Urinary Metabolic Profile of Patients with Transfusion-Dependent β-Thalassemia Major Undergoing Deferasirox Therapy

Introduction: Renal dysfunction is a frequent complication in patients suffering from β-thalassemia major (β-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of β-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. Methods and Subjects: 40 patients affected by β-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. Results: The study of renal function in β-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was <30 mg/g. The analysis of tubular function showed normal basal plasma electrolyte levels; 60% of patients presented hypercalciuria and many subjects showed defective urine concentration. Several amino acids, N-methyl compounds, and organic acids were overexcreted in the urine of thalassemic patients compared with controls. Discussion: The major finding of this work is that β-TM patients and controls exhibit different concentrations of some metabolites in the urine. Early recognition of urinary abnormalities may be useful to detect and prevent kidney damage

Longitudinal follow‐up of patients with thalassaemia intermedia who started transfusion therapy in adulthood: a cohort study

SummaryWe longitudinally evaluated the effects of regular blood transfusions (BTs), in the real‐life context of the Myocardial Iron Overload in Thalassaemia network, in patients with thalassaemia intermedia (TI). We considered 88 patients with TI (52 females) who started regular BTs after the age of 18 years. Magnetic resonance imaging was used to quantify iron overload and biventricular function. For 56·8% of the patients there were more than two indications for the transition to regular BTs, with anaemia present in 94·0% of the cases. A significant decrease in nucleated red blood cells, platelets, lactate dehydrogenase, bilirubin, and uric acid levels was detected 6 months after starting regular BTs. After the transition to the regular BT regimen there was a significant increase only in the frequency of hypothyroidism and osteopenia, and a significant decrease in liver iron and cardiac index. The percentage of chelated patients increased significantly after starting regular BTs. The decision to regularly transfuse patients with TI may represent a way to prevent or slow down the natural progression of the disease, despite the more complex initial management

Setting for &ldquo;Normal&rdquo; Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia: Our Current Strategy

This cross-sectional study aimed to establish the association between serum ferritin levels and organ iron overload (IO) and overall morbidity in transfusion-dependent thalassemia (TDT) patients. One hundred and three TDT patients (40.03 &plusmn; 9.15 years; 57.3% females) with serum ferritin &lt; 2500 ng/mL were included. IO was assessed by T2* magnetic resonance imaging. Three groups were identified based on mean serum ferritin levels: &lt;500 ng/mL (group 0; N = 32), 500&ndash;1000 ng/mL (group 1; N = 43), and 1000&ndash;2500 ng/mL (group 2; N = 28). All demographic and biochemical parameters were comparable among the three groups, with the exception of the triglycerides being significantly lower in group 0 than in group 2. No difference was found in the frequency of hepatic, endocrine, and cardiac complications. Hepatic IO was significantly less frequent in group 0 versus both groups 1 and 2. No patient with a serum ferritin level &lt; 500 ng/mL had significant myocardial IO and alterations in the main hematological parameters. No difference in the distribution of the different chelation regimens was found. Serum ferritin &lt; 500 ng/mL appears to be achievable and safe for several TDT patients. This target is associated with the absence of significant cardiac iron and significantly lower hepatic IO and triglycerides that are well-demonstrated markers for cardiac and liver complications

A useful relationship between the presence of extramedullary erythropoeisis and the level of the soluble form of the transferrin receptor in a large cohort of adult patients with thalassemia intermedia: A prospective study

In thalassemia intermedia (TI), the increase in bone marrow hemopoietic activity frequently leads to extramedullary erythropoeisis (EMH), but its relationship with the soluble form of transferrin receptor (sTfR) which fully reflects the marrow erythropoietic activity, has not yet been explored. From January 2007 to December 2010, all TI patients attending at our center were prospectively enrolled to undergo sTfR assay and MRI or CT (if claustrophobic) scan evaluation for the presence of paraspinal EMH. A total of 59 patients with TI were studied; EMH involved 23 (39%) patients; overall, the concentration of sTfR varied from 2.6 to 20.6 (mean=8.7) mg/L, but in splenectomized group and in unsplenectomized group, it varied from 4.2 to 17.8 (mean±SD=9. 86±3.33) mg/L and from 2.6 to 20.6 (mean±SD=7.25±3.9) mg/L, respectively with a statistically significant intergroup difference (p<0.01). The cutoff point at 8.6 mg/L using the ROC curve showed a sensitivity of 78.3% and a specificity of 72.2%, in predicting EMH but, in unsplenectomized subgroup, they raised to 100% and 90.9%, respectively. These data showed that in TI the level of sTfR could represent a predictive factor of EMH particularly in patients with spleen. © Springer-Verlag 2012

Retinal and Choriocapillaris Vascular Changes in Patients Affected by Different Clinical Phenotypes of β-Thalassemia: An Optical Coherence Tomography Angiography Study

