Assessment Of Liver Iron Content Research Articles

Iron overload status in patients with non-transfusion-dependent thalassemia in China.

Background:Iron overload is one of the main factors that increase morbidity and mortality in patients with non-transfusion dependent thalassemia (NTDT).Aim:This study aimed at investigating the prevalence and severity of iron overload in Chinese NTDT patients.Methods:we analyzed serum ferritin (SF), liver iron concentration (LIC) and cardiac T2* in 178 Chinese NTDT in this cross-sectional study.Results:The median SF level was 996.00(27.15–19704.00) ng/ml and the median LIC value was 8.90(0.60–43.00) mg Fe/g dry weight (dw). The youngest patient with liver iron overload was 5 years old with 5.6 mg Fe/g dw in LIC. The median cardiac T2* was 33.06(7.46–75.08) ms. 6 patients had cardiac T2*⩽20ms. The patients with β thalassemia intermedia and HbE/β thalassemia showed a statistically significant lower Hb and higher values of SF and LIC than those of hemoglobin H disease patients. On multivariate logistic regression analysis, patients in ⩾ age 30-year old had a significant higher risk for iron overload (OR: 77.75, 95% CI: 8.76–690.49) in the age group. The detailed analysis of proportions of different LIC indicate in > 30-year old group, 76.8% patients suffered from moderate and severe LIC.Conclusion:Our study provides a strong support for the novel findings that Chinese NTDT patients have a high prevalence of iron overload. The first assessment of MRI LIC should be performed as early as 5 years old. Then, NTDT patients > 30 years old may suffer with a high burden of iron overload.

Effects of B1+ Heterogeneity on Spin Echo-Based Liver Iron Estimates.

Liver iron concentration (LIC) measured by MRI has become the clinical reference standard for managing iron overload in chronically transfused patients. Transverse relaxivity (R2 or R2* ) measurements are converted to LIC units using empirically derived calibration curves. That flip angle (FA) error due to B1+ spatial heterogeneity causes significant LIC quantitation error. B1+ scale (b1 , [FAactual /FAspecified ]) variation is a major problem at 3 T which could reduce the accuracy of transverse relaxivity measurements. Prospective. Forty-seven subjects with chronic transfusional iron overload undergoing clinically indicated LIC assessment. 5 T/3 T dual-repetition time B1+ mapping sequence ASSESSMENT: We quantified the average/standard deviation b1 in the right and left lobes of the liver from B1+ maps acquired at 1.5 T and 3 T. The impact of b1 variation on spin echo LIC estimates was determined using a Monte Carlo model. Mean, median, and standard deviation in whole liver and right and left lobes; two-sided t-test between whole-liver b1 means. Average b1 within the liver was 99.3% ± 12.3% at 1.5 T versus 69.6% ± 14.6% at 3 T and was independent of iron burden (P< 0.05). Monte Carlo simulations demonstrated that b1 systematically increased R2 estimates at lower LIC (<~25 mg/g at 1.5 T, <~15 mg/g at 3 T) but flattened or even inverted the R2 -LIC relationship at higher LIC (≥~25 mg/g to 1.5 T, ≥~15 mg/g to 3 T); changes in the R2 -LIC relationship were symmetric with respect to over and under excitation and were similar at 1.5 T and 3 T (for the same R2 value). The R2* -LIC relationship was independent of b1 . Spin echo R2 measurement of LIC at 3 T is error-prone without correction for b1 errors. The impact of b1 error on current 1.5 T spin echo-based techniques for LIC quantification is large enough to introduce measurable intersubject variability but the in vivo effect size needs a dedicated validation study. 2.

Serum Ferritin Underestimates Liver Iron Concentration in Patients with Homozygous Alpha-0 Thalassemia

