Liver T2 Research Articles

Targeted Screening in Pediatric and Young Adult Oncology Patients Identifies Transfusional Iron Overload

Introduction: Pediatric and young adult oncology patients often require supportive red blood cell transfusions throughout their therapy course, which may result in iron overload. Despite this, screening recommendations to identify transfusional iron overload in childhood cancer survivors are lacking. Iron deposition can lead to end-organ damage and complications including heart failure, arrhythmias, liver abnormalities, endocrine dysfunction, ineffective erythropoiesis, and increased cancer and mortality risk. Little is known about long-term complications of iron overload in pediatric cancer survivors and treatment guidelines for iron overload in this patient population have not been developed. We instituted an algorithm to identify pediatric and young adult oncology patients with iron overload and refer them for treatment.Methods: This quality improvement project identified pediatric and young adult oncology patients for screening of transfusional iron overload, recommended diagnostic testing, and referred those with iron overload (as defined by liver T2* <20) to Hematology for treatment. Patients screened met the following criteria: 1) treatment for cancer or cancer relapse 2) greater than 10 transfusions and/or greater than 150 ml/kg of packed red blood cells (pRBCs) since the start of our electronic medical record (11/3/2012) and 3) completed treatment or in maintenance therapy for acute lymphoblastic leukemia. Exclusion criteria included: status less than 100 days post allogeneic hematopoietic stem cell transplantation, in palliative phase of care or receiving therapy for relapsed disease. Providers were notified of their patients meeting criteria for screening and asked to follow the screening, diagnosis and referral algorithm (Figure 1). Provider recognition of need for screening and compliance with the algorithm at 6 months after institution were tracked. Descriptive statistics were used to describe the characteristics of the study population. Spearman correlations were used to determine the association between number and volume of transfusions, and ferritin and liver T2* results.Results: Thirty patients were screened for iron overload. The mean age was 10.3 years (SD 7.5), 12 (40%) were female and 17 (57%) had a diagnosis of leukemia or lymphoma. The median number of transfusions received was 15 (10-47) and the median volume of blood received was 129 mL/kg (33-572).Thirty-six pediatric and young adult oncology patients were identified for iron overload screening, of whom only 2 (6%) had already received appropriate screening, 4 (11%) had received partial screening and 30 (83%) had received no screening. After the initial 6 months, 30 of the 34 patients who had undergone no or partial screening completed the recommended algorithm (88% compliance, see Figure 1). Nineteen (95%) of 20 patients with positive screening labs had iron overload by MRI. Fourteen (74%) of 19 patients with iron overload were seen by Hematology and 9/14 (64%) started treatment for iron overload (8-phlebotomy and 1-oral chelation).Nineteen patients (63%) were diagnosed with iron overload. The mean age was 11.8 years (SD 7.5), 6 (32%) were female and 12 (63%) had leukemia or lymphoma. The median number of transfusions received was 18 (10-47) and the median volume of blood received was 139 mL/kg (33-572). The median ferritin was 942 ng/mL (316-2340), median liver T2* was 6.6 (2.6-12.9) and median cardiac T2* was 26.7 (19.6-36). Number of transfusions (r=-0.79, p<0.0001), volume of blood in mL/kg (r=-0.58, p=0.014) and ferritin (r=-0.51, p=0.023) were strongly associated with liver T2* results (Figure 2). No patients had isolated cardiac iron overload.Conclusion: Targeted screening of pediatric and young adult oncology patients identified a high percentage of transfusional iron overload. Provider recognition of the need for iron overload screening in this high risk group was poor prior to institution of this quality improvement initiative. Prospective studies are required to determine if identification and subsequent treatment of transfusional iron overload can alter long-term complications of iron deposition and decrease morbidity of oncology treatment in pediatric and young adult survivors. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Iron Overload of the Kidneys of Patients with Thalassemia and Sickle-Cell Disease: Final Results of a Prospective Study in 224 Patients Using Magnetic Resonance Imaging T2 and R2* Techniques

