Liver Iron Concentration Estimates Research Articles

Can Automated 3-Dimensional Dixon-Based Methods Be Used in Patients With Liver Iron Overload?

Accurate quantification of liver iron concentration (LIC) can be achieved via magnetic resonance imaging (MRI). Maps of liver T2*/R2* are provided by commercially available, vendor-provided, 3-dimensional (3D) multiecho Dixon sequences and allow automated, inline postprocessing, which removes the need for manual curve fitting associated with conventional 2-dimensional (2D) gradient echo (GRE)-based postprocessing. The main goal of our study was to investigate the relationship among LIC estimates generated by 3D multiecho Dixon sequence to values generated by 2D GRE-based R2* relaxometry as the reference standard. A retrospective review of patients who had undergone MRI scans for estimation of LIC with conventional T2* relaxometry and 3D multiecho Dixon sequences was performed. A 1.5 T scanner was used to acquire the magnetic resonance studies. Acquisition of standard multislice multiecho T2*-based sequences was performed, and R2* values with corresponding LIC were estimated. The comparison between R2* and corresponding LIC estimates obtained by the 2 methods was analyzed via the correlation coefficients and Bland-Altman difference plots. This study included 104 patients (51 male and 53 female patients) with 158 MRI scans. The mean age of the patients at the time of scan was 15.2 (SD, 8.8) years. There was a very strong correlation between the 2 LIC estimation methods for LIC values up to 3.2 mg/g (LIC quantitative multiecho Dixon [qDixon; from region of interest R2*] vs LIC GRE [in-house]: r = 0.83, P < 0.01; LIC qDixon [from segmentation volume R2*] vs LIC GRE [in-house]: r = 0.92, P < 0.01); and very weak correlation between the 2 methods at liver iron levels >7 mg/g. Three-dimensional-based multiecho Dixon technique can accurately measure LIC up to 7 mg/g and has the potential to replace 2D GRE-based relaxometry methods.

Multi-Center, Multi-Vendor Reproducibility and Calibration of MRI-Based R2* for Liver Iron Quantification

Introduction: Excessive accumulation of iron is caused by a variety of conditions, including hereditary hemochromatosis and transfusional hemosiderosis. If untreated, iron overload can lead to damage in those organs where iron accumulates. Therefore, accurate and reproducible evaluation of body iron stores is needed to guide diagnosis, grading, and treatment monitoring of iron overload. While serum ferritin is the simplest means to assess body iron, it is also an acute phase reactant and therefore is not a reliable biomarker of body iron. Liver iron concentration (LIC) is directly and linearly related to total body iron stores. As such, LIC is widely recognized as a useful surrogate biomarker for the evaluation of iron overload. Liver biopsy is limited by its invasive nature and is contraindicated in many patients (eg. thrombocytopenia) due to bleeding risk. Magnetic resonance imaging (MRI) is a standard of care tool to measure LIC. Arguably the most practical method is R2* MRI due to its speed and ease of use, but the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Therefore, we evaluated the reproducibility and calibration of R2*-based LIC measurement via a single-breath-hold, confounder-corrected R2*-MRI at both 1.5T and 3T, through a multi-center, multi-vendor study.Methods: Four centers (University of Wisconsin-Madison, University of Texas-Southwestern, Johns Hopkins University, and Stanford University) using MRI scanners of different vendors (GE, Philips, and Siemens) participated in this HIPAA-compliant IRB-approved prospective cross-sectional study. This study recruited subjects with known or suspected iron overload from a variety of etiologies, including hereditary hemochromatosis, transfusional hemosiderosis (due to non-malignant or malignant conditions), and chronic liver disease. Subjects with were recruited for same day multiecho gradient-echo MRI for R2* mapping at both 1.5T and 3T (UW, UTSW, Stanford: 3.0T; JHU: 2.89T). R2* maps were reconstructed from the raw multiecho images and analyzed at a single center. Spin-echo MRI were also performed at 1.5T according to a standardized protocol (FerriScan, Resonance Health, Australia) and processed by a commercial algorithm to obtain FDA-approved reference standard LIC estimates. R2*-vs.-LIC calibrations were generated across centers and field strengths using linear regression and compared using F-tests. A predicted 2.89T calibration was interpolated from the 1.5T and 3.0T calibrations, and compared to the measured (JHU) calibration. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic accuracy of R2* MRI for detection of clinically relevant LIC thresholds.Results: A total of 200 subjects were recruited and successfully scanned for this study. We confirmed a linear relationship between R2* and LIC. All calibrations within the same field strength (see Figure 1) were highly reproducible showing no statistically significant center-specific differences (F > 3.0461). Pooled calibrations for 1.5T, 2.89T, and 3.0T were generated. At either field strength and for each of the LIC thresholds under consideration (1.8, 3.2, 7.0, 15.0 mg/g), estimated areas under the ROC curve (AUCs) of 0.98 or higher were observed.Discussion and Conclusions: In conclusion, confounder-corrected R2* MRI enables accurate and reproducible quantification of liver iron overload, over clinically relevant ranges of LIC. The data generated in this study provide the necessary calibrations for broad dissemination of R2*-based LIC quantification. [Display omitted] DisclosuresHernando: Calimetrix: Current holder of individual stocks in a privately-held company. Pedrosa: Merck: Honoraria; Bayer Healthcare: Honoraria; Health Tech International: Current holder of stock options in a privately-held company. Vasanawala: HeartVista: Current holder of individual stocks in a privately-held company; InkSpace: Current holder of individual stocks in a privately-held company; Arterys: Current holder of individual stocks in a privately-held company. Reeder: Bayer: Research Funding; Pfizer: Research Funding; Calimetrix, LLC: Current holder of individual stocks in a privately-held company; Reveal Pharmaceuticals: Current holder of individual stocks in a privately-held company; Elucent Medical: Current holder of individual stocks in a privately-held company; Cellectar Biosciences: Current holder of individual stocks in a privately-held company; HeartVista: Current holder of individual stocks in a privately-held company.

