Thalassemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Shyam Patel [3]
Overview
Thalassemia (British spelling, "thalassaemia") is an inherited autosomal recessive blood disease which are characterized by reduced or deficient production of Hemoglobin with chronic anemia. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.
Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell disease (a hemoglobinopathy) is a qualitative problem of synthesis of a non-functioning globin. Thalassemias usually result in under production of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves [1]. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not. Either or both of these conditions may cause anemia.
Historical Perspective
Our knowledge about the origins of thalassemia date back to more than 6000 years ago. At that time, persons of Mediterranean descent began their migrations to other regions of the world, carrying gene variants that eventually gave rise to thalassemias. The expansion of empires led to further propagation of the defective globin genes throughout the world. It was soon noted that persons with thalassemia were relatively resistant to malaria, and further molecular studies were done to identify the underlying pathophysiology of thalassemias. The initial treatment approach to thalassemia was supportive care, especially red blood cell transfusions. In the recent years, bone marrow transplant and gene therapy have been exploited as possible treatments to treat thalassemias. These treatment strategies are still being explored.
Classification
The thalassemias are classified into two broad disease groups: alpha-thalassemia and beta-thalassemia. Alpha-thalassemia is characterized by a decrease in or defective production of alpha-globin chains. There are four major type of alpha-thalassemia, and each depends of on the number of alpha-globin alleles that are lost. These include the silent carrier state, alpha-thalassemia trait, HbH disease, and hydrops fetalis (Hb Barts). Beta-thalassemia is characterized by a decrease in or defective production of beta-globin chains. There are three major types of beta-thalassemia, and each depends on the degree of production of beta-globin chains. These include beta-thalassemia minor, beta-thalassemia intermedia, and beta-thalassemia major (Cooley's anemia). The beta-thalassemias can also be categorized by the degree of beta-globin chain production (B0 or B+ phenotypes).
Pathophysiology
The pathophysiology of alpha- and beta-thalassemia involves abnormal production of globin chains. Alpha- and beta-thalassemias are both monogenic disorders, meaning that defects in one gene result in the disease. The pathogenesis of thalassemias can involve a various of mutational events, such as deletions, insertions, or point mutations (substitutions). The altered genetic sequence results in a gene product (protein) that is nonfunctional or dysfunctional, such that the new globin chain cannot effective deliver oxygen to peripheral tissues. The number of alleles that are lost on each globin-cluster determines the severity of the disease. Regardless of the type of mutation, the thalassemias are inherited in a Mendelian autosomal recessive fashion.
Differentiating Thalassemia from Other Diseases
A variety of diseases can mimic thalassemia. These include sickle cell anemia, iron-deficiency anemia, hemolytic anemia, sideroblastic anemia, anemia of chronic disease, vitamin B12 deficiency, and erythropoietin deficiency. It is important to distinguish amongst these conditions, as each condition has different clinical consequences and treatment considerations.
Epidemiology and Demographics
Overall, thalassemia is a rare condition with a low incidence and prevalence in the United States. However, non-US countries have a higher incidence and prevalence. These include countries of the Mediterranean basis and Southeast Asia. The exact incidence and prevalence are unknown, but various estimates have been reported.
Risk Factors
The risks factors for thalassemia include birth to parents of Mediterranean or Southeast Asian descent. There are some other geographic areas that have a high prevalence of thalassemia such that ancestry from these areas constitute a risk factor for development of thalassemia. Since this is a monogenic disorder, there are no other particular risk factors. Environmental factors do not play a role in development of thalassemia.
Screening
Screening programs have been instituted in a variety of countries recently to help prevent birth of children with thalassemia. In Iran, for example, a national screening program has been intacted and has been successful. Screening programs employ molecular diagnostics such as polymerase chain reaction (PCR) or hemoglobin electrophoresis in order to detect thalassemias. However, there are numerous barriers to screening including high costs and lack of education about thalassemias.
Natural History, Complications, and Prognosis
Natural History
The natural history of thalassemia depends on the severity of the globin chain defect. Mild thalassemias have an indolent clinical course, and patients can be asymptomatic for years.
Complications
Complications of iron deposition in various organs must be managed accordingly.
Prognosis
The prognosis is favorable for mild thalassemias. Major thalassemia usually result in significant symptoms. The prognosis of major thalassemias is worse, and patients typically die from complications of iron overload in various organs due to excess red blood cell transfusions.
Diagnosis
History and Symptoms
The history and symptoms of thalassemia are related to the underlying defective hemoglobin production and decreased delivery of oxygen to peripheral tissues. Family history is the most important aspect of a patient's medical history when assessing for thalassemia, since this is a monogenic disorder with Mendelian autosomal recessive inheritance. Typical symptoms include fatigue, shortness of breath, bone deformities (for beta-thalassemia major), jaundice, scleral icterus.
Physical Examination
The physical exam findings of thalassemia relate to compensatory organ or tissue responses to decreased oxygen delivery. Physical exam features typically include tachypnea, jaundice, scleral icterus (if hemolysis is present), splenomegaly, and bony enlargement. In most cases of mild thalassemias, there are no physical exam abnormalities. In severe thalassemias, physical exam findings can be quite remarkable and unique to thalassemia.
Laboratory Findings
Laboratory findings in patients with thalassemia include anemia with microcytosis, abnormal bands on hemoglobin electrophoresis, and abnormal peripheral blood smear findings. Sequencing of the globin genes will reveal mutations that lead to defective globin production. In the case of hemolysis from thalassemia, laboratory findings include elevated LDH, elevated total bilirubin, elevated indirect bilirubin, high reticulocyte count, and low haptoglobin. Importantly, the range of laboratory findings is quite diverse depending on the severity of the disease.
Imaging Findings
The role for X-rays in thalassemia is limited. In some cases it can be useful to address a particular clinical question. Imaging considerations for thalassemia includes ultrasound, CT, MRI, or MRI with T2 star sequence. An ultrasound is the least expensive test though provides the least anatomic discrimination. MRI is the most expensive test but provides the best anatomic discrimination.
Other Diagnostic Studies
There are no other diagnostic studies for thalassemia.
Treatment
Medical Therapy
The treatment of thalassemia ranges from conservative treatments like supportive measures to intensive approaches like bone marrow transplant and gene therapy. Supportive measures include red blood cell transfusions. However, this can be complicated by iron overload, with iron deposition in various organs. This can sometimes require iron chelation therapy. Stem cell transplant has been done for thalassemia, with the goal of eliminating the cells with defective globin chains and substituting them for cells with normal globin chains. Gene therapy involves in vitro or ex vivo manipulation of the beta-globin gene such that normal gene function can be restored. Other therapies that have been tried with limited success include hydroxyurea and anti-oxidant therapy. Overall, these therapies have low efficacy.
Prevention
Primary prevention for thalassemia focuses on education and genetic counseling. These measures can help to prevent the birth of patients with thalassemia. Primary prevention strategies are currently employed in various countries. There is some role for genetic counseling and education as a means of secondary prevention of thalassemia.