▪Iron overload is a significant complication of hemoglobinopathies, despite the adequate iron chelation, which is administered to patients nowadays. Recently, magnetic resonance imaging (MRI) gradient echo (T2*), the reciprocal of T2* (known as R2*) and spin echo (T2) techniques have been developed to quantify tissue iron in the liver and the heart. Patients with thalassemia or sickle-cell disease (SCD) may develop kidney impairment during the course of their disease. However, the significance of iron overload in the kidneys of these patients in the development of renal impairment is poorly understood and, according to our knowledge, it has not been evaluated in a prospective study. Thus, the aim of our study was to evaluate kidney R2* and T2 MRI as surrogates for kidney iron of patients with different hemoglobinopathies and correlate these results with markers of renal impairment, markers of hemolysis and other disease features.We prospectively studied 224 patients with hemoglobinopathies who are followed and treated in a single center: 109 had thalassemia major (TM), 58 thalassemia intermedia (TI) and 57 SCD (35% of those were double heterozygous for SC/beta-thalassemia; HbS/beta-thal). All patients had MR examinations of the kidneys, liver and heart. For T2* mapping a gradient echo, multi echo FSPGR sequence was used, while for T2 mapping a T2-prepared single shot SSFP technique with multi echoes was performed. The normal reference values of T2 in our lab was <80 msec, while for R2* normal range we used the one previously described by Schein et al (J Magn Reson Imaging 2008;28:698-704), which was 21.3±5.8 Hz with a 95% confidence upper limit of 33.7 Hz. Regarding renal function, patients were divided in the 5 chronic kidney disease (CKD) stages of the KDIGO classification, according to eGFR evaluated by the CKD-EPI formula.Kidney T2 values were (mean±SD) 109.7±12.1 msec, 101.4±12.3 msec and 100.1±11.3 msec for patients with TM, TI and SCD, respectively; 9/109 (8.2%) TM, 3/57 (5.2%) SCD and 2/58 (3.4%) TI patients had T2 values lower than the normal limit of <80 msec. Of interest, none of the HbS/beta-thal patients had T2 values lower than the normal limit. Kidney R2* values were 17.3±10.8 Hz, 21.5±15.4 Hz and 19.1±13.6, for patients with TM, TI and SCD, respectively. Compared to historic controls, 5/109 (4.5%) TM, 8/58 (13.7%) TI and 4/57 (7%) SCD patients had R2* >upper normal limit of 33.7 Hz. There was no difference between the different groups regarding T2 or R2* values.eGFR values were 102±21, 111±12 and 98±28 ml/min/1.73m2, for patients with TM, TI and SCD, respectively. Patients with TI had higher eGFR than TM and SCD patients (p=0.014 and p=0.001, respectively). Six (5.5%) patients with TM and six (10.5%) with SCD had renal impairment of CKD stage 3-5. No patient with TI presented with stage 3-5 renal impairment. There was no correlation between T2 or R2* values and eGFR or serum creatinine in all patients groups. This may be due to the different T2 or R2* values between the two kidneys of the same patient (p=0.001 and p=0.01, for T2 and R2*, respectively).Patients with low T2 values (<80 msec) had higher serum ferritin and lower Hb (p=0.001 and p=0.01, respectively). Patients with high R2* values (>33.7 Hz) had higher serum LDH and reticulocyte counts (p=0.012 and p=0.01, respectively). Renal R2* (r=-0.286, p=0.001) but not T2 values correlated also with liver T2* values. In TM patients there was a negative correlation of T2 values with ferritin (r=-0.300, p<0.01) and LDH (r=-0.340, p<0.01), a positive correlation of R2* with ferritin (r=0.4, p<0.001) and LDH (r=0.382, p<0.001) and a negative correlation with Hb (r=-0.278, p=0.01).Our study provides evidence that T2 and R2* reflects kidney iron deposition in patients with different hemoglobinopathies: from 4.5% of TM patients who regularly receive iron chelation to 13.7% of TI patients. Importantly we found differences in iron overload between the two kidneys of the same patient in all studied group; finding which needs further evaluation and examination of possible correlations with each kidney's function. In TM patients both MRI techniques correlated with serum ferritin and LDH. Further studies, possibly with the performance of renal biopsies, will reveal the best MRI technique for detecting iron overload in the kidneys of patients with hemoglobinopathies as well as their role in the development of renal impairment in some of these patients. DisclosuresVoskaridou:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travelling, Research Funding. Terpos:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Celgene: Honoraria, Other: travel expenses; Novartis: Honoraria.

