MRI Survey In Transfusion-Dependent and Non-Transfusion-Dependent MDS Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2819-2819
Author(s):  
Alessia Pepe ◽  
Antonella Meloni ◽  
Giancarlo Carulli ◽  
Esther Natalie Oliva ◽  
Francesco Arcioni ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Conflicts Of Interest ◽  
Iron Concentration ◽  
Left Ventricular ◽  
Volume Index ◽  
Hepatic Iron ◽  
Myocardial Iron ◽  
Hepatic Iron Overload ◽  
The Mean

Abstract Introduction Several studies have shown cardiac diseases as causes of death in myelodisplastic (MDS) patients receiving transfusions. So iron overload may be considered an independent negative prognostic factor. There are few and rather contradictory studies using Magnetic Resonance Imaging (MRI) in the evaluation of myelodysplastic syndromes. We report the baseline MRI findings at the end of the recruitment in the MIOMED (Myocardial Iron Overload in MyElodysplastic Diseases) study. In particular, we investigated myocardial iron overload (MIO), hepatic iron overload and biventricular functional parameters in MDS patients, outlying the differences between transfusion dependent and non transfusion dependent patients. Methods MIOMED is an observational, MRI multicentre study in low and intermediate-1 risk MDS patients who have not received regular iron chelation therapy. Out of the 51 MDS patients enrolled, 48 underwent the baseline MRI exam. Mean age was 71.7±8.5 years and 17 patients were females. Hepatic T2* values were assessed in a homogeneous tissue area and converted into liver iron concentration (LIC). MIO was assessed using a multislice multiecho T2* approach. Biventricular function parameters were quantified by cine sequences. Results The mean global heart T2* was 38.7±8.3 ms while the mean LIC was 7.6±8.8 mg/g/dw. Global heart T2* values were not significantly correlated with LIC or serum ferritin levels while a significant association between LIC and serum ferritin was detected (R=0.689; P<0.0001). Thirty-two (66.6%) patients were non-transfusion dependent while 16 patients were transfusion-dependent. The two groups were homogeneous for age, sex and hemoglobin levels but transfusion-dependent patients had significantly higher serum ferritin levels (1612±864 vs 711±430; P<0.0001). The percentage of patients with detectable hepatic iron (LIC≥3 mg/g/dw) was significantly higher in the transfusion-dependent group (Figure 1, left). Mean LIC was 14.4±11.1 mg/g/dw in the transfusion-dependent group and 4.2±4.6 mg/g/dw in the non-transfusion-dependent group (P<0.0001). A significant heart iron (global heart T2* value <20 ms) was found in two patients, in both patients an heterogeneous pattern (some segments with T2* values >20 ms and other segments with T2* values <20 ms) was detected. Out of two patients with significant heart iron one patient was not transfused and he did not show significant hepatic iron (LIC=2.12 mg/g/dw). The other one patient was regularly transfused and he received sporadically (less than two weeks/month) chelation treatment with deferoxamine in the 2 years before the MRI. The global heart T2* (Figure 1, right), the pattern of iron burden and the number of segments with T2*<20 ms were comparable between the two groups. Biventricular end-diastolic volume index, biventricular ejection fraction and left ventricular (LV) mass index were comparable between the two groups. Conclusions As expected, regularly transfused MDS patients showed significantly higher levels of hepatic iron overload, that, however, was present in almost the 30% of non-transfusion-dependent patients, mainly due to increased intestinal iron and augmented erythropoiesis. MIO is not frequent in MDS patients and it is not correlated with LIC and serum ferritin levels. Conversely, MIO can be present also in non-transfusion dependent patients and in absence of detectable hepatic iron. These data remark the importance to check directly for heart iron with a more sensitive segmental approach avoiding to estimate heart iron burden from indirect indicators such as LIC, serum ferritin or transfusion state. Disclosures: No relevant conflicts of interest to declare.

