Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Emanuele Angelucci ◽  
Pietro Muretto ◽  
Antonio Nicolucci ◽  
Donatella Baronciani ◽  
Buket Erer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Iron Content ◽  
Hazard Rate ◽  
Iron Concentration ◽  
Dry Weight ◽  
Interquartile Range ◽  
Hepatic Iron ◽  
Fibrosis Progression

Abstract To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 ± 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

Ineffective Erythropoiesis in β-Thalassemia Is Characterized by Increased Iron Absorption Mediated by down Regulation of Hepcidin and up Regulation of Ferroportin.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1543-1543 ◽  
Author(s):  
Sara Gardenghi ◽  
Maria Marongiu ◽  
Pedro Ramos ◽  
Ella Guy ◽  
Laura Breda ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Absorption ◽  
Hematological Parameters ◽  
Iron Concentration ◽  
Dry Weight ◽  
Heme Iron ◽  
Ineffective Erythropoiesis ◽  
Transfusion Therapy ◽  
Expression Levels

Abstract Progressive iron overload occurs in β-thalassemia as a result of increased gastrointestinal absorption. Our goal is to investigate the relationship between ineffective erythropoiesis (IE), iron-related genes and organ iron distribution in mice that exhibit levels of anemia consistent with thalassemia intermedia (th3/+) and major (th3/th3), as we described previously. The th3/th3 mice die in 8 weeks due to severe anemia but can be rescued by transfusion therapy. We analyzed up to 90 animals at 2, 5 and 12 months, as appropriate. We monitored various hematological parameters, tissue iron content and quantitative-PCR levels of Hamp, Fpn1, Smad4, Cebpa, Hfe, Tfr1 and other genes involved in iron metabolism in liver, spleen, kidney, heart and duodenum. At 2 months, th3/th3 mice had the highest total body iron content and highest degree of IE. The total iron was 53.6±21.0, 406.1±156.1, 657.7±40.3 μg in the spleen, and 107.5±35.7, 208.5±24.9 and 1298.7±427.5 μg in the liver of +/+, th3/+ and th3/th3, respectively (n≥5 per genotype). However, if the organ size was not taken in account, the iron concentration in the spleen of th3/+ was higher, in average, than that of th3/th3 mice (3.8±1.5 and 2.9±0.5 μg/mg), while in the liver was the opposite (0.6±0.1 and 5.1±2.0 μg/mg of dry weight, P<0.001). Heme and non-heme iron analyses provided similar results. Surprisingly, the distribution of iron within organs also differed. In th3/+ mice, the hepatic iron was almost exclusively located in Kupffer cells, whereas in th3/th3 mice in parenchymal cells. Our data suggest that Hamp is responsible for the increased iron absorption, being reduced to 20% and 70% in 2 month-old th3/+ and th3/th3 mice compared to +/+ animals (P<0.001). Hfe was reduced by 50% (P<0.05) in the liver of the animals that expressed low Hamp levels, indicating that Hfe could be directly responsible for Hamp regulation or share the same regulatory pathway. Low levels of Smad4 and Cebpa were observed only in the liver of mice with the lowest Hamp expression (P<0.05), indicating that these proteins might contribute to further decreased Hamp synthesis. In addition, while Tfr1 in th3/+ mice was 40% lower in the liver, it was up-regulated (400%) in th3/th3 mice (P<0.001), which may explain why iron is increased more in the liver of th3/th3 mice. In 5 and 12 month-old th3/+ mice, the surprising observation was the normal expression level of Hamp. However, in the duodenum, the Fpn1 RNA and protein levels were augmented (300%, P<0.001). In transfused th3/+ and th3/th3 animals, Hamp, Hfe, Cbpa and Smad4 expression levels were normalized or increased, while Tfr1 was down-regulated in both groups, which may explain the increased splenic iron deposition in these animals. Our data suggest that IE, together with the relative expression levels of Hamp and Tfr1, is largely responsible for the organ iron overload observed in young thalassemic mice. However, in older mice, it is the increase of Fpn1 levels in the duodenum that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the genesis of iron overload in β-thalassemia.

