Non-Invasive Monitoring of Hepatic Iron Concentration during Oral Chelation in Patients with Non-Regularly Transfused β-Thalassemia/Hb E Disease.

Abstract Current non-invasive measurement techniques of hepatic iron concentration (HIC) include magnetic susceptometry (SQUID) and the magnetic resonance imaging (MRI) methods utilising T2 and T2*. HIC can be quantified through image measurement of the proton transverse relaxation rate (R2) (St. Pierre et al Blood 2004). The potential for using the St Pierre method to monitor changes in HIC of patients with β-thalassemia/Hb E undergoing iron chelation therapy was investigated. Seventeen non-tansfusion dependant β-thal/Hb E patients who had not previously undergone chelation were studied. Subjects were chelated with the oral iron chelator Deferiprone (DFP) and had their HIC measured using both the R2-MRI and biopsy non-heme iron techniques pre and post treatment. Ferritin levels were also assayed for comparison. The subjects ages ranged from of 13 to 53 years (mean 31.6, SD 11.5). DFP was administered at a low dose of 50 mg/kg/Day with divided doses 2 –3 times daily. The periods of drug exposure ranged between 53 and 77 weeks (mean 64.1, SD 8.4). HIC by R2-MRI and tissue iron chemical analysis, and serum ferritin Measurement R2-HIC (mg/g DW) Biopsy-HIC (mg/g DW) Serum Ferritin (ng/ml) Mean ± SD Range Mean ± SD Range G.Mean ± SE Range Initial 17.8 ± 6.6 5.7 – 29.7 18.3 ± 9.0 6.0 – 40.1 2526 ± 432 842 – 6072 Final 8.4 ± 7.9 1.0 – 23.9 7.4 ± 7.3 0.2 – 25.5 416 ± 236 113 – 4030 The results show a significant decrease of HIC after long term administration of DFP with MRI and biopsy (p= .0004 and p<0.0001 respectively). Spearman rank correlations of R2-HIC with the liver non-heme Fe and serum ferritin measures gave positive values of 0.866 (p < 0.0001) and 0.768 (p < 0.0001) respectively. The mean reduction of R2-HIC, biopsy-HIC and serum ferritin were 53%, 69%, and 74%, respectively. A decrease of 20.5% (SD ±14.9%) in the standard deviation of the R2 distribution was observed suggesting a decrease in iron heterogeneity accompanied the mean HIC decrease. The results suggest that R2 MRI has the potential to be used as a clinical monitoring tool in chelation therapy.

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Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major

British Journal of Haematology ◽

10.1046/j.1365-2141.2000.02298.x ◽

2000 ◽

Vol 110 (4) ◽

pp. 971-977 ◽

Cited By ~ 145

Author(s):

P. T. Telfer ◽

E. Prestcott ◽

S. Holden ◽

M. Walker ◽

A. V. Hoffbrand ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Hepatic Iron ◽

Thalassaemia Major ◽

Long Term Monitoring ◽

Term Monitoring ◽

Hepatic Iron Concentration

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

Blood ◽

10.1182/blood.v122.21.179.179 ◽

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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Sa1606 – Is Serum Ferritin a Reliable Measure of Iron Overload When Compared to Hepatic Iron Concentration?

Gastroenterology ◽

10.1016/s0016-5085(19)40129-7 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-1251

Author(s):

Barra P. Neary ◽

Mohammad Tayyub ◽

Asya Tacheva ◽

Aidan Quinn ◽

Greg Martin ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Hepatic Iron ◽

Reliable Measure ◽

Hepatic Iron Concentration

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Iron overload in Brazilian thalassemic patients

Einstein (São Paulo) ◽

10.1590/s1679-45082011ao1897 ◽

2011 ◽

Vol 9 (2) ◽

pp. 165-172 ◽

Cited By ~ 2

Author(s):

Reijane Alves de Assis ◽

Fernando Uliana Kay ◽

Laércio Alberto Rosemberg ◽

Alexandre Henrique C. Parma ◽

Cesar Higa Nomura ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Resonance Imaging ◽