Myocardial and Hepatic Iron Overload and Cardiac Function In Sickle/Thalassemia Patients Of Italian Origin

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2252-2252
Author(s):  
Antonella Meloni ◽  
Giovan Battista Ruffo ◽  
Daniele De Marchi ◽  
Antonio Cardinale ◽  
Anna Pietrapertosa ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Iron Overload ◽  
Conflicts Of Interest ◽  
Iron Concentration ◽  
Hepatic Iron ◽  
Liver Iron ◽  
Hepatic Iron Overload ◽  
The Mean ◽  
Magnetic Resonance Imaging Mri ◽  
Italian Origin

Abstract Introduction Sickle-thalassemia results from the combined heterozygosity for sickle-cell and β-thalassemia genes. This study evaluates myocardial and hepatic iron overload and cardiac function in Italian patients and explores their correlation with transfusions, age and sex. Methods Fifty-nine sickle-thalassemia patients (29 males, mean age 35.6±14.1 years), enrolled in the MIOT network underwent magnetic resonance imaging (MRI). T2* value for all 16 myocardial segments and global heart T2* value were calculated. Hepatic T2* value was converted into liver iron concentration (LIC). Cine images were acquired to quantify biventricular volumes and ejection fraction (EF). Results 55 (93%) patients had all segmental T2* values normal (>20 ms). Of the 4 patients with abnormal segmental T2* values, all showed an heterogeneous myocardial iron overload (some segments with T2*>20 ms and other with T2*<20 ms) and only one had a global T2*<20 ms. The mean global heart T2* value was 34.4±6.2 ms. The mean LIC was 5.9±6.5 mg/g/dw and 30 patients (50.8%) had a pathological value (≥ 3 mg/g dw). There was a statistically significant positive correlation between global heart T2* and age but with poor linearity (R=0.368; P=0.004) and there was not a significant correlation between age and LIC. Males and females had comparable global heart T2* values and LIC values. Twenty patients were regularly transfused, 32 received sporadic transfusions while 7 were not transfused. The comparison among the three groups is shown in Table 1. We did not find significant differences in the global heart T2* value while patients regularly transfused had significantly higher LIC than sporadically transfused patients. Biventricular volumes indexed by body surface area and ejection fractions were comparable among the groups. Conclusions In respect of MIO, the sickle/thalassemia patients are similar to patients with homozygous SCD for which iron overloading is relatively rare. Hepatic iron overload may develop also in no regularly-transfused patients, maybe due to increased absorption of iron from the digestive tract, characteristic of both SCD and thalassemia intermedia patients. This finding underlines the importance to monitor by MRI also no regularly transfused sickle/thalassemia patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Effect of Chronic Viral Hepatitis on Serum Ferritin Level in Thalassemia Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4819-4819
Author(s):  
Natthapat Rujeerapaiboon ◽  
Adisak Tantiworawit ◽  
Pokpong Piriyakhuntorn ◽  
Thanawat Rattanathammethee ◽  
Sasinee Hantrakool ◽  
...  
Keyword(s):  
Viral Load ◽  
Iron Overload ◽  
Viral Hepatitis ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Conflicts Of Interest ◽  
Ferritin Level ◽  
Iron Concentration ◽  
Chronic Viral Hepatitis ◽  
The Mean

Background: Serum ferritin is widely used as a marker of iron overload in thalassemia patients. However, the ferritin level is affected by active infections or inflammation. The association between viral hepatitis and serum ferritin level in thalassemia patients is still unclear. This study aimed to determine the effect of chronic viral hepatitis on serum ferritin level in thalassemia patients. Methods: This was a cross-sectional study in thalassemia patients aged ≥15 years-old at Chiang Mai University hospital. We expected that thalassemic patients in our clinic have a mean serum ferritin of 767 ng/mL with a standard deviation of 210 ng/mL. As a result, we have to enroll a total of 28 patients to demonstrate 30% difference of mean serum ferritin when the power was set at 80% with alpha level of 0.05. Information on chronic viral hepatitis, mean serum ferritin and liver iron concentration (LIC) as measured by T2* MRI were collected. Chronic viral hepatitis status was confirmed by either HBV DNA or HCV RNA testing. Patients were categorized to hepatitis and non-hepatitis group. Serum ferritin levels were compared between two groups. LIC measurement was used as a gold standard for iron overload. Subgroup analysis was performed according to iron overload and transfusion requirement status. Categorical and continuous variables were compared using the Chi-squared test and T-test, respectively. The correlation between viral loads and mean serum ferritin levels was analyzed by Pearson's correlation. Result: Of 32 thalassemia patients (25 non-transfusion dependent [NTDT] and 7 transfusion dependents [TDT]), 13 patients had chronic viral hepatitis (7 with hepatitis B and 6 with hepatitis C infections). The LIC between hepatitis and non-hepatitis groups were not significantly different (7.28 [SD 4.7] vs 9.08 [SD 5.2] mg Fe/g, p=0.19). In the higher LIC group (≥ 5 mg Fe/g), the mean serum ferritin level was higher in the hepatitis group than non-hepatitis group (1,776 [SD 488] vs 967 [SD 860] ng/mL, p=0.03). For the lower LIC group (<5 mg Fe/g), the mean ferritin levels were not significantly different between the hepatitis and non-hepatitis groups (646 [SD 224] vs 459 [SD 205] ng/mL, p=0.22). The correlation between the viral load and mean ferritin level in NTDT group showed a significant linear correlation with R=0.7 (p=0.04). Conclusions: We observe a higher serum ferritin level among thalassemia patients who concurrently have chronic viral hepatitis. Chronic viral hepatitis is a possible cause of a falsely high ferritin level in these patient population. Furthermore, the viral load is positively correlated with serum ferritin level. Disclosures No relevant conflicts of interest to declare.

