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Query: UMLS:C0039730 (thalassemia)
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New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these developments are likely to have an even greater impact in the next few years. Demographic changes have required an awareness and understanding of the unique features of thalassemia disorders that were previously uncommon in North America but are now seen more frequently in children and recognized more consistently in adults. New methods for measuring tissue iron accumulation and new drugs to remove excessive iron are advancing two of the most challenging areas in the management of thalassemia as well as other transfusion-dependent disorders. Improved survival of patients with thalassemia has given new importance to adult complications such as endocrinopathies and hepatitis that have a major impact on the quality of life. This chapter describes how these changes are redefining the clinical management of thalassemia. In Section I, Dr. Renzo Galanello describes recent advances in iron chelation therapy. Several new chelators are either licensed in some countries, are in clinical trials or are in the late stages of preclinical development. Some of these iron chelators, such as deferiprone (DFP) and ICL670, are orally active. Others, such as hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, require parenteral administration but may be effective with less frequent administration than is currently required for deferoxamine. Chelation therapy employing two chelators offers the possibility of more effective removal of iron without compromising safety or compliance. Other strategies for chelation therapy may take advantage of the ability of particular chelators to remove iron from specific target organs such as the heart and the liver. In Section II, Dr. Dudley Pennell addresses cardiac iron overload, the most frequent cause of death from chronic transfusion therapy. The cardiac complications related to excessive iron may result from long-term iron deposition in vulnerable areas or may be due to the more immediate effects of nontransferrin-bound iron. Cardiac disease is reversible in some patients with intensive iron chelation therapy, but identification of cardiac problems prior to the onset of serious arrhythmias or congestive heart failure has proven difficult. New methods using magnetic resonance imaging (MRI) have recently been developed to assess cardiac iron loading, and studies suggest a clinically useful relationship between the results using these techniques and critical measures of cardiac function. Measurements such as T2* may help guide chelation therapy in individual patients and may also enhance the assessment of new chelators in clinical trials. The use of MRI-based technology also holds promise for wider application of non-invasive assessment of cardiac iron in the management of patients with thalassemia. In Section III, Dr. Melody Cunningham describes some of the important complications of thalassemia that are emerging as patients survive into adulthood. Hepatitis C infection is present in the majority of patients older than 25 years. However, antiviral therapy in patients with thalassemia has been held back by the absence of large clinical trials and concern about ribavirin-induced hemolysis. More aggressive approaches to the treatment of hepatitis C may be particularly valuable because of the additive risks for cirrhosis and hepatocellular carcinoma that are posed by infection and iron overload. Thrombosis is recognized with increasing frequency as a significant complication of thalassemia major and thalassemia intermedia, and pulmonary hypertension is now the focus of intense study. Risk factors for thrombosis such as splenectomy are being identified and new approaches to anticoagulation are being initiated. Pregnancies in women with thalassemia are increasingly common with and without hormonal therapy, and require a better understanding of the risks of iron overload and cardiac disease in the mother and exposure of the fetus to iron chelators. In Section IV, Dr. Elliott Vichinsky describes the dramatic changes in the epidemiology of thalassemia in North America. Hemoglobin E-beta thalassemia is seen with increasing frequency and poses a particular challenge because of the wide variability in clinical severity. Some affected patients may require little or no intervention, while others need chronic transfusion therapy and may be appropriate candidates for hematopoietic stem cell transplantation. Enhancers of fetal hemoglobin production may have a unique role in Hb E-beta thalassemia since a modest increase in hemoglobin level may confer substantial clinical benefits. Alpha thalassemia is also being recognized with increasing frequency in North America, and newborn screening for Hemoglobin Barts in some states is leading to early detection of Hb H disease and Hb H Constant Spring. New data clarify the importance of distinguishing these two disorders because of the increased severity associated with Hb H Constant Spring. The use of intrauterine transfusions to sustain the viability of fetuses with homozygous alpha thalassemia has created a new population of patients with severe thalassemia and has raised new and complex issues in genetic counseling for parents with alpha thalassemia trait.
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PMID:Thalassemia. 1556 74

A 52-year-old woman with nonspecific left leg pain was examined by Tc-99m methylene diphosphonate (MDP) bone scintigraphy. The patient had been a marble quarry worker for 10 years and had developed chronic congestive heart failure secondary to pneumoconiosis. Her hemoglobin analysis and hematologic findings were interpreted as being consistent with sickle cell beta+ thalassemia and also hypersplenism. Bone scintigraphy showed intense and diffuse MDP accumulation in the enlarged spleen without ultrasonographic or radiologic evidence of calcification.
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PMID:Diffuse splenic Tc-99m MDP uptake in hypersplenic patient. 1568 53