MRI for assessment of iron overload in patients with hematologic disease

目的比较磁共振成像（MRI）肝横向弛豫时间（T2*）、心T2*检测和血清铁蛋白（SF）评估铁过载的特征。方法对2011年11月至2014年6月69例患者进行肝脏、心脏MRI检查，并采集其各项临床数据进行分析。结果肝T2*与调整后铁蛋白（ASF）水平明显相关（P=0.003）。心T2*与肝T2*、ASF水平均无明显相关性。69例患者中，62例肝T2*诊断为铁过载，其中重度铁过载20例（32.26%）；47例ASF诊断为铁过载，其中重度14例（29.79%）；25例心T2*诊断为铁过载，无一例为重度铁过载。结论SF易受其他因素影响而无法完全客观地反映机体铁沉积水平；肝T2*检测可信度强、重复性好。心T2*不能正确评估全身铁过载的情况，仅仅是检测心脏铁沉积的一种手段。

Initial evaluation of hepatic T1 relaxation time as an imaging marker of liver disease associated with autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) is a potentially lethal multi-organ disease affecting both the kidneys and the liver. Unfortunately, there are currently no non-invasive methods to monitor liver disease progression in ARPKD patients, limiting the study of potential therapeutic interventions. Herein, we perform an initial investigation of T1 relaxation time as a potential imaging biomarker to quantitatively assess the two primary pathologic hallmarks of ARPKD liver disease: biliary dilatation and periportal fibrosis in the PCK rat model of ARPKD. T1 relaxation time results were obtained for five PCK rats at 3 months of age using a Look-Locker acquisition on a Bruker BioSpec 7.0 T MRI scanner. Six three-month-old Sprague-Dawley (SD) rats were also scanned as controls. All animals were euthanized after the three-month scans for histological and biochemical assessments of bile duct dilatation and hepatic fibrosis for comparison. PCK rats exhibited significantly increased liver T1 values (mean ± standard deviation = 935 ± 39 ms) compared with age-matched SD control rats (847 ± 26 ms, p = 0.01). One PCK rat exhibited severe cholangitis (mean T1 = 1413 ms), which occurs periodically in ARPKD patients. The observed increase in the in vivo liver T1 relaxation time correlated significantly with three histological and biochemical indicators of biliary dilatation and fibrosis: bile duct area percent (R = 0.85, p = 0.002), periportal fibrosis area percent (R = 0.82, p = 0.004), and hydroxyproline content (R = 0.76, p = 0.01). These results suggest that hepatic T1 relaxation time may provide a sensitive and non-invasive imaging biomarker to monitor ARPKD liver disease.

Automatic T2* determination for quantification of iron load in heart and liver: a comparison between automatic inline Maximum Likelihood Estimate and the truncation and offset methods

To validate ironload T2* by automatic inline Maximum Likelihood Estimate (MLE) with k-space Rician noise correction, against the manual and automated truncation, as well as offset methods, in phantoms and in heart and liver in patients. Twenty-five patients and an iron-oxide phantom were scanned at 1.5T using 2 multi-echo gradient-echo sequences. All parameters were identical (voxel 2-3×2-3×10mm3 , 10 echoes, TR=26ms, FA=20°, BW=833Hz, SENSE=2) except for TE (cardiac: TE1 =2·5ms, ΔTE=2·5ms; liver: TE1 =1·2ms, ΔTE=1·5ms). Phantoms were scanned at 1 and 32 signal averages (NSA), with NSA32 representing low-noise reference. Phantoms: MLE showed low variability between NSA1 and NSA32 (0·02±0·29ms, CI±0·21ms). Between methods, no difference was shown (MLE versus all: <0·31ms, CI<±0·35ms). No differences were found between methods in heart (MLE versus all: <-0·22ms, CI<±0·75ms) or liver (MLE versus all: <0·12ms, CI<±0·26ms). The automatic inline MLE method is comparable to the general reference standards for determining cardiac and liver T2* for ironload in man. An automatic inline method may simplify ironload assessment, particularly in centres seeing fewer cases.

