Thalassemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Shyam Patel [3]

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.

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.

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).

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.

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.

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.

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 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.

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 of iron deposition in various organs must be managed accordingly.

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.

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.

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 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.

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.

There are no other diagnostic studies for thalassemia.

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.

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]Neel Patel, M.B.B.S[3]

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, it explains high prevalence of Thalassemia in mediterranean basin, south east Asia, sub-Saharan Africa and the middle east. 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.

• In 4000 B.C., persons of eastern Mediterranean descent migrated to Sicily, carrying thalassemia gene variants with them.^[1]
• In the 800s-900s, there was mass migration of Arabs, who harbored globin gene mutations.
• In the 1400s-1500s, there was further influx of beta-thalassemia mutations with the expansion of the Ottoman Empire.^[1] The Ottoman Expire expanded to Eastern Europe, Central Asia, and Northern Africa, leading to additional globin mutations to develop in the population.
• In 1948, the biologist J.B.S. Haldane hypothesized that a heterozygote advantage existed for patients with beta-thalassemia in the context of malaria infection. This theory was similar to that of the heterozygote advantage conferred by sickle cell trait for malaria resistance. It was thought that thalassemia mutations would be selected for and would propagate in areas of high prevalence of malaria. Microcytic erythrocytes are less susceptible to malaria infection.
• In 1952, Silvestroni and colleagues noted that beta-thalassemia trait was highly prevalent in the Po River’s delta region.^[1]
• In the 1970s, the predilection of beta-thalassemia to affect Mediterranean populations was recognized, and pilot prevention programs were established to raise awareness and provide education about thalassemia. During this time, red blood cell transfusions were a mainstay for therapy. Transfusions were complicated by the risk for infections with hepatitis B, hepatitis C, and HIV.
• In the 1970s-1980s, scientists began to understand the mutational landscape of thalassemias.^[2] Further insight into the molecular basis for thalassemia was made as biotechnology developed over the coming years.
• In 1978, the concept of the hematopoietic niche in the bone marrow was introduced by Dr. Schofield.^[3] This was important because hematopoietic stem cells in the bone marrow give rise to mature red blood cells via the megakaryocyte-erythrocyte progenitor.
• In the 1980s, the concept of allogeneic bone marrow transplant was introduced with the goal of correcting the nonfunctional globin chain. The donor cells in from a bone marrow transplant contain the normal globin gene product, and this could reconstitute normal erythropoiesis, or red blood cell production.
• In 1989, Higgs and colleagues reported on the molecular basis of thalassemias.^[2]
• In the 2000s, gene therapy was conceptualized for thalassemias. Efforts were made to introduce exogenous wild-type globin genes into patients to restore normal globin function.^[4] The goal was to achieve highly efficient transduction of hematopoietic stem and progenitor cells (HSPCs) such that a normal functional globin could be produced.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2] Neel Patel, M.B.B.S[3]

The thalassemias are categorized 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 types of alpha-thalassemia, and each depends 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).

The thalassemias are classified according to which chain of the hemoglobin molecule is affected.

Alpha-thalassemias are caused by decreased production of alpha-globin chains from chromosome 16. Alpha-thalassemia is a monogenic disorder, meaning that one gene abnormality causes one disease.^[1] This is an autosomal recessive disorder with clinical manifestations that can be mild or severe, depending on the degree of alpha-globin loss. Mild clinical symptoms occur if there is a loss of one alpha-globin chain, and severe symptoms can occur if there is a loss of four alpha-globin chains. The hemoglobin molecules are that reduced in alpha-thalassemias include:

• major adult hemoglobin (HbA) (consisting of tetramers of alpha2-beta2)
• minor adult hemoglobin (HbA2) (consisting of tetramers of alpha2-delta2)
• fetal hemoglobin (HbF) (consisting of tetramers of alpha2-gamma2)

This is known as the silent carrier state. These patients are asymptomatic, since there are three remaining functional alpha-globin chains.

This is known as alpha-thalassemia trait. These patients are generally asymptomatic, since there are two remaining functional alpha-globin chains.