Onset of Cardiac Iron Loading in a Large and Homogeneous Cohort of Thalassemia Major Paediatric Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2157-2157
Author(s):  
Alessia Pepe ◽  
Antonella Meloni ◽  
Brunella Favilli ◽  
Marcello Capra ◽  
Domenico Giuseppe D'Ascola ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Conflicts Of Interest ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
Myocardial Iron ◽  
Cardiac Iron ◽  
Paediatric Patients ◽  
Biventricular Function ◽  
Significant Difference

Abstract Abstract 2157 Introduction: Magnetic Resonance Imaging (MRI) by the T2* technique allows highly reproducible and non invasive quantifications of myocardial iron burden and it is the gold standard for quantifying biventricular function parameters. It is important to determine the appropriate age to start MRI screening, because its high cost. Few data are available in the literature and they are contrasting. So the aim of this study was to address this issue in our paediatric patients with thalassemia major (TM). Methods: We studied retrospectively 72 patients (47 males, 4.2–17.9 years old, mean age 13.03 ± 3.70 years), enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network. Myocardial iron overload was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The global heart T2* value was 29.7 ± 11.2 ms (range 6.2 – 48.0 ms). No significant correlation was found between global heart T2* value and age (see figure). The global heart T2* value did not show significant differences according to the sex (male 30.2 ± 11.0 ms versus female 28.7 ± 11.8 ms, P=0.568). Sixteen patients (22%) showed an abnormal global heart T2* value (<20 ms) and none of them was under 8 years of age. Global heart T2* value was negatively correlated with mean serum ferritin levels. Odds Ratio for high serum ferritin levels (≥ 1500 ng/ml) was 8.4 (1.01–69.37, OR 95%CI) for abnormal global heart T2* values (< 20 ms). The global heart T2* value did not show a significant difference with respect to the chelation therapy (P=0.322). No significant correlations were found between the global heart T2* values and the bi-atrial areas or the LV and RV morphological and functional parameters. Eight patients showed a left ventricular (LV) ejection fraction (EF) < 57% and none of them was under 7 years of age. Two patients showed a right ventricular (RV) EF < 52% and none of them was under 14 years of age. Conclusion: The MRI screening for both cardiac iron overload and function assessment can be started for TM patients at the age of 7 years. At this age not sedation is generally needed. If the availability of cardiac MRI is low, the serum ferritin levels could be used as a discriminating factor. Disclosures: No relevant conflicts of interest to declare.

T2* MRI in Hypertransfused Children with Thalassemia Intermedia: Serum Ferritin Does Not Reflect the Reality

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5304-5304
Author(s):  
Surekha Tony ◽  
Shahina Daar ◽  
Shoaib Al Zadjali ◽  
Murtadha K. Al-Khabori ◽  
Mohammed El Shinawy ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Conflicts Of Interest ◽  
Iron Deposition ◽  
Hepatic Iron ◽  
Thalassemia Intermedia ◽  
Hepatic Iron Overload ◽  
T2 Mri ◽  
Beta Gene ◽  
Group 1

