance in Man (OMIM): 141850), inherited in an autosomal co-dominant fashion. α thalassemias result in excess β chain production in adults and excess γ chains in newborns. The excess β chains form unstable tetramers that have abnormal oxygen dissociation curves.

There are four genetic loci for α globin. The more of these loci that are deleted or affected by mutation, the more severe will be the manifestations of the disease:

• If all four loci are affected, the fetus cannot live once outside the uterus: most such infants are dead at birth with hydrops fetalis, and those who are born alive die shortly after birth. They are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts). Usually, this involves homozygous inheritance of an alpha thalassemia trait, type 1.

• If three loci are affected, Hemoglobin H disease results. Two unstable hemoglobins are present in the blood, both hemoglobin Barts and hemoglobin H (tetrameric β chains). There is a microcytic hypochromic anemia with target cells and Heinz bodies on the peripheral blood smear. The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted. This is usually due to compound heterozygous inheritance of alpha thalassemia type 1 and type 2 traits.

• If two of the four α loci are affected, alpha thalassemia trait, type 1 results. Two α loci permit nearly normal erythropoiesis, though there is a mild microcytic hypochromic anemia. There is a high prevalence (about 30%) of deletion of one of the two α loci on chromosomes of people of recent African origin, and so the inheritance of two such chromosomes is not uncommon. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron. Two modes of alpha thalassemia trait, type 1 has been noted. One involves cis deletion of two alpha loci on the same chromosome; another involves trans deletion of allelelic genes on homologous chromosomes (no. 16).

• If one of the four α loci is affected, alpha minor or alpha+ thalassemia trait or alpha thalassemia trait, type 2 results and there is minimal effect. Three α-globin loci are enough to permit normal hemoglobin production, and there is no anemia or hypochromia in these people. They have been called α thalassemia carriers.

Beta (β) thalassemias

Beta thalassemia is due to mutations in the HBB gene on chromosome 11 (Online Mendelian Inheritance in Man (OMIM): 141900), also inherited in an autosomal co-dominant fashion. In β thalassemia, excess α chains are produced, but these do not form tetramers: rather, they bind to the red blood cell membranes producing membrane damage, and at high concentrations have the tendency to form toxic aggregates. The severity of the damage depends on the nature of the mutation. Some mutations (β^o) prevent any formation of β chains; others (β⁺) allow some β chain formation to occur. Recently, increasing reports suggest that upto 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and use of hydroxyurea also has a tendency to increase the production of HbF, by as yet unexplained mechanisms.

There are two β globin genes:

• If both have thalassemia mutations, a severe microcytic, hypochromic anemia called β thalassemia major or Cooley's anemia results. Untreated, this results in death before age twenty: treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation.

• If only one β globin gene bears a mutation, β thalassemia minor results (sometimes referred to as β thalassemia trait). This is a mild anemia with microcytosis. Symptoms include weakness and fatigue - in most cases β thalassemia minor may be asymptomatic and many people may be unaware they have this disorder. Detection usually involves counting the mean corpuscular volume (size of red blood cells) and noticing a slightly decreased mean volume than normal.

• Thallassemia intermedia is a condition intermediate between the major and minor forms. Sufferers can often manage a normal life but may need occasional transfusions e.g. at times of illness or pregnancy. This really depends on the severity of their anemia.

The actual genetic cause of β thalassemias are actually very diverse and a number of different mutations can cause reduced or absent β globin synthesis. Usually, superscripts 0 and + are added to β to indicate complete absence, and deficient synthesis of β globins respectively.

Mainly there are two forms of genetic defects which produce β thalaseemias:

• Nondeletion forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most commonly, mutations occur in the promotor regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.

• Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (β^o) or hereditary presistance of fetal hemoglobin syndromes.

Delta (δ) thalassemia

As well as alpha and beta chains being present in Hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. The gene for delta chains is very close to the gene for beta hemoglobin and damage to this gene can also effect the beta chain gene, thus delta thalassemia is usually very similar in effect to Beta thalassemia.