This condition occurs when alpha-globin chain synthesis is reduced to 25% or less.^[2] This is also know as hemoglobin H (HbH). HbH consists of tetramers of beta chains (beta-4).^[2] These beta-globin chain tetramers form because of insufficient alpha-globin chain synthesis. Symptoms typically include severe hemolytic anemia, but not death. This condition is less severe than Hb Barts but more severe than alpha-thalassemia silent carrier or trait.

Complete loss of alpha-globin chain production results in a severe, clinically incapacitating anemia with production of 4 gamma-globin chains as a tetramer. The clinical syndrome is hydrops fetalis. The tetramer of 4 gamma-globin chains (gamma-4) is also known as hemoglobin Barts (Hb Barts). This condition is not compatible with life. There can be severe intrauterine anemia. These patients typically die in utero or shortly after birth.

This is a variant alpha-hemoglobinopathy but is not formally classified as a thalassemia. Hemoglobin Constant Spring is characterized by a point mutation (substitution) in the alpha2-globin chain at the translation termination codon. This is a nondeletional alpha-thalassemia. The point mutation converts TAA to CAA, resulting in a prolonged peptide chain of 172 amino acids instead of the usual 141 amino acids. The peptide product is an elongated and unstable alpha-globin chain. This hemoglobinopathy is found in persons of Chinese and Southeast Asian descent.^[3]

Beta-thalassemias are caused by decreased production of beta-globin chains from chromosome 11. Beta-thalassemia is a monogenic disorder, meaning that one gene abnormality causes one disease, similar to alpha-thalassemia.^[1] This is an autosomal recessive disorder with clinical manifestations that can be mild or severe, depending on the degree of beta-globin loss. Mild clinical symptoms occur if there is a loss of one beta-globin chain, and severe symptoms can occur if there is loss of two beta-globin chains.

This is the most mild form of beta-thalassemia, which involves nearly intact beta-globin production. It is associated the B+ thalassemia phenotype.

This is a beta-thalassemia of moderate severity, which involves some loss of beta-globin production.

This is the most severe form of beta-thalassemia, which involves loss of all beta-globin production. It is associated the B0 thalassemia phenotype.

Patients with B0 thalassemia have absent beta-globin production. They have high red blood cell counts despite anemia. Red blood cells in B0 thalassemia heterozygotes are hypochromic and microcytic, meaning that they have loss of central pallor and small size, respectively. This disease is characterized by unbalanced or unequal globin chain synthesis and increased HbA2 (which consists of two alpha-globin chains and two delta-globin chains).^[4] B0 thalassemia is commonly seen in beta-thalassemia major, or Cooley’s anemia.

Patients with B+ thalassemia have some beta-globin production. They have high red blood cell counts despite anemia. Red blood cells in B+ thalassemia are hypochromic and microcytic also. This disease is characterized by unbalanced or unequal globin chain synthesis and increased HbA2 (which consists of two alpha-globin chains and two delta-globin chains).^[4] The difference between patients with B0 thalassemia and B+ thalassemia is that patients with B+ thalassemia produce some functional beta-globin and thus synthesize some functional red blood cells. B+ thalassemia can be found in patients with beta-thalassemia intermedia or beta-thalassemia minor.

This is a beta-globin variant that is found in high prevalence in certain Asian countries.^[5] It is characterized by a point mutation in beta-globin at codon 26, in which GAG is converted to AAG, converting glutamic acid to lysine. This amino acid substitution results in altered messenger RNA processing. Given the high prevalence of beta-thalassemia in Asian countries, some patients can have HbBE disease, in which one allele harbors a beta-globin defect and the other harbors the beta-globin variant.^[5] The rate of production of hemoglobin for patients with HbE disease is slightly decreased, so the thalassemia is mild. In patients with HbE, this hemoglobin variant constitutes 25-30% of the total hemoglobin. HbE has mild sensitivity to oxidative stress. This hemoglobin variant is unstable at high temperatures, so patients with HbE may experience hemolysis in the heat.