Background: Homozygous α0-thalassemia (Hemoglobin Bart's hydrops fetalis, HBHF) results from deletion of all α-globin genes. Similar to patients with transfusion-dependent beta-thalassemia (TDT-β), survivors of HBHF require life-long transfusions which over time will inevitably lead to significant tissue iron overload (IO). We have recently reported that the underlying disease process in HBHF is different from that of TDT-β (Amid A. et al. Blood, 2016). Unlike TDT-β, hemolysis is the major pathophysiologic process in HBHF and chronically transfused HBHF patients continue to have significant erythropoietic activity and tissue hypoxia (with increased serum erythropoietin) due to the indegenous nonfunctional hemoglobin-H. In addition, almost all survivors of HBHF would have commenced their transfusion therapy in-utero, potentially resulting in earlier IO compared to their TDT-β counterparts. Considering these differences, we hypothesized that the pattern of IO in patients with HBHF would likely differ from those with TDT-β.Methods: Following research ethics board approval, we retrospectively collected longitudinal data on transfusion and chelation history, serum ferritin, and liver iron concentration (LIC) measured by MRI or biopsy, in 7 HBHF (5 males; mean age: 7.3 years) and 14 TDT-β (8 males; mean age: 11.1 years) patients. None of the HBHF or TDT-β patients were splenectomized. Corresponding pairs of serum ferritin and LIC assessment (defined as measurements of not more than two weeks apart with no transfusions in between) were used to calculate ferritin-to-LIC ratios. All patients were treated with the same transfusion protocol to maintain pre-transfusion hemoglobin of >90 g/L and LIC of <5 mg/g of dry liver weight, until 2014. Since April 2014, five patients with HBHF have been commenced on a more aggressive transfusion strategy to decrease the nonfunctional HbH, suppress erythropoiesis, increase tissue oxygenation, and reduce hemolysis. We used linear mixed models to assess the associations between serum ferritin, LIC, and ferritin-to-LIC ratio with age, disease type (HBHF vs. TDT-β), chelation type, and method of LIC assessment. Correlations within a subject and between different ages were effectively accounted for in this model.Results: At 12 month of age, chelation-naïve HBHF patients had significantly higher serum ferritin level reflecting earlier IO compared to chelation-naïve TDT-β patients [1242.4 μg/dL (SD 419.4) vs. 418.3 μg/dL (SD 113.3), p<0.001]. On longitudinal assessments in both chelated HBHF and TDT-β patients, ferritin was significantly correlated with LIC (ρ = 0.88, p <0.001 and ρ = 0.46, p <0.001, respectively). Serum ferritin was significantly lower in HBHF vs. TDT- β [849 μg/dL (SD 573) vs. 2036 μg/dL (SD 1495), p<0.001] but there was no difference in LIC between the two groups [9.68 mg/g (SD 5.73) vs. 8.63 mg/g (SD 7.99), p=0.48]. Consequently, HBHF patients had significantly lower ferritin-to-LIC ratios [86.8 (SD 33.2) vs. 308.5 (SD 182.4), p<0.0001]. In addition, in the HBHF patients, serum ferritin-to-LIC ratio was corrolated with reticulocyte count (ρ = 0.41, p <0.042). In two mixed model analyses that included age, disease type, and method of LIC assessement or chelation type as variable of interset, disease type remained a highly signifiant predictor of serum ferritin-to-LIC ratio (p<0.0001). However, after the implementation of aggressive transfusion strategy (and suppression of erythropoeitic activity and improvement of tissue oxygenation) in HBHF patients, ferritin-to-LIC ratios were significantly higher [304.2 (SD 121.5) vs. 86.87 (SD 33.2), p=0.0003], becoming similar to ratios in TDT-β patients (p=0.88).Conclusion: Patient with HBHF are at-risk of significant IO early in life which poses potential challenges with iron chelation at an early age. Furthermore, in these patients, ferritin significantly underestimates LIC. This finding has important implications for clinical care and surveillance of IO in these patients, especially in areas with limited resources where non-invasive assessement of LIC (MRI) may not be widely available. The lower ferritin-to-LIC ratio observed in HBHF patients and its relation to erythropoietic activity indirectly suggest that in addition to transfusional iron loading, increased gastrointestinal absorption of iron due to suppressed hepcidin may also contribute to siderosis in these patients. DisclosuresNo relevant conflicts of interest to declare.

R2 and R2* MRI assessment of liver iron content in an undifferentiated diagnostic population with hyperferritinaemia, and impact on clinical decision making

PurposeTo confirm the linear correlation between Ferriscan® R2 (1/T2 Relaxomatry) and R2* (1/T2* Relaxometry) derived 3D Gradient echo (GRE) mDIXON-Quant sequence (Philips) with simultaneous production of a proton density fat fraction (PDFF) in undifferentiated patients with hyperferritinaemia, and to prospectively determine the clinical utility of this tool in these patients by recording the impact on clinical decision-making. Materials and MethodsParticipants referred to a hospital haematology outpatient clinic for investigation and management of elevated serum ferritin (two serum ferritin levels > 500 μg/L 4 weeks apart) were included in the study. Exclusion criteria: contraindications to MRI; clinically relevant investigations for alternative causes of hyperferritinaemia pending; and terminal illness. Thirty-two participants were recruited: 27 men, 5 women. All MRIs performed at 1.5 T. For R2* quantification, 3D six echo GRE sequence (mDIXON-Quant) was acquired. R2 images were acquired over 20 min as dictated and reported by the licensee (Ferriscan®). Clinician interpretation and patient management based on R2* and liver iron content derived from R2 (LICR2) was recorded. Pearson’s correlations, linear regression analyses, and ROC curves were calculated. P value <0.05 was considered significant. ResultsA high degree of correlation between mean R2* and LICR2 was observed in this novel patient population (slope ± SE of 43.35 ± 1.88 s−1 permg/g; 95 % CI 39.5–47.2; P < 0.001; R2 = 0.87). Clinical decision making was amended in 14/32 (44 %) patients with hyperferritinaemia following the disclosure of R2* results to clinicians, compared with serum ferritin alone. Liver biopsy was avoided in one patient based on LICR2 and R2*. Unrecognised hepatic steatosis was diagnosed in one patient from the PDFF map. ConclusionWe have confirmed the linear correlation between R2 and R2* in a real-world diagnostic population with hyperferritinaemia. Non-invasive assessment of liver iron content (LIC) by R2 and R2* MRI is a useful clinical tool and alters management in these patients.

Brain Iron Content in Egyptian Patients with Sickle Cell Disease: Impact on Neurocognitive Functions