In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosomiasis [corrected

BackgroundSchistosomiasis (or bilharzia), a major parasitic disease, affects more than 260 million people worldwide. In chronic cases of intestinal schistosomiasis caused by trematodes of the Schistosoma genus, hepatic fibrosis develops as a host immune response to the helminth eggs, followed by potentially lethal portal hypertension. In this study, we characterized hepatic and splenic features of a murine model of intestinal schistosomiasis using in vivo magnetic resonance imaging (MRI) and evaluated the transverse relaxation time T2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis.Methodology/Principal FindingsCBA/J mice were imaged at 11.75T two, six and ten weeks after percutaneous infection with Schistosoma mansoni. In vivo imaging studies were completed with histology at the last two time points. Anatomical MRI allowed detection of typical manifestations of the intestinal disease such as significant hepato- and splenomegaly, and dilation of the portal vein as early as six weeks, with further aggravation at 10 weeks after infection. Liver multifocal lesions observed by MRI in infected animals at 10 weeks post infection corresponded to granulomatous inflammation and intergranulomatous fibrosis with METAVIR scores up to A2F2. While most healthy hepatic tissue showed T2 values below 14 ms, these lesions were characterized by a T2 greater than 16 ms. The area fraction of increased T2 correlated (rS = 0.83) with the area fraction of Sirius Red stained collagen in histological sections. A continuous liver T2* decrease was also measured while brown pigments in macrophages were detected at histology. These findings suggest accumulation of hematin in infected livers.Conclusions/SignificanceOur multiparametric MRI approach confirms that this murine model replicates hepatic and splenic manifestations of human intestinal schistosomiasis. Quantitative T2 mapping proved sensitive to assess liver fibrogenesis non-invasively and may therefore constitute an objective imaging biomarker for treatment monitoring in diseases involving hepatic fibrosis.

T1ρ MRI of healthy and fibrotic human livers at 1.5T.

BackgroundLiver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based methods for better diagnosis of this disease. In the current study, we aim to evaluate the potential of T1ρ MRI technique in detecting and characterizing different grades of liver fibrosis in vivo in humans.MethodsHealthy subjects and patients with liver fibrosis were prospectively recruited for T1ρ MRI of liver on a 1.5 T MR scanner. Single slice T1ρ weighted images were acquired at different spin lock duration (0, 10, 20 and 30 ms) with spin lock amplitude of 500 Hz in a single breath-hold. Additionally, liver’s T1ρ images were acquired from five healthy subjects on the same day (n = 2) and different day (n = 2) sessions for test–retest study. Liver biopsy samples from patients were obtained and used to calculate the METAVIR score to define the stage of fibrosis and inflammation grade. T1ρ maps were generated followed by computation of mean and standard deviation (SD) values. Coefficient of variation (COV) of T1ρ values between two MRI scans was computed to determine reproducibility in liver. T test was used to compare T1ρ values between healthy and fibrotic liver. Pearson correlation was performed between stages of liver fibrosis and T1ρ values.ResultsThe mean (SD) T1ρ value among subject with healthy liver was 51.04 (3.06) ms. The COV of T1ρ values between two repetitions in the same day session was 0.83 ± 0.8 % and in different day session was 5.4 ± 2.7 %. T1ρ values in fibrotic liver were significantly higher compared to those of healthy liver (p < 0.05). A statically significant correlation between stages of fibrosis and T1ρ values was observed (r = 0.99, p < 0.05). Inflammation score for one patient was 2 and for remaining patients it was 1.ConclusionsProposed T1ρ pulse sequence design and protocol enabled acquisition of a single slice T1ρ weighted images in a single breath-hold and hence mitigated breathing motion related artifacts. Preliminary results have shown the sensitivity of T1ρ values to changes induced by liver fibrosis, and may potentially be used as a clinical biomarker to delineate the stages of liver fibrosis. Further, studies on a large number of subjects are required to validate the observations of the current study. Nevertheless, T1ρ imaging can be easily setup on a clinical scanner to monitor the progression of liver fibrosis and to the evaluate efficacy of anti-fibrotic drugs.