Abstract Abstract 5304 Background: Non-transfused patients with thalassemia intermedia (TI) accumulate iron in their body due to increased gastrointestinal absorption of iron and release of iron from the macrophages. Earlier studies have revealed that serum ferritin does not reflect the severity of iron overload in non-transfused TI patients. The current study aims at evaluating the iron overload status in a group of young hypertransfused TI children. Materials and Methods: Eleven patients (mean age 13.18±4.094 years) with TI on regular follow-up at the Pediatric Thalassemia Day Care Centre, Sultan Qaboos University Hospital, Oman were included in the study after approval by the Medical Research and Ethics Committee. All patients had beta gene mutational analysis. They were diagnosed as intermedia because of their definitive TI mutation, late age at presentation (>5 years) and transfusion independence (mean baseline Hb 6.9 g/dl). Patients were treated conventionally with hypertransfusion, and chelation, as guided by their serum ferritin levels. Serum ferritin (2 monthly) was analyzed using the Beckman Coulter Access 2 Immunoassay System. Based on serum ferritin levels, patients were classified into 2 groups, group 1(six patients) and 2 (five patients) with serum ferritin levels below and above 1000 ng/ml respectively. All patients underwent cardiac T2* MRI assessment. Based on local reference values for T2*MRI, quantification of cardiac iron deposition was categorized as normal, mild, moderate and severe iron overload at values > 20 ms, 14–20 ms, 10–14 ms and < 10 ms respectively. Simultaneous liver iron T2* values were categorized into normal, mild, moderate and severe iron overload at values > 9.1 ms, 7.1–9.0 ms, 3.1– 7.0 ms and <3.0 ms respectively. Results: Patients in group 1 and 2 had mean serum ferritin levels of 817.300±244.690 ng/ml and 1983.80±662.862 ng/ml respectively (p = 0.003). Despite this very high variation in serum ferritin values, T2* MRI showed comparable hepatic iron overload status in both the groups with mean hepatic T2* value of 2.51±0.46 ms and 3.4±1.63 ms in group 1 and group 2 respectively. The difference in hepatic T2* between the 2 groups is −0.88 (95% confidence interval −2.44 to 0.68) which is statistically insignificant (p =0.23, t-test). None of the studied patients had myocardial iron deposition (overall mean 36.86±7.8 ms). Other confounders like initial ages at presentation, pre-transfusion hemoglobin levels, durations of transfusion and chelation therapies were statistically insignificant for the 2 groups. No specific pattern of beta gene sequence was noted in either group. Conclusions: We conclude in our patients with TI on hypertransfusion, serum ferritin does not reflect their moderate to severe hepatic iron overload status. Inspite of steady serum ferritin trends, evaluation of iron overload by T2* MRI and optimal chelation is strongly recommended in hypertransfused TI patients. Disclosures: No relevant conflicts of interest to declare.

The Role of Labile Plasmatic Iron (LPI) In the Assessment of Iron Overload In β-Thalassemic Patients and Its Correlation with MRI Findings

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2072-2072
Author(s):  
Reiĵne Alves de Assis ◽  
Breno Pannia Espósito ◽  
Fernando Uliana Kay ◽  
Ronaldo Hueb Baroni ◽  
Laercio Alberto Rosemberg ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Strong Correlation ◽  
Conflicts Of Interest ◽  
Iron Concentration ◽  
Diabetic Patients ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Tissue Iron ◽  
The Mean

Abstract Abstract 2072 Introduction: The labile plasmatic iron (LPI) represents part of non-transferrin-bound iron (NTBI) capable of entering the tissues and causing oxidative injury. It might be related to certain types of brain damage, especially in those with ischemia, cognitive defects in Alzheimer's disease, endothelial dysfunction in thalassemic children, complications in myelodysplastic syndrome (MDS), in particular infection and tissue injury, and to the increase in mortality rates in transfused and diabetic patients. LPI determination has been used by several authors as a means to monitor the efficacy of different protocols of iron chelation in thalassemic and MDS patients. Efficacy studies of vitamin C and E antioxidant activity, which blocks iron-induced oxidative damage, have also used this methodology. LPI has been suggested as an alternative method to assess iron load. Objective: Establish a correlation between LPI and serum ferritin levels and tissue iron estimated by magnetic resonance imaging (MRI) T2*/R2* in the heart, pancreas and liver. Methods: Data from 83 patients with thalassemia major were analyzed. LPI was measured using a fluorescent method and values <0.5μM were considered normal. Serum ferritin was measured by chemiluminescence and MRI was performed with a General Electric 1.5 T device. Cardiac, pancreatic and liver iron were determined by T2*/R2* methodology, and liver T2* was used to calculate the liver iron concentration (LIC). The statistical analysis was performed using ANOVA. Results: Eighty three patients were studied, of which 44.6% were males and 55.4% females. The median number of red blood cell packs used per year was 29.3±7.4. The mean LPI was 1.04±2.39μM (range 0.001 – 11.45). The mean LIC and serum ferritin were 8.96±3.35 mg/g dry liver weight (1.31-18.34) and 2,928.19 ± 2,398.4 ng/ml (101-12,958), respectively. Cardiac T2* values varied from 3.4 to 59.52ms, of which 33.7% (28) showed cardiac iron overload (T2*<20ms). Pancreatic R2*values varied from 19.8–500 Hz. Considering abnormal pancreatic R2*values >43Hz, 86.3% (69) were classified as pancreatic siderosis. After ANOVA analysis, we found a strong correlation between LPI and LIC (p<0.0007). Conclusion: A strong correlation was found between LPI and liver iron concentration. It is still premature to use this correlation as a predictor of iron overload. However, it might be useful as a complementary method to monitor chelation therapy and does not preclude the MRI studies to assess tissue iron in clinical practice. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Correlation of Serum Ferritin Levels with Liver and Heart Mri T2 and Liver Iron Concentration in Beta Thalassemia Intermediate Patients: A Contemporary Issue