• Mutation: Given the high prevalence of beta-thalassemia in Asian countries and the relative abundance of HbE amongst Asians, some patients can have HbBE disease, in which one allele harbors a beta-globin defect and the other harbors the beta-globin variant.^[5] This point mutation results in a cryptic splice site and abnormal processing of messenger RNA. This results in reduced rate of synthesis of the beta-globin chain, which impairs red blood cell production and leads to apopotosis, oxidative damage, and anemia.
• Geography: The areas of highest prevalance include India, Laos, Cambodia, Bangladesh, Thailand. The incidence of HbE in Thailand is about 3000 per year.^[6] The prevalence is about 100,000. This is a compound heterozygote condition and results in an intermediate severity of thalassemia. HbE can also be inherited with certain forms of alpha-thalassemia. It accounts for nearly 50% of all major beta-thalassemias.^[6]

This is a hemoglobin variant characterized by a point mutation at the 6th codon of the beta-globin chain. It results in conversion of glutamic acid to lysine. Note that this is distinct from hemoglobin E, in which a similar amino acid substitution occurs in codon 26.

This is a rare hemoglobinopathy in which there is co-existence of hemoglobin A, hemoglobin E, hemoglobin Barts (complete loss of alpha chains).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Neel Patel, M.B.B.S[3]

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.

In order to understand the pathophysiology of thalassemia, one must first understand the normal physiology of globin gene synthesis and hemoglobin production.

• Normal adult hemoglobin: Normal adult hemoglobin is hemoglobin A (HbA), which consists of 2 alpha-globin chains and 2 beta-globin chains.^[1] This forms a tetramer of alpha2-beta2. Normal adults also harbor a small component of hemoglobin A2 (HbA2), which consists of 2 alpha-globin chains and 2 delta-globin chains. This forms a tetramer of alpha2-delta2. In the center of each globin chain tetramer is a heme molecule, which binds to iron. Thus the molecular ratio of globin to heme to iron is 4:1:1. Oxygen binds to heme, and heme thus transports iron throughout the body. Normal adults do not have any circulating hemoglobin containing beta-4 tetramers, gamma-4 tetramers, or sickled hemoglobin.^[1]

• Normal alpha-globin gene cluster: The alpha-globin gene cluster is near the telomere of the short arm of chromosome 16 (16p13.3). The globin genes located on the alpha-globin cluster on chromosome 16 are transcribed from the 5′ to 3′ direction of the chromosome. The first globin gene transcribed from the alpha-globin cluster is zeta2-globin, then zeta1-globin, then alpha2-globin, then alpha1-globin (from telomere to centromere).^[2] Upstream of the alpha-globin gene cluster are four conserved noncoding DNA sequences that are thought to serve a regulatory role in alpha-globin chain synthesis.

• Normal beta-globin gene cluster: The genes located on the beta-globin cluster on chromosome 11 are transcribed from the 5′ to 3′ direction of the chromosome. The first globin that is transcribed is epsilon-globin. This is followed by transcription of the G-gamma-globin, then A-gamma-globin, then delta-globin, then the normal adult beta-globin ^[2]

• Hemoglobin tetramer synthesis: In order to produce a hemoglobin molecule, two proteins (gene products) from the alpha-globin gene cluster must pair with two proteins (gene products) from the beta-globin gene cluster. A variety of tetrameric combinations can result. The order of synthesis of hemoglobin tetramers during human development recapitulates the location of the globin genes on their respective chromosomes. For example, the genes that are transcribed first are the genes that constitute embryonic and fetal hemoglobin. The genes that are transcribed last are the genes that constitute mature adult hemoglobin.

• Compensatory globin production: If there is defective alpha-globin chain production, alpha-thalassemia results, with excess of beta-globin chains. If there is defective beta-globin chain production, beta-thalassemia results, with excess of alpha-globin chains.^[1]

The alpha-thalassemias involve defects in the genes HBA1 (Online Mendelian Inheritance in Man (OMIM) 141800) and HBA2 (Online Mendelian Inheritance in Man (OMIM) 141850), inherited in a Mendelian autosomal recessive fashion. It is also related to the deletion of the 16p chromosome, where the alpha-globin gene cluster resides. Alpha-thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of beta-chains in adults and excess gamma-globin chains in newborns. The excess beta-chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. In the presence of excess beta-globin chains, red blood cell membrane instability develops and hemolysis ensues.