In combination with other hemoglobinopathies

Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

• hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to β thalassemia major or thalassemia intermedia.
• hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly
• hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/β^o thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β⁺ thalassemia produces a milder disease.

Treatment and complications

Anyone with thalassemia should consult a properly qualified hematologist.

Thalassemias may co-exist with other deficiencies such as folic acid (or folate, a B-complex vitamin) and iron deficiency (only in Thalassemia Minor).

Thalassemia Major and Intermedia

Thalassemia Major patients receive frequent blood transfusions that lead to iron overload. Iron chelation treatment is necessary to prevent iron overload damage to the internal organs in patients with Thalassemia Major. Because of recent advances in iron chelation treatments, patients with Thalassemia Major can live long lives if they have access to proper treatment. Popular chelators include deferoxamine and deferiprone. Of the two, deferoxamine is preferred; it is associated with fewer side-effects.[1]

The most common complaint by patients is that it is difficult to comply with the intravenous chelation treatments because they are painful and inconvenient. The oral chelator Exjade was recently approved for use in some countries and may offer some hope with compliance.

Untreated thalassemia Major eventually leads to death usually by heart failure, therefore birth screening is very important.

In recent years, bone marrow transplant has shown promise with some patients of thalassemia major. Successful transplant can eliminate the patients dependencies in transfusions.

All Thalassemia patients are prone to health complications that involve the spleen (which is often enlarged and frequently removed) and gall stones. These complications are mostly prevalent to thalassemia Major and Intermedia patients.

Thalassemia Intermedia patients vary a lot in their treatment needs depending on the severity of their anemia.

Thalassemia Minor

Contrary to popular belief, Thalassemia Minor patients should not avoid iron-rich foods by default. A serum ferritin test can determine what their iron levels are and guide them to further treatment if necessary. Thalassemia Minor, although not life threatening on its own, can affect quality of life due to the effects of a mild to moderate anemia. Studies have shown that thalassemia Minor often coexists with other diseases such as asthma [2], and even bipolar disorder [3].

Thalassemia prevention and management

Autosomal recessive inheritance

α and β thalassemia are often inherited in an autosomal recessive fashion although this is not always the case. Reports of dominantly inherited α and β thalassemias have been reported the first of which was in an Irish family who had a two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait.

There an estimated 60-80 million people in the world who carry the beta thalassemia trait alone. This is a very rough estimate and the actual number of thalassemia Major patients is unknown due to the prevalance of thalassemia in less developed countries in the Middle East and Asia. Countries such as India, Pakistan and Iran are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening. There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the world's blood bank supplies and the health system in general. There is an estimated 1,000 people living with thalassemia Major in the United States and an unknown number of carriers. Because of the rarity of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.

As with other genetically acquired disorders, aggressive birth screening and genetic counseling is recommended for prevention of a world crisis.

A screening policy exists on both sides of the island of Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero.

Benefits

Being a carrier of the disease may confer a degree of protection against malaria, and is quite common among people from Italian or Greek origin, probably because malaria was widespread in those countries many centuries ago. In that respect it resembles another genetic disorder, sickle-cell disease.

References

1. Maggio A, D'Amico G, et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis. 2002 Mar-Apr;28(2):196-208. PMID 12064916.

2. Palma-Carlos AG, Palma-Carlos ML, Costa AC. "Minor" hemoglobinopathies: a risk factor for asthma. Allerg Immunol (Paris). 2005 May;37(5):177-82.

3. Bernard B. Brodie. Heterozygous β-thalassaemia as a susceptibility factor in mood disorders: excessive prevalence in bipolar patients. Clinical Practice and Epidemiology in Mental Health 2005, 1:6 doi:10.1186/1745-0179-1-6

4. Leung NT, Lau TK, Chung TKH. "Thalassemia screening in pregnancy". Curr Opinion in Ob Gyn 2005, 17:129-34.

External links

• Overview of thalassemia biomedically
• Thalassemia Minor

{{Diseases of RBCs and megakaryocytes}} may refer to:

• {{Diseases of RBCs}}, a navigational template for diseases of red blood cells
• {{Diseases of megakaryocytes}}, a navigational template for diseases of clotting