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4829-4829 ◽  
Author(s):  
Mehran Karimi ◽  
Fatemeh Amirmoezi ◽  
Sezaneh Haghpanah ◽  
Seyed pouria Ostad ◽  
Mehrzad Lotfi ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Beta Thalassemia ◽  
P Value ◽  
Hepatic Iron ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Hepatic Iron Overload ◽  
T2 Mri

Abstract Background: B-Thalassemia intermediate (B-TI) is a genetic disease that is milder than beta thalassemia major. The accumulation of iron in different organs causes tissue damage. The T2* magnetic resonance imaging (MRI) technique is currently the gold standard for iron load detection. However, it is expensive and needs an expert radiologist to report findings. Therefore, we conducted this study to determine an optimal cut-off value of ferritin in proportion to T2 MRI for early detection of cardiac and hepatic iron overload in patients with beta thalassemia intermediate. Methods: This cross-sectional study was conducted on 108 patients with B-TI who referred to tertiary Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Serum ferritin, hepatic and cardiac T2 MRI were assessed. The ROC curve was used to determine the sensitivity and specificity of cut-off value. Results: Serum ferritin levels showed a statistically significant negative correlation with T2 hepatic MRI (r= -0.290, P value=0.003) and positive correlation with LIC (r= 0.426, P value ˂ 0.001) in the patients with BTI. However, T2 cardiac MRI was not significantly correlated with serum ferritin levels (P value= 0.073).According to the analysis of ROC curves, the best cut-off value for ferritin to show early diagnosis of liver iron overload was 412 ng/ml. calculated sensitivities and specificities were 0.78 and 0.82 for T2 liver MRI and 0.76 and 0.86 for liver iron concentration (LIC) respectively. Conclusion: Serum ferritin levels of 412 ng/ml might be considered as a cut-off point to evaluate hepatic iron overload before using expensive, not readily available T2 MRI. This level of serum ferritin (around 500 ng/ml) could be considered for starting iron chelation therapy in patients with B-TI in areas where T2 MRI is not available. Disclosures No relevant conflicts of interest to declare.

Myocardial T2* Is Not Affected by the Structural Effects of Myocardial Fibrosis, Ageing or Impaired Left Ventricular Function.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1675-1675
Author(s):  
Paul Kirk ◽  
Dudley J. Pennell
Keyword(s):  
Myocardial Infarction ◽  
Iron Overload ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Age Distribution ◽  
Left Ventricular ◽  
Lv Function ◽  
Chronic Myocardial Infarction ◽  
Myocardial Iron ◽  
The Mean

