Liver disease in adult transfusion-dependent beta-thalassaemic patients: investigating the role of iron overload and chronic HCV infection.

BACKGROUND: Iron overload and hepatitis-C virus (HCV) infection, have been implicated in the evolution of liver disease, in patients with transfusion-dependent beta-thalassaemia major (BTM). However, the impact of these factors in late stages of liver disease in adults with BTM, has not been extensively studied. AIMS: To investigate serum indices of iron overload, HCV infection and liver disease, in a cohort of 211 adult Greek patients with BTM, in relation with the findings from liver biopsies. METHODS: In this cross-sectional study, 211 patients with BTM were enrolled and studied, in relation with HCV infection, ferritin, transaminases, chelation treatment and antiviral treatment. Based on 109 patients biopsied, we correlated liver fibrosis, haemosiderosis and inflammation, with serum indices and HCV status RESULTS: Among all patients, 74.4% were anti-HCV positive (HCV+). Ferritin was positively correlated with transaminases and negatively correlated with age, while it was not significantly different among HCV+ and HCV- patients. Among the HCV+ patients, 55.4% reported antiviral treatment, while genotype 1 predominated. In a subfraction of 109 patients, in which liver biopsy was performed, 89% were HCV+ and 11% HCV-. Fibrosis was significantly correlated with age (P = 0.046), AST (P = 0.004), ALT (P = 0.044) and inflammation (P < 0.001). Advanced fibrosis was present with even minimal haemosiderosis, independently of ferritin values or HCV history. CONCLUSIONS: These data suggest that in the late stages of liver disease in BTM patients, iron overload may be the critical determinant, since fibrosis is related to the minimal haemosiderosis, independently of HCV history.

A novel α(0) -thalassemia deletion in a Greek patient with HbH disease and ß-thalassemia trait.

OBJECTIVES: To determine the molecular basis in a Greek child suspected of having HbH disease and ß-thalassemia trait. METHODS: Standard hematology, Hb electrophoresis, and HPLC. Multiplex ligation-dependent probe amplification (MLPA), direct sequencing, and breakpoint characterization by NimbleGen fine-tiling array analysis. RESULTS: The index patient showed a moderate microcytic hypochromic anemia with normal ZPP and elevated HbA(2) , indicative for ß-thalassemia trait. However, the moderate microcytic hypochromic anemia along with the observation of HbH inclusions in occasional red blood cells suggested a coexisting α-thalassemia. Molecular analysis indicated that the propositus inherited the ß(+) -thalassemia mutation IVS2-745 (c>g) and a novel α(0) -thalassemia deletion from the mother, and the common non-deletion α-thalassemia allele α(2) (-5nt)α from the father. The α(0) -thalassemia deletion, named - -(BGS) , is approximately 131.6 kb in length. It removes the major regulatory elements along with the functional α-globin genes but leaves the theta-gene intact. CONCLUSIONS: The compound interaction of a ß-thalassemia defect along with a single functional α-globin gene is quite rare. Although patients with HbH/ß-thal and simple HbH disease have comparable levels of Hb, the absence of free ß-globin chains and thus detectable non-functional HbH means that in HbH/ß-thal, the levels of functional Hb are higher, resulting in a better compensated functional anemia. Rare large deletions as the one described here remain undetected by gap-PCR in routine molecular screening. The introduction of MLPA as a diagnostic screening tool may improve laboratory diagnostics for these defects. The use of NimbleGen fine-tiling arrays may give additional information about the precise location of breakpoints.

Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload.

BACKGROUND: Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs. METHODS: In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment. RESULTS: From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p=0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p=0.001). This was associated with a 27% increase in T2* (p<0.001) and 3.1% increase in LVEF (p<0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p=0.38), or RVEF (70.0 to 69.9%, p=0.93) whereas the T2* increased by 13% (p<0.001), but with no change in LVEF (0.32%; p=0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p=0.014) and 1.16% for RVEF (p=0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p<0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p=0.012). CONCLUSION: In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.