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.

Improving CPMG liver iron estimates with a -corrected proton density estimator.

CPMG spin echo acquisitions are attractive for diagnosing and monitoring liver iron concentration in iron overload disorders due to their time efficiency and potential to reveal unique information about tissue iron distribution. Clinical adoption remains low due to the insensitivity of CPMG-based estimates to liver iron concentration (LIC) when common fitting techniques are applied. In this work, we demonstrate that the inclusion of a proton density estimator (PDE) derived from the CPMG acquisition increase the sensitivity of CPMG estimates to LIC in both simulated and in-vivo human data. CPMG acquisitions from 50 clinically indicated MRI studies in patients with iron overload were analyzed with and without PDE constraints. Liver regions of interest were fit to monoexpontial and nonexponential signal decay equations. LIC by served as the reference standard. The observed calibration between CPMG values and LIC were compared to results predicted from a previously validated Monte Carlo model. The sensitivity of CPMG-derived triples when a proton density constraint is applied. When compared with -LIC estimates, both monoexponential and nonexponential models were unbiased but demonstrated broad 95% confidence intervals particularly for LIC values below 12mg/g. Absolute error did not increase with LIC. A proton density constraint can increase the sensitivity of CPMG-based models to iron. CPMG acquisitions are time-efficient and could potentially improve the dynamic range of single spin echo techniques as well as providing insight into tissue iron distribution.

Reproducibility of liver iron concentration estimates in MRI through R2* measurement determined by least-squares curve fitting.

Measuring transverse relaxation rate (R2* = 1/T2*) via MRI allows for noninvasive evaluation of multiple clinical parameters, including liver iron concentration (LIC) and fat fraction. Both fat and iron contribute to diffuse liver disease when stored in excess in the liver. This liver damage leads to fibrosis and cirrhosis with an increased risk of developing hepatocellular carcinoma. Liver iron concentration is linearly related to R2* measurements using MRI. A phantom was constructed to assess R2* quantification variability on 1.5 and 3 T MRI systems. Quantification was executed using least‐squares curve fitting techniques. The phantom was created using readily available, low‐cost materials. It contains four vials with R2* values that cover a clinically relevant range (100 to 420 Hz at 1.5 T). Iron content was achieved using ferric chloride solutions contained in glass vials, each affixed in a three‐dimensional (3D)‐printed polylactide (PLA) structure, surrounded by distilled water, all housed in a sealed acrylic cylinder. Multiple phantom stands were also 3D‐printed using PLA for precise orientation of the phantom with respect to the direction of the static magnetic field. Acquisitions at different phantom angles, across multiple MRI systems, and with different pulse sequence parameters were evaluated. The variability between any two R2* measurements, taken in the same vial under these various acquisition conditions, on a 1.5 T MRI system, was <7% for each of the four vials. For 3 T MRI systems, variability was less than 14% in all cases. Variability was <6% for both 1.5 and 3 T acquisitions when unchanged pulse sequence parameters were used. The phantom can be used to mimic a range of clinically relevant levels of R2* relaxation rates, as measured using MRI. These measurements were found to be reproducible relative to the gold‐standard method, liver biopsy, across several different image acquisition conditions.