Abstract Background The myocardial T2* technique has been validated as a reproducible non-invasive measurement of myocardial iron load and is now widely used for measurement of myocardial iron in iron overload diseases such as thalassaemia. The reduction in myocardial T2* seen in iron overload conditions is substantially greater than is seen in any other clinical circumstance, but there has been no direct comparison of myocardial T2* in normals and other conditions such as increasing age, myocardial infarction or impairment in left ventricular function. We aimed therefore to compare the findings in patients affected by these conditions with normals. Method A total of 38 patients in total were scanned using the myocardial T2* technique. Fifteen patients had normal hearts, 18 had impaired LV function and 6 had chronic myocardial infarction affecting the anteroseptal wall, where myocardial T2* measurements are normally made. Results The mean myocardial T2* in normals was 36.0 +/− 6.4 ms, yielding a lower limit of normal of 23ms. In patients with impaired LV function, the mean myocardial T2* was 39.0 +/− 11.7ms (p= 0.37 vs normals). In patients with anteroseptal myocardial infarction, the mean myocardial T2* was 34.7ms +/− 3.9ms (p= 0.64 vs normals). The frequency distribution of the myocardial T2* values are shown in figure 1. These approximate to normal, and are very similar in distribution. In addition, the age distribution of myocardial T2* in the 15 normals is shown in figure 2. There was no significant relation between myocardial T2* and age (r2 = 0.066, p=0.82). Conclusion There is no significant reduction in myocardial T2* associated with fibrosis from chronic myocardial infarction, impairment of left ventricular function, or increasing age. This suggests that structural changes associated with remodelling, infarction and fibrosis, and ageing do not have significant effects on the absolute measure of myocardial T2*, and in particular do not cause a reduction below 20ms as is seen in myocardial overload conditions. Thus these date suggest that myocardial T2* is robust to these structural alterations, and that myocardial iron overload can be ascertained from reduced myocardial T2* values, in a similar manner to that which can be achieved in normals. Figure 1 Figure 1. Figure 2 Figure 2.

Prospective Survey on Heart and Liver Iron and Heart Function in Thalassemia Major Patients Treated with Sequential deferiprone–desferrioxamine Versus Deferiprone and Desferrioxamine in Monotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5298-5298
Author(s):  
Alessia Pepe ◽  
Antonella Meloni ◽  
Giuseppe Rossi ◽  
Anna Spasiano ◽  
Domenico Giuseppe D'Ascola ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Iron Overload ◽  
Heart Function ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
The Other ◽  
Hepatic Iron ◽  
Myocardial Iron ◽  
Liver Iron ◽  
Biventricular Function

Abstract Abstract 5298 Introduction: Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluate quantitatively the changes in cardiac and hepatic iron and in cardiac function in thalassemia major (TM) patients under different chelation regimens. This study aimed to prospectively assess the efficacy of the sequential deferiprone–deferrioxamine (DFP-DFO) versus deferiprone (DFP) and deferrioxamine (DFO) in monotherapy in a large cohort of TM patients by quantitative MR. Methods: Among the first 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 392 patients performed a MR follow up study at 18±3 months. We evaluated prospectively the 35 patients treated with DFP-DFO versus the 39 patients treated with DFP and the 74 patients treated with DFO between the 2 MR scans. Iron concentrations were measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: Excellent/good levels of compliance were similar in the DFP-DFO (97.1%) versus DFP (94.9%) and DFO (95.9%) groups. No significant differences were found in the frequency of side effects in DFP-DFO (15.6%) versus DFP group (9.4%). The percentage of patients who maintained a normal global heart T2* value (≥20 ms) was comparable between DFP-DFO (96%) versus DFP (100%) and DFO (98.1%) groups. Among the patients with myocardial iron overload (MIO) at baseline (global heart T2*<20 ms), in all three groups there was a significant improvement in the global heart T2* value (DFO-DFP: P=0.004, DFP: P=0.015 and DFO: ms P=0.007) and a significant reduction in the number of pathological segments (DFO-DFP: P=0.026, DFP: P=0.012 and DFO: P=0.002). In DFO-DFP and DFP groups there was a significant increment in the left ventricular (LV) ejection fraction (EF) (P=0.035 and P=0.045, respectively) as well as in the right ventricular (RV) EF (P=0.017 and P=0.001, respectively). The improvement in the global heart T2* and in biventricular function were not significantly different in DFO-DFP compared to the other groups (Table 1). Among the patients with hepatic iron at baseline (T2*<9.2 ms), only in DFO group there was a significant improvement in the liver T2* value (2.0±3.5 ms P=0.010). Liver T2*changes were not significantly different in DFO-DFP versus the other groups. Conclusions: Prospectively we did not find significant differences on cardiac and hepatic iron or in cardiac function in TM patients treated with sequential DFP–DFO therapy versus the TM patients treated with DFO or DFP in monotherapy. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy. Lai:Novartis: Honoraria, Research Funding.