Any given individual has four alpha-globin alleles. Two of these are maternal in origin and two of these are paternal in origin. The severity of the α thalassemias is correlated with the number of affected α globin loci: the greater the number of affected loci, the more severe will be the manifestations of the disease.

• If one of the four alpha-globin loci is affected, there is minimal effect. Three alpha-globin loci are enough to permit normal hemoglobin production, and there is no anemia or hypochromia in these people. They have been called silent carriers.
• If two of the four alpha-globin loci are affected, the condition is called alpha thalassemia trait. Two alpha-globin loci permit nearly normal erythropoiesis, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron-deficiency anemia and treated inappropriately with iron. Alpha-thalassemia trait can exist in two forms: one form, associated with Asians, involves cis deletion of two alpha loci on the same chromosome; the other, associated with Blacks, involves trans deletion of alpha loci on different (homologous) chromosomes.
• If three of the four alpha-globin loci are affected, the condition is called Hemoglobin H disease. Hemoglobin H is a tetrameric beta-globin protein complex. This has a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. There is a microcytic hypochromic anemia with target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear, as well as splenomegaly. The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted.
• If all four of the alpha-globin loci are affected, the fetus cannot live once outside the uterus and may not survive gestation: 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 gamma-globin chains (hemoglobin Barts).

Beta-thalassemias are caused by defects in the HBB gene (beta-globin chain) on chromosome 11 (Online Mendelian Inheritance in Man (OMIM) 141900), also inherited in an Mendelian autosomal recessive fashion. There are over 300 known mutations that occur in beta-globin that can cause thalassemia.^[3] The severity of the disease, need for transfusion and morbidity depends on the nature of the mutation and imbalance between alpha and beta subunits.^[4] Mutations are characterized as B0 if they prevent any formation of beta-globin chains; they are characterized as B+ if they allow some beta-globin chain formation to occur. In either case there is a relative excess of alpha-globin 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. In beta thalassemia, red cell precursors can detoxify and tolerate a moderate amount of free alpha globin, that is stabilized by alpha hemoglobin stabilizing protein and eliminated by ubiquitin proteasome system and autophagy. The synthesis of gamma globin gene and HbF can reduce the degree of imbalance between alpha and beta chains. BCL11A(a multi zinc finger transcription regulator) plays a key role in switch from fetal to adult hemoglobin and silencing of the fetal hemoglobin. Genetic variations in BCL11A causing persistent HbF production reduce the clinical severity of beta thalassemia.

Any given individual has two beta-globin globin alleles, one inherited from the mother and one inherited from the father.

• If only one beta-globin allele bears a mutation, the disease is called beta-thalassemia minor (or sometimes called beta-thalassemia trait). This is a mild microcytic anemia. In most cases beta-thalassemia minor is asymptomatic, and many affected people are unaware of the disorder. Detection usually involves measuring the mean corpuscular volume (size of red blood cells) and noticing a slightly decreased mean volume than normal. The patient will have an increased fraction of Hemoglobin A2 (>2.5%) and a decreased fraction of Hemoglobin A (<97.5%).
• If both alleles have thalassemia mutations, the disease is called beta-thalassemia major or Cooley’s anemia. This is a severe microcytic, hypochromic anemia. Untreated, this progresses to 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.
• Thalassemia intermedia is 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.

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

• Nondeletion forms: These defects generally involve a single base substitution or small deletion or inserts near or upstream of the beta-globin gene. Most commonly, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease. Most beta-thalassemia mutations are point mutations, in which one nucleotide becomes substituted for another nucleotide.
• Deletion forms: Deletions of different sizes involving the beta-globin gene produce different syndromes such as (B0 thalassemia) or hereditary persistence of fetal hemoglobin syndromes.