With the introduction of "hypertransfusion" regimens the extent of disease- and therapy-related hemosiderosis has become the survival limiting factor for patients with beta-thalassemia major as iron transferred with transfusions cannot be excreted by physiological means. Subsequent introduction of deferoxamine therapy for iron elimination and prophylaxis of hemosiderosis has improved prognosis and life quality of these patients considerably. We report our experience with seven adolescent patients with beta-thalassemia and ineffective subcutaneous therapy and severe hemosiderosis-related organ complications. For that reason they received i. v. intensified chelate therapy. The patients were given 70 to 120 mg/kg DFO 7 days a week continuously via a Port-a-cath or Hickman central venous line. Under high-dose i. v. DFO therapy, serum ferritin levels significantly decreased in all patients. Target serum ferritin levels of 3 000 ng/ml were reached after 12 to 20 months of treatment. In 3 of the 5 patients that were treated for longer than 43 months serum ferritin levels even dropped below 2 000 ng/ml. Serum ferritin levels also correlated well with SQUID examinations. Therefore, monitoring of serum ferritin may be useful to monitor patient's compliance and control intensified DFO therapy. Continuous administration of the intensified DFO therapy induced normalization of liver function and left ventricular cardiac function in all patients who are still alive. Two patients died due to cardiac decompensation. In five patients 19 episodes of central catheter-related infections were observed (1.5 infections per 1 000 catheter days). No DFO-associated allergic reactions nor irreversible organ dysfunction were observed. Our results indicate that intensified i. v. DFO therapy is an effective and safe method for treatment of severe organ dysfunction in patients with thalassemia major. The most severe problems are catheter-related infections and inconsistent long-term compliance.
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PMID:Intensification of chelating-therapy in patients with thalassemia major. 1585 2

Congestive heart failure (CHF) remains the primary cause of death in patients suffering from beta-thalassaemia major. Its early detection allows the prompt initiation of aggressive chelation therapy, when the condition can still be reversed. We aimed at identifying echocardiographic indices for the early detection of left ventricular (LV) systolic dysfunction, the physiological abnormality underlying CHF, in these patients. We used Self-Organizing Maps (SOMs)--an artificial neural network--for identifying novel correlations within our Electronic Healthcare Record (EHCR) database on beta-thalassaemia. We sought echocardiographic parameters that are correlated to future deterioration of the LV ejection fraction and therefore constitute early signs of LV systolic dysfunction. At the same time, we evaluated SOMs as tools for exploring clinical datasets and make recommendations on the setup of the SOM algorithm that is appropriate for such tasks. We found that high values of the LV end-systolic diameter index and of the E/A ratio are early indications of LV systolic dysfunction. From a technical point of view, zero-mean unit-variance normalization of the input data, a large initial neighbourhood radius and a rectangular SOM grid produced optimal maps for the purpose of detecting clinical correlations. We have successfully used SOMs for exploring a clinical dataset and for creating novel medical hypotheses. A clinical study has been launched to confirm these hypotheses, and initial results are encouraging.
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PMID:Identification of echocardiographic indices for the early detection of left-ventricular systolic dysfunction in beta-thalassaemia via Self-Organizing Maps: a data-exploration study. 1603 29

The incidence of cardiomyopathy was monitored in a 6-year follow-up study involving 56 transfused thalassemia patients treated with deferoxamine (DFO), deferiprone (L1) or their combination. During this period, five female patients on regular subcutaneous or intravenous DFO presented with cardiac complications. Three patients suffered congestive heart failure and the other two arrhythmias. Four of the five patients maintained serum ferritin levels of about 1 mg/L or below and the fifth about 1.5 mg/L for several years prior to the cardiomyopathy. Cardiac magnetic resonance imaging (MRI) T2* and T2 was performed in four patients after the cardiomyopathy, identifying the presence of moderate-to-heavy siderosis. The treatment of the five patients has since changed, involving mainly the use of L1. Low serum ferritin levels appear to be misleading for detecting cardiac iron overload and this may increase the risk of cardiomyopathy. The MRI T2 and T2* relaxation time measurements are a more accurate method of detecting cardiac iron overload. Chelation therapy using L1 or appropriate L1/DFO combinations can reduce cardiac iron overload and the mortality rate in thalassemia patients.
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PMID:Low serum ferritin levels are misleading for detecting cardiac iron overload and increase the risk of cardiomyopathy in thalassemia patients. The importance of cardiac iron overload monitoring using magnetic resonance imaging T2 and T2*. 1679 47

