Thalassemia comes from two Greek words “Thalassa” and “emia” meaning “sea” and “blood”. This naming has a unique meaning as the disease affects the hemoglobin and was described almost 90 years ago by Cooley and Lee. Two gene clusters controlling haemoglobin synthesis are located on chromosome 16 (α-like globins) and chromosome 11 (β-like globins) in such a manner that they are differentially expressed at different stages of development like embryonic, foetal and adult. This is seen in β-globin gene cluster where, ε-gene is only expressed in early embryos and two γ-genes, which are expressed during gestation, are found in foetal haemoglobin (Hb F, α2γ2). The δ-gene used in diagnosing thalassemias is a component of Hb A2 (α2δ2), whereas α and β-globins combine to form major haemoglobin component Hb A (α2β2) carried by adult red blood cells. The heritable mutations in α and β gene clusters in thalassemias results in defective haemoglobin which binds to less oxygen and also reduces the transport of oxygen.
There are three types of β-thalassemia, based on the β-globin chain imbalance and severity of anaemia; namely minor, intermedia and major. Several mutations have been identified and were classified into silent — which have no effect, mild — leading to a reduction in β-globin production levels, and severe — causing a complete absence of the β-globin gene product. The minor trait or carrier patients have heterozygous inheritance of mutations and are often clinically asymptomatic. Patients with the major trait have severe anaemia from infancy and become life-long dependents on transfusion. However, β –thalassemia intermedia has variable anaemia of mild to moderate requiring variable transfusions. β-thalassemia major and intermedia can be due to several homozygous or compound heterozygous inheritances of mutations in β-globin gene. Different modifications like the extent of α-globin to β-globin chain imbalance, ineffective erythropoiesis and the severity of anaemia cause β-thalessemia intermedia, rather than β-thalessemia major in most patients. Most frequent are mutations in the β-globin gene, second are co-inheritance of α-thalassemia, higher levels of γ-chains of globin and sustained production of foetal haemoglobin after infancy. The last factor — hereditary persistence of foetal haemoglobin — can be due to several rare mutations like deletions of upstream promoter or regulatory region but the presence of an intact gene, and the complete deletion of δ-globin and β-globin genes. These patients have one intact γ-globin gene which is called δβ-thalassemia. Some of the other complications, such as dominant inclusion body β-thalassemia, have a triplicated or quadruplicated α-genotype along with β-heterozygosity or E/ β-thalassemia where β-thalassemia is co-inherited with a structural variant of hemoglobin E.
The classification of α-thalassemia is dependent on how both the α-globin genes are deleted or reduced in activity due to mutations. The first group of α+-thalassemias are of several types, but are dominated by –α3.7 and –α4.2 that correspond to the lengths of deletion in the α-globin gene. The other α+-thalassemias have several point mutations, the most common being chain-termination mutant haemoglobin Constant Spring called αCSα. The second group α0-thalassemias are due to deletion of both the α-globin genes (-/-), which might occur in heterozygous condition with α+-thalassemias (-α/- or αCSα/-). The ATR-16 syndrome, which involves α-globin gene on chromosome 16, was shown to be associated with mental retardation, also called α-thalassemia x-linked intellectual disability (ATRX).
The clinical categorization of thalassemias is being simplified based on clinical-management criteria. As transfusion remains the major form of therapy, the patients are divided into transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The NTDT may still need a transfusion but not at the same rate as TDT, primarily for the prevention or management of certain diseases. Patients with β-thalassemia intermedia, haemoglobin H and moderate forms of haemoglobin E/β-thalassemia usually constitute NTDT. The TDT patients have β-thalassemia major and severe forms of haemoglobin E/β-thalassemia. Suppressing the abnormal erythropoiesis by transfusion can control downstream pathological mechanisms in thalassemia. Some of the long-term follow-up studies which evaluated birth cohorts of patients with β-thalassemia major found that transfusion along with iron-chelation improves survival. Transfusion therapy, however, does have the risk of secondary-iron overload as the human body does not have a means to excrete iron. Patients receiving 2-4 units of blood per month will have 5,000-10,000 mg of iron per year. This leads to more iron than the capacity of transferrin, thus causing hepatic and extrahepatic tissue damage. The extra non transferrin-bound iron also can transport into cardiomyocytes, hepatocytes, pancreatic β cells and anterior pituitary cells, generating reactive-oxygen species damaging subcellular organelles.
Controlling iron overload
The iron overload warrants prompt diagnosis in NTDT as it can cause substantial morbidity and mortality and in patients with TDT, excess iron can be seen as early as 2-6 years of age. Cardiomyopathy has been observed as a leading cause of mortality in TDT patients, whereas osteoporosis, thrombosis, pulmonary hypertension, silent strokes, hypogonadism, hypothyroidism and renal diseases are strongly associated with NTDT iron overload. Of the several methods, serum ferritin assessment is commonly used to indicate the need for initiation of iron-chelation therapy, for example in TD. Maintaining concentrations lower than 1000µg/L of ferritin leads to better-sustained therapy. Serum ferritin concentrations above 2500 µg/L are strongly associated with an increased risk of cardiac and other diseases. Superconducting Quantum Interference Device (SQUID) is one of the important technologies to assess liver iron concentration, but is not widely used. Magnetic Resonance Imaging (MRI) has become the best alternative for non-invasive liver iron concentration evaluation. There are three iron chelators currently available for iron overload namely deferoxamine, deferasirox and deferiprone.
Traditionally, splenectomy is performed as an alternative or as an adjunct to transfusion therapy. However, it has become obsolete in patients with TDT due to potential infections, but is used in NTDT. In patients with β-thalessemia intermedia, there is an increased risk of long-term thrombosis along with end-organ damage as the spleen also acts as a reservoir of toxic iron. Presently, splenectomy is recommended only for patients who are unable to receive transfusion and iron-chelating therapy and also have clinical symptoms of splenomegaly or hypersplenism. One of the best cures available for thalassemia with more than 80% disease-free survival is the replacement of mutant haematopoietic cells with haematopoietic stem cells when matched sibling donors are available. Further improvements in the graft-versus-host disease and inducing graft tolerance have resulted in more unrelated donors with overall survival of 65%. These improvements are showing that more novel therapies are in good progress and might result in better treatment regimes for thalassemia.
The author is medical scientist and former director of SGRF, Bangalore