Background:Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment which may be due to iron overload in brain tissue or hemoglobin polymerization and endothelial dysfunction.Primary objectivewas measuring brain iron content (using R2* values) in the caudate and thalamic regions through quantitative brain MRI in Egyptian adolescents and young adults with multi-transfused SCD in comparison to beta thalassemia major (BTM) and age- and sex-matched healthy controls.Secondary objectiveswere evaluating the impact of brain iron content on neurocognitive functions of SCD patients and its association with MRI assessment of liver iron concentration (LIC) and cardiac iron (myocardial T2*).Methods: 32 children and young adults with SCD (mean age: 15.3 ± 3.7, 19 males and 13 females), 15 BTM (mean age: 19.4 ± 4.3, 7 males and 8 females) and 11 healthy control age- and gender-matched were recruited. Thorough clinical assessment, hematological and serum ferritin were performed. Brain MRI study using multi-echo fast gradient echo sequence was performed only for 15 patients with SCD, 15 patients with BTM and 11 controls and brain R2* values of both caudate and thalamic regions (right and left sides) were calculated. LIC and myocardial T2 were performed for; 15 with SCD and 15 with BTM. 32 SCD patients were examined for the neurocognitive functions; Wechsler IV Intelligence scale (verbal, perceptual, memory, processing and total IQ), Benton Visual Retention Test and Brief Psychiatric Rating Scale (BPRS).Results:For SCD patients their mean transfusion index was 174.70±63.98ml/kg/year and mean iron overload/day 0.30±0.12 mg/kg. 30 (93.8%) all SCD patients were on regular chelation therapy; 16 were on deferiprone and 16 were on combined chelation over last 5 years. Of those 32 SCD patients; 20 received concomitantly hydroxyurea therapy. Mean total IQ for SCD patients was 86.9±10.7; 68.9% had under- threshold &amp;lt;90 IQ and 27.5% had average (90-109) IQ. 12.5% of SCD patients had moderate to severe anxiety and 60.8% had of SCD patients had depression. No significant differences were found between SCD, BTM as regards LIC (p=0.102) No significant differences were found between SCD, BTM and control group in all regions of interests in brain MRI except that left thalamus R2* higher in BTM patients than both SCD and controls (p=0.032). R2* values of different regions of brain in relation with the studied parameters of SCD patients was not significant except that mean right caudate R2* was higher in female 17.4±0.8 than male 15.6±1.7 (p=0.044). The correlation coefficients showed no significant association between brain R2* and LIC or heart R2* values of SCD patients. There were positive correlation between left caudate R2* and both age and HbS%, negative correlation between transfusion index and right thalamus R2*, negative correlation between HbA% and left caudate R2* among SCD patients.Conclusion:Brain iron content in adolescents and young adults with SCD was not significantly different from either controls or BTM; SCD had high prevalence of neurocognitive dysfunction, which could not be explained by brain iron content or distribution. Figure 1 Disclosures No relevant conflicts of interest to declare.

Quantification of Liver Iron Overload: Correlation of MRI and Liver Tissue Biopsy in Pediatric Thalassemia Major Patients Undergoing Bone Marrow Transplant.

Determination of the magnitude of body iron stores helps to identify individuals at risk of iron-induced organ damage in Thalassemia patients. The most direct clinical method of measuring liver iron concentration (LIC) is through chemical analysis of needle biopsy specimens. Here we present a noninvasive method for the measurement of LIC in vivo using magnetic resonance imaging (MRI). Twenty-three pediatric Thalassemia major patients undergoing bone marrow transplantation at our centre were studied. All 23 patients had MRI T2* and R2* decay time for evaluation of LIC on a 1.5Tesla MRI system followed by liver tissue biopsy for the assessment of iron concentration using an atomic absorption spectrometry. Simultaneously, serum ferritin levels were measured by enzymatic assay. We have correlated biopsy LIC with liver T2* and serum ferritin values with liver R2*. Of the 23 patients 11 were males, the mean age was 8.3 ± 3.7years. The study results showed a significant correlation between biopsy LIC and liver T2* MRI (r = 0.768; p < 0.001). Also, there was a significant correlation between serum ferritin levels and liver R2* MRI (r = 0.5647; p < 0.01). Two patients had high variance in serum ferritin levels (2100 and 4100mg/g) while their LIC was around 24mg/g, whereas the difference was not seen in T2* MRI. Hence, the liver T2* MRI is a better modality for assessing LIC. Serum ferritin is less reliable than quantitative MRI. The liver T2* MRI is a safe, reliable, feasible and cost-effective method compared to liver tissue biopsy for LIC assessment.

Comparison of automated and manual protocols for magnetic resonance imaging assessment of liver iron concentration.

ObjectiveTo compare automated and manual magnetic resonance imaging protocols for estimating liver iron concentrations at 1.5 T.Materials and MethodsMagnetic resonance imaging examination of the liver was performed in 53 patients with clinically suspected hepatic iron overload and in 21 control subjects. Liver iron concentrations were then estimated by two examiners who were blinded to the groups. The examiners employed automated T2* and T1 mapping, as well as manual T2* and signal-intensity-ratio method. We analyzed accuracy by using ROC curves. Interobserver and intraobserver agreement were analyzed by calculating two-way intraclass correlation coefficients.ResultsThe area under the ROC curve (to discriminate between patients and controls) was 0.912 for automated T2* mapping, 0.934 for the signal-intensity-ratio method, 0.908 for manual T2*, and 0.80 for T1 mapping, the last method differing significantly from the other three. The level of interobserver and intraobserver agreement was good (intraclass correlation coefficient, 0.938-0.998; p < 0.05). Correlations involving T1 mapping, although still significant, were lower.ConclusionAt 1.5 T, T2* mapping is a rapid tool that shows promise for the diagnosis of liver iron overload, whereas T1 mapping shows less accuracy. The performance of T1 mapping is poorer than is that of T2* methods.