Exome Sequencing Identifies Genes and Variant Alleles Associated With Severity Of Iron Overload In Hemochromatosis HFE C282Y Homozygotes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 179-179
Author(s):  
Christine E. McLaren ◽  
Mary J. Emond ◽  
Pradyumna D. Phatak ◽  
Paul C. Adams ◽  
V. Nathan Subramaniam ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Missense Variant ◽  
Dry Weight ◽  
P Value ◽  
Hepatic Iron ◽  
Common Variants ◽  
Iron Stores ◽  
Hepatic Iron Concentration

Abstract Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major problems extant in our understanding of hereditary hemochromatosis (HH). We conducted exome sequencing of DNA from C282Y homozygotes with markedly increased iron stores (cases) and C282Y homozygotes with normal or mildly increased iron stores (controls) to identify rare and common causal variants associated with variability of disease expression in HH. Criteria for cases included serum ferritin >1000 µg/L at diagnosis, and (a) mobilized body iron >10 g by quantitative phlebotomy, and/or (b) hepatic iron concentration >236 µmol/g dry weight. Criteria for controls included (a) serum ferritin <300 µg/L, or (b) age ≥50 y with ≤3.0 g iron removed by phlebotomy or age ≥40 y with ≤2.5 g iron removed by phlebotomy to achieve serum ferritin <50 µg/L. Deep sequencing of the full exome was performed in 33 cases and 14 controls. After quality control filtering, the dataset included 82,068 SNPs and 1,403 insertions/deletions (indels). Our initial analysis tested for differences in the distribution of variants between groups for each gene separately using the Sequence Kernel Association Test (SKAT) that includes rare and common variants but downweights the contribution of common variants to the test statistic. Only non-synonymous variants were included in the by-gene tests. Principal components were constructed from the exome variants to adjust for possible confounding by ancestry and to confirm no ancestral outliers. All study participants were male, and all clustered closely together within a larger group of Europeans in a principal components analysis of ancestry. Mean (SD) ages at presentation were 54 (11.0) y and 56 (9.4) y for cases and controls, respectively. Median serum ferritin was 2788 µg/L in those with increased iron stores and 309 μg/L in those with normal or mildly increased iron stores. The median transferrin saturation (94%) was greater in cases than in the comparison group (70%). In a preliminary analysis, we found 9 genes associated with case-control status. To separate effects of alcohol use and/or alcohol addiction variants, an analysis was conducted to compare the 13 controls and 22 cases who reported never using alcohol or only very light use. The two most significant genes identified in this comparison were GNPAT (p=7.4x10-6) and CDHR2 (p=2.8x10-4). A quantile-quantile (QQ) plot is shown in the Figure, comparing the observed distribution of –(log10p-values) from 10,337 genes to the expected uniform distribution if there were no variants modifying severity of expression, and gives evidence of the effect of the GNPAT gene.Figure 1Figure 1. Inspection of the two variants contributing to the GNPAT by-gene p-value revealed one missense variant (rs11558492) for which 0/13 controls had a polymorphism, while 16/22 cases had at least one missense variant, and one case was homozygous for this missense variant. The latter case presented at the early age of 26 with a serum ferritin of 1762 µg/L, 4+ hepatocellular iron and hepatic iron concentration of 284.4 µmol/g dry weight. GNPAT (aka DHAPAT) mutations/deletions have been found in peroxisomal disease, a class of diseases in which increased hepatic iron is observed (Biochim Biophys Acta 1801:272-280, 2010). GNPAT rs11558492 is common among people of European descent but might interact with aberrant HFE to increase risk of hepatic iron overload. Three rare variants in CDHR2 accounted for its low p-value, having a cumulative frequency of 4/13 among controls and 0/22 among cases: rs115050587, rs752138, rs143224505 with minor allele frequencies, MAF = 1.4%, 4.7% and 0.06%, respectively. The first two polymorphisms are predicted to be highly damaging by PolyPhen2 and the third probably damaging. Expression levels of CDHR2 recently have been associated with increased hepatocyte iron and elevated serum ferritin in liver allograft patients (J Clin Invest 122:368-382, 2012). These data indicate associations between iron status in HFE C282Y homozygotes and genes with previous links to iron overload that may modify severity of disease expression. Of note, the data suggest that more than one modifier gene may be involved in determining severity of disease in HFE C282Y homozygotes. Our results identify candidate genes for expanded studies that would examine their functional significance for iron absorption and metabolism. Disclosures: No relevant conflicts of interest to declare.

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