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.

scholarly journals Non Invasive Evaluation of Hepatic Iron Concentration By Fibroscan in Transfusion-Dependent Egyptian Patients with Chronic Hemolytic Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1061-1061
Author(s):  
Amal El-Beshlawy ◽  
Dalia Omran ◽  
Hala Mohsen Abdullatif ◽  
Niveen Salama ◽  
Mohamed Ahmed Abdel Naeem ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Sensitivity And Specificity ◽  
Transient Elastography ◽  
Iron Concentration ◽  
Hepatic Iron ◽  
Cell Disease ◽  
Non Invasive ◽  
Cutoff Values ◽  
Chronic Hemolytic Anemia

Abstract Background: Transient elastography (Fibroscan®) is an ultrasound technique used to measure liver stiffness (LS), and thus assess for liver fibrosis, in patients with various chronic hepatic disorders. It can also be used to predict severity in multiple other diseases that might affect LS such as amyloidosis and possibly conditions associated with iron overload. Objectives: To assess the frequency of liver fibrosis in patients with chronic hemolytic anemia using Transient elastography (Fibroscan®), and to determine the reliability of this tool as a non-invasive method to predict hepatic iron content as compared to liver iron concentration (LIC) measured by magnetic resonance imaging (MRI). Patients and methods: Seventy-five transfusion dependent patients (50 β-thalassemia major;25 sickle cell disease) with a mean age of 13.4±5.2 years in addition to 75 -age and sex matched- healthy children were recruited. All subjects underwent assessment of LS in kilopascals (kPa), by Transient elastography measurement using FibroScan (Echosens, Paris, France І). Steady state serum ferritin (SF), and hepatitis B serologies (HBsAg and antiHB core antibodies) were assessed by enzyme linked immunoassay (ELISA). LIC values, within 6 months' duration, as identified by quantitative MRI of hepatic iron stores as a signal intensity ratio method based on T1 and T2* contrast imaging without gadolinium were retrieved. Informed consent was obtained from patients' legal guardians prior to enrollment in the study. Results: The median SF was 2280 ng/ml (84% had values exceeding 1000 ng/ml). The median LIC was 13.86 mg/g dw (78.7% patients showed LIC above 7 mg/g dw). The median cardiac T2* was 30.8 ms (3 patients had values below 20). Fifty-two (69.3%) patients were categorized as F0-1 and 21 (28%) were stage F2, 2 (1.3%) were stage F3, and 2 patients had severe fibrosis. The mean and median fibroscan (FS) values were 6.19 ±1.76 kPa and 5.9 kPa (range 3 to 14.1) respectively. Patients had significantly higher mean FS compared to control group (p ˂0.001). Patients with no or mild fibrosis (F0-1) had lower FS values (5.3kPa) compared to patients with fibrosis grades 2-4 (p ˂0.001). FS values were not affected by disease type (thalassemia or sickle cell disease), age (above 12 years), or HCV sero-positivity. FS values correlated with SF (r=0.410, p˂ 0.001). Simple regression analysis of the two variables suggested that changes in SF were associated with minimal but significant changes in FS values (p=0.04) with good agreement (kappa =0.324, p=0.003). LIC did not differ in relation to grade of fibrosis (p>0.05), did not correlate with FS values (r= 0.014, p=0.908), and no changes in FS were expected with LIC changes on regression analysis (p=0.466) with low agreement between LIC and FS at cutoff value 5.3 kPa (kappa = 0.015, p=0.9). Sensitivity and specificity of FS values to predict LIC were high at cutoff values ranging between 3.2 to 3.75 kPa but decreased markedly at higher cutoff values. On comparing sensitivity and specificity of FS values in prediction of iron overload at different cutoff values by ROC curve, it could not significantly predict iron overload (p=0.7). No correlations were found between LIC and other variables including SF (r=0.2), and changes in SF were not significantly associated with changes in LIC values (p =0.089). However, sensitivity and specificity of SF in predicting LIC were good at cutoff 1003.85 ng/ml but decreased markedly at higher cutoff values. Comparing its sensitivity and specificity to that of SF in the prediction of iron overload at different cutoff values by ROC curve, FS could not predict iron overload accurately (p=0.9) and the degree of agreement between these two variables as indicators of iron overload was low (kappa=0.063, p=0.478). Conclusion: Fibroscan could be a valuable tool to assess the degree of liver fibrosis in patients with elevated SF, but it does not appear to reliably predict LIC in such group of patients especially with severe iron overload. FS values were not affected by disease type, age above 12 years, or HCV sero-positivity. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hepatic iron load differs strikingly between peritoneal dialysis and hemodialysis patients