Uncertainty in the R2 Calibration Curve for High Iron Concentration

Introduction: MRI assessment of liver iron concentration (LIC) has become the standard of care for monitoring iron chelation strategies. The Ferriscan R2 quantification of LIC has been validated against 338 biopsies in two large cohorts, demonstrates good interstudy reproducibility, and has strong quality control practices. However, its cost remains a challenge for many institutions, making iron measurements by R2* acquisitions more attractive. Several studies comparing LIC by R2* and by Ferriscan R2 have identified substantial bias between R2* and R2 LIC estimates. We postulated that the original Ferriscan R2 calibration overestimates LIC at high iron concentrations, causing the disagreement between the two techniques. Methods: We identified three studies comparing single echo R2 to liver biopsy (362 biopsies). We used a publicly available digital capture program(www.arizona-software.ch/graphclick) to capture the values of R2 for each liver iron concentration level. We fit the data to the existing FDA-approved calibration and compared Bland Altman agreement to liver biopsy against two other calibration curves. The first was data-derived from the aggregate liver biopsy results using a linear fit in log transformed LIC and R2 coordinates (resulting in a Power Law fit). The second was derived from a spline fit to data generated from previously published Monte Carlo simulation model from our laboratory. This model generates "synthetic" R2-iron pairs over the entire physiological range of iron overload, using ideal mathematical approximations to the MRI imaging physics. Results: Panel A demonstrates R2-LIC pairs for the aggregate liver biopsy data and the three evaluated R2-iron calibration curves. Using Bland-Altman analysis, both the Power Law (0.5 ± 4.9 mg/g) and Simulation (1.7 ± 5.1 mg/g) calibrations had 17-22% lower variance than the Ferriscan calibration (-1.1 ± 6.2 mg/g), p&amp;lt;0.0001 by two sample variance test. More importantly, the predicted LIC values diverge dramatically for R2 values greater than 155 Hz (roughly 14 mg/g) (Panel B). For example, a R2 value of 300 Hz will yield an estimated LIC of 48 mg/g by Ferriscan but only 34 mg/g and 32.5 mg/g by the Power Law and Simulation calibrations respectively. Discussion: These data suggest that Ferriscan overestimates true liver iron concentration for R2 values exceeding 155 Hz, with the differences growing geometrically. The calibration error is sufficient to completely explain the differences between LIC by R2* and Ferriscan R2 described in previously studies. Importantly, any future attempt to "calibrate" R2* or other MRI methods against Ferriscan need to account for this bias. Fortunately, the clinical impact of the observed calibration bias is manageable. Patients with LIC below 14 mg/g are being accurately risk stratified. Patients with LIC greater than 14 mg/g in their liver are universally at high risk and should be treated aggressively, regardless. Serial trends in LIC-R2 values also lessen the impact of calibration bias. Both Ferriscan and R2* LIC estimates and provide accurate estimates of chelator efficiency on an annual basis. Further, both Ferriscan and liver R2* LIC estimates are more accurate than liver biopsy in tracking changes in total body iron concentration. However, hematologists should treat Ferriscan predicted LIC values of more than 14 mg/g with appropriate caution and integrate the predicted LIC values with the patient's entire clinical picture to avoid over-reacting to large changes in predicted LIC. ACKNOWLEDGEMENTS This work supported by the National Institutes of Health, Diabetes, Digestive and Kidney Diseases (1R01DK097115-01A1). DISCLOSURES Dr. Wood serves as a consultant to Apopharma, Biomedinformatics, Bluebirdbio, Celgene, Ionis Pharmaceuticals, Imago Biosciences, Silence Therapeutics, and World Care Clinical. Figure Disclosures Wood: National Institutes of Health: Research Funding; Celgene: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy; BluebirdBio: Consultancy; Imago Biosciences: Consultancy; BiomedInformatics: Consultancy; Philips Healthcare: Research Funding. Coates:celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria, Speakers Bureau; agios pharma: Consultancy, Honoraria.

Liver R2* is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease.

Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement. To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD. Prospective. Eighty-one patients with suspected CLD. 1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF. Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated. Pearson correlation, linear regression, and area under the receiver operating curve. There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively. PDFF increases R2*. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.

The value of magnetic resonance imaging in evaluation of myocardial and liver iron overload in a thalassaemia endemic population: a report from Northeastern Thailand

PurposePatients with chronic haemolytic anaemia, such as in thalassaemia, require repeated blood transfusions, which leads to iron overload and cellular damage, especially in the heart and liver. Classically, serum ferritin and liver biopsy have been used to monitor patient response to chelation therapy. Magnetic resonance imaging (MRI) has proven to be effective in detecting and quantifying iron in the heart and liver. The aim of the paper is to evaluate the accuracy of the MRI T2* procedure in the assessment of liver iron concentration and myocardial iron overload.Material and methodsIn 210 cases of monthly transfused patients, hepatic and myocardial iron overload was measured by multi-breath-hold MRI T2* and compared to serum ferritin (a traditional marker of iron overload).ResultsNo significant correlation was observed between serum ferritin level and cardiac T2* MRI (p = 0.68, r = 0.06). However, a significant correlation was observed between serum ferritin and liver iron concentration evaluated by MRI (p = 0.04, r = 0.68).ConclusionRoutine evaluation of liver and heart iron content using MRI T2* is suggested to better evaluate the haemosiderosis status in thalassaemic patients.

MRI Evaluation of Hepatic Iron Overload in b-Thalassemic Children

AbstractBackground: b-Thalassaemia major is a hereditary hemo-lytic anemia that have amajor complication iron overload. Assessment of Liver Iron Concentration (LIC) is necessary for detection and quantitative staging of iron overload and monitoring of iron-reducing treatments. MRI represents the most available noninvasive technique to assess LIC.The aim of this study was to assess LIC by MRI in multitransfused b-Thalassemic children.Patients and Methods: Forty multi-transfused b-thalassemic children were subjected to clinical evaluation, appropriate laboratory assessment and assessment of LIC by MRI.T2* weighted gradient echosequence MRI was performed with 1.5T scanner.Results:- Significant reduction in signal intensity ratio of the liver was show in all patients.- Highly significant correlation between MRI parameter (R2* and T2*) and LIC (p 0.05).- Splenectomizied patients had significant lower SIR of liver (decrease R2* and increase T2*) compared to non splenec-tomized patients (p<0.007).Conclusion: In conclusion based on results of our study MRI is the best noninvasive method for assessment and evaluation of hepatic iron overload and determine its severity in multi-transfused b-thalassemic patients.

Serum ferritin is not a reliable predictor to determine iron overload in thalassemia major patients post-hematopoietic stem cell transplantation.