Real-World Experience Measurement of Liver Iron Concentration by R2 vs. R2 Star MRI in Hemoglobinopathies.

Background: Non-invasive determination of liver iron concentration (LIC) is a valuable tool that guides iron chelation therapy in transfusion-dependent patients. Multiple methods have been utilized to measure LIC by MRI. The purpose of this study was to compare free breathing R2* (1/T2*) to whole-liver Ferriscan R2 method for estimation of LIC in a pediatric and young adult population who predominantly have hemoglobinopathies. Methods: Clinical liver and cardiac MRI scans from April 2016 to May 2018 on a Phillips 1.5 T scanner were reviewed. Free breathing T2 and T2* weighted images were acquired on each patient. For T2, multi-slice spin echo sequences were obtained. For T2*, a single mid-liver slice fast gradient echo was performed starting at 0.6 ms with 1.2 ms increments with signal averaging. R2 measurements were performed by Ferriscan analysis. R2* measurements were performed by quantitative T2* map analysis. Results: 107 patients underwent liver scans with the following diagnoses: 76 sickle cell anemia, 20 Thalassemia, 9 malignancies and 2 Blackfan Diamond anemia. Mean age was 12.5 ± 4.5 years. Average scan time for R2 sequences was 10 min, while R2* sequence time was 20 s. R2* estimation of LIC correlated closely with R2 with a correlation coefficient of 0.94. Agreement was strongest for LIC < 15 mg Fe/g dry weight. Overall bias from Bland–Altman plot was 0.66 with a standard deviation of 2.8 and 95% limits of agreement −4.8 to 6.1. Conclusion: LIC estimation by R2* correlates well with R2-Ferriscan in the pediatric age group. Due to the very short scan time of R2*, it allows imaging without sedation or anesthesia. Cardiac involvement was uncommon in this cohort.

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.

Evaluating the Volumetric Liver Fat Fraction in Patients Referred for Investigation of Hyperferritinemia

Introduction Elevated serum ferritin (hyperferritinemia, HF) can result from increased iron load, increased inflammation or from liver damage. In the most common forms of hereditary hemochromatosis (HH), elevated ferritin is usually seen with elevated transferrin saturations, [1,2]. In patients with HF but without raised liver iron concentration (LIC, mg/g dry wt [dw]), increased liver fat (hepatic steatosis, HS), either in isolation or as part of a metabolic syndrome, needs to be considered. HS is important to identify as it may progress to chronic liver damage and is potentially reversible with lifestyle interventions. Hepatic fat can now be quantified with magnetic resonance imaging (Hepafat-Scan®)[3]. Here, we evaluate the usefulness of this method in the diagnosis and subsequent management of patients referred with HF. Methods A total of 132 patients (median age 48 years, range 21-86 ; female: male ratio 1:2.5) referred for investigation of HF and who underwent estimation of liver iron concentration (LIC) by R2-MRI (FerriScan®) over a four-year period (January 2015 - December 2018) are included in this analysis. Data on patient demographics, presenting serum ferritin (SF) and transferrin saturation were obtained. Genetic testing for C282Y and H63D was also performed. Genetic testing for rarer forms of haemochromatosis was confined to patients with unexplained raised LIC. Patients with iron overload secondary to chronic iron ingestion or blood transfusion were excluded from this analysis. Results Patients were subdivided by genetic diagnosis: C282Y homozygote (26, 19.7%), C282Y/H63D (18, 13.6%), H63D homozygote (10, 7.6%), C282Y heterozygote (8, 6.1%), H63D heterozygote (18, 13.6%), autosomal dominant ferroportin disease (4, 3%) and negative HFE gene testing (48, 36.4%). There was no statistical difference between mean presenting SF (p= 0.307) between the different groups. C282Y homozygotes, and those with autosomal ferroportin disease had a significantly higher LIC than others (p&amp;lt;0.001). C282Y homozygotes and compound heterozygotes had a significantly higher transferrin saturation than other groups (p&amp;lt;0.001). SF positively correlated with LIC (p&amp;lt;0.001). After genetic testing and LIC quantification, 32 patients underwent a HepaFat-Scan®. Median age was 63 years, range 23 - 74 years; female: male ratio 1:3.5. 54.5% had a volumetric liver fat fraction (VLFF) &amp;gt; 5%. 7.4% of patients, who did not undergo Hepafat-Scan®, had HS based on sonographic findings. Patients with definitive evidence of HS as defined by VLFF &amp;gt;5% had mean LIC of 1.36mg/g dw, and a higher mean presenting SF of 926 µg/L than those with HS &amp;lt;5% (NS, p= 0.47). Those with VLFF &amp;lt;5% had a mean presenting SF of 783 mg/ml and mean LIC of 2.2 mg/g dw. In patients with LIC ≤3mg/g dw (n= 91, mean 1.6), mean presenting SF was 728 mg/ml. 28 of these patients went onto have a Hepafat-Scan®, 16 of which (57.1%) had confirmed steatosis with VLFF &amp;gt;5%. In patients with LIC &amp;gt;3mg/g dw (n= 41, mean LIC 6.9), mean presenting SF was significantly higher at 1056 mg/ml (p=0.021). 4 patients with LIC &amp;gt;3mg/g dw also had a Hepafat-Scan®, with 1 patient having VLFF &amp;gt;5%. Patients with confirmed steatosis were referred for specialist hepatology consultation. Conclusion In patients referred for investigation of HF, demonstrable steatosis (VLFF &amp;gt;5%) by Hepafat-Scan® is remarkably high (13.3% of all referred patients and 54% of patients who received Hepafat-Scan®). The Hepafat-Scan® data show that HS is generally confined to patients with low LIC (≤3mg/g dw) (Figure 1) reflecting the selective decision pathway adopted of excluding hepatic siderosis before proceeding to Hepafat-Scan®. SF is significantly higher in non-iron overloaded patients with HS (VLFF &amp;gt;5%) than those without HS (Figure 1). Estimation of HS should be considered in the diagnostic pathway of patients referred for investigation of HF, particularly when LIC values are not found to be meaningfully increased.