2019 ◽  
Vol 2 (4) ◽  
pp. 181-191
Author(s):  
Guy Rostoker ◽  
Mireille Griuncelli ◽  
Nasredine Ghali ◽  
Séverine Beaudreuil ◽  
Yves Cohen ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Iron Overload ◽  
Iron Concentration ◽  
Dry Weight ◽  
Hemodialysis Patients ◽  
Hepatic Iron ◽  
Dialysis Patients ◽  
Liver Iron ◽  
Iron Load ◽  
Magnetic Resonance Imaging Mri

Introduction Iron overload is one of the most controversial topics in the management of anemic dialysis patients. Parenteral iron supplementation is commonly prescribed to hemodialysis (HD) patients but less frequently to peritoneal dialysis (PD) patients. Moreover, ferritin targets are far lower and more physiological in PD than in HD.  Methods We compared the liver iron concentration (LIC) measured by means of Signal-Intensity ratio (SIR) magnetic resonance imaging (MRI) according to Rennes University method in a cohort of 32 PD patients living in the Paris region published in 2017, with two cohorts of French HD patients studied in the same way (119 patients reported in 2012 and 80 further patients reported in 2014). Results Normal hepatic iron load (LIC ≤ 50 µmol/g of dry weight) was observed in 81.3% of the 32 PD patients (CI: 64.3-91.5%), as compared to only 16% (CI: 10.4-23.7%) in the first HD cohort and 35% (CI: 25.4-45.9%) in the second HD cohort (p<0.0001 for both comparisons; X2 test). Mild iron overload (50 < LIC ≤ 100 µmol/g) was found in 5 PD patients and severe overload (LIC > 200 µmol/g) in only one PD patient (who had received IV iron) (3.1%; CI: 0-17.1%). Conversely, severe iron overload was found in 30.3% of patients in the first HD cohort (CI: 22.7-39%) and 11.3% of those in the second HD cohort (CI: 5.8-20.2%) (p= 0.0033 versus the first HD cohort, X2 test). Conclusion Contrary to hemodialysis patients, iron overload is rare and mostly mild in peritoneal dialysis patients.

Association Between Cardiac Iron Clereance and Hepatic Siderosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4833-4833
Author(s):  
Alessia Pepe ◽  
Laura Pistoia ◽  
Domenico D'Ascola ◽  
Maria Rita Gamberini ◽  
Francesco Gagliardotto ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Hepatic Iron ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Follow Up Study ◽  
Hepatic Iron Overload

Abstract Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months. Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values. Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO). Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1). Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001). Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values. In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2). Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes. In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..

scholarly journals Male Gender Increases the Risk of Liver Fibrosis in Patients with Thalassemia Major Independent of Iron Overload

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3630-3630
Author(s):  
Murtadha K. Al-Khabori ◽  
Said Al Busaifi ◽  
Al Ghaliya Al Omairi ◽  
Moez Hassan ◽  
Humoud Al Dhuhli ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Liver Fibrosis ◽  
Iron Overload ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Male Gender ◽  
Ultrasound Elastography ◽  
P Value ◽  
Positive Serology ◽  
Multivariable Logistic Regression

