Cardiac aspects of ß-Thalassemia

Epidemiology 

Thalassemias are among the commonest genetic disorders worldwide, with 94 million homozygotes born each year. The homozygous form of ß-Thalassemia major (Cooley’s anemia) is caused by the defective production of ß-chains of globin. The excess a chains that are formed do not self-associate to form tetramers but instead are bound to the red cell membrane, producing membrane damage. The severity of the disease varies with different mutations. Some mutations prevent the formation of any ß-chains at all; others allow some formation to occur. Thus depending on which mutation is inherited, a broad spectrum of compromise of ß-chains formation can be found. It is the most severe form of congenital hemolytic anemia and the first cause of cardiac death in people under 35 years in Mediterranean and Asian countries. These mutations are concentrated in populations in which they have conferred an advantage upon the carrier. This is the resistance to infection with malaria, which counterbalances the deleterious effect of the homozygous state.

Treatment

Patients usually require regular blood transfusions to survive beyond the second decade of life. This intervention prolongs survival, however, the chronic administration of large amounts of blood combined with extravascular hemolysis and an increase in the intestinal absorption of iron inevitably leads -despite chelation therapy- to significant hemosiderosis of all organs, including the heart. Chelation treatment is the only way to avoid tissue iron overload. Untreated patients with bone marrow changes due to increased erythropoiesis have a characteristic “chipmunk” face and often growth retardation. The skin may have a peculiar copper color from pallor, icterus and melanin deposition.  Hepato-splenomegaly is common. The disease, if left untreated, is uniformly fatal in childhood.

Diagnosis

Measurement of globin chain synthetic ratios is a definite method of diagnosis. In ß-Thalassemia major there are also elevated levels of fetal hemoglobin. Although ß-Thalassemia major is traditionally considered as an iron storage disease, it is not a simple haemochromatosis, but a combination of chronic hemolytic anemia, iron storage disease and myopericarditis, which is possibly related to high incidences of infections due to abnormalities of the immune system. The role of myocarditis has been reported as an important factor in the development of heart failure in these patients (1).

Prognosis

Heart failure and arrhythmias are the major cause of death in patients with b-thalassemia. Iron cardiomyopathy is reversible, if chelation starts in time, but the diagnosis is often delayed due to late appearence of symptoms and echocardiographic abnormalities. Once heart failure develops, the prognosis is poor with precipitous deterioration and death, despite intensive chelation. Heart failure should be treated by the same way as other causes of heart failure and simultaneously chelation therapy should be intensified. Conventional chelation treatment with subcutaneous desferrioxamine does not prevent cardiac iron deposition in 2/3 of patients, placing them at risk of heart failure. Additionally, desferrioxamine may cause skin reactions at the injection site or neurologic side effects, particularly visual and auditory. Oral deferiprone is more effective than desferrioxamine in removal of myocardial iron (2).

Cure

Bone-marrow transplantation offers the only complete cure for ß-thalassemia, but can only be applied in selected patients. Although this method carries some risk of death due to the procedure itself, and in some patients the thalassemic cells regrow, displacing the graft, it plays an important role in the treatment.  After successful bone marrow transplantation (BMT), thalassemic patients reach the normal haemoglobin concentrations using the donor bone-marrow and require no more transfusions. However, if transplantation is performed in patients with advanced disease, the correction of thalassemic defect is not sufficient, because they still have a degree of organ iron overload and dysfunction, acquired during the pre-transplantation years. According to recent data, serum ferritin and unbound iron binding capacity (UIBC) were moderately abnormal 7 years after transplantation, in a moderate iron loaded group, and highly abnormal in a high-loaded group (3). These findings confirm the presence of iron overload at the time of transplantation and support the need for iron depletion treatment after BMT. There is a great concern about persistent long-term iron liver overload, because it increases the risk of fibrosis, cirrhosis and hepatoma in these patients. Also long-term myocardial iron overload can also contribute to cardiomyopathy and heart failure.  

Prevention

Therefore, it is imperative to document precisely the myocardial iron deposition in order to understand the pathogenesis of heart dysfunction. Clinically it is difficult to predict at an early stage, which patients are at high risk of dying from iron related heart failure. Many indirect indices such as serum ferritin, liver biopsy, ECG and echocardiograms have been proposed. The measurement of plasma ferritin provides an indirect index to estimate the body iron stores, but the usefulness of this measurement is limited by many common clinical conditions in which plasma ferritin is not a reliable index of body iron. Serum ferritin is influenced by many factors such as inflammation, fever, liver disease, infections, hemolysis, ineffective erythropoiesis, and ascorbic deficiency. Although liver biopsy generally represents total body iron load, it does not reflect myocardial iron deposition, which usually takes place later and in a lesser degree compared to the liver (4). Additionally it is an invasive procedure, which can not be repeated for routine follow-up.  Some studies suggest that maintenance of serum ferritin below 2500 mcg/l as satisfactory, but many patients with ferritin below this level have died from heart failure. Echocardiography does not detect iron deposition and it is a late indicator of heart involvement in ß-Thalassemia, revealing the cases where impaired heart function is already present.
 
Recently, magnetic resonance imaging (MRI) has been used for the detection of iron deposition. The technique is based upon the ability of stored intracellular iron to enhance the magnetic susceptibility of the tissues. Tissue iron is detected indirectly by the effects on relaxation times of ferritin and hemosiderin iron, interacting with hydrogen nuclei. Paramagnetic ferritin and hemosiderin iron shorten proton relaxation times, particularly T2 and T2*. Conventional MRI measurements are affected by iron excess, the instrumentation used, the applied field strength, the repetition time used in the imaging sequence, and other technical aspects. Myocardial T2* seems to be the most sensitive and easily reproducible index of myocardial iron deposition. MRI parameters correlate with biopsy results from both liver and heart and are accurate indices to assess noninvasively liver and heart iron deposition (5, 6). Since heart failure remains the commonest cause of death, the effectiveness of chelation therapy should be evaluated by monitoring both cardiac and liver iron deposition using MRI.

Figure 1. MRI of myocardium and liver of a thalassemic patient with high (top) and low (bottom) iron deposition. Heavier iron deposition is indicated by darker appearance of heart and myocardium.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.