R2 relaxometry based MR imaging for estimation of liver iron content: A comparison between two methods

To compare the reproducibility and accuracy of R2-relaxometry MRI for estimationof liver iron concentration (LIC) between in-house analysis and FDA-approved commercially available third party results. All MR studies were performed on a 1.5T scanner.Multi-echo spin-echo scans with a fixed TR and increasing TE values of 6ms, 9ms, 12ms, 15ms, and 18ms (spaced at 3ms intervals) were used. Post-processing of the images to calculate mean relaxivity, R2, included drawing of regions of interest to include the whole liver on mid-slice. The relationship between liver R2 values and estimated LIC calculated with in-house analysis and valuesreported by an external company (FerriScan®, Resonance Health, Australia) were assessed with correlation coefficients and Bland-Altman difference plots. Continuous variables are presented as mean ± standard deviation. Significance was set at p value < 0.05. 474 studies from 175 patients were included in the study (mean age 10.4 ± 4.2years (range 1-18years); 254 studies from girls, 220 studies from boys). LIC ranged from 0.6 to 43mg/g dry tissue, covering a broad range from normal levels to extremely high iron levels. Linearity between proprietary and in-house methods was excellent across the observed range for R2 (31.5 to 334.8s-1); showing a correlation coefficient of r = 0.87, p < 0.001. Bland-Altman R2 difference plot between the two methods shows a mean bias of + 21.5s-1 (range - 47.0 to + 90.0s-1 between two standard deviations). LIC reported by FerriScan® compared with LIC estimated in-house with R2 as reported by FerriScan® agreed strongly, (r = 1.0, p < 0.001). R2 relaxometry MR imaging for liver iron concentration estimation is reproducible between proprietary FDA-approved commercial software and in-house analysis methods.