In this cross-sectional study we assessed the vascular alterations in retinal and choriocapillaris perfusion in patients affected by β-thalassemia, by means of optical coherence tomography angiography (OCTA). A total of 124 eyes of 62 patients (mean age 44.74 ± 5.79 years old) affected by β-thalassemia (transfusion dependent thalassemia (TDT), non-transfusion dependent thalassemia (NTDT) and minor) were compared to 40 eyes of twenty healthy subjects. We evaluated the vessel density (VD) in superficial capillary plexus, deep capillary plexus, radial peripapillary capillary, choriocapillaris and the foveal avascular zone area. The TDT group showed a statistically significant reduction in retinal and choriocapillaris VD respect to controls and the other groups (p &lt; 0.05). No statistically significant difference was found in OCTA parameters between β-thalassemia minor and controls. The NTDT group showed a significant reduction in VD in deep capillary plexus respect to controls and β-thalassemia minor. Significant negative correlations were shown in TDT group between foveal avascular zone and hemoglobin (r = −0.437, p = 0.044) and between ferritin levels and VD of choriocapillaris (r = −0.431, p = 0.038). The OCTA parameters provided a deeper understanding on retinal and choriocapillaris vascular impairment affected by tissue hypoxia levels and the oxidative stress in different clinical phenotypes of the β-thalassemia

Atrial Fibrillation and Beta Thalassemia Major: The Predictive Role of the 12-lead Electrocardiogram Analysis

Background: Paroxysmal atrial tachyarrhythmias frequently occur in beta-thalassemia major (β-TM) patients.The aim of our study was to investigate the role of maximum P-wave duration (P max) and dispersion (PD), calculated trough a new manually performed measurement with the use of computer software from all 12-ECG-leads, as predictors of atrial-fibrillation (AF)in β-TM patients with conserved systolic or diastolic cardiac function during a twelve-months follow-up. Materials and Methods: 50 β-TM-patients (age38.4±10.1; 38M) and 50-healthy subjects used as controls, matched for age and gender, were studied for the occurrence of atrial arrhythmias during a 1-year follow-up, through ECG-Holter-monitoring performed every three months. The β-TM-patients were divided into two groups according to number and complexity of premature-supraventricular-complexes at the Holter-Monitoring (Group1: 30/h or couplets, or run of supraventricular tachycardia and AF, n:15). Results: Compared to the healthy control-group, β-TM patients presented increased P-max (107.5± 21.2 vs 92.1±11ms, P=0.03) and PD-values (41.2±13 vs 25.1±5 ms, P=0.03). In the β-TM population, the Group2 showed a statistically significant increase in PD (42.8±8.6 vs 33.2±6.5ms, P<0.001) and P-max (118.1±8.7 vs 103.1±7.5ms, P<0.001) compared to the Group1. Seven β-TM patients who showed paroxysmal AF during this study had significantly increased P-max and PD than the other patients of the Group2. Moreover, P-max (OR:2.01; CI:1.12-3.59; P=0.01) and PD (OR=2.06;CI:1.17-3.64;P=0.01) demonstrated a statistically significant association with the occurrence of paroxysmal AF, P min was not associated with AF-risk (OR=0.99; CI:0.25-3.40; P=0.9) in β-TM-patients. A cut-off value of 111ms for P- max had a sensitivity of 80% and a specificity of 87%, a cut-off value of 35.5ms for PD had a sensitivity of 90% and a specificity of 85% in identifying β-TM patients at risk for AF. Conclusion: Our results indicate that P-max and PD are useful electrocardiographic markers for identifying the β-TM-high-risk patients for AF onset, even when the cardiac function is conserved

Fully Automated Regional Analysis of Myocardial T2* Values for Iron Quantification Using Deep Learning

Cardiovascular magnetic resonance (CMR) T2* mapping is the gold standard technique for the assessment of iron overload in the heart. The quantitative analysis of T2* values requires the manual segmentation of T2* images, which is a time-consuming and operator-dependent procedure. This study describes a fully-automated method for the regional analysis of myocardial T2* distribution using a deep convolutional neural network (CNN). A CNN with U-Net architecture was trained to segment multi-echo T2*-weighted images in 16 sectors in accordance with the American Heart Association (AHA) model. We used images from 210 patients (three slices, 10 multi-echo images) with iron overload diseases to train and test the CNN. The performance of the proposed method was quantitatively evaluated on an independent holdout test set by comparing the segmentation accuracy of the CNN and the T2* values obtained by the automated method against ground-truth labels provided by two experts. Segmentation metrics and global and regional T2* values assessed by the proposed DL method closely matched those obtained by experts with excellent intraclass correlation in all myocardial sectors of the AHA model (ICC range [0.944, 0.996]). This method could be effectively adopted in the clinical setting for fast and accurate analysis of myocardial T2*

Fully Automated Regional Analysis of Myocardial T2* Values for Iron Quantification Using Deep Learning

Cardiovascular magnetic resonance (CMR) T2* mapping is the gold standard technique for the assessment of iron overload in the heart. The quantitative analysis of T2* values requires the manual segmentation of T2* images, which is a time-consuming and operator-dependent procedure. This study describes a fully-automated method for the regional analysis of myocardial T2* distribution using a deep convolutional neural network (CNN). A CNN with U-Net architecture was trained to segment multi-echo T2*-weighted images in 16 sectors in accordance with the American Heart Association (AHA) model. We used images from 210 patients (three slices, 10 multi-echo images) with iron overload diseases to train and test the CNN. The performance of the proposed method was quantitatively evaluated on an independent holdout test set by comparing the segmentation accuracy of the CNN and the T2* values obtained by the automated method against ground-truth labels provided by two experts. Segmentation metrics and global and regional T2* values assessed by the proposed DL method closely matched those obtained by experts with excellent intraclass correlation in all myocardial sectors of the AHA model (ICC range [0.944, 0.996]). This method could be effectively adopted in the clinical setting for fast and accurate analysis of myocardial T2*