Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia

BACKGROUND: Heart disease represents the main determinant of survival in beta-thalassemia, but its particular features in the two clinical forms of the disease, thalassemia major (TM) and thalassemia intermedia (TI), are not completely clarified. METHODS: We compared clinical and echocardiographic global parameters in 131 TM patients who received regular chelation transfusions and were highly compliant with treatment (mean age, 28 +/- 6 years [+/- SD]), and 74 age-matched, TI patients who did not receive chelation transfusions. RESULTS: Congestive heart failure was encountered in five patients with TM (3.8%; age range, 25 to 29 years) and in two patients with TI (2.7%; age range, 37 to 40 years). Systolic left ventricular (LV) dysfunction (ejection fraction < 55% or shortening fraction < 35%) was only encountered in patients with TM (8.4%). Considerable pulmonary hypertension (systolic tricuspid gradient > 35 mm Hg) was only present in TI (23.0%). In the remaining patients without evident heart disease, cardiac dimensions, LV mass, LV shortening and ejection fractions, and cardiac output were significantly higher in patients with TI. LV afterload was higher in patients with TM. LV diastolic early transmitral diastolic peak flow velocity (E)/late transmitral diastolic peak flow velocity (A) ratio was also higher in TM. Systolic and mean pulmonary artery pressures and total pulmonary resistance were higher in both young and old TI patients. CONCLUSION: Regular lifelong transfusion and chelation therapy in TM prevented premature heart disease and pulmonary hypertension, although LV dysfunction still occurred and led to heart failure. The absence of regular therapy in TI, in contrast, preserved systolic LV function but allowed pulmonary hypertension development, which also led to heart failure, starting within the fourth decade of life, a decade later compared to TM.     

Serum inhibitors to granulopoiesis in thalassemia major

Peripheral blood (pb) and bone marrow CFU-C were evaluated in patients with thalassemia major. A decrease in both pb and marrow CFU-C was noted when compared to normal donors and individuals with hemolytic anemia requiring transfusion therapy. Experiments suggested that a nondialyzable serum factor was resonsible for the depressed pb CFU-C in 6 and of 6 children with thalassemia. Serum lipoprotein electrophoresis revealed type IV pattern in 9 out of 18 children with elevation of the pre-beta fraction. These experiments suggest (1) decreased stem cell CFU-C, (2) decreased pb CFU-C, and (3) a serum inhibitor that may be contributing to the depressed pb CFU-C.     

Echocardiographic finding in beta‐thalassemia intermedia and major: absence of pulmonary hypertension following hydroxyurea treatment in beta‐thalassemia intermedia

Objectives: The aim of this study was to investigate the echocardigraphic finding in β‐thalassemia intermedia (TI) and β‐thalassemia major (TM) and to compare this finding together and with healthy control subjects. Methods: Fifty TI, who have been treated with hydroxyurea (HU) for 7 yrs and 51 transfusion dependent TM were compared with 50 age and sex matched healthy control subjects. Left and right ventricular parameters, systolic and diastolic functions, stroke volume, cardiac index and indices of pulmonary hypertension (PHT) were determined by two‐dimensional, M‐mode echocardiography and Doppler echocardiography. Results: Left ventricular parameters such as left ventricular end diastolic diameter, left ventricular end systolic diameter and also interventricular septal diameter in systole and diastole were significantly higher in TI patients compared with TM and control group (P < 0.05). There was elevated left ventricular mass (LV mass) in TI and TM patients compared with controls (P < 0.05). Regarding the LV diastolic function indices, E and A were significantly higher in TI patients compared with TM patients and control which were compatible with high output state. Measurement of pulmonary acceleration time and tricuspid and pulmonary valve continuous‐wave Doppler tracing in patients with tricuspid regurgitation and pulmonary insufficiency showed no difference between TI, TM and control group. Conclusion: Both TI and TM patients who have no clinical signs of cardiac involvement have significant abnormalities in volume, mass and shape of the LV which may be the consequence of chronic anemia. We found the unexpected absence of PHT in TI patients who have been treated with HU. In conclusion Low dose HU treatment of TI patients may prevent the devastating complication of PHT.     

Serum erythropoietin and erythropoiesis in high- and low-fetal hemoglobin beta-thalassemia intermedia patients

Clinical data suggest that in beta-thalassemia-intermedia patients, higher levels of circulating fetal hemoglobin (HbF) are associated with greater disease severity at comparable degrees of anemia. We assessed the influence of the amount of circulating HbF on serum erythropoietin (s-Epo) levels and on serum transferrin receptor, a measure of erythropoiesis, in 30 beta-thalassemia-intermedia patients. Twenty-four showed more than 40% HbF (21 of whom with beta (0)-thalassemia) and 6 presented lower HbF levels (beta(+)-thalassemia). The two groups of patients did not differ in age (15.3 v 19 years, respectively) or degree of anemia (Hb = 8.8 g/dL in both groups). Log (s-Epo) was correlated inversely with Hb (r = -0.47; P < .01), and directly with HbF (r = .55; P < .001). Multivariate regression analysis showed that Hb and HbF were independently correlated with s-Epo levels. High-HbF patients had greater s-Epo values at the same Hb level than low-HbF patients. Considering that iron-deficiency anemia control patients represented the predicted physiologic response of s-Epo to anemia, the observed/predicted s-Epo ratio in low-HbF thalassemic patients was no different from controls, but was increased in the high-HbF group. High- HbF patients also showed an expansion of erythropoiesis as much as four to nine times the normal value at the same Hb level as low-HbF patients. We conclude that HbF exerts an independent regulatory effect on erythropoietin production and erythropoiesis that is detectable only when HbF levels exceed 40%.     

