Distribution of serum lipids and lipoproteins in patients with beta thalassaemia major; an epidemiological study in young adults from Greece

BACKGROUND: Beta-thalassaemia major (b-TM) has been defined as a combination of chronic hemolytic anemia, iron storage disease and myocarditis, and it has been associated with premature death especially due to heart failure. To the best of our knowledge the status of blood lipids in these patients has rarely been investigated. Thus, we assessed the levels of lipids and lipoproteins in a sample of cardiovascular disease free adult men and women with b-TM. METHODS: During 2003 we enrolled 192 consecutive patients with b-TM that visited our Institution for routine examinations. The Institution is considered the major reference center for b-TM in Greece. Of the 192 patients, 88 were men (25 ± 6 years old) and 104 women (26 ± 6 years old). Fasting blood lipid levels were measured in all participants. RESULTS: Data analysis revealed that 4% of men and 2% of women had total serum cholesterol levels > 200 mg/dl, and 11% of men and 17% of women had triglyceride levels > 150 mg/dl. In addition, mean HDL cholesterol levels were 32 ± 11 mg/dl in men and 38 ± 10 mg/dl in women, lipoprotein-a levels were 8.3 ± 9 mg/dl in men and 8.8 ± 9 mg/dl in women, apolipoprotein-A1 levels were 111 ± 17 mg/dl in men and 123 ± 29 mg/dl in women, and apolipoprotein-B levels were 60 ± 20 mg/dl in men and 59 ± 14 mg/dl in women. Total-to-HDL cholesterol ratios were 3.7 ± 1.2 and 3.8 ± 1.5 in men and women, respectively. CONCLUSIONS: The majority of the patients had blood lipid levels (by the exception of HDL-cholesterol) within the normal range, and consequently the prevalence of lipid and lipoprotein abnormalities was much lower as compared to the general population of the same age. Interestingly, is that the total – to HDL cholesterol ratio was high in our patients, and may underline the importance of this index for the prognosis of future cardiac events in these patients

Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit

Background. HCV infection and transfusional iron overload in Thalassemic patients may result in liver disease. HCV treatment in Thalassemia has raised safety concerns.Aim. Estimate effectiveness and tolerability of interferon-based therapy in HCV-infected Thalassemic patients.Material and methods. Over a 12-year period, consecutive patients with β Thalassemia major (TM) and chronic hepatitis C received treatment. Liver biopsy, HCV-RNA and genotyping were performed beforehand. Sustained virological response (SVR) was defined as negative HCV-RNA 6 months post-treatment. Forty eight patients (26 M-22 F, mean age 39.8) were enrolled. Twenty nine patients were treated with conventional interferon alpha (IFNa) for 48 weeks (group A). Nineteen patients (10 naïve-9 previously IFNa experienced) received pegylated interferon (PEG-IFN) (group B).Results. HCV-1 was found in 44%, HCV-2 in 14%, HCV-3 in 23% and HCV-4 in 19%. Group A: ten patients (38.5%) achieved SVR, 2 (7.5%) relapsed and 17 (54%) were non responders. Group B: five (28%) achieved SVR, 8 (44%) relapsed and 6 (28%) never responded. High HCV-RNA levels, genotype 1 and advanced liver fibrosis were independently associated with no response. Four patients (3 treated with IFNα, 1 with PEG-IFN) had to discontinue treatment due to complications.Conclusions. The response rate of IFN monotherapy in multi-transfused, HCV-infected Thalassemic patients is not inferior to that in non-multi-transfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting

Cardiac involvement in sickle beta-thalassemia

Cardiovascular involvement is a leading cause of mortality and morbidity in patients with inherited hemoglobinopathies, but it has not been adequately assessed in sickle beta-thalassemia. We evaluated 115 sickle beta-thalassemia patients, aged 34 +/- 14 years, along with 50 healthy controls, by resting echocardiography. Patients with systolic left ventricular (LV) dysfunction or severe pulmonary hypertension (PHT) also underwent left and right cardiac catheterization and cardiac magnetic resonance imaging (CMR). Left and right chamber dimensions, LV mass, and cardiac index were significantly higher in patients compared to controls (p < 0.001 in most cases). Three patients (2.9%) had reduced LV ejection fraction (< 55%); mean LV ejection fraction was significantly lower in patients (p < 0.001). Left and right ventricular systolic tissue Doppler indices and LV diastolic tissue Doppler indices were also impaired in patients. All three patients with systolic LV dysfunction had normal coronary arteries and mild myocardial iron load (CMR T2* values, 18-25 ms). Systolic pulmonary artery pressure was significantly higher in patients compared to controls (p = 0.002); PHT was present in 28 patients (27%), while severe PHT in three (2.9%). In three patients with severe PHT, only one had impaired LV ejection fraction and increased pulmonary wedge pressure. Overall, three patients (2.9%) had a history of heart failure, two with systolic LV dysfunction, and one with severe PHT. Cardiac involvement in sickle beta-thalassemia concerns biventricular dilatation and dysfunction along with PHT, leading to congestive heart failure

Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit

Background. HCV infection and transfusional iron overload in Thalassemic patients may result in liver disease. HCV treatment in Thalassemia has raised safety concerns. Aim. Estimate effectiveness and tolerability of interferon-based therapy in HCV-infected Thalassemic patients. Material and methods. Over a 12-year period, consecutive patients with p Thalassemia major (TM) and chronic hepatitis C received treatment. Liver biopsy, HCV-RNA and genotyping were performed beforehand. Sustained virological response (SVR) was defined as negative HCV-RNA 6 months post-treatment. Forty eight patients (26 M-22 F, mean age 39.8) were enrolled. Twenty nine patients were treated with conventional interferon alpha (IFNa) for 48 weeks (group A). Nineteen patients (10 naive-9 previously IFNa experienced) received pegylated interferon (PEG-IFN) (group B). Results. HCV-1 was found in 44%, HCV-2 in 14%, HCV-3 in 23% and HCV-4 in 19%. Group A: ten patients (38.5%) achieved SVR, 2 (7.5%) relapsed and 17 (54%) were non responders. Group B: five (28%) achieved SVR, 8 (44%) relapsed and 6 (28%) never responded. High HCV-RNA levels, genotype 1 and advanced liver fibrosis were independently associated with no response. Four patients (3 treated with IFNa, 1 with PEG-IFN) had to discontinue treatment due to complications. Conclusions. The response rate of IFN monotherapy in multi-transfused, HCV-infected Thalassemic patients is not inferior to that in non-multi-transfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting

The New Self-Inactivating Lentiviral Vector for Thalassemia Gene Therapy Combining Two HPFH Activating Elements Corrects Human Thalassemic Hematopoietic Stem Cells

To address how low titer, variable expression, and gene silencing affect gene therapy vectors for hemoglobinopathies, in a previous study we successfully used the HPFH (hereditary persistence of fetal hemoglobin)-2 enhancer in a series of oncoretroviral vectors. On the basis of these data, we generated a novel insulated self-inactivating (SIN) lentiviral vector, termed GGHI, carrying the (A)gamma-globin gene with the -117 HPFH point mutation and the HPFH-2 enhancer and exhibiting a pancellular pattern of (A)gamma-globin gene expression in MEL-585 clones. To assess the eventual clinical feasibility of this vector, GGHI was tested on CD34(+) hematopoietic stem cells from nonmobilized peripheral blood or bone marrow from 20 patients with beta-thalassemia. Our results show that GGHI increased the production of gamma-globin by 32.9% as measured by high-performance liquid chromatography ( p=0.001), with a mean vector copy number per cell of 1.1 and a mean transduction efficiency of 40.3%. Transduced populations also exhibited a lower rate of apoptosis and resulted in improvement of erythropoiesis with a higher percentage of orthochromatic erythroblasts. This is the first report of a locus control region (LCR)-free SIN insulated lentiviral vector that can be used to efficiently produce the anticipated therapeutic levels of gamma-globin protein in the erythroid progeny of primary human thalassemic hematopoietic stem cells in vitro

Plasma B-type natriuretic peptide concentration in beta-thalassaemia patients

Background: Plasma B-type natriuretic peptide (BNP) concentration has significant diagnostic accuracy and prognostic value in various forms of heart disease. Whether BNP is also useful in the evaluation and management of thalassaemia heart disease remains to be determined. Methods and results: Eighty three thalassaemia major patients; 8 with acutely decompensated heart failure (New York Heart Association [NYHA] class III or IV, group A), 25 with NYHA class 11 symptoms and impaired systolic left ventricular function (ejection fraction <55% or fractional shortening <30%, group B) and 50 with normal systolic function (group C), as well as 50 healthy controls, were studied. Assessment included history, physical examination, Doppler echocardiography and plasma BNP determination. Mean BNP levels were 431 219 pg/mL (range, 283-890 pg/mL) in group A, 158 +/- 31 pg/mL in group B, 1763 +/- 54 pg/mL in group C and 43 +/- 24 pg/mL in controls. BNP levels were significantly higher in group A (p < 0.001), but did not differ between groups B and C. Moreover, BNP was not correlated with left ventricular end-diastolic diameter, left ventricular mass, right ventricular diameter index, Doppler diastolic indexes (except in group C), the mean 2-year serum ferritin concentration or the peak serum ferritin concentration in any of the three patient groups. Conclusion: A potential deficiency of BNP-related neurohormonal mechanisms may impair its clinical usefulness in thalassaemia major. (C) 2006 European Society of Cardiology. Published by Elsevier B.V All rights reserved

Endothelial function and arterial stiffness in sickle-thalassemia patients

Background: Homozygous sickle-cell anemia and beta-thalassemia are characterized by impaired endothelial function, while data on arterial stiffness have hitherto been conflicting. We sought to investigate aortic elastic properties and endothelial function in sickle-thalassemia, which combines molecular and clinical features of the above conditions. Methods and results: Forty-seven sickle-thalassemia patients, younger than 45 years, with preserved left ventricular (LV) function and no history of smoking, systemic or pulmonary hypertension, diabetes mellitus, dyslipidemia or thyroid disease, along with 40 healthy controls were studied. Aortic strain, distensibility and stiffness index were calculated by echocardiographically-obtained aortic root diameters. Brachial artery endothelial function was assessed by ultrasonographic evaluation of flow-mediated dilatation (FMD) and nitrate-mediated dilatation (NMD). Left ventricle was assessed by echocardiography. Patients had an impaired FMD (4.2 +/- 2.9% versus 9.2 +/- 3.8% in controls, p < 0.001) with a preserved NMD (16.9 +/- 5.6% versus 15.2 +/- 4.8% in controls, p > 0.05). Aortic strain and distensibility were lower and aortic stiffness index was higher in patients compared to controls (8.1 +/- 4.6 versus 5.8 +/- 2.9, p < 0.01). Indexed LV diameters and mass were higher in patients. Systolic LV function was preserved, while 14.9% of patients had an impaired relaxation transmitral inflow pattern. Patients’ LV mass index and diastolic mitral E wave deceleration time were positively correlated with aortic stiffness index (p < 0.001). Conclusion: Sickle-thalassemia is characterized by a complex vasculopathy, consisting of endothelial dysfunction and increased arterial stiffness, with a global effect on cardiovascular function. (c) 2006 Elsevier Ireland Ltd. All rights reserved