Thalassemias are a group of inherited blood dyscrasias that were first described in the Mediterranean region.In Greek”Thalassa” means sea and “haema “ means blood.
Thalassemia is caused by variant or missing genes that affect how the body makes hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen. People with thalassemia make less hemoglobin and fewer circulating red blood cells than normal, which results in mild or severe anemia. Thalassemia presents as microcytic hypochromic anemia which may be differentiated from iron deficiency anemia using various indices .
The incidence of thalassemia is very high, with over 30 million people carrying the defective gene.It is mainly prevalent in South east Asia and the Mediterranean countries. Carrier frequency varies from 3 to 17% in different populations.Over 9000 thalassemic children are born every year and the treatment is very expensive. The most effective approach to reduce the disease incidence and the associated morbidity is by implementation of a carrier screening program offering genetic counselling, prenatal diagnosis and selective termination of affected fetuses.
Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β globin chains arranged into a heterotetramer. In thalassemia, patients have defects in either the α or β globin chain causing production of abnormal red blood cells.
The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.
Alpha (α) thalassemias
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.
Beta (β) thalassemia
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 either βo or β thalassemia major if they prevent any formation of β chains, the most severe form of β thalassemia. In these cases regular blood transfusions are required for survival.
They are characterized as β+ or β thalassemia intermedia if they allow some β chain formation to occur.Such cases have moderate degree of anemia and may/may not require transfusions. 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.
β thalassemia minor / trait/carrier state is characterized by a mild form of anemia,often asymptomatic.
Both α and β thalassemias are often inherited in an autosomal recessive fashion, although this is not always the case
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% risk with each pregnancy for an affected child.Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait. For the test you can visit Blood test labs in New Delhi
Iron overload: People with thalassemia often get an overload of iron in their bodies, either from the disease itself or from frequent blood transfusions. Too much iron can result in damage to the heart, liver and endocrine system. The damage is characterized by excessive deposits of iron. Without adequate iron chelation therapy, almost all patients with beta-thalassemia will accumulate potentially fatal iron levels.
Infection: people with thalassemia have an increased risk of infection.
Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow expansion also makes bones thin and brittle, increasing the risk of broken bones.
Slowed growth rates: Anemia can cause growth retardation. Puberty also may be delayed in children with thalassemia.
Heart problems: such as congestive heart failure and abnormal heart rhythms (arrhythmias), may be associated with severe thalassemia.
Spleen enlargement:In thalassemia,there is destruction of large no. of RBCs which leads to splenic enlargement.Splenomegaly aggravates anemia and can reduce the life of transfused red blood cells.
Mild thalassemia: People with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made. People with β-thalassemia trait should be warned that their condition can be misdiagnosed as the more common iron deficiency anemia. They should avoid routine use of iron supplements; yet iron deficiency can develop during pregnancy or from chronic bleeding. Counseling is indicated in all persons with genetic disorders, especially when the family is at risk of a severe form of disease that may be prevented.
Severe thalassemia: People with severe thalassemia require medical treatment. A blood transfusion regimen is the first measure effective in prolonging life. Book you test from Blood test labs Delhi
Carrier Screening Methods to reduce incidence of thalassemia :
The best option is to test expectant mothers antenatally in early pregnancy preferably in the first trimester. The parents are often receptive and usually agree to get any tests done for the well being of their baby. If the mother is found to be a carrier, her husband can be tested for carrier status and if he is also a carrier, prenatal diagnosis can be offered after proper genetic counselling.
There are various methods available for carrier screening.
1. Red Cell Indices
Red cell indices obtained through standard electronic cell counters provide a valuable tool for preliminary screening of thalassemic traits. Thalassemic traits in general have reduced mean corpuscular volume (MCV) and reduced mean corpuscular hemoglobin (MCH) with normal mean corpuscular hemoglobin concentration (MCHC). Specific cut off points for each index varies from laboratory to laboratory. However, selection of both MCV (<77 fl) and MCH (<27 pg) is ideally suited for further rapid confirmation of carrier status.
Low MCV or MCH sometimes poses a problem by giving false positive results due to iron deficiency anemia or other nonthalassemic microcytosis. Various formulae like Bessman index, Shine and Lal index, England index, Mentzler index are used as good indicators to differentiate between thalassemic and nonthalassemic microcytosis.
2. Hemoglobin A2 Estimation
Raised hemoglobin A2 level is the gold standard for diagnosis of thalassemic trait. HbA2 levels can be measured by various methods such as microcolumn chromatography & high performance liquid chromatography (HPLC ). Currently a number of instruments are available for Hb A2quantitation by HPLC. HPLC is a sensitive and precise method for the identification of Hb A2, Hb F and abnormal haemoglobins. It has become the method of choice for thalassaemia screening because of its speed and reliability. An automatic HPLC system, the Bio-Rad D 10 is available primarily for the detection of β-thalassaemia carriers and the common abnormal haemoglobins (Hb S, Hb C, HbE) in our laboratory. In this subjects with HbA2 levels of 3.5 per cent and above are considered to have thalassemic trait.
3. DNA Mutation Analysis
Once the carrier status of the couple is confirmed, the next step is to prevent the birth of thalassemic child by offering prenatal diagnosis and selective abortion of the fetuses affected with thalassemia. To offer prenatal diagnosis to the couples it is essential to characterize the DNA mutations of the parents. More than 150 mutations causing b-thalassemia have been reported from different parts of the world. Studies conducted in India have identified about 28 mutations in Indian population.
Of these five to six mutations are found to be common.
Until the development of DNA technologies, prenatal diagnosis was carried out by estimating the rate of globin chain synthesis in fetal blood samples and it is still a method of choice where DNA mutations are unidentified in parents, or when the couples report for the first time with advanced pregnancy.In this procedure fetal blood sample is collected after 18 weeks of gestation and globin chains are separated on CM cellulose column. Ratio of b/a chains is studied.
Fetal DNA analysis could be done by extracting DNA from amniotic fluid after 15 weeks of gestation and chorionic villus samples (CVS) between 10-12 weeks or later gestation.
CVS is preferable as the result of prenatal diagnosis are available early in pregnancy.
Usual reporting time is about one week.
With the availability of a battery of cost effective preliminary screening tests and advent of DNA based diagnostic technologies, it will be possible, in the years to come, to reduce the burden of the disease on the society and in turn reduce its frequency in the population at large.