A comparison of heart function and arrhythmia in clinically asymptomatic patients with beta thalassemia intermedia and beta thalassemia major

Background: The goal of this study was to compare heart function and arrhythmia in clinically asymptomatic patients with beta thalassemia intermedia and beta thalassemia major.

Method: In this cross-sectional study, 60 patients with beta thalassemia major and 60 patients with beta thalassemia intermedia who had clinically no symptoms of arrhythmia and clinically normal heart function were evaluated using 24-hour ambulatory electrocardiogram monitoring and echocardiography. For data analysis SPSS ver.20 software was used. A P-value of less than 0.05 was considered statistically significant.

Results: The mean age of the beta thalassemia intermedia patients was 24.18 ± 7.9 years and the mean age in beta thalassemia major was 24.38 ± 7.7 years (P>0.05). Premature atrial contractions (PACs) were observed in 14 (23.3%) patients with beta thalassemia intermedia and in 22 (36.6%) beta thalassemia major patients. Premature ventricular contractions (PVCs) were detected in 8 (13.3%) patients in the beta thalassemia intermediate group and 16 (26.6) patients in the beta thalassemia major group, respectively. The left ventricular diastolic dimension, end-diastolic volume, and stroke volume were significantly higher in beta thalassemia intermedia group (P<0.05). Pulmonary acceleration time as an indicator of pulmonary pressure was lower in beta thalassemia intermedia group.

Conclusion: Both atrial and ventricular arrhythmias were more common in the beta thalassemia major group. Higher end-diastolic volume and stroke volume were detected in the beta thalassemia intermedia group. Pulmonary acceleration time was lower in the beta thalassemia intermedia group, which can be an indicator of higher pulmonary pressure.     

Molecular, hematological and clinical aspects of thalassemia major and thalassemia intermedia associated with Hb E-beta-thalassemia in Northeast Thailand

Hb E-beta-thalassemia is the most common form of beta-thalassemia found in Thailand. The disease exhibits a varied clinical expression ranging from severe transfusion dependence to relatively mild thalassemia intermedia. We evaluated the effects of primary and secondary genetic factors in modulating the hematological and clinical presentation of 148 northeast Thai patients including 103 severe thalassemia major (TM) and 45 thalassemia intermedia (TI). Among 148 cases examined, eleven different mutations including two novel ones; (beta(33/34 (-G)) and beta(IVS2#815 C-T)) were identified in trans to the beta(E) gene in two TM cases. The other 9 known mutations included beta(41/42), beta(17), beta(IVS2#654), beta(-28), beta(71/72), beta(35), beta(IVS1#5), beta(IVS1#1) and beta(41). Except for the beta(-28) mutation which was found only in the TI group, others mutations were identified in both TM and TI. Co-inheritance of alpha-thalassemia as a phenotype modulating factor was not evident in this study, nor was the presence of the -158 (G)gamma-globin Xmn I polymorphism. Further analysis of the polymorphic (TG)n(CG)m repeats within the IVS2 of the two gamma-globin genes revealed no different proportions of the polymorphic patterns among TM and TI groups of patients either. Our data reveals that in the majority of these Hb E-beta-thalassemia patients, it is very hard to predict the clinical phenotype of the patients from the beta-globin mutations and these secondary genetic modifiers.     

Intervertebral disc calcification in thalassemia intermedia

Objectives:  Intervertebral disc calcification, an age-related phenomenon of variable clinical significance is described in hemochromatosis. As β-thalassemia is characterized by excessive tissue iron deposition and secondary hemosiderosis, and skeletal abnormalities are often observed in these patients, this study is conducted to identify the prevalence of Intervertebral Disc Calcification (IDC) in thalassemia intermedia population.
Methods:  We investigated all the elder than 30 years β-thalassemia intermedia patients of our Department thalassemia unit . Patients underwent thoracic and lumbar spinal X-rays for IDC presence. Patients presenting IDC were compared to those not presenting, regarding back pain anamnesis, presence of back pain, extramedullary hemopoiesis, sex, age, Hb levels, ferritin levels, reticulocytes, bilirubin values, thyroid–parathyroid abnormalities. Student's t- test was used to compare variables between patients with and without IDC. A P- value under 0.05 was considered statistically significant.
Results:  We investigated 30 β-thalassemia intermedia patients (19 women) with an age range 38–61 yr (42.5 ± 11.46 yr ). Intervertebral disc calcifications were observed in seven patients (23.33%). No sex and laboratory parameters statistically significant differences were observed differences for IDC prevalence, while mean age and back pain history was statistically significantly different between the two groups.
Conclusions:  In thalassemia patients, the big variety of spinal deformities may hide the presence of IDC and thus, this entity may be overlooked or underestimated. The clinical significance of IDC development as well as the possible prevention by early transfusion chelation therapy should be further investigated.     

