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 ß 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 (PEGIFN) (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-multitransfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting.

A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births.

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.

Bone health evaluation of children and adolescents with homozygous ß-thalassemia: implications for practice.

OBJECTIVE: Bone tissue is adversely affected in patients with homozygous ß-thalassemia. The aim of this study was to find warning signs of bone loss in young patients with ß-thalassemia and allow prompt therapeutic interventions. METHODS: Thirty-eight patients were studied, 20 boys and 18 girls, aged 5 to 18 years (median = 14.13 y), on regular transfusions and chelation treatments. Their bone mineral density (BMD) was measured with dual x-ray absorptiometry. The recorded parameters were weight, height, bone age (BA), transfusion adequacy (mean fetal hemoglobin value), and chelation efficacy (mean ferritin value, compliance). Tanner stage was also evaluated: 8 prepubertal subjects (stage 1), 18 peripubertal subjects (stages 2 and 3), and 12 postpubertal patients (stages 4 and 5). Blood and urine samples were collected for biochemical analysis. RESULTS: Mean BMD z score was -1.56 ± 1.25. Thirteen patients had normal BMD (z score >-1), 17 patients had low BMD (z score: -1 up to -2.4), and 8 patients had very low BMD (z score <-2.5). Low BMD was observed in patients older than 12 years and was associated with short stature (r = 0.33, P = 0.04), delayed BA (r = 0.61, P = 0.01), and increased bone formation markers. There was no correlation of BMD z score with sex, fetal hemoglobin value, ferritin, and compliance. Regarding Tanner stage, it was associated strongly with short stature (r = 0.57, P = 0.01), ferritin (r = -0.38, P = 0.02), and compliance (r = 0.58, P = 0.01). CONCLUSIONS: [corrected] The decline in BMD may start early, even in the well-transfused patients. This study targets the young patients who are mostly at the risk for bone loss, that is short adolescents with delayed BA. Their prompt recognition in everyday practice is important, as they will need close monitoring of their BMD and metabolic bone profile. In addition, therapeutic interventions, such as adequate calcium intake and sunlight exposure, weight-bearing exercise and, in cases of vitamin D insufficiency, proper supplementation could be suggested.

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.

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.

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 II 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, 176+/-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.

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.

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.

Incidence, risk factors, and outcome of portal vein thrombosis after laparoscopic-assisted splenectomy in ß-thalassemia patients: a prospective exploratory study.

BACKGROUND: Portal vein system thrombosis (PVT) is an infrequent but potentially serious complication after laparoscopic splenectomy. Patients with ß-thalassemia are at higher risk as they have splenomegaly and hypercoagulability. SUBJECTS AND METHODS: Forty-eight ß-thalassemia patients who underwent hand-assisted laparoscopic splenectomy or laparoscopic splenectomy were studied prospectively with pre- and postoperative Doppler ultrasonography or computed tomography scanning. RESULTS: The incidence of PVT was 8.3% (95% confidence interval [CI] 0.2%-16.4%) (4 of 48 patients). Spleen weight was the only independent factor associated with the presence of PVT. The odds ratio for spleen weight (100 g increase) was 1.46 (95% CI 1.10-1.94, P=.010). Receiver operator characteristic curve analysis showed that the optimal cutoff of spleen weight to the prediction of PVT was 1543 g. Thrombosis resolution was observed after a median of 165 days. CONCLUSIONS: Patients with ß-thalassemia who undergo laparoscopic-assisted splenectomy are at high risk of postoperative PVT. Close postoperative surveillance and aggressive coagulation prophylaxis are needed in these patients. Larger studies are required to confirm the present findings.

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)γ-globin gene with the -117 HPFH point mutation and the HPFH-2 enhancer and exhibiting a pancellular pattern of (A)γ-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 ß-thalassemia. Our results show that GGHI increased the production of γ-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 γ-globin protein in the erythroid progeny of primary human thalassemic hematopoietic stem cells in vitro.

Hand-assisted laparoscopic surgery with a Pfannenstiel incision in beta-thalassemia patients: initial experience.