In addition to alpha-globin and beta-globin chains being present in hemoglobin, about 3% of adult hemoglobin is made of alpha-globin and delta-globin tetramers (hemoglobin A2) (HbA2).^[5]

• Mutation: Just as with beta-thalassemia, mutations can occur which affect the ability of this gene to produce delta chains. A mutation that prevents formation of any delta chains is termed a delta0 mutation, whereas one that decreases but does not eliminate production of delta chain is termed a delta+ mutation. When one inherits two delta0 mutations in a Mendelian fashion, no HbA2 (alpha2-delta2) can be formed.
• Clinical manifestations: Hematologically, however, this is innocuous because only 2-3% of normal adult hemoglobin is HbA2. The individual will have normal hematological parameters (erythrocyte count, total hemoglobin, mean corpuscular volume, red cell distribution width). Individuals who inherit only one delta-thalassemia mutation will have a decreased HbA2, but also no hematological consequences. In some cases, co-inheritance of delta-globin and beta-globin mutations can cause elevated fetal hemoglobin.^[6]
• Distinguishing delta-thalassemia from beta-thalassemia: The importance of recognizing the existence of delta thalassemia is seen best in cases where it may mask the diagnosis of beta-thalassemia trait. In beta-thalassemia, there is an increase in HbA2, typically in the range of 4-6% (normal is 2-3%). However, the co-existence of a delta-thalassemia mutation will decrease the value of the HbA2 into the normal range, thereby obscurring the diagnosis of beta-thalassemia trait. This can be important in genetic counseling, because a child who is the product of parents each of whom has B0 thalassemia trait has a one in four chance of having beta-thalassemia major, or Cooley’s anemia.

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.

alpha- and beta-thalassemias are often inherited in an autosomal recessive fashion although this is not always the case. Reports of dominantly inherited alpha- and beta-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 are 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 prevalence 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 are an estimated 1,000 people living with thalassemia major in the United States and an unknown number of carriers. Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.

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, and also in some African and Indian regions. This is probably by making the red blood cells more susceptible to the less lethal species Plasmodium vivax, simultaneously making the host RBC environment unsuitable for the merozoites of the lethal strain Plasmodium falciparum. This is believed to be a selective survival advantage for patients with the various thalassemia traits. In that respect it resembles another genetic disorder, sickle-cell disease.

Epidemiological evidence from Kenya suggests another reason: protection against severe anemia may be the advantage.^[7].

People diagnosed with heterozygous (carrier) Beta-Thalassemia have some protection against coronary heart disease.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2] Neel Patel, M.B.B.S[3]

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.

• The incidence of thalassemia is about 300,000 to 400,000 per year.^{[1] [2]}
• The incidence of beta-thalassemia is 42,000 per year.^[3]

• Worldwide, the prevalence of thalassemia 3000 per 100000.^[4]
• The estimated prevalence of thalassemia worldwide is 300,000,000^[5]
• Beta thalassemia carriers are approximately 1.5% of the world population.
• Almost 90% patients with beta thalassemia live in geographic belt extending from Africa to Southern Europe and the middle east extending to southeast Asia. The estimated prevalence of thalassemias is 16% in people from Cyprus, 3-14% in Thailand, and 3-8% in populations from India, Pakistan, Bangladesh, Malaysia and China. There are also prevalences in descendants of people from Latin America, and Mediterranean countries (e.g. Spain, Portugal, Italy, Greece and others). A very low prevalence has been reported from people in Africa (0.9%), with those in northern Africa having the highest prevalence, and northern Europe (0.1%). Thalassemia is the most common monogenic disease in Iran.
• The carrier rate of beta-thalassemia in Cyprus is estimated to be 12,000 to 15,000 per 100,000 persons.^[6] every year 40,000 affected infants are born, half of which are transfusion dependent.
  • The carrier rate of beta-thalassemia in Greece is estimated to be 7,400 per 100,000 persons.^[6]
• The carrier rate of beta-thalassemia in Turkey is estimated to be 600 to 13,000 per 100,000 persons.^[6]
  • In Turkey, approximately 1.6 million people (of 80 million) have thalassemia trait.
  • In Turkey, approximately 5,500 people are homozygous for thalassemia.

Thalassemia affects men and women equally, since this is a disease with autosomal recessive, not sex-linked, inheritance.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

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.

