Beta thalassemia

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Beta thalassemia
Classification and external resources
ICD-10 D56.1
ICD-9 282.44
OMIM 141900
DiseasesDB 3087 1373
eMedicine article/199534
MeSH D017086

Beta thalassemias (β thalassemias) are a group of inherited blood disorders caused by reduced or absent synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world.[1][dubious ] Individuals with beta thalassemia major usually present within the first two years of life with severe anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major.[2] Transmission is primarily autosomal recessive; however, dominant mutations have also been reported. Genetic counseling is recommended and prenatal diagnosis may be offered.[3]

The beta form of thalassemia is particularly prevalent among Mediterranean people and this geographical association is responsible for its naming: Thalassa (θάλασσα) is the Greek word for sea and Haema (αἷμα) is the Greek word for blood. In Europe, the highest concentrations of the disease are found in Greece,[citation needed] coastal regions in Turkey[citation needed] (particularly the Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya, Adana, Mersin), in parts of Italy, particularly Southern Italy[citation needed] and the lower Po valley.[citation needed] The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus (18%),[4] and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including people from West Asia and North Africa. Far from the Mediterranean, South Asians are also affected,[citation needed] with the region's highest concentration of carriers (16% of the population) being in the Maldives.[citation needed]

The thalassemia trait may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers (known as heterozygous advantage), thus perpetuating the mutation. In that respect, the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.[5] [6]


Beta thalassemia is a hereditary disease affecting the hemoglobin which makes red blood cells red. As with about half of all hereditary diseases,[7] the inherited DNA mutation causes errors in assembling the working gene or messenger-type RNA (mRNA) that is transcribed from a chromosome's long strand of DNA. DNA contains both the instructions (genes) for stringing amino acids together into the chains we call proteins, as well as stretches of DNA which do not code for proteins (noncoding DNA), but which may play important roles in regulating the level of working genes and proteins ultimately produced (see the expression of genes and gene translation into protein). Once there is a raw transcription of DNA into RNA, producing working mRNA for protein production requires stringing together the coding sections with the non-coding sections all spliced out. This is accomplished by another protein, the spliceosome, which selects more than one coding section (the exonic sections), and excises the interruption(s) in the gene, called the introns. The spliceosome then joins the selected pieces together. Ultimately the resultant mRNA can be put into production making hemoglobin components, by serving as the "programming input" to ribosomes.

In thalassemia, the working gene (mRNA) assembly error typically consists of not finding the (mutated) boundary between the intronic and exonic portions of the DNA strand (as reflected in the raw mRNA transcript), and consequently including an additional, contiguous length of non-coding instructions into the mRNA, or adding just a discontinuous fragment of it.[8] Because all the correct instructions can be present, sometimes normal hemoglobin is produced and the added genetic material, if it produces pathology, interferes with the regulation of desired levels of protein production, enough to ultimately produce anemia. The normal alpha and beta subunits of hemoglobin each have an iron-containing central portion (heme), and this central heme allows the protein chain of a subunit to fold around it. Normal adult hemoglobin contains 2 alpha and 2 beta subunits. Thalassemias typically affect only the mRNAs for production of the beta chains, hence the term "beta thalassemia". Since the mutation that prevents the spliceosome from finding the correct boundary between intronic and exonic portions of the raw RNA transcript can be a change in only a single base (a "Single Nucleotide Polymorphism"), there are on-going efforts to find gene therapies able to correct it.[9][10][11]

Symptoms and Prolonged Disorders Excess amounts of iron overload within the body causes serious complications within the liver, heart, and endocrine glands. Severe symptoms include liver cirrhosis, liver fibrosis, and in extreme cases liver cancer. Heart failure, growth impairment, diabetes, and osteoporosis are major life-threatening contributors brought upon by TM. The main cardiac abnormalities seen to have resulted from Thalassemia and iron overload, include, specifically left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valveulopathies, arrhythmias, and pericarditis.[12][13]

Factors Affecting the Regulation of Iron Absorption: The regulation of iron absorption within the gut ultimately depends upon 3 factors. The first factor consists of the degree of impaired red-blood cell production that has taken place within the body. The second factor respectively correlates with the degree of iron overload within the blood. In continuation with this iron overload, the third factor deals with the expression and balance of Fpn 1 and Hamp 1 proteins controlling ferroportin levels in the gut respectively. Since iron loading depends on the volume of blood transfused and the amount of iron accumulated from the food displaced in the gut, these factors are significantly important in the regulation of total iron absorption within the human body.[13]

Diagnostic categories[edit]

Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with beta thalassemia major usually present within the first two years of life with severe anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major.[2] Transmission is autosomal recessive; however, dominant mutations, and compound heterozygotes have also been reported. Genetic counseling is recommended and prenatal diagnosis may be offered.[3]

Beta thalassemia (β thalassemia) is a form of thalassemia due to mutations in the HBB gene on chromosome 11 [1], inherited in an autosomal recessive fashion.

The severity of the disease depends on the nature of the mutation.

Alleles without a mutation that reduces function are characterized as (β). Mutations are characterized as (βo) if they prevent any formation of β chains. Mutations are characterized as (β+) if they allow some β chain formation to occur. (Note that the "+" in β+ is relative to βo, not β.) In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.