Iron overload (IO) in transfusion-dependent anemia persists after hematopoietic stem cell transplantation (HSCT) and can cause long-term organ damage. In many studies, the diagnosis of IO before and after HSCT is based on serum ferritin (SF) levels rather than on assessment of liver iron concentration (LIC) by MRI or SQUID. In a retrospective multicenter study, we analyzed the concordance for indication of iron depletion therapy and correlation between LIC and SF of 36 thalassemia patients after HSCT. LIC was determined either by MRI-R2 (FerriScan®) or SQUID. The concordance between LIC and SF varies over time after transplant (P=0.011). The correlation between SF and LIC was strong in the first year (Spearman's rho 0.75; P<0.001). In agreement, the concordance between SF and LIC concerning indication for treatment was close to 1 with an overall error rate ca. of 10%. In particular in the first year after HSCT, SF underestimates the degree of iron overload. However, in the longitudinal analysis since the second year post-HSCT onward no association was found between LIC and SF (P=0.217). Furthermore, in the second year after HSCT, the overall error rate was 35%, whereas in the 3rd, 4th, and >4th year, it was 58%, 60%, and 25%, respectively. Our data suggest serum ferritin is not a reliable predictor to determine iron overload in thalassemia patients after HSCT.

Phlebotomy for Pediatric and Young Adult Oncology Patients Treats Transfusional Iron Overload

Introduction:Pediatric and young adult oncology patients treated with intense chemotherapy and stem cell transplant regimens have a high incidence of transfusional iron overload.(Acquazzino and Schloemer et al, ASH 2015). Iron deposition can lead to significant complications including heart failure, arrhythmias, liver abnormalities, endocrine dysfunction and ineffective erythropoiesis, as well as increased cancer and mortality risk. However there is a paucity of data regarding recommendations for management of transfusionial iron overload in childhood cancer survivors. Consequently, long-term complications of transfusional iron overload specific to pediatric cancer survivors have not been assessed. We have instituted screening and phlebotomy based treatment algorithms for pediatric and young adult oncology patients with transfusional iron overload.Methods:We conducted a retrospective chart review of pediatric and young adults who after having completed oncology management, were diagnosed with transfusional iron overload through a screening algorithm, and then initiated phlebotomy treatment. Tiered screening occurred in patients who received at least 5 packed red blood cell (pRBC) transfusions. Patients were recommended for further evaluation and discussion of possible phlebotomy treatment if they had: (1) liver iron concentration (LIC) greater than 5 mg of iron/gram dry weight liver tissue as measured by ferriscan and/or (2) cardiac MRI T2* < 20 ms. Management of phlebotomy treatment was conducted according to Table 1. During phlebotomy patient iron status was assessed at least quarterly and phlebotomy discontinued with achievement of LIC <5 or normalization of ferritin and followed by imaging LIC assessment verification. Inclusion criteria: (1) diagnosis of childhood malignancy, (2) completed active cancer therapy, (3) received phlebotomy treatment for transfusional iron overload. Exclusion criteria included: Patients with known hereditary hemochromatosis and patients who received photopheresis. Descriptive statistics were employed to report the characteristics of the study population. Spearman correlations were utilized to describe the association between number of transfusions, LIC, ferritin, iron saturation and number of phlebotomy sessions. This study was approved by the Children's Hospital of Wisconsin Institutional Review Board prior to data collection.Results:Patient Demographics: We identified 25 pediatric and young adult childhood cancer survivors who underwent phlebotomy for transfusional iron overload. The mean age was 11.6 years (SD 6.1) and 10 (40%) were female. Oncologic diagnoses included ALL (36%), AML (8%), NHL (12%), Ewing sarcoma (16%), Osteosarcoma (4%), Neuroblastoma (12%) and CNS malignancies (12%).Transfusions/Phlebotomy/Diagnostic Tests: (Table 2) Patients received a median of 25.0 (IQR 17 - 34) pRBC transfusions. No patient had fewer than 10 transfusions. Median number of phlebotomy sessions was 6 (IQR 4-8) occurring over a median period of 0.36 years (IQR 0.28 - 0.59). Prior to phlebotomy, the median LIC was 7.5 mg/g (IQR 5.6-9.0) and median ferritin was 1110.0 ng/mL (IQR 700 - 2030). No patients demonstrated cardiac transfusional iron overload on T2* MRI (n=18). 23 (92%) patients have completed phlebotomy. One patient discontinued phlebotomy due to inability to safely obtain vascular access and no patients developed iron deficiency anemia. LIC was reduced by a median of 2.4 mg/g (IQR 1.1 - 3.6) and ferritin was reduced by median of 586 ng/mL (IQR 366-875). Correlation between number of transfusions received and phlebotomy sessions administered was poor (R2=0.017).Conclusions:Management guidelines are absent for transfusional iron overload in pediatric and young adult survivors of cancer. We demonstrate a phlebotomy algorithm that is an effective and well tolerated treatment for pediatric and young adult oncology patients with therapy related transfusional iron overload. Correlation between number of transfusions received and phlebotomy treatments required to remove deposited iron was poor necessitating serial assessments of iron status. Using this management algorithm, prospective studies can evaluate the effect of excess iron removal on iron overload complications in pediatric and young adult cancer survivors. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of liver magnetic resonance imaging in hyperferritinaemia and the diagnosis of iron overload.

Hyperferritinaemia is a frequent clinical problem. Elevated serum ferritin levels can be detected in different genetic and acquired diseases and can occur with or without anaemia. It is therefore important to determine whether hyperferritinaemia is due to iron overload or due to a secondary cause. The main causes of iron overload are intestinal iron hyperabsorption disorders and transfusion-dependent disorders. Iron homeostasis and iron overload are quantified by different diagnostic approaches. The evaluation of serum ferritin and transferrin saturation is the first diagnostic step to identify the cause of hyperferritinaemia. The assessment of liver iron concentration by liver biopsy or magnetic resonance imaging (MRI) may guide the further diagnostic and therapeutic workup. Liver biopsy is invasive and poorly accepted by patients and should only be carried out in selected patients with hereditary haemochromatosis. As a non-invasive approach, MRI is considered the standard method to diagnose and to monitor both hepatic iron overload and the effectiveness of iron chelation therapy in many clinical conditions such as thalassaemia and myelodysplastic syndromes. Accurate evaluation and monitoring of iron overload has major implications regarding adherence, quality of life and prognosis. There are different technical MRI approaches to measuring the liver iron content. Of these, T2 and T2* relaxometry are considered the standard of care. MRI with cardiac T2* mapping is also suitable for the assessment of cardiac iron. Currently there is no consensus which technique should be preferred. The choice depends on local availability and patient population. However, it is important to use the same MRI technique in subsequent visits in the same patient to get comparable results. Signal intensity ratio may be a good adjunct to R2 and R2* methods as it allows easy visual estimation of the liver iron concentration. In this review a group of Swiss haematologists and radiologists give an overview of different conditions leading to primary or secondary iron overload and on diagnostic methods to assess hyperferritinaemia with a focus on the role of liver MRI. They summarise the standard practice in Switzerland on the use of liver iron concentration MRI as well as disease-specific guideline recommendations.