• Ethnicity: Patients at high risk include persons of Mediterranean countries, Southeast Asia, Indian subcontinent, and the Middle East.^[1]
• Gender: There is no gender predilection for thalassemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2] Neel Patel, M.B.B.S[3]

Screening programs have been instituted in a variety of countries recently to help prevent the birth of children with thalassemia. In Iran, for example, a national screening program has been contacted 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.

Premarital screening is employed in countries that are endemic to thalassemia. In countries where screening is done, this can be an effective way to avoid the birth of children with thalassemia.^[1] However, certain countries with high prevalence of thalassemia do not incorporate screening methods due to a variety of reasons (below).^[1] 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.^[2] In Iran, the Ministry of Health approved a national screening program in 1996 for premarital screening. This national screening program was enacted after a 5-year pilot program was in place. The screening program provided counseling to couples at risk. The goal of this program was to reduce the social and financial burden of thalassemia in Iran.^[3] This program has been found to be effective and feasible.PMC527661

• Polymerase chain reaction (PCR): The preferred method of thalassemia screening is PCR amplification of DNA from fetal trophoblastic tissue or amniotic fluid. Amniotic fluid is obtained from amniocentesis or from chorionic villus sampling.^[4] If a newborn has the mutant globin chain within its germline DNA, PCR will amplify this DNA and will the mutation will be readily detectable.
  • Risks: There is a risk for false negative testing, in which a patient truly has thalassemia but no mutant PCR product is amplified. Maternal DNA contamination can also a false negative test result. In order to bypass the possibility of false negatives, multiple confirmatory tests can be done, including the amplification refractory mutation system and reverse oligonucleotide hybridization.^[4]
  • Benefits: The advantages of PCR are the high sensitivity and low cost of the test.
• Hemoglobin electrophoresis: Analysis of globin gene products on gel electrophoresis can help make a diagnosis of thalassemia.^[4]

There are numerous barriers to effective screening for thalassemia.^[3]

• Costs of screening
• Lack of awareness of availability screening
• Unwillingness to participate in screening
• Lack of concern about thalassemia
• Absence of formalized screening initiatives or programs in certain countries

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2] Neel Patel, M.B.B.S[3]

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. The prognosis is favorable for mild thalassemias. Major thalassemia usually results 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. Complications of iron deposition in various organs must be managed accordingly.

The natural history of thalassemia depends on the subtype of thalassemia.

• Mild thalassemias: For patients with mild thalassemias, such as alpha-thalassemia silent carrier, alpha-thalassemia trait, or beta-thalassemia minor, the disease course does not result in significant symptoms or complications. These patients sometimes require transfusions throughout their lives. In most cases, these patients can lead normal lives. The natural history of mild thalassemias does not alter life expectancy in most cases.
• Severe thalassemias: For patients with severe thalassemias, such as HbH disease, Hb Barts, or beta-thalassemia major, the disease course begins with severe symptoms including shortness of breath and fatigue. Children born with beta-thalassemia major (Cooley’s anemia) can be normal at birth but develop severe anemia during the first two years of life. This is followed by the need for transfusions, initially at a low frequency. The frequency of transfusions increases as the disease course progresses. After many transfusions, iron deposition begins to occur in various organs, including the heart, thyroid, and liver. This process, known as hemosiderosis, cause results in organ failure. Death is an unfortunate and inevitable part of the natural history of major thalassemias. The most severe form of alpha-thalassemia major (Hb Barts or hydrops fetalis) causes stillbirth (death of the unborn baby during birth or the late stages of pregnancy).^[1] In some cases, a live baby can be delivered, but death occurs soon after birth. Mothers who deliver a baby with hydrops fetalis from alpha-thalassemia major have a 75% risk for toxemia of pregnancy.^[1]
• Natural history in the setting of pregnancy: In some cases, persons with thalassemia major can have normal pregnancies.^[2] Greater than 400 successful pregnancies have been documents in women with thalassemia. Ovarian hyperstimulation syndrome has been described in patients with thalassemia. Other clinical findings that have been noted in pregnant patients with thalassemia include hypersplenic crises and worsening cardiac function. Twin and triplet pregnancies are more common in patients with thalassemia. Importantly, there is no increased risk of miscarriage in pregnant patients with thalassemia compared to the general population.^[2]

The complications of thalassemia are largely related to iron overload from repeated transfusions. Each unit of packed red blood cells contains 200mg of iron. Iron overload is further exacerbated by the costs of iron chelation therapy to treat iron overload and the nonadherence with chelation therapy. The mortality rate is nearly 50% from iron overload complications.^[3] Iron deposition can occur in various organs.