Abstract Introduction and Objectives: Iron overload in patients with Thalassemia Major (TM) leads to various complications including liver fibrosis. The independent impact of gender on this risk has been previously investigated but not yet confirmed. We, therefore, planned to assess the independent impact of gender in patients with TM on the risk of liver fibrosis. Methods: We included 96 patients with TM followed and transfused in one academic tertiary hospital. Patients underwent assessment of liver fibrosis using ultrasound elastography (FibroScan device) with a cut off value of 7.8 kPa. The mean ferritin in the 5 years prior to elastography assessment was used to represent iron overload. Association was tested using Chi-squared and the independent impact of gender was confirmed in the multivariable logistic regression with a model that included mean ferritin and gender. Results: The median age of the 96 included patients was 26 years (Interquartile range [IQR]: 22-30). Males constituted 45% of patients and 33% of patients were splenectomised. The median alanine transaminase, aspartate transaminase, albumin and total bilirubin were 30 U/L (IQR: 18-64), 30 U/L (IQR: 18-46), 46 g/L (IQR: 44-48) and 21 µmol/L (IQR: 14-32) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1293 µg/L (IQR: 753-2715) and 6.7 mg/gdw (IQR: 3.5-16.1) respectively. Thirty seven percent of patients had positive serology for HCV while 1% of patients had positive serology for HBV. The proportion of patients with fibrosis as assessed by elastography was 59%. The proportion of male patients with fibrosis was 70% compared to 51% in female patients with a trend towards statistical significance (odds ratio [OR] of 2.2 with a p value of 0.094). In the multivariable logistic regression model, both gender (OR of 3.0, P value of 0.0188) and ferritin (OR of 1.0004, p value of 0.0036) were statistically significant independent predictors of liver fibrosis. Conclusion: Male gender increases the risk of liver fibrosis independent from iron overload. Our study confirms the previously suspected but unproven association. Follow up and therapy may be tailored to include gender as a decision factor. Larger studies are needed to further confirm these results. Disclosures No relevant conflicts of interest to declare.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 884-893 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Leyla Agaoglu ◽  
Duran Canatan ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Efficacy And Safety ◽  
Liver Iron ◽  
Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Magnetic Ressonance Imaging (MRI) in the Evaluation of Iron Overload in Patients with Beta Thalassaemia. The Brazilian National Program Preliminary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3825-3825
Author(s):  
Nelson Hamerschlak ◽  
Laercio Rosemberg ◽  
Alexandre Parma ◽  
Fernanda F. Assir ◽  
Frederico R. Moreira ◽  
...  
Keyword(s):  
Iron Overload ◽  
Ventricular Function ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Inverse Correlation ◽  
Liver Iron ◽  
Liver Iron Content ◽  
Cooperative Program

Abstract Magnetic Ressonance Imaging (MRI) using T2 star (T2*) tecnique appears to be a very useful method for monitoring iron overload and iron chelation therapy in thalassaemia. In Brazil, we have around 400 thalassaemic major patients all over the country. They were treated with hipertransfusion protocols and desferroxamine and/or deferiprone chelation. We developed a cooperative program with the Brazilian Thalassaemic Patients Association (ABRASTA) in order to developT2* tecnique in Brazil to submit brazilian patients to an annual iron overload monitoring process with MRI.. We performed the magnetic ressonance T2* using GE equipment (GE, Milwaukee USA), with validation to chemical estimation of iron in patients undergoing liver biopsy. Until now, 60 patients were scanned, median age=23,2 (12–54); gender: 18 male (30%) and 42 female (70%). The median ferritin levels were 2030 ng/ml (Q1=1466; Q3=3296). As other authors described before, there was a curvilinear inverse correlation between iron concentration by biopsy, liver T2*(r=0,92) and also there were a correlation with ferritin levels. We also correlated myocardial iron measured by T2* with ventricular function.. As miocardial iron increased, there was a progressive decline in ejection fraction and no significant correlation was found between miocardial T2* and the ferritin levels. Liver iron content can be predicted by ferritin levels. On the other hand, cardiac disfunction is the most important cause of mortality among thalassaemic patients. Since Miocardio iron content cannot be predicted from serum ferritin or liver iron, and ventricular function can only detect those with advance disease, intensification and combination of chelation therapy, guided by T2* MRI tecnique should reduce mortality from the reversible cardiomyopathy among thalassaemic patients.