Serum erythropoietin levels in the elderly.

We evaluated the relationship between erythropoietin (EPO) and hemoglobin (Hb) concentrations in 156 normal subjects ranging from 60 to 98 years old. EPO was determined by a radioimmunoassay. The serum EPO concentration in subjects with Hb concentrations greater than 12.0 g/dl (26.9 +/- 15.2 mU/ml), was significantly higher than that in younger controls (15.8 +/- 5.0 mU/ml, p less than 0.001). No sex difference in serum EPO level was detected. In addition, there was an inverse semilogarithmic relationship between EPO and Hb concentrations in subjects with Hb concentrations less than 12.0 g/dl (r = -0.559, p less than 0.001). EPO concentrations in the elderly were lower than those in young subjects with iron deficiency anemia with the same Hb level. Thus, in the elderly, a high EPO concentration may be preventing a decrease in the Hb concentration. However, a decreased EPO response to low Hb concentrations may be a contributing factor in anemia in the elderly.     

Radiotherapy combined with erythropoietin for the treatment of extramedullary hematopoiesis in an alloimmunized patient with thalassemia intermedia

 We report a patient with thalassemia intermedia who developed a mediastinal syndrome due to the growth of paravertebral hematopoietic masses in the posterior mediastinum. Because the patient did not receive blood transfusions due to alloimmunization, she was first treated with human recombinant erythropoietin (escalating low-moderate doses) to recover hemoglobin levels, then in association with radiotherapy to prevent a worsening of her anemia. The mean Hb level dramatically increased and peaked at week 11, to 83 g/l, and remained unchanged before and after radiotherapy (81 versus 78 g/l). Immediately after radiotherapy extramedullary hematopoiesis volume decreased by 16.4%. Received: 12 December 1995 / Accepted: 7 March 1996     

Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia

Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The reported effects of these agents in increasing total Hb, however, have been inconsistent and there have been no studies on the combination of these medications. We describe the clinical response, as determined by increases in total Hb and decreased transfusion needs, in five patients with thalassemia intermedia treated with HU alone or in combination with SPB. All of the patients responded with increased levels of Hb F, but the responses in total Hb varied. Of the five patients, two had a marked response in total Hb in excess of 3 g/dl, two responded modestly with an increase in total Hb of 1-2 g/dl, and one did not respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day) and higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increases in Hb. Sodium phenylbutyrate was added to treatment with HU in two patients, but failed to produce an increase in total Hb despite increasing Hb F levels. Of the four patients who responded to HU with an increase in total Hb, all reported symptomatic improvement and three have not required further transfusions. We conclude that low-dose HU therapy in patients with thalassemia intermedia may increase total Hb levels sufficiently to eliminate the need for transfusions. We, therefore, recommend a trial of HU for thalassemia intermedia patients in whom chronic transfusion therapy is being contemplated.     

Molecular basis of thalassemia intermedia in Iran

Thalassemia intermedia shows considerable heterogenity in phenotype and molecular basis. The aim of this study was to evaluate the prevalence and effect of different beta-globin mutations, alpha-globin defects and (G)gamma XmnI polymorphisms in Iranian patients. Forty-five Iranian patients with clinical criteria of thalassemia intermedia were studied. The molecular background of the diseases was investigated. The mean age of onset varied from 1.5 to 30 years. Only 22.2% of cases received occasional blood transfusions. The hemoglobin (Hb) level in more than half of the cases was stable (10-12 g/dL) with no need for blood transfusions. In most cases (88.9%) the Hb F level was more than 50%. Sixty-eight point nine percent of patients were homozygous for beta(0)-thalassemia (beta-thal) mutations. The positive XmnI polymorphism with the capability of enhancing Hb F production was seen in 60% of the studied chromosomes. Co-inheritance of alpha-globin gene defects was seen in 22.2% of cases. Only 8.9% of patients had beta(+) or beta(++) mutations. We concluded that the main molecular basis of the thalassemia intermedia phenotype in Iranian cases is co-inheritance of a positive XmnI polymorphism with beta-globin mutations, which can enhance the capability of Hb F production. Co-inheritance of alpha-globin defects and mild beta-globin mutations are second and third causes of thalassemia intermedia phenotypes respectively. These factors must be considered in genetic counseling, prediction of disease prognosis and treatment and prenatal diagnosis.     

Molecular characterization of thalassemia intermedia in Indians

Thalassemia intermedia shows considerable heterogeneity. The purpose of this study was to evaluate the prevalence and effect of common molecular determinants in thalassemia intermedia. In 73 cases of thalassemia intermedia, the possible molecular basis was co-existent a-deletions (n=16/50), homozygous XmnI polymorphism (n=17/50), both factors (n=3/50), and milder beta-alleles (n=9/50) in homozygous beta-thalassemia (total 50 cases). In heterozygous beta-thalassemia, alphaalphaalphaanti-3.7 triplication was the predominant factor (14/23 cases).