PB2047 COMPARATIVE ANALYSIS OF DEFERASIROX DISPERSIBLE TABLETS VS FILM‐COATED TABLETS IN SEVERE CONGENITAL ANEMIAS: RESTROSPECTIVE STUDY IN A TERTIARY HOSPITAL

Background:Several congenital anemias are defined by ineffective erythropoiesis, sometimes even exarcerbated by chronic hemolysis, which in combination with periodic transfusions required on the most severe forms lead to iron overload in the organism, which settle on body tissues leading to their disfunction, with significant impact on morbimortality.Iron chelators aim to decrease iron load, as well as prevent or delay long term complications. Deferasirox (DF) is an oral chelator whose efficacy and security had been well defined since its approval. New film‐coated formulation proved similar efficacy as well as better palatability and tolerance on the ECLIPSE trial, achieving better treatment compliance.Aims:Conducting a comparative study between deferasirox dispersable tablets (DF‐D) versus film‐coated tablets (DF‐FC) amidst severe congenital anemias, analyzing chelating capacity as well as treatment compliance and side effects in both formulations.Methods:Retrospective case series. We collected data from patients diagnosed with severe congenital anemias and active follow up visits in our hospital, who were treated with DF‐D as well as DF‐FC over 12 months each. Qualitative variables are presented as absolute frequencies and percentages; and the quantitative ones as median and standard deviation. Exact Fisher test was performed when comparing qualitative variables, and Mann Whitney test when analyzing quantitative ones. Data was analized by SPSS Statistics.Results:We collected data from 7 patients: 6 of them diagnosed as thalassemia major and 1 as Blackfan Diamond anemia. 85,7% of our patients were female and 14,3% were male, median age 44 years old.Mean red blood cells concentrates tranfused were 20 units per year for both formulations. Median DF dosing was 1500 mg over DF‐D treatment and 1080 mg over DF‐FC treatment, which translates into equivalent dosing given DF‐FC better bioavailability.We got 6,2% mean increasing percentage of serum ferritin levels with DF‐D versus 1,3% with DF‐FC; however, when analyzing liver iron concentration (LIC) we observed an 8,3% decrease in iron load with DF‐D as opposite to 39,7% with DF‐FC, as well as a similar decrease in cardiac iron concentration (CIC) comparing both formulations (9,5% with DF‐D vs 6,5% with DF‐FC).71,4% patients showed poor treatment compliance over DF‐D treatment, due to the development of side effects, outlining digestive disturbances (80%) and less frequently renal impairment or nonspecific disturbances (10% each), conditioning a change in therapy in 40% of cases. We did not find adherence problems with DF‐FC formulation, side effects rate decreased to 28,6% and no patient required a change in therapy.Summary/Conclusion:Our data revealed a high rate of side effects associated with DF‐D, mainly digestive disturbances, conditioning poor therapeutic adherence as well as changes to treatment in 40% of our patients. New formulation substantially decreased side effects rate, no patients required a change in treatment and we found a 100% therapy compliance.imageSerum ferritin levels showed an slight increase over both treatments, with hardly any diffence between the two, which did not correlate with LIC levels, that showed a significant decrease in iron load, or cardiac deposits. In our opinion this data could be explained given ferritin low specificity quantifying iron load, whose levels fluctuate with inflammatory or infectious states; as compared to LIC and CIC estimation by magnetic resonance imaging, which have shown higher reliability when quantifying iron burden.

Biexponential R2* relaxometry for estimation of liver iron concentration in children: A better fit for high liver iron states.

R2* relaxometry's capacity to calculate liver iron concentration (LIC) is limited in patients with severe overload. Hemosiderin increases in these patients, which exhibits a non-monoexponential decay that renders a failed R2* analysis. To evaluate a biexponential R2* relaxometry model in children with different ranges of iron overload. Retrospective. In all, 181 children with different conditions associated with iron overload. 1.5T, T2 *-weighted gradient echo sequence. Bi- and monoexponential R2* relaxometry were measured in the liver using two regions of interest (ROIs) using a nonproprietary software: one encompassing the whole liver parenchyma (ROI-1) and the other only the periphery (ROI-2). These were drawn by a single trained observer. The residuals for each fitting model were estimated. A ratio between the residuals of the mono- and biexponential models was calculated to identify the best fitting model. Patients with 1) residual ratio ≥1.5 and 2) R2*fast ≥R2*slow were considered as having a predominant biexponential behavior. Nonparametric tests, Bland-Altman plots, linear correlation, intraclass correlation coefficient. Patients were divided according to their LIC into stable (n = 23), mild (n = 58), moderate (n = 61), and severe (n = 39). The biexponential model was more suitable for patients with severe iron overload when compared with the other three LIC categories (P < 0.001) for both ROIs. For ROI-1, 37 subjects met criteria for a predominant biexponential behavior. The slow component (5.7%) had a lower fraction than the fast component (94.2%). For ROI-2, 22 subjects met criteria for a predominant biexponential behavior. The slow component (4.7%) had a lower fraction than the fast component (95.2%). The intraobserver variability between both ROIs was excellent. The biexponential R2* relaxometry model is more suitable in children with severe iron overload. 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1191-1198.