Plasma Iron ◽

Imaging Results ◽

The Mean ◽

Hepatic Iron Concentration

ABSTRACT Objectives: To evaluate the use of magnetic resonance imaging in patients with β-thalassemia and to compare T2* magnetic resonance imaging results with serum ferritin levels and the redox active fraction of labile plasma iron. Methods: We have retrospectively evaluated 115 chronically transfused patients (65 women). We tested serum ferritin with chemiluminescence, fraction of labile plasma iron by cellular fluorescence and used T2* MRI to assess iron content in the heart, liver, and pancreas. Hepatic iron concentration was determined in liver biopsies of 11 patients and the results were compared with liver T2* magnetic resonance imaging. Results: The mean serum ferritin was 2,676.5 +/- 2,051.7 ng/mL. A fraction of labile plasma iron was abnormal (> 0,6 Units/mL) in 48/83 patients (57%). The mean liver T2* value was 3.91 ± 3.95 ms, suggesting liver siderosis in most patients (92.1%). The mean myocardial T2* value was 24.96 ± 14.17 ms and the incidence of cardiac siderosis (T2* < 20 ms) was 36%, of which 19% (22/115) were severe cases (T2* < 10 ms). The mean pancreas T2* value was 11.12 ± 11.20 ms, and 83.5% of patients had pancreatic iron deposition (T2* < 21 ms). There was significant curvilinear and inverse correlation between liver T2* magnetic resonance imaging and hepatic iron concentration (r= −0.878; p < 0.001) and moderate correlation between pancreas and myocardial T2* MRI (r = 0.546; p < 0.0001). Conclusion: A high rate of hepatic, pancreatic and cardiac impairment by iron overload was demonstrated. Ferritin levels could not predict liver, heart or pancreas iron overload as measured by T2* magnetic resonance imaging. There was no correlation between liver, pancreas, liver and myocardial iron overload, neither between ferritin and fraction of labile plasma iron with liver, heart and pancreas T2* values

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Utility of Transient Elastography (Fibroscan) in Estimating Hepatic Iron Concentration in Comparison to MRI in Patients with Transfusion Dependent Hemoglobinopathies

Blood ◽

10.1182/blood.v124.21.4888.4888 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4888-4888

Author(s):

Hatoon Ezzat

Keyword(s):

Regression Analysis ◽

Linear Regression ◽

Iron Overload ◽

Serum Ferritin ◽

Transient Elastography ◽

Linear Regression Analysis ◽

Iron Concentration ◽

Thalassemia Major ◽

Hepatic Iron ◽

Hepatic Iron Concentration

Abstract Background Patients with severe hereditary anemias (e.g. β-Thalassemia Major) are transfusion-dependent for survival. Current guidelines suggest monitoring serum ferritin every three months and annual MRI to assess hepatic and cardiac iron load1. However, MRI, particularly the R2 sequence (FerriScan) which has high specificity and sensitivity in estimating the liver iron concentration, is expensive and not always readily available. Transient elastography (FibroScan) measures liver's stiffness and predicts fibrosis. Previous studies have suggested its utility in other conditions that increase liver stiffness, such as amyloidosis2and perhaps iron overload. Aim To determine if FibroScan value correlates with hepatic iron concentration estimated using R2 MRI (FerriScan), and/or serum ferritin level. Methods A prospective cross-sectional study was conducted at a university-affiliated tertiary care center (St. Paul’s Hospital, Vancouver, BC) in 2013 and 2014. Inclusion criteria: Age ≥ 19 years with transfusion-dependent hereditary anemias. Exclusion criteria: liver cirrhosis, primary liver disease (e.g. Wilson’s disease, hereditary hemochromatosis), and chronic viral hepatitis (e.g. Hepatitis B, C and HIV). In addition to having annual MRI and ferritin levels monitored every three months, subjects underwent FibroScan within six months of MRI in 2013. In 2014, participants were invited to undergo repeat FibroScan within three months of the annual MRI. Linear regression analysis was used to determine if there is any correlation/linear fit between FibroScan result, MRI result, and ferritin levels. This study was approved by the University of British Columbia Research Ethics Board. Results 20 subjects have been recruited as of August 1, 2014, with 35 and 33 complete FibroScan and MRI results, respectively. 14 (70%) were female. Mean age was 30.7±9.8 years. Most common primary diagnosis was transfusion-dependent beta-thalassemia (Major and intermedia) (n=17). Linear regression analysis showed a weakly positive correlation between hepatic iron concentrations estimated with R2 MRI (FerriScan) and ferritin levels (R2=0.29; p=0.004), when they are performed within four weeks apart. The correlation remained statistically significant when all subjects were included regardless of time lapse between the two investigations (R2=0.30; p=0.001). However, FibroScan values did not appear to correlate with MRI, regardless of whether the scans are performed within six months (R2=0.011; p=0.58) or three months apart (R2=0.035; p=0.44). Similarly, there was no correlation between FibroScan and Ferritin (R2=0.022; p=0.49) when the investigations were performed within 4 weeks part. Conclusion Interim analysis did not demonstrate any correlation between FibroScan result and MRI-estimated hepatic iron concentration. A final analysis will be performed upon complete formal evaluation of the remaining MRI and FibroScan data. References Remacha A, Sanz C, Contreras E, et al. Guidelines on haemovigilance of post-transfusional iron overload. Blood Transfus. 2013; 11(1): 128-139Loustaud-Ratti V, Cypierre A, Rousseau A, et al. Non-invasive detection of hepatic amyloidosis: Fibroscan, a new tool. Amyloid 2013; 18(1): 19-24 Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.2819.2819 ◽

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.

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