Thalassemia

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Overview
Thalassemia (British spelling, "thalassaemia") is an inherited autosomal recessive blood disease. 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. 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.

The disease is particularly prevalent among Mediterranean peoples, and this geographical association was responsible for its naming: Thalassa (θάλασσα) is Greek for the sea, Haema (αίμα) is Greek for blood.

Prevalence
Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic, but affects all races. Thalassemias are particularly associated with Arab-Americans, people of Mediterranean origin, and Asians. The estimated prevalence 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%).(4)

Pathophysiology
The thalassemias are classified according to which chain of the hemoglobin molecule is affected (see hemoglobin for a description of the chains). In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.

Thalassemia produces a deficiency of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.

β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16. Thus in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain.

Deletion of one of the α loci has a high prevalence in people of African-American or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in African-Americans, but also in Greeks and Italians.

Alpha (α) thalassemias
The α thalassemias involve the genes HBA1 and HBA2 , inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.

There are four genetic loci for α globin, two of which are maternal in origin and two of which 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 α loci is affected, there is minimal effect. Three α-globin loci are enough to permit normal hemoglobin production, and there is no anemia or hypochromia in these people. They have been called silent carriers.
 * If two of the four α loci are affected, the condition is called alpha thalassemia trait. Two α 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 loci are affected, the condition is called Hemoglobin H disease. Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have 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 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 γ chains (hemoglobin Barts).

Beta (β) thalassemias
Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (βo) if they prevent any formation of β chains; they are characterized as (β+) if they allow some β chain formation to occur. 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.

Any given individual has two β globin alleles.
 * If only one β globin allele bears a mutation, the disease is called β thalassemia minor (or sometimes called β thalassemia trait). This is a mild microcytic anemia. In most cases β 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 β 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 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 generally involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most commonly, mutations occur in the 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.

Delta (δ) thalassemia
As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. 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, no hemoglobin A2 (alpha2,delta2) can be formed. Hematologically, however, this is innocuous because only 2-3% of normal adult hemoglobin is hemoglobin A2. 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 gene will have a decreased hemoglobin A2, but also no hematological consequences. 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 hemoglobin A2, 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 hemoglobin A2 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 beta0 thalassemia trait has a one in four chance of having beta thalassemia major.

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


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

Diagnosis
(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Kyoto University - Japan, and Hospital Universitario La Fe Servicio Hematologia)

Treatment and complications
Anyone with thalassemia should consult a properly qualified hematologist.

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

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

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

Untreated thalassemia Major eventually leads to death usually by heart failure, therefore birth screening is very important. β-Thalassemia cardiomyopathy takes on two phenotypes:
 * Dilated phenotype: Left ventricular dilatation and impaired contractility are present
 * Restrictive phenotype: Restrictive left ventricular filling is present along with pulmonary hypertension, and right heart failure.

The pathophysiology of β-Thalassemia cardiomyopathy is multifactorial, with myocardial iron overload and immunoinflammatory processes being the predominant mechanisms.

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

All Thalassemia patients are 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.

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

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

Genetic prevalence


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

There 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.

As with other genetically acquired disorders, genetic counseling is recommended.

Treatment and management
The antioxidant indicaxanthin, found in beets, in a spectrophotometric study showed that indicaxanthin can reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or Vitamin C. Collectively our results demonstrate that indicaxanthin can be incorporated into the redox machinery of β-thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.

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

Benefits
Being a carrier of the disease may confer a degree of protection against malaria, and is quite common among people from Italian or Greek origin, 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. .

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

Additional facts
Recently, increasing reports suggest that up to 5% of patients with beta-thalassemias produce fetal hemoglobin (HbF), and use of hydroxyurea also has a tendency to increase the production of HbF, by as yet unexplained mechanisms.