eMedicine Specialties > Hematology > Red Blood Cells and Disorders
Thalassemia, Beta
Updated: Aug 24, 2009
Introduction
Background
Beta thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of beta-globin chains. In the homozygous state, beta thalassemia (ie, thalassemia major) causes severe transfusion-dependent anemia. In the heterozygous state, the beta thalassemia trait (ie, thalassemia minor) causes mild-to-moderate microcytic anemia. In addition, hemoglobin (Hb) E, a common Hb variant found in Southeast Asia, is associated with a beta thalassemia phenotype, and this variant is included in the beta thalassemia category of diseases.
Pathophysiology
Mutations in globin genes cause thalassemias. Alpha thalassemia affects the alpha-globin gene(s). Beta thalassemia affects one or both of the beta-globin genes. These mutations result in the impaired synthesis of the beta globin protein portion, a component of Hb, thus causing anemia.
In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carrier-type), one of the beta-globin genes is defective. The defect can be a complete absence of the beta-globin protein (ie, beta-zero thalassemia) or a reduced synthesis of the beta-globin protein (ie, beta-plus thalassemia) (see Image 1 or below).
Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
The genetic defect usually is a missense or nonsense mutation in the beta-globin gene, although occasional defects due to gene deletions of the beta-globin gene and surrounding regions also have been reported.
In beta thalassemia major (ie, homozygous beta thalassemia), the production of beta-globin chains is severely impaired, because both beta-globin genes are mutated. The severe imbalance of globin chain synthesis (alpha >> beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia (see Image 2 or below).
Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. The profound anemia typically is associated with erythroid hyperplasia and extramedullary hematopoiesis.
Frequency
United States
The frequency of disease varies widely, depending on the ethnic population. Beta thalassemia is reported most commonly in Mediterranean, African, and Southeast Asian populations.
International
The disease is found most commonly in the Mediterranean region, Africa, and Southeast Asia, presumably as an adaptive association to endemic malaria. The incidence may be as high as 10% in these areas.
Mortality/Morbidity
The major causes of morbidity and mortality are anemia and iron overload.
- The severe anemia resulting from this disease, if untreated, can result in high-output cardiac failure; the intramedullary erythroid expansion may result in associated skeletal changes such as cortical bone thinning. The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones.
- Increased iron deposition resulting from multiple life-long transfusions and enhanced iron absorption results in secondary iron overload. This overload causes clinical problems similar to those observed with primary hemochromatosis (eg, endocrine dysfunction, liver dysfunction, cardiac dysfunction).
Race
Beta thalassemia genes are reported throughout the world, although more frequently in Mediterranean, African, and Southeast Asian populations. Patients of Mediterranean extraction are more likely to be anemic with thalassemia trait than Africans because they have beta-zero thalassemia rather than beta-plus thalassemia.
- The genetic defect in Mediterranean populations is caused most commonly by (1) a mutation creating an abnormal splicing site or (2) a mutation creating a premature translation termination codon.
- Southeast Asian populations also have a significant prevalence of Hb E and alpha thalassemia.
- African populations more commonly have genetic defects leading to alpha thalassemia.
Sex
This genetic disorder is caused by abnormalities in the beta-globin gene, located on chromosome 11. It is not a sex-linked genetic trait.
Age
The manifestations of the disease may not be apparent until a complete switch from fetal to adult Hb synthesis occurs. This switch typically is completed by the sixth month after birth.
Clinical
History
Thalassemia minor usually presents as an asymptomatic mild microcytic anemia and is detected through routine blood tests. Thalassemia major is a severe anemia that presents during the first few months after birth.
- Thalassemia minor (beta thalassemia trait) usually is asymptomatic, and it typically is identified during routine blood count evaluation.
- Thalassemia major (homozygous beta thalassemia) is detected during the first few months of life, when the patient's level of fetal Hb decreases.
Physical
- Patients with the beta thalassemia trait generally have no unusual physical findings.
- Beta thalassemia major
- The physical findings are related to severe anemia, ineffective erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from transfusion and increased iron absorption.
- Skin may show pallor from anemia and jaundice from hyperbilirubinemia.
- The skull and other bones may be deformed secondary to erythroid hyperplasia with intramedullary expansion and cortical bone thinning.
- Heart examination may reveal findings of cardiac failure and arrhythmia, related to either severe anemia or iron overload.
- Abdominal examination may reveal changes in the liver, gall bladder, and spleen. Hepatomegaly related to significant extramedullary hematopoiesis typically is observed. Patients who have received blood transfusions may have hepatomegaly or chronic hepatitis due to iron overload; transfusion-associated viral hepatitis resulting in cirrhosis or portal hypertension also may be seen. The gall bladder may contain bilirubin stones formed as a result of the patient's life-long hemolytic state. Splenomegaly typically is observed as part of the extramedullary hematopoiesis or as a hypertrophic response related to the extravascular hemolysis.
- Extremities may demonstrate skin ulceration.
- Iron overload also may cause endocrine dysfunction, especially affecting the pancreas, testes, and thyroid.
Causes
Beta thalassemia is caused by a genetic mutation in the beta-globin gene; however, many additional factors influence the clinical manifestations of disease. That is, the same mutations may have different clinical manifestations in different patients. The following factors are known to influence the clinical phenotype:
- Intracellular fetal Hb concentrations
- The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) determines, in part, the severity of the disease.