Iron Overload Status in Patients with Non-Transfusion-Dependent Thalassemia in China

▪Background: Non-transfusion-dependent thalassemia (NTDT) is a genetic disorder most commonly including beta-thalassemia intermedia (Beta-TI), HbE/Beta thalassemia (HbE/Beta thalassemia), and hemoglobin H disease (HbH disease). NTDT patients can be at risk of iron overload due to increased intestinal iron absorption triggered by chronic anemia, ineffective erythropoiesis and, possibly, decreased serum hepcidin. Despite NTDT is popular in southern China, there is little data evaluating iron overload in Chinese patients. This study aimed at investigating the occurrence, prevalence and severity of iron overload in Chinese population with NTDT.Methods: We evaluated the serum ferritin (SF), liver iron concentration (LIC) and cardiac T2* in 158 NTDT patients (83 with HbH disease, 45 with Beta-TI and 30 with HbE/Beta thalassemia) in China. The median age was 22 years old. The main characteristics of these patients along with the main results of the study were summarized in Table 1. Blood samples were obtained for the assessment of hemoglobin (Hb) and serum ferritin (SF) levels. LIC was assessed by using validated R2 magnetic resonance imaging [MRI] (FerriScan®). Cardiac iron level was measured by MRI T2*. Patients were scanned with MRI 1.5 T (Siemens Avanto, Germany). The study was performed at the First Affiliated Hospital of Guangxi Medical University. LIC < 3mg Fe/g dw and cardiac T2* > 20ms was considered normal. Abnormal LIC can be divided into mild: 3-7mg Fe/g dw, moderate: 7-15mg Fe/g dw, severe: >15mg Fe/g dw. All patients or parents/guardians provided their written informed consent to participate in this study. The study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University.Results: The median SF level of 158 NTDT patients was 1,037(27.0-19,704) ng/ ml. LIC was detected in 155 patients (98.1%) and the median LIC value was 8.9(0.6-43) mg Fe/g dw. There were 15 patients (60%) (8 with HbH disease, 5 with Beta-TI and 2 with HbE/Beta thalassemia)<10 years old found liver iron overload. The youngest patient with liver iron overload was 5 years old with 5.6mg Fe/g dw in LIC. Cardiac T2*was assessed in 111 patients (70.2%) and the median cardiac T2* was 32.8(7.5-75.1)ms. The 7 patients (4.4%) (4 with HbH disease and 3 with Beta-TI) had cardiac T2*=<20ms. There was a significant correlation between LIC and SF (r=0.809, p<0.001). No correlation between LIC and Hb, cardiac T2* values can be verified.There was a significant correlation between LIC and age (r=0.497, p<0.001)(Fig 1). The levels of LIC in patients > 30-year old group are significantly higher than those in other groups (Fig 2).The patients with Beta-TI and HbE/Beta thalassemia showed a statistically significant lower Hb and higher values of SF and LIC than those of HbH disease patients.Conclusions: Chinese NTDT patients have a high prevalence of iron overload. The iron overload in patients with Beta-TI and HbE/Beta thalassemia are more serious than those in HbH disease patients. The age of patient is a risk factor of iron overload in NTDT patient. Patients > 30 years old have a high burden of iron overload. Our data shows that the first assessment of MRI LIC should be performed as early as 5 years old. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET.

Real-life data on the use of R2 MRI for the assessment of liver iron concentration (LIC) remain limited. We conducted a cross-sectional analysis on 363 patients (mean age 35.6 yr, 44.1% men) with hemoglobinopathies (204 β-thalassemia major [TM], 102 β-thalassemia intermedia [TI], and 57 sickle cell disease [SCD]) that were evaluated with R2 MRI as part of LICNET, an MRI network of 13 Italian treatment centers. The mean LIC was 7.8 mg/g (median: 4.0), with high LIC (>7 mg/g) noted in both transfused (TM, TI 37%; SCD 38%) and non-transfused (TI 20%) patients. Ferritin levels correlated with LIC in both transfused (TM, TI, SCD) and non-transfused (TI) patients (P < 0.001), although lower values predicted high LIC in non-transfused patients (1900 vs. 650 ng/mL in TM vs. non-transfused TI). A correlation between LIC and ALT levels was only noted in HCV-negative patients (rs = 0.316, P < 0.001). The proportion of patients with high LIC was significantly different between iron chelators used (P = 0.023), with the lowest proportion in deferasirox (30%) and highest in deferiprone (53%)-treated patients. High LIC values persist in subgroups of patients with hemoglobinopathy, warranting closer monitoring and management optimization, even for non-transfused patients with relatively low ferritin levels.