Prospective Evaluation of an R2* Method for Assessing Liver Iron Concentration (LIC) Against FerriScan: Derivation of the Calibration Curve and Characterization of the Nature and Source of Uncertainty in the Relationship

FerriScan is the method-of-choice for noninvasive liver iron concentration (LIC) quantification. However, it has a number of drawbacks including cost and expediency. To characterize an R2*-based MRI technique that may potentially be used as an alternative to FerriScan. This was accomplished through the derivation of a calibration curve that characterized the relationship between FerriScan-derived LIC and R2*. The nature and source of uncertainty in this curve were investigated. It was hypothesized that the source of uncertainty is heterogeneity of LIC across the liver. Prospective. In all, 125 patients (69 women, 56 men) undergoing chelation treatment for iron overload prospectively underwent FerriScan and R2* MRI during the same exam. Pulse sequences included 2D multislice spin-echo pulse for FerriScan, and a prototype 3D 6-echo gradient echo acquisition for R2* mapping at 1.5T. A linear calibration curve was derived from the relationship between FerriScan-derived LIC estimates and R2* through least-squares fitting. The nature of the uncertainty in the curve was characterized through tests of normality and homoscedasticity. The source of uncertainty was tested by comparing the magnitude of LIC variation over the FerriScan ROI to the observed uncertainty in the R2*-derived LIC estimates. A linear relationship between logarithmically transformed FerriScan-derived LIC and R2* (log{FerriScan-derived LIC} = 1.029 log{R2*} - 3.822) was confirmed. Uncertainty was random, with a behaviour that was normal and homoscedastic. The source of uncertainty was confirmed as iron heterogeneity across the liver. The nontransformed calibration curve was: FerriScan-derived LIC = 0.0266⋅R2*, with a constant coefficient-of-variation of 0.32. FerriScan and R2* techniques were found to provide equivalent quantification of LIC in this study. Any difference in accuracy or precision was at a level lower than the uncertainty caused by variation in LIC over the liver. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1467-1474.

Inter-method reproducibility of biexponential R2 MR relaxometry for estimation of liver iron concentration.

To assess the reproducibility of biexponential R2 -relaxometry MRI for estimation of liver iron concentration (LIC) between proprietary and nonproprietary analysis methods. This single-center retrospective study, approved by investigational review board and compliant with the Health Insurance Portability and Accountability Act, included 40 liver MRI exams in 38 subjects with suspected or known iron overload. From spin-echo images of the liver, acquired at 5 different echo times (TE = 6-18 ms), biexponential R2 maps were calculated using 1 proprietary (FerriScan, Resonance Health Ltd., Claremont WA, Australia) and 3 nonproprietary (simulated annealing, nonlinear least squares, dictionary search) analysis methods. Each subject's average liver R2 value was converted to LIC using a previously validated calibration curve. Inter-method reproducibility for liver R2 and LIC were assessed for linearity using linear regression analysis and absolute agreement using intraclass correlation and Bland-Altman analysis. For point estimates, 95% confidence intervals were calculated; P values < 0.05 were considered statistically significant. Linearity between the proprietary and nonproprietary methods was excellent across the observed range for R2 (20-312 s-1 ) and LIC (0.4-52.2 mg/g), with all coefficients of determination (R2 ) ≥ 0.95. No statistically significant bias was found (slope estimates ∼ 1; intercept estimates ∼ 0; P values > 0.05). Agreement between the 4 methods was excellent for both liver R2 and LIC (intraclass correlations ≥ 0.97). Bland-Altman 95% limits of agreement in % difference between the proprietary and nonproprietary methods were ≤ 9% and ≤ 16% for R2 and LIC, respectively. Biexponential R2 -relaxometry MRI for LIC estimation is reproducible between proprietary and nonproprietary analysis methods.

Quantitative susceptibility mapping (QSM) minimizes interference from cellular pathology in R2* estimation of liver iron concentration.