- Patients with high fetal Hb have milder disease.
- Co-inheritance of alpha thalassemia
- Patients with co-inheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance.
- The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell disease. Unlike sickle cell trait, in which most Hb-on-Hb electrophoresis is Hb A (AS), S is the dominant Hb (SA) and usually constitutes about 60% of the circulating Hb.
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| Treatment & Medication: Thalassemia, Beta |
| Follow-up: Thalassemia, Beta |
| Multimedia: Thalassemia, Beta |
| References |
| Further Reading |
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References
Lucarelli G, Galimberti M, Polchi P. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med. Sep 16 1993;329(12):840-4. [Medline]. [Full Text].
Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med. Aug 13 1998;339(7):417-23. [Medline]. [Full Text].
Cohen AR, Galanello R, Pennell DJ, et al. Thalassemia. In: Hematology (Am Soc Hematol Educ Program). 2004:14-34.
Forget BG. Thalassemia Syndromes. In: Hematology: Basic Principles and Practice. 2000:485-509.
Fucharoen S, Winichagoon P. Clinical and hematologic aspects of hemoglobin E beta-thalassemia. Current Opinion in Hematology. 2000;7:106-112. [Medline].
Hoffbrand AV, AL-Refaie F, Davis B. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood. 1998;91:295-300. [Medline].
Ikuta T, Atweh G, Boosalis V. Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis. Ann N Y Acad Sci. 1998;850:87-99. [Medline].
Koshy M, Dorn L, Bressler L. 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood. 2000;96:2379-2384. [Medline].
Malik P, Arumugam PI. Gene Therapy for {beta}-Thalassemia. In: Hematology (Am Soc Hematol Educ Program). 2005:45-50.
May C, Rivella S, Callegari J. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature. 2000;406:82-86. [Medline].
Perrine SP. Fetal Globin Induction--Can It Cure {beta} Thalassemia?. In: Hematology (Am Soc Hematol Educ Program). 2005:38-44.
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Schrier SL, Angelucci E. New strategies in the treatment of the thalassemias. Annu Rev Med. 2005;56:157-71. [Medline].
Thein SL. Pathophysiology of {beta} Thalassemia--A Guide to Molecular Therapies. In: Hematology (Am Soc Hematol Educ Program). 2005:31-7.
Weatherall DJ, Clegg JB. Genetic disorders of hemoglobin. Semin Hematol. Oct 1999;36(4 Suppl 7):24-37. [Medline].
Italia KY, Jijina FJ, Merchant R, et al. Response to hydroxyurea in beta thalassemia major and intermedia: experience in western India. Clin Chim Acta. Sep 2009;407(1-2):10-5. [Medline].
Tan JA, Tan KL, Omar KZ, et al. Interaction of Hb South Florida (codon 1; GTG-->ATG) and HbE, with beta-thalassemia (IVS1-1; G-->A): expression of different clinical phenotypes. Eur J Pediatr. Sep 2009;168(9):1049-54. [Medline].
Galanello R, Sanna S, Perseu L, et al. Amelioration of Sardinian beta-zero thalassemia by genetic modifiers. Blood. Aug 20 2009;epub ahead of print. [Medline].
Further Reading
- Cooley Anemia
- Hematologic Disease and Pregnancy [in the Obstetrics and Gynecology section]
- Hemoglobin H Disease [in the Pediatrics: General Medicine section]
- Iron Deficiency Anemia
- Thalassemia [in the Pediatrics: General Medicine section]
- Thalassemia [in the Radiology section]
- Thalassemia, Alpha
- Thalassemia Intermedia [in the Pediatrics: General Medicine section]
Clinical Trials
- Assess the Feasibility and Safety of Granulocyte Colony Stimulating Factor (GCSF) Mobilization of CD34+ Hematopoietic Progenitor Cells in Patients With Betathalassemia Major
- Evaluating the Efficacy of Deferasirox in Transfusion Dependent Chronic Anaemias (Myelodysplastic Syndrome, Beta-Thalassaemia Patients) With Chronic Iron Overload
- Evaluating the Safety of G-CSF Mobilization in Individuals With Beta Thalassemia Major
- Genetic Factors Affecting the Severity of Beta Thalassemia
- Phase 1/2 Study of HQK-1001 in Patients With Beta Thalassemia
- Stem Cell Transplant in Sickle Cell Disease and Thalassemia
National Guideline Clearinghouse
- Carrier screening for thalassemia and hemoglobinopathies in Canada. Society of Obstetricians and Gynaecologists of Canada - Medical Specialty Society. 2008 Oct. 10 pages. NGC:006773
- Hemoglobinopathies in pregnancy. American College of Obstetricians and Gynecologists - Medical Specialty Society. 2007 Jan. 9 pages. NGC:005700
- Screening for iron deficiency anemia - including iron supplementation for children and pregnant women. United States Preventive Services Task Force - Independent Expert Panel. 1996 (revised 2006). 12 pages. NGC:004965
- Surgical treatment of disease and injuries of the spleen. Society for Surgery of the Alimentary Tract, Inc - Medical Specialty Society. 2004 Feb 21. 3 pages. NGC:003836
Keywords
beta-thalassemia, beta thalassemia syndromes, Cooley anemia, Mediterranean anemia, thalassemia major, thalassemia intermedia, thalassemia minor, erythroblastic anemia, thalassemia trait, hemoglobin E, hereditary disorder