Assessment of Cardiac Iron Overload in Chonically Transfused Patients with Thalassemia, Sickle Cell Anemia, and Myelodysplastic Syndromes

▪Background. Cardiac iron overload is the major cause for death in regularly transfused thalassemic (Thal) patients. Its impact in myelodysplastic syndrome (MDS) patients is debated. Heart seems to be spared in regularly transfused patients with sickle cell anemia (SCA), which is supposed to be related to a later onset on transfusions and to the use of erythrocytapheresis rather than simple transfusion. Our aim was to assess the prevalence of cardiac iron overload, defined as a T2*cardiovascular magnetic resonance (MR) <20ms, and to look for predisposing factors.Patients and methods. Patients were enrolled if they were regularly followed in a center where the exact number of erythrocyte concentrates (EC) could be obtained, had received in the previous year more than 8 EC, were older than 6 years (limit for MRI without sedation), had no known heart disease related to another pathology, and had given informed consent.All patients underwent 1.5T myocardial T2*MR imaging after validation of the procedures in the different sites. Assessment of Liver Iron Content (LIC) used two signal intensity ratio of gradient echo imaging (R2*) MRI protocols. Serum Non-Transferrin Bound Iron (NTBI) was measured by the FeROSTM eLPI kit, and serum hepcidin by LC-MSMS.Results. 20 Thal, 41 SCA and 25 MDS patients were evaluable. We divided SCA in 2 groups, according to the procedure recorded at the time of the study, manual exchange transfusion (G1, N = 30 patients), or erythrocytapheresis (G2, N=11 patients).We found cardiac overload in 0, 3 (15%), and 4 (16%) of SCA, Thal, and MDS patients respectively. Serum ferritins at beginning of chelation were not statistically different in all categories of patients, as well as Ferritin and LIC at the time of the study. Increased LIC and abnormal T2* were associated in Thal and MDS patients (p=0.04), with no correlation between abnormal T2* and parameters of transfusion and chelation.Plasmatic iron level was increased in Thal and MDS patients but remained at normal range in SCA patients. NTBI level was high in Thal and MDS but completely absent in SCA groups.The major discrepancy was in the values of hepcidin, which were collapsed in Thal, at normal range in SCA, and highly elevated in MDS patients.Discussion and conclusion.We confirm that SCA patients are relatively protected from cardiac iron overload. This results probably from massive consummation of iron through effective erythropoiesis, making toxic free iron (NTBI) less available in the circulation. In addition, since iron overload in SCA results from a massive outflow of hemoglobin (Hb) due to intravascular hemolysis and transfusion, the heme/Hb-bound iron must be efficiently handled in liver macrophages, limiting its release in the bloodstream.In Thal patients, underlying defects in erythropoietic processes, together with low hepcidin that stimulates intestinal iron absorption and increases NTBI, must provoke more organ damages. Hepcidin levels were high in MDS patients, suggesting that transfusion-dependent iron overload was a more effective regulator of hepcidin production than dyserythropoiesis. The % of T2*<20 ms we observed in MDS patients (16%) was quite comparable with previous publications.Finally, we observe that, in opposition with previous reports, SCA patients undergoing eythrocytapheresis may experience severe iron overload and need iron chelation.Table 1ThalSCA G1SCA G2MDSpAge at beginning of transfusion (yrs)8.5[0-45]7[0-45]16.5[1-55]66[38-83]<0.001Duration of transfusion (yrs)10[1-39]7[1-22]10.5[0-25]3[1-10]<0.001N EC since diagnosis359[21-1360]139[24-791]201[14-888]77[16-544]0.0005N CE/yr24[8-67]21[4-62]35[17-58]27[7-65]0.09G1vsG2=0.03% patientschelated959072.7720.12Age at beginning of chelation (yrs)11[1-48]9[2-47]18[6-31]68[38-84]<0.0005Ferritin at beginning of chelation (ng/ml)1148[713-2400]2075[448-3670]1500[905-2804]2398[482-5140]0.22N T2*<20 ms3(15%)004(16%)0.01LIC (mg/g d.w.)10.4[0.8-20.2]10.7[0.8-37.1]14[0.8-19.7]15.2[3.0-45.3]0.29Plasmatic iron(μmol/l)36.9[31-57]22.5[6-42.2]21[13-46]38.2[11.9-72]<0.001NTBI (mg/ml)7.1[0-31.1]0[0-18.3]0[0-12.4]4.45[0-25.5]0.0005Ferritin (ng/ml)870[169-4339]2739[393-5596]2404[33-20030]1611[223-6813]0.08Hepcidin (ng/ml)1.35[0-12.3]9.95[0-67.9]2.10[0-52.4]36.35[3-143.2]<0.001Deferasirox dosage<0.5 μg/ml3/8(38%)3/10(29%)3/5(60%)0/11(0%)0.03 DisclosuresDe Montalembert:Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau.

Improved R2* liver iron concentration assessment using a novel fuzzy c-mean clustering scheme.

BackgroundIn thalassemia patients, R2* liver iron concentration (LIC) measurement is a common clinical tool for assessing iron overload and for determining necessary chelator dose and evaluating its efficacy. Despite the importance of accurate LIC measurement, existing methods suffer from LIC variability, especially at the severe iron overload range due to inclusion of vessel parts in LIC calculation. In this study, we build upon previous Fuzzy C-Mean (FCM) clustering work to formulate a scheme with superior performance in segmenting vessel pixels from the parenchyma. Our method (MIX-FCM) combines our novel 2D-FCM with the existing 1D-FCM algorithm. This study further assessed possible optimal clustering parameters (OP scheme) and proposed a semi-automatic (SA) scheme for routine clinical application.MethodsSegmentation of liver parenchyma and vessels was performed on T2* images and their LIC maps in 196 studies from 147 thalassemia major patients. We used manual segmentation as the reference. 1D-FCM clustering was performed on the acquired image alone and 2D-FCM used both the acquired image and its LIC data. To execute the MIX-FCM method, the best outcome (OP-MIX-FCM) was selected from the aforementioned methods and was compared to the SA-MIX-FCM scheme. We used the percent value of the normalized interquartile range (nIQR) to its median to evaluate the variability of all methods.Results2D-FCM clustering is more effective than 1D-FCM clustering at the severe overload range only, but inferior for other ranges (where 1D-FCM provides suitable results). This complementary performance between the two methods allows MIX-FCM to improve results for all ranges. OP-MIX-FCM clustering error was 2.1 ± 2.3 %, compared with 10.3 ± 9.9 % and 7.0 ± 11.9 % from 1D- and 2D-FCM clustering, respectively. SA-MIX-FCM result was comparable to OP-MIX-FCM result, with both schemes showing ability to decrease overall nIQR by approximately 30 %.ConclusionOur proposed 2D-FCM algorithm is not as superior to 1D-FCM as hypothesized. In contrast, our MIX-FCM method benefits from the best of both methods to obtain the highest segmentation accuracy at all ranges. Moreover, segmentation accuracy of the practical scheme (SA-MIX-FCM) is comparable to segmentation accuracy of the reference scheme (OP-MIX-FCM). Finally, we confirmed that segmentation is crucial to improving LIC assessments, especially at the severe iron overload range.