Heart disease is the leading cause of mortality and one of the main causes of morbidity in beta-thalassemia. The clinical spectrum of the thalassemia syndrome ranges from the severe, transfusion--dependent thalassemia major and the asymptomatic carrier state. Thalassemia intermedia represents a milder form and is usually transfusion-independent. Two main factors determine cardiac disease in this form. One is the high output state that results from chronic tissue hypoxia and from hypoxia-induced compensatory reactions. The other is the vascular involvement that leads to an increased pulmonary vascular resistance and an increased systemic vascular stiffness. Valvular abnormalities and iron overload also contribute to a less extent. As a result, both right and left ventricles have to maintain a high cardiac output level through a stiff vascular bed. Right heart involvement with age-related pulmonary hypertension followed by congestive heart failure dominates the clinical picture. Although the left heart is also affected, systolic left ventricular function is usually preserved but this may also be decompensated under conditions characterized by excessive cardiac work load.
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PMID:Heart disease in thalassemia intermedia: a review of the underlying pathophysiology. 1748 90

Beta-thalassaemia major is a chronic haemolytic anaemia, and congestive heart failure (CHF) is the most common cause of death in this disease. N terminal pro B type natriuretic peptide (NT-proBNP) increases with the severity of CHF and predicts the prognosis. The aim of this study was to investigate the relation between left ventricular systolic and diastolic function determined by standard pulsed wave Doppler (PWD), tissue Doppler imaging (TDI) and NT-proBNP in patients with beta-thalassaemia major. Thirty-four patients with beta-thalassaemia major and 34 healthy individuals were included in the study. Blood samples were taken for NT-proBNP. All patients and controls underwent echocardiographic examination. All cardiac chambers were significantly increased in the patient group. Left and right ventricular (LV, RV) ejection fractions and all diastolic parameters were normal in the patients and controls. Tissue Doppler imaging (TDI) showed a significant decrease in LV and RV Sm velocities in patients compared to the controls. NT-proBNP levels were also significantly higher in the patient group. There was a negative correlation between serum NT-proBNP levels and LV Sm and RV Sm velocities in patients (r = -0.426, P = 0.006 and r = -0.409, P = 0.009, respectively). Linear regression analysis showed that LV Sm and RV Sm were independent predictors for NT-proBNP. Our findings suggest that although iron overload in patients with beta-thalassaemia major impairs the systolic and diastolic functions of both ventricles, it impairs the systolic function earlier than diastolic function. Tissue Doppler imaging is an easy and reliable method in the early determination of ventricular dysfunction in these patients.
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PMID:Tissue doppler imaging and NT-proBNP levels show the early impairment of ventricular function in patients with beta-thalassaemia major. 1760 95

Chronic hypercoagulable state expressed clinically by thromboembolic events has been described in thalassemia. One of the affected organs is the brain where symptomatic and asymptomatic damage has been reported. The present report describes seven cases who presented with the signs of cerebrovascular accident (CVA), five ischemic and two with hemorrhage. Two of them died. All patients were splenectomized, five received regular blood transfusions, and their ferritin levels were between 1,200 and 3,000 mg %. In addition, four patients had congestive heart failure and atrial fibrillation, and three had "Bronze diabetes," The recommendation on the basis of the results is that well-designed clinical trials are indicated to monitor asymptomatic brain damage by magnetic resonance imaging in splenectomized patients over the age of 20 years, who are not regularly transfused and have a high risk to develop thromboembolic events. In this subset of patients, anticoagulant and/or antiplatelet therapy should be considered. Moreover, treatment of additional complications resulting from iron overload, which may contribute to the etiology of CVA such as cardiac failure and arrhythmia with or without "bronze diabetes," is mandatory.
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PMID:Cerebrovascular accident in beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI). 1818 11

Congestive heart failure is the most common cause of death in patients with thalassemia, as chronic accumulation of iron due to regular blood transfusions leads to biventricular systolic dysfunction and death at a very young age. The quantity of iron deposited in the heart is a key determinant of outcome. Early diagnosis and intensive chelation of the cardiac iron can avert heart failure and its fatal outcome.
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PMID:Getting the iron out: preventing and treating heart failure in transfusion-dependent thalassemia. 1802

Cardiac disease remains the major cause of death in thalassaemia major. This review deals with the mechanisms involved in heart failure development, the peculiar clinical presentation of congestive heart failure and provides guidelines for diagnosis and management of the acute phase of cardiac failure. It emphasizes the need for intensive medical--cardiac care and aggressive iron chelating management as, with such approaches, today, the patients outcomes can be favourable in the long term. It covers advances in the assessment of cardiac iron overload with the use of magnetic resonance imaging and makes recommendations for preventing the onset of cardiac problems by tailoring iron chelation therapy appropriate to the degree of cardiac iron loading found.
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PMID:The heart in transfusion dependent homozygous thalassaemia today--prediction, prevention and management. 1808 19


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