A challenge for R2 and R2* methods in measuring liver iron concentration (LIC) is that fibrosis, fat, and other hepatic cellular pathology contribute to R2 and R2* and interfere with LIC estimation. To examine the interfering effects of fibrosis, fat, and other lesions on R2* LIC estimation and to use quantitative susceptibility mapping (QSM) to reduce these distortions. Prospective. Water phantoms with various concentrations of gadolinium (Gd), collagen (Cl, modeling fibrosis), and fat; nine healthy controls with no known hepatic disease, nine patients with known or suspected hepatic iron overload, and nine patients with focal liver lesions. The phantoms and human subjects were imaged using a 3D multiecho gradient-echo on clinical 1.5T and 3T MRI systems. QSM and R2* images were postprocessed from the same gradient-echo data. Fat contributions to susceptibility and R2* were corrected in signal models for LIC estimation. Polynomial regression analyses were performed to examine relations among susceptibility, R2* and true [Gd] and [Cl] in phantoms, and among susceptibility and R2* in patient livers. In phantoms, R2* had a strong nonlinear dependency on [Cl], [fat], and [Gd], while susceptibility was linearly dependent (R2 > 0.98). In patients, R2* was highly sensitive to liver pathological changes, including fat, fibrosis, and tumors, while QSM was relatively insensitive to these abnormalities (P = 0.015). With moderate iron overload, liver susceptibility and R2* were not linearly correlated over a common R2* range [0, 100] sec-1 (P = 0.35). R2* estimation of LIC is prone to substantial nonlinear interference from fat, fibrosis, and other lesions. QSM processing of the same gradient echo MRI data can effectively minimize the effects of cellular pathology. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1069-1079.

Ultra-short echo time images quantify high liver iron.

1.5T gradient echo-based R2∗ estimates are standard-of-care for assessing liver iron concentration (LIC). Despite growing popularity of 3T, echo time (TE) limitations prevent 3T liver iron quantitation in the upper half of the clinical range (LIC ⪆20 mg/g). In this work, a 3D radial pulse sequence was assessed to double the dynamic range of 3T LIC estimates. The minimum TE limits the dynamic range of pulse sequences to estimate R2∗. 23 chronically-transfused human volunteers were imaged with 1.5T Cartesian gradient echo (1.5T-GRE), 3T Cartesian gradient echo (3T-GRE), and 3T ultrashort TE radial (3T-UTE) pulse sequences; minimum TEs were 0.96, 0.76, and 0.19 ms, respectively. R2∗ was estimated with an exponential signal model, normalized to 1.5T equivalents, and converted to LIC. Bland-Altman analysis compared 3T-based estimates to 1.5T-GRE. LIC by 3T-GRE was unbiased versus 1.5T-GRE for LIC ≤ 25 mg/g (sd = 9.6%); 3T-GRE failed to quantify LIC > 25 mg/g. At high iron loads, 3T-UTE was unbiased (sd = 14.5%) compared to 1.5T-GRE. Further, 3T-UTE estimated LIC up to 50 mg/g, exceeding 1.5T-GRE limits. 3T-UTE imaging can reliably estimate high liver iron burdens. In conjunction with 3T-GRE, 3T-UTE allows clinical LIC estimation across a wide range of liver iron loads. Magn Reson Med 79:1579-1585, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century.

Iron overload used to be considered rare in hemodialysis patients but its clinical frequency is now increasingly realized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosideroses and genetic hemochromatosis. Magnetic resonance imaging is now the gold standard method for LIC estimation and monitoring in non-renal patients. Studies of LIC in hemodialysis patients by quantitative magnetic resonance imaging and magnetic susceptometry have demonstrated a strong relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Three long-term observational studies have recently suggested that excessive IV iron doses may be associated with an increased risk of cardiovascular events and death in hemodialysis patients. We postulate that iatrogenic iron overload in the era of erythropoiesis-stimulating agents may silently increase complications in dialysis patients without creating frank clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It is therefore tempting to postulate that the main pathophysiological pathway leading to these events may involve the pleiotropic master hormone hepcidin (synergized by fibroblast growth factor 23), which regulates iron metabolism. Oxidative stress as a result of IV iron infusions and iron overload, by releasing labile non-transferrin-bound iron, might represent a ‘second hit’ on the vascular bed. Finally, iron deposition in the myocardium of patients with severe iron overload might also play a role in the pathogenesis of sudden death in some patients.

Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results

PurposeLiver biopsy was long considered the reference standard for measuring liver iron concentration. However, its high sampling variability and invasive nature make it poorly suited for serial analyses. To demonstrate the fallibility of liver biopsy, we use serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI liver iron concentration (LIC) estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability) to compare the robustness of these three techniques. Materials and MethodsR2, R2*, transfusional volume, and chelator compliance were obtained from 49 participants in a phase II clinical trial of deferitazole over two years. Liver biopsy LIC results were simulated using sampling errors of 0%, 10%, 20%, 30%, 40% and iron assay variability of 12%. LIC estimates by R2, R2*, and simulated biopsy were used to calculate ICE over time. Bland–Altman limits of agreement were compared across observation intervals of 12, 24, and 48weeks. ResultsAt 48week intervals, LIC estimates by R2, R2* and “perfect” liver biopsy had comparable accuracy in predicting ICE; both MRI methods were superior to any physically realizable liver biopsy (sampling error 10% or higher). LIC by R2* demonstrated the most robust ICE estimates at monitoring intervals of 24 and 12weeks, but this difference did not remain significant at 48week intervals. ConclusionMRI relaxometry is superior to liver biopsy for serial LIC observations, such as used in the care of tranfusional siderosis patients, and should also be considered the new standard of LIC determination for regulatory purposes. Among relaxometry techniques, LIC estimates by R2* are more robust for tracking changes in iron balance over intermediate time scales (<=24 weeks).

Liver Iron Concentration and Liver Impairment in Relation to Serum IGF-1 Levels in Thalassaemia Major Patients: A Retrospective Study.

Not available

R2 and R2* are equally effective in evaluating chronic response to iron chelation

MRI relaxometry (R2, R2*) has generally replaced liver biopsy for estimation of liver iron stores in response to iron chelation, but there have been no longitudinal studies comparing R2 and R2* techniques. We use R2 and R2* liver iron concentration (LIC) estimates, transfusional iron burdens, and drug compliance data to calculate iron chelation efficiency (ICE) in patients undergoing a Phase II trial of SPD602. Fifty-one patients underwent a baseline examination, 39 patients completed 1 year, and 26 patients completed 2 years. Baseline LICR2 and LICR2* estimates were unbiased, but had limits of agreement exceeding 50%, suggesting that these techniques cannot be interchanged with one another in the same patient. However, ICE estimates across the two techniques compared more favorably, with r(2) values reaching 0.89 at 2 years. 95 confidence intervals for efficiency estimates were 0.0 ± 4.1%. These data indicate that clinical trial and clinical effectiveness data calculated using LICR2 and LICR2* estimates can be compared to one another, even though LIC estimates may be disparate on cross-sectional analysis. While the choice of MRI assessment technique for clinical trials and for clinical management depends on many logistical considerations, one can have confidence comparing conclusions on clinical effectiveness.

Magnetic susceptibility as a B0 field strength independent MRI biomarker of liver iron overload.

MR-based quantification of liver magnetic susceptibility may enable field strength-independent measurement of liver iron concentration (LIC). However, susceptibility quantification is challenging, due to nonlocal effects of susceptibility on the B0 field. The purpose of this work is to demonstrate feasibility of susceptibility-based LIC quantification using a fat-referenced approach. Phantoms consisting of vials with increasing iron concentrations immersed between oil/water layers, and 27 subjects (9 controls/18 subjects with liver iron overload) were scanned. Ferriscan (1.5 T) provided R2-based reference LIC. Multiecho three-dimensional-SPGR (1.5 T/3 T) enabled fat-water, B0- and R2*-mapping. Phantom iron concentration (mg Fe L(-1)) was estimated from B0 differences (ΔB0) between vials and neighboring oil. Liver susceptibility and LIC (mg Fe g(-1) dry tissue) was estimated from ΔB0 between the lateral right lobe of the liver and adjacent subcutaneous adipose tissue. Estimated phantom iron concentrations had good correlation with true iron concentrations (1.5 T:slope = 0.86, intercept = 0.72, r(2) = 0.98; 3 T:slope = 0.85, intercept = 1.73, r(2) = 0.98). In liver, ΔB0 correlated strongly with R2* (1.5 T:r(2) = 0.86; 3 T:r(2) = 0.93) and B0-LIC had good agreement with Ferriscan-LIC (slopes/intercepts nearly 1.0/0.0, 1.5 T:r(2) = 0.67, slope = 0.93 ± 0.13, P ≈ 0.50, intercept = 1.93 ± 0.78, P ≈ 0.02; 3 T:r(2) = 0.84, slope = 1.01 ± 0.09, P ≈ 0.90, intercept = 0.23 ± 0.52, P ≈ 0.68). Fat-referenced, susceptibility-based LIC estimation is feasible at both field strengths. This approach may enable improved susceptibility mapping in the abdomen.