• Cardiac failure: Thalassemia can cause increased cardiac workload, since the heart must pump more forcefully and/or more quickly in order to compensate for the relative oxygen deficit from abnormal red blood cells.^[4] Infiltrative cardiomyopathy can occur with iron overload from repeated transfusions from thalassemia. This usually manifests as diastolic dysfunction. There are two phenotypes for cardiac failure: the dilated phenotype which consists of left ventricular dilatation and impaired contractility, and the restrictive phenotype which consists of restrictive left ventricular filling along with pulmonary hypertension and right heart failure. Signs and symptoms of iron overload in the heart include shortness of breath, chest pain, decreased exercise tolerate, edema, elevated jugular venous pressure, crackles, and occasionally abdominal distension. The diagnosis of cardiac iron overload typically involves obtaining an echocardiogram (to assess for diastolic and systolic dysfunction). Echocardiogram can show a sparkled appearance of the involved chambers (from iron deposits) and sometimes a decreased ejection fraction). EKG typically shows low-voltage QRS complexes, due to the impaired electrical conduction through a disease heart containing significant iron. MRI with T2 star sequences can be of great benefit, as this particularly assess for iron deposition in the heart.^[5] Laboratory workup that can assist with diagnosis includes measurement of troponin and nt-proBNP.^[5] Treatment of iron deposition in the heart involves use of beta-blockers, ACE inhibitors, inotropes (which improve systolic dysfunction), and lusitropes (which improve diastolic dysfunction).

• Thyroiditis: Infiltrative thyroiditis can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms of iron overload in the thyroid gland include fatigue, cold intolerance, coarse hair, constipation, weight gain, palpable thyroid (goiter), decreased deep-tendon reflexes. Iron deposition in the thyroid can be assessed via thyroid ultrasound and measurement of thyroid-stimulating hormone (TSH) and free thyroxine (t4) levels. Treatment of iron deposition in the thyroid involves thyroid hormone replacement, typically with levothyroxine 1.7 mcg/kg/day.^[5]

• Hepatic failure: Infiltrative hepatitis can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms include right upper quadrant pain, jaundice, dark urine, clay-colored stools, nausea, and tender hepatomegaly. Diagnostic considerations include liver ultrasound, CT of the abdomen, MRI of the abdomen, assessment of liver function tests (total bilirubin, AST, ALT, albumin, alkaline phosphatase. Treatment of iron overload in the liver involves consideration of liver transplant and diuretics.^[5]

• Pancreatic insufficiency: Infiltrative pancreatitis can occur with iron overload from repeated transfusions from thalassemia. Iron deposition in the pancreas causes both exocrine and endocrine dysfunction. Exocrine dysfunction involves the inability of the pancreas to release digestive enzymes, and endocrine dysfunction involves the inability of the pancreas to release insulin and glucagon. Signs and symptoms include hyperglycemia (which can lead to diabetes), diarrhea, steatorrhea, weight loss. Diagnostic workup involves CT or ultrasound of the pancreas, measurement of lipase, measurement of amylase, and measurement of insulin and glucagon levels. Therapy involves the replacement of pancreatic enzymes and hormones. The treatment regimen can consist of a complex combination of enzymes and hormones which sometimes requires close monitoring by an endocrinologist.

• Hyperpigmentation: Infiltrative dermatitis can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms include bronze discoloration of the skin or hyperpigmentation. A skin biopsy can be done to confirm iron deposition in the skin, but this is not typically needed. There is no particular treatment for this, aside from iron chelation.

• Hypogonotropic hypogonadism: Gonadal dysfunction can occur with iron overload from repeated transfusions from thalassemia. Signs and symptoms include decreased sexual desire, decreased fertility, and loss of secondary sexual characteristics associated with decline in sex hormones.^[2] Treatment sometimes involves testosterone supplementation.