INTRODUCTION: beta-Thalassemia patients have splenomegaly significant enough to require splenectomy; furthermore, these patients also often require concurrent procedures. METHODS: Between January and October 2005, seven patients with beta-thalassemia underwent hand-assisted laparoscopic splenectomy with cholecystectomy, appendectomy, and liver biopsy with the hand-port device introduced through a Pfannenstiel incision. RESULTS: The median age of the patients was 28 years, and the median spleen length was 23 cm. The median operating time was 210 minutes; there were no conversions to an open procedure; and the median spleen weight was 1072 g. One major postoperative complication occurred. The median hospital stay was 6 days. CONCLUSIONS: The proposed hand-assisted laparoscopic approach is safe and feasible. It provides a minimally invasive alternative that may become the treatment of choice in beta-thalassemia patients who require concurrent operations.

A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with beta-thalassemia major.

OBJECTIVES: To apply magnetic resonance imaging (MRI) for the assessment of myocardial iron deposition in patients with beta-thalassemia and compare the results with cardiac biopsy data. BACKGROUND: Myocardial iron accumulation is the main cause for cardiac complications in beta-thalassemia. METHODS: Twenty-five consecutive thalassemic patients were studied using a 0.5-T (Tesla) system, ECG-gated, with echo time (TE) = 17-68 ms. T2 relaxation time of the interventricular septum was calculated assuming simple monoexponential decay. A heart T2 relaxation time value of 32 ms was used for the discrimination between high and low iron deposition. Heart biopsy was performed within a week after the MRI study. Patients with stainable iron in more than 50% of the myofibrils were graded as having severe iron deposition. A serum ferritin level below 2000 ng/mL was considered as an indication of successful chelation. RESULTS: Seven of the 25 patients had heart biopsy indicative of low iron deposition (Group L) and the remaining 18 patients had heart biopsy indicative of high iron deposition (Group H). T2 relaxation time of the heart (T2H) was lower in Group H compared to Group L (31.5 +/- 3.9 (range: 28-40) ms vs. 35.7 +/- 3.7 (range: 29-40) ms, P = 0.026). The T2H was in agreement with heart biopsy in 86% of the patients in Group L and in 78% of the patients in Group H (overall agreement 80%). Similarly, serum ferritin levels were in agreement with heart biopsy in 28% and 88%, respectively (overall agreement 72%). In Group L, MRI was in better agreement with biopsy compared to serum ferritin (86% vs. 28%, P < 0.05). A receiver operating characteristic curve (ROC) analysis confirmed that a T2 relaxation time of 32 ms had the highest discriminating ability for the corresponding biopsy outcome. CONCLUSIONS: Heart T2 relaxation time appears in agreement with cardiac biopsy, both in high and low iron deposition, and may become a useful non-invasive index in beta-thalassemia.

Staphylococcus aureus abscess of the spleen in a beta-thalassemia patient.

Splenic abscesses are rare among abdominal abscesses. We present a case of splenic abscess due to Staphylococcus aureus in a beta-thalassemia major patient. Such a complication may not be coincidental, as beta-thalassemia major patients have an increased susceptibility to infection, which is attributable to a number of immune abnormalities.

Cardiac status in well-treated patients with thalassemia major.

OBJECTIVE: To assess cardiac status in a large group of patients with thalassemia major who had been treated in a standard way since their early infancy with intensive transfusions and deferoxamine chelation therapy and who had good compliance with this regimen. METHODS AND RESULTS: We assessed clinically and echocardiographically 202 thalassemia major patients aged 27.3 +/- 6.3 yr and 75 age and sex-matched healthy controls. Overt cardiac disease was encountered in 14 patients (6.9%), including 5 (2.5%) with congestive heart failure, aged 26-37 yr, and 9 with systolic left ventricular (LV) dysfunction, aged 23-37 yr. Ten patients (5.0%) had a history of pericarditis. Left atrial and LV diameters, LV mass and cardiac output were significantly higher in patients than in controls, while peripheral resistance and LV afterload were significantly lower. Relative LV wall thickness did not differ between patients and controls, but it was significantly lower in patients with overt cardiac disease compared to those without (P < 0.05). Restrictive LV filling was observed in 37.6% of patients and was significantly more frequent in cases with overt cardiac disease (P < 0.01). Pulmonary hypertension was practically absent. Hematological parameters and pulmonary artery pressure levels were not independently associated with the presence of overt cardiac disease. CONCLUSION: Strict lifelong adherence to the standard transfusion and deferoxamine therapy reduces considerably the occurrence of heart failure, LV dysfunction and pericarditis, prevents early heart failure and pulmonary hypertension, but does not eliminate completely cardiac disease in patients with thalassemia major.