Iron overload, cardiac and other factors affecting pregnancy in thalassemia major.

The reproductive thalassemic population is growing older and doctors confront the challenge of the thalassemic pregnancy. Pregnancy is characterized by dynamic multiple system changes, resulting in increased basal oxygen consumption, changes in energy substrate use by different organs and increased susceptibility to oxidative stress, while homozygous transfusion-dependent beta-thalassemia (beta-thal) patients manifest cardiac, hepatic, endocrine, and metabolic disorders attributable to chronic anoxia and iron overload. Pregnant thalassemic patients require significantly larger amount of total blood transfusion during pregnancy and iron overload increases the oxidative stress of pregnancy, while the risk for cardiovascular events, in a high cardiac output state, is augmented and chelation treatment is generally avoided due to the potential teratogenicity. Pregnancy in thalassemia major should be considered high risk, and be cared for by an expert team with special caution and sensitivity.

Cardiac magnetic resonance imaging R2* assessments and analysis of historical parameters in patients with transfusion-dependent thalassemia.

Recent advances in magnetic resonance imaging (MRI) techniques allow the assessment of iron overload in tissues 1 especially the heart, 2 in transfusion-dependent thalassemia patients. The R2* value (1/T2*) recorded in the intraventricular septum of the heart indirectly measures the degree of cardiac iron load. Applying this new technology we looked at a number of historical and biochemical parameters in order to determine their relationship to cardiac iron overload and the effect of cardiac iron on functional and structural changes of the heart in transfusion-dependent thalassemics.

Predictive echo-Doppler indices of left ventricular impairment in B-thalassemic patients.

Early detection of cardiac-function impairment by echo-Doppler indices can assist in preventing further cardiac damage by modifying disease progression and treatment. We analyzed our thalassemia major patients database with 10 years cardiac follow-up. Included patients were under constant therapy and should have an initial echo-Doppler study with normal Shortening Fraction (SF > 30%) and reexamination within the last year. We identified patients who developed impaired left ventricular (LV) function in the last Echo and we attempted to find which measured indices could predict LV function impairment. Three hundred fifteen of the 632 database patients were enrolled. Twelve of them developed LV systolic dysfunction. There were no statistically significant differences in mean age, ferritin, and pretransfusion hemoglobin levels of the two groups. LV-systolic-dysfunction group was presenting statistically significantly higher LF end-systolic diameter (LVESD) index, lower SF, higher early transmitral peak flow velocities/late transmitral peak flow velocities (A) ratios, lower A value. All other echocardiographic parameters did not differ significantly. By receiver-operating characteristic analysis, we determined systolic and diastolic indices specificity and sensitivity for LV impairment: LVESD 97% specificity, 11% sensitivity (cutoff value 2.44 cm/m(2) ), SF 92.1 and 33.3% (cutoff value 33%). Regarding diastolic indices, A index was the best criterion (97.7% specificity, 25% sensitivity, cutoff value

Correlation of echocardiography parameters with cardiac magnetic resonance imaging in transfusion-dependent thalassaemia major.

BACKGROUND AND OBJECTIVE: Heart iron load (cardiac Fe) can be indirectly quantified by cardiac magnetic resonance (CMR) T2*. CMR accessibility is limited, whereas echocardiography (Echo) is relatively inexpensive and readily available. The objective was to find Echo parameters that may be useful for predicting cardiac Fe. DESIGN AND METHODS: We compared a number of parameters derived from Echo to cardiac Fe in 142 thalassaemia major patients who had undergone a CMR study. RESULTS: All patients with decreased left ventricular (LV) function had cardiac Fe. After removing those patients from the analysis, the total diameter index (Tdi) >5.57 cms/m2, left atrial diameter index >2.41 cm/m2, and the diastolic parameter E/A > 1.96 were highly specific (91.4%, 97.1% and 96.9% respectively) but had low sensitivity (31.8%, 20.45% and 21.8%) in predicting iron load. A right ventricular index >1.47 cm/m2, LV systolic index >2.26 cm/m2 or Tdi >6.26 cm/m2 discriminated between patients with no, or mild to moderate cardiac Fe from those with heavy load, with specificity of 91%, 98.5%, and 98.5%, respectively, but with low sensitivity. INTERPRETATION AND CONCLUSIONS: Echo parameters for cardiac Fe prediction have restricted value, whereas CMR is essential to assess cardiac Fe. However, patients with decreased LV systolic function should be considered a priori as having cardiac Fe, and chelation therapy should be intensified. This also applies to patients who have the above-described Echo criterion values, even if CMR is not available. Once a patient is found by CMR to have cardiac Fe, then the above Echo criterion values may be useful for ongoing monitoring.

Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis.

Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2(*)) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% +/- 5.3% and 93% +/- 9.7% (P = .81), respectively. The improvement in myocardial T2(*) was significantly greater for deferiprone than deferoxamine (27% vs 13%; P = .023). Left ventricular ejection fraction increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P = .003). The changes in liver iron level (-0.93 mg/g dry weight vs -1.54 mg/g dry weight; P = .40) and serum ferritin level (-181 microg/L vs -466 microg/L; P = .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferiprone-treated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major.

Echocardiographic and electrocardiographic prognostic factors of heart failure in young patients with beta-thalassemia major: a 10-year (1995--2004) follow-up.

Despite intense iron-chelation therapy, the life expectancy of patients with beta-thalassemia major (beta-TM) is still limited by the occurrence of heart failure. In the present study, we sought to evaluate the prognostic significance of several clinical factors on the outcome of heart failure or arrhythmias in patients with beta-TM. The study group consisted of 131 consecutive young patients with beta-TM (71 men aged 21+/-4 years, 60 women aged 22+/-5 years) who were initially examined during 1995. The clinical and vital statuses of all patients were biannually reviewed from 1995 to 2004. Cox proportional hazards models were used to evaluate the association of the occurrence of death or nonfatal events due to heart failure or arrhythmias with clinical factors (systolic and diastolic blood pressures), echocardiographic factors (left and right ventricular diameters, left atrial and aortic root dimensions, left ventricular ejection fraction), electrocardiographic factors (T-wave inversion in leads V1-V3, QRS duration, heart rate), and serum ferritin levels, after controlling for age, sex, and body mass index. During the follow-up, 11 men (16%) and 5 women (8%) had an event (men versus women, P = .212). The age-adjusted event rate was 16 events per 913 person-years (2%). The presence of T-wave inversion in right precordial leads (hazard ratio = 3.06; 95% confidence interval [CI], 1.1-8.8), increased heart rate (hazard ratio = 1.28; 95% CI, 1.03-1.58), decreased aortic root diameter (hazard ratio = 0.84; 95% CI, 0.73-0.96), and decreased ejection fraction (hazard ratio per 1% change = 0.95; 95% CI, 0.91-0.99) were associated with a higher risk for a cardiac event. We revealed that the presence of T-wave inversions, increased heart rate, low ejection fraction of the left ventricle, and decreased aortic root diameter appear to confer higher risk for cardiac events in young patients with beta-TM.

Unusual phenotypic observations associated with a rare HbH disease genotype (- -Med/alphaTSaudialpha): implications for clinical management.

A single patient with a rare Haemoglobin H (HbH) disease genotype (- -Med/alphaTSaudialpha) was observed to have exceptionally high levels of HbH (> 60%) and paradoxically high total haemoglobin levels. Studies of haematological parameters, blood biochemistry and oxygen transport properties revealed a severe functional anaemia, associated with marked erythropoietic stimulation and a markedly raised cardiac output. This rare case illustrates the complexity of interactions that may be associated with the clinical course of HbH disease, highlighting that haematological parameters alone may lead to spurious evaluation of clinical status. Issues related to the therapeutic management of unusual cases are raised.