Thalassemias can adversely effect a person’s psychologic well-being.^[6] It has been shown that thalassemia is associated with a higher rate of various psychiatric conditions, including:

• Depression
• Anxiety
• Stress

For these reasons, it is highly important to assess for these conditions proactively in patients with thalassemia.^[6]

Infections are also a complication of frequent transfusions. Certain infections were found to be present in high prevalence in patients undergoing transfusions in the 1980s. The infections that have been associated with repeated transfusions for thalassemia include:

• Hepatitis B: This has been found at a seroprevalance of 3% in patients who were transfused for thalassemia.^[7]
• Hepatitis C: This has been found at a seroprevalance of 18.2% in patients who were transfused for thalassemia.^[7]
• HIV: This has been found at a seroprevalance of 1.5% in patients who were transfused for thalassemia.^[7]
• Syphilis: This has been found at a seroprevalance of 0% in patients who were transfused for thalassemia. Although it was not found to be present in this study, there still exists a theoretical risk for acquiring syphilis from blood transfusion.^[7]
• Cytomegalovirus: This virus can exacerbate the low hemoglobin found in patients with thalassemia since the virus causes bone marrow suppression and further blood count suppression.
• Parvovirus B19: This virus can exacerbate the low hemoglobin found in patients with thalassemia since the virus causes pure red cell aplasia (PRCA).
• Malaria: This parasite can exacerbate the low hemoglobin found in patients with thalassemia since the parasite causes hemolysis and further decreases in hemoglobin. However, patients with thalassemia can have heterozygote advantage, in which patients who are heterozygote for thalassemia are protected against infection with malaria.

Over the past 20 years, the prognosis for thalassemia has improved significant, as supportive measures like transfusions are now more readily available and safer.^[8] Advanced in iron chelation therapy have also contributed to the improved outcomes for patients with thalassemia. In general, the prognosis of thalassemias depends on the subtype: severe defects in globin chain production are more likely to result in worse prognosis.

• Alpha-thalassemias
  • Alpha-thalassemia silent carrier: The prognosis for silent carriers of alpha-thalassemia (loss of 1 alpha-globin chain) is excellent. This patient lives normal lives with no significant transfusion requirements. Life expectancy is similar as persons with no thalassemia.
  • Alpha-thalassemia trait: Patients with alpha-thalassemia trait (loss of 2 alpha-globin chains) have an excellent prognosis. In rare cases, patients with the alpha-thalassemia traits require transfusions, but their life expectancy is similar as persons without thalassemia.
  • HbH disease: Patients with HbH disease (loss of 3 alpha-globin chains) have a somewhat poor prognosis, as these patients can have significant transfusion requirements. One major causes of death include iron overload leading to cardiac failure.
  • Hb Barts: Patients with Hb Barts (loss of 4 alpha-globin chains) have the worst prognosis amongst all thalassemias. These patients typically die in utero from hydrops fetalis.
• Beta-thalassemias
  • Beta-thalassemia minor: These patients are usually asymptomatic. Prognosis is favorable and is excellent compared to all other forms of beta-thalassemia.
  • Beta-thalassemia intermedia: The prognosis for beta-thalassemia intermedia is fairly good. Iron accumulation in organs is less common since they do not receive many blood transfusions. These patients generally do not develop hypothyroidism or hypogonadism. Women with beta-thalassemia intermedia can have normal pregnancies. Given that cardiac systolic function is usually preserved, the cardiac disease does not usually contribute towards a poor prognosis for patients with beta-thalassemia intermedia.
  • Beta-thalassemia major (Cooley’s anemia): The prognosis for beta-thalassemia major is generally poor, as patients have severe defects in beta-globin production and thus are susceptible to treatment-related complications. These patients typically die from iron deposition in the heart (infiltrative cardiomyopathy) due to repeated blood transfusions. In 71% of patients with beta-thalassemia major, cardiovascular etiology will be the cause of death.^[8] Other common complications that contribute to a poor prognosis are development of hepatitis B, hepatitis C, and HIV from blood transfusions. Venous thrombosis contributes to morbidity and sometimes mortality.

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