Iron Stores in Patients with Myelodysplasia and Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3726-3726
Author(s):  
Peter Nielsen ◽  
Tim H. Bruemmendorf ◽  
Regine Grosse ◽  
Rainer Engelhardt ◽  
Nicolaus Kroeger ◽  
...  
Keyword(s):  
Risk Factor ◽  
Iron Overload ◽  
Aplastic Anemia ◽  
Myelodysplastic Syndromes ◽  
Iron Concentration ◽  
Dry Weight ◽  
Iron Toxicity ◽  
Intervention Threshold ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract Patients with myelodysplastic syndromes (MDS), osteomyelofibrosis (OMF), or severe aplastic anemia (SAA) suffer from ineffective erythropoiesis due to pancytopenia, which is treated with red blood cell transfusion leading to iron overload. Especially in low-risk patients with mean survival times of > 5 years, potentially toxic levels of liver iron concentration (LIC) can be reached. We hypothesize that the higher morbidity seen in transfused patients may be influenced by iron toxicity. Following a meeting in Nagasaki 2005, a consensus statement on iron overload in myelodysplastic syndromes has been published, however, there is still no common agreement about the initiation of chelation treatment in MDS patients. In the present study, a total of 67 transfused patients with MDS (n = 20, age: 17 – 75 y), OMF (n = 4, age: 48 – 68 y), SAA (n = 43, age: 5 – 64 y) were measured by SQUID biomagnetic liver susceptometry (BLS) and their liver and spleen volumes were scanned by ultrasound at the Hamburg biosusceptometer. Less than 50 % were treated with DFO. LIC (μg/g-liver wet weight, conversion factor of about 6 for μg/g-dry weight) and volume data were retrospectively analyzed in comparison to ferritin values. Additionally, 15 patients (age: 8 – 55 y) between 1 and 78 months after hematopoietic cell transplantation (HCT) were measured and analyzed. LIC values ranged from 149 to 8404 with a median value of 2705 μg/g-liver, while serum ferritin (SF) concentrations were between 500 and 10396 μg/l with a median ratio of SF/LIC = 0.9 [(μg/l)/(μg/g-liver)] (range: 0.4 to 5.2). The Spearman rank correlation between SF and LIC was found to be highly significant (RS = 0.80, p < 0.0001), however, prediction by the linear regression LIC = (0.83± 0.08)·SF was poor (R2 = 0.5) as found also in other iron overload diseases. Although iron toxicity is a long-term risk factor, progression of hepatic fibrosis has been observed for LIC > 16 mg/g dry weight or 2667 μg/g-liver (Angelucci et al. Blood2002; 100:17–21) within 60 months and significant cardiac iron levels have been observed for LIC > 350 μmol/g or 3258 μg/g-liver (Jensen et al. Blood2003; 101:4632-9). The Angelucci threshold of hepatic fibrosis progression was exceeded by 51 % of our patients, while 39 % were exceeding the Jensen threshold of potential risk of cardiac iron toxicity. The total body iron burden is even higher as more than 50 % of the patients had hepatomegaly (median liver enlargement factor 1.2 of normal). A liver iron concentration of about 3000 μg/g-liver or 18 mg/g-dry weight has to be seen as latest intervention threshold for chelation treatment as MDS patients are affected by more than one risk factor. A more secure intervention threshold would be a LIC of 1000 μg/g-liver or 4 – 6 mg/g-dry weight, corresponding with a ferritin level of 900 μg/l for transfused MDS patients. Such a LIC value is not exceeded by most subjects with heterozygous HFE-associated hemochromatosis and is well tolerated without treatment during life-time. Non-invasive liver iron quantification offers a more reliable information on the individual range of iron loading in MDS which is also important for a more rational indication for a chelation treatment in a given patient.

Sign in / Sign up

Export Citation Format

Share Document