Vitamin D Insufficiency and Liver Iron Concentration in Transfusion Dependent Hemoglobinopathies in British Columbia

Patients with thalassemia major (TM) and other chronically transfused hereditary anemias are at increased risk of complications including endocrinopathies and bone disease due to iron overload. Vitamin D is important for bone health. Vitamin D deficiency is common in patients with transfusional iron overload, and the mechanism remains unclear. The first step in vitamin D metabolism, hydroxylation, occurs in the liver and liver iron overload may interfere with this step. This study investigates an association between degree of liver iron overload and vitamin D levels in patients with transfusion dependent hemoglobinopathies. Patients with TM, hemoglobin Eβ TM (Eβ TM), and congenital dyserythropiotc anemia (CDA) attending the Inherited Bleeding and Red Blood Cell Disorder Program in British Columbia (IBRBCD BC), Canada were identified. Included patients had an assessment of liver iron concentration (LIC) by MRI and endocrinology assessment including 25 hydroxy vitamin D level. Thirty patients were identified. The mean LIC was 5.13 mg/g dry weight (DW). Vitamin D deficiency/insufficiency was identified in 19 (63.3%). Eleven (36.7%) patients had an LIC ≥5 mg/gDW, 8 of whom had a vitamin D level 5 mg/gDW and vitamin D level <60nmol/L (P= 0.027) and there was a significant inverse correlation between LIC and vitamin D (R=-0.33). These results indicate an association between increased LIC and vitamin D insufficiency/deficiency, suggesting that liver iron overload may indeed affect vitamin D metabolism. Prospective trials are needed to confirm these results.

Liver Iron Concentration By MRI In Chronically Transfused Children With Sickle Cell Anemia In The Twitch Trial

IntroductionChronic transfusion therapy represents the standard of care for sickle cell anemia (SCA) patients with abnormal transcranial Doppler (TCD) ultrasound or prior stroke. While effective, monthly transfusions produce iron overload and toxicity if not controlled with chelation therapies. Liver iron concentration (LIC) is a powerful surrogate for total body iron stores. Unfortunately, liver biopsy is not suited for longitudinal analysis because it is invasive, expensive, and prone to sampling variability. MRI transverse relaxation rates, R2 and R2*, are highly correlated with LIC and have mostly supplanted liver biopsy for iron quantification in clinical practice and clinical trials. Since R2 and R2* have different sensitivity to the size and scale of tissue iron distribution, we compared the agreement of LIC values predicted by R2 and R2* in children with SCA and transfusional iron overload from the prospective multicenter TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial (ClinicalTrials.gov; NCT01425307). Methods133 patients underwent LIC assessment using both R2 and R2* techniques at 22 MRI sites. All sites used 1.5 Tesla magnets and torso phased array coils. Images for R2 measurements were collected on validated scanners and analyzed centrally according to the FerriScan” protocol (Resonance Health, Western Australia, see St Pierre, T.G., et al. Blood,105, 855-861, 2005). Images for R2* assessment were collected using multiple-echo gradient echo sequences (see Wood, J.C., et al. Blood,106, 1460-1465, 2005). Images were analyzed centrally at Children's Hospital Los Angeles, using an exponential-plus-constant fit to the signal decay. Bland-Altman analysis on log-transformed LIC values was used to test agreement between LICR2 and LICR2*; the residuals of this relationship were probed for association with transfusion/chelation history, markers of inflammation, and markers of hemolysis. [Display omitted] [Display omitted] ResultsFigure 1A illustrates the scattergram between LICR2* and LICR2. The variance of the disagreement between the two techniques increases with LIC, so log-transformation was performed prior to Bland Altman analysis. LICR2* was systematically higher than LICR2 below about 5 mg Fe/g dw and systematically lower above 5 mg Fe/g dw. Bland Altman comparison of the log-transformed data (Figure 1B) reveals a downward trend (r2 of 0.203, p<0.0001). After correcting for the trend, 95% limits of agreement were -0.42 to 0.42, translating to 95% limits of agreement of the ratio of the two LIC measurements of 0.66 to 1.52. After controlling for mean log LIC, differences in log LIC values were not associated with transfusion or chelation history, markers of inflammation, or markers of hemolysis. DiscussionSystematic bias is present between LICR2 and LICR2* in a cohort of children with SCA and transfusional iron overload. Even after correcting these differences, LICR2 and LICR2* also demonstrate significant intrasubject variability, comparable to the error both techniques displayed with respect to biopsy, precluding use of these metrics interchangeably. This implies that LICR2 and LICR2* have potentially clinically significant deviations from true LIC. Rather than sampling or MRI measurement errors, which are consistently < 10% in multiple studies, these disparities likely reflect calibration bias introduced by intersubject differences in tissue iron distribution. Longitudinal LIC determination should lessen their impact, however, and the changes in LIC predicted by R2 and R2* will be compared using one and two year data from the TWiTCH trial. Disclosures:Wood:Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Kwiatkowski:Shire: Consultancy; Resonance Health: Research Funding. St. Pierre:Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.