The overall biochemical mechanism in Beta thalassemia is initiated by the blockage of the Beta-Globlin Gene. This sudden blockage over time leads to a decrease in the synthesis of the specific aforementioned Beta-chains listed above. The body’s inability to construct new Beta-chains leads to the underproduction of Hb A. Reductions in Hb A available overall to fill the red blood cells in turn leads to microcytic anemia. Microcytic anemia ultimately develops in respect to not enough Beta-Globin being around for sufficient red blood cell functioning. Due to this factor, the patient must undergo a blood transfusion for survival to make up for the blockage in the Beta-chains. Overall, blood transfusions can only be given over a course of so many times before there will be a build-up of iron overload ultimately resulting in iron toxicity. This iron toxicity is thus what produces myocardial siderosis and heart failure leading to the patient’s death.[12] [14]


Any given individual has two β globin alleles:

Name Description Alleles
Thalassemia minor Only one of β globin alleles bears a mutation. Individuals will suffer from microcytic anemia. Detection usually involves lower than normal MCV value (<80 fL). Plus an increase in fraction of Hemoglobin A2 (>3.5%) and a decrease in fraction of Hemoglobin A (<97.5%). β+/β or βo
Thalassemia intermedia A condition intermediate between the major and minor forms. Affected individuals can often manage a normal life but may need occasional transfusions, e.g., at times of illness or pregnancy, depending on the severity of their anemia. β++ or βo+
Thalassemia major If both alleles have thalassemia mutations. This is a severe microcytic, hypochromic anemia. Untreated, it causes anemia, splenomegaly, and severe bone deformities. It progresses to death before age 20. 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. Cooley's anemia is named after Thomas Benton Cooley.[15] βoo

Note that βo/β can be associated with β thalassemia minor or β thalassemia intermedia, and β++ with thalassemia major or intermedia.

The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished:

  • Nondeletion forms: These defects, in general, involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most often, mutations occur in the promoter 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 (βo) or hereditary persistence of fetal hemoglobin syndromes.

Testing, treatment, and complications[edit]

All beta thalassemias may exhibit abnormal red blood cells such as codocyte, anisocytosis, poikilocytosis, elliptocytosis, Hypochromic anemia, and schistocyte.

DNA analysis[edit]

This test is used to investigate deletions and mutations in the alpha- and beta-globin-producing genes. Family studies can be done to evaluate carrier status and the types of mutations present in other family members. DNA testing is not routinely done but can be used to help diagnose thalassemia and to determine carrier status. In most cases it is likely the treating physician will use a clinical prediagnosis by symptoms of anemia: tiredness, breathlessness, and poor exercise tolerance. Furthermore, abdominal pain due to hypersplenism and splenic infarction may occur and right-upper quadrant pain caused by gallstones may occur are major clinical manifestations. However, to coin thalassemiæ under signs and symptoms would be misleading when giving a diagnosis. Physicians will note these signs as associative due to the complexity of the nature of this disease. The following are also associative signs that can attest to the severity of the phenotype: pallor, poor growth, inadequate food intake, splenomegaly, jaundice, maxillary hyperplasia, dental malocclusion, cholelithiasis, systolic ejection murmur in the presence of severe anemia, and pathologic fractures. Based on a number of key symptoms tests are ordered for the differential diagnosis. These tests include CBC; Hemoglobin electrophoresis; Serum Transferrin, Ferritin, Fe Binding Capacity; Urine urobilin & Urobilogen; Peripheral Blood Smear; Hematocrit; Serum Bilirubin. Further genetic analysis may include HPLC should routine electrophoresis prove difficult. But, before any of these tests are ordered, a physician should inquire into a detailed family history.[16]

Thalassemia major and intermedia[edit]

Thalassemia major patients receive frequent blood transfusions that lead to or potentiate 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 more effective and is associated with fewer side-effects.[17]

The most common complaint by patients receiving deferoxamine is that it is difficult to comply with the subcutaneous chelation treatments because they are painful and inconvenient. The oral chelator deferasirox (marketed as Exjade by Novartis) was approved for use in 2005 in some countries. It offers some hope with compliance but is more expensive ($100 per day).

Untreated thalassemia major eventually leads to death usually by heart failure; therefore, birth screening is very important. Bone marrow transplantation is the only cure for thalassemia, and is indicated for patients with severe thalassemia major. Transplantation can eliminate a patient's dependence on transfusions. If there is no matching related donor or unrelated donor from a volunteer registry for a child with thalassemia, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to be free of the disease as well as match the recipient's human leucocyte antigen (HLA) type in order to be a donor for the sick child.

Thalassemia intermedia patients vary a lot in their treatment needs, depending on the severity of their anemia. All thalassemia patients are susceptible 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.

Those with thalassemia also show an increased number and higher degree activity of neutrophil elastase, which can effect other possible comorbidities such as alpha 1 antitrypsin deficiency.

Thalassemia minor[edit]

Thalassemia minor is not always actively treated, rather frequently monitored.[18] While many of those with minor status do not require blood transfusion therapy they still present at risk of iron overload, particularly in the liver.[citation needed] Increased gastrointestinal iron absorption is seen in all grades of beta thalassemia, and increased red blood cell destruction by the spleen due to ineffective erythropoiesis further releases additional iron into the bloodstream.[citation needed] A serum ferritin test should be done to check their iron levels and guide them to further treatment if necessary.[citation needed] 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,[19] and mood disorders,[20] and can cause iron overload of the liver and in those with non-alcoholic fatty liver disease lead to more severe outcomes.[21][22]

See also[edit]

United States[edit]

United Kingdom[edit]


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Further reading[edit]