Transplantation of MSCs Overexpressing HGF into a Rat Model of Liver Fibrosis

The aim of this study is to evaluate the effect of overexpressing human hepatocyte growth factor (HGF) for mesenchymal stem cells (MSCs) in liver fibrosis regeneration and magnetic resonance (MR) tracking of MSCs in rat liver. MSCs were transfected with ad-HGF/ad-green fluorescent protein (GFP) and labeled with superparamagnetic iron oxide (SPIO). The characteristics of SPIO-HGF/MSCs were investigated. Prussian blue staining for iron assessment was conducted in vitro and in vivo. SPIO-HGF/MSCs (group A) or SPIO-GFP/MSCs (group B) were transplanted into a rat model of liver fibrosis, and MR imaging of the rat liver was performed. The signal to noise ratio (SNR) and R2* (1/T2*) value were measured. Prussian blue staining was performed to detect the in vivo distribution of MSCs, and liver Ki67 immunohistochemistry (IHC) staining was studied. The serum levels of HGF, alanine aminotransferase (ALT) and hyaluronic acid (HA) were determined. The positive rate of HGF transfection was 93.17 % and the HGF/MSCs were labeled with SPIO successfully (97.80 ± 1.06 %). Labeling of MSCs with SPIO did not alter cell proliferation in vitro. The signal intensity of liver T2* WI images decreased on day 1 after cell transplantation and recovered to pre-transplantation level on day 15 (group A) and day 13 (group B). The SNR of group A were significantly lower than that of group B (P = 0.006), and the R2* values of group A were significantly higher than those of group B (P < 0.001). The R2* value had a significantly negative correlation with SNR. There were more Prussian blue-positive cells in of group A were more than in group B in vivo. The positive rate of Ki67 was 16.11 ± 2.13 %, and the serum level of ALT/HA was decreased in group A. HGF transfection improved MSCs localization in the liver and aided liver repair. The R2* value might be a feasible index in addition to SNR to track the SPIO-MSC transplantation in the liver.

MRI assessment of excess cardiac iron in thalassemia major: When to initiate?

To determine optimal initial age of cardiac iron screening with magnetic resonance imaging (MRI) T2* in patients with thalassemia major (TM). We retrospectively reviewed black blood cardiac T2* assessments from 102 TM patients from the ages of 3 to 32 years. Cases of patients under and above 7 years old with detectable cardiac iron overload were analyzed separately. Associations between cardiac T2* and various factors, such as serum ferritin (SF), patient age and hepatic T2*, were assessed using either scatterplots or regression. Images were evaluated by two independent radiologists. With a T2* cut-off value of 20 ms, no patient under 5 years old showed cardiac iron overload. Three of 19 (15.8%) patients under 7 years of age had a cardiac T2* ≤ 20 ms (5.5 to 7 years) but none had ≤10 ms, while 35 of 83 (42.2%) patients above 7 years old had a cardiac T2* ≤ 20 ms (8 to 32 years) and 18 of them ≤10 ms. Cardiac T2* correlated weakly with serum ferritin and liver T2* (r = -0.39 and 0.41, respectively, both P < 0.001), but not with patient age (P > 0.05). Cardiac iron overload can occur in young TM patients, even as young as 5.5 years old. Assessment of cardiac iron with T2* might need to begin as early as 5 years old if suboptimal chelation therapy is administered.

Reassessing the value of MRI T2∗ in evaluation of hepatic and myocardial iron concentration: An institutional study

Patients with chronic hemolytic anemia like thalassemia and sickle cell anemia need repeated blood transfusions which lead 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 been proved effective in detecting and quantifying iron in the heart and liver. ObjectiveTo assess the accuracy of MRI T2∗ procedure in assessment of hepatic (LIC) and myocardial iron concentration (MIC). MethodsIn 70 cases of monthly transfused patients, hepatic and myocardial iron overload was measured by multibreath holds 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=0.528, r=−0.077). However, a significant correlation was observed between serum ferritin and liver T2∗ MRI (p=0.007, r=−0.318). ConclusionRoutine evaluation of liver and heart iron content using MRI T2∗ is suggested to better evaluate the hemosiderosis status in thalassemic and sickle cell patients.

An online open-source tool for automated quantification of liver and myocardial iron concentrations by T2* magnetic resonance imaging.

To assess whether an online open-source tool would provide accurate calculations of T2(*) values for iron concentrations in the liver and heart compared with a standard reference software. An online open-source tool, written in pure HTML5/Javascript, was tested in 50 patients (age 26.0 ± 18.9 years, 46% males) who underwent T2(*) MRI of the liver and heart for iron overload assessment as part of their routine workup. Automated truncation correction was the default with optional manual adjustment provided if needed. The results were compared against a standard reference measurement using commercial software with manual truncation (CVI(42)(®) v. 5.1; Circle Cardiovascular Imaging; Calgary, AB). The mean liver T2(*) values calculated with the automated tool was 4.3 ms [95% confidence interval (CI) 3.1 to 5.5 ms] vs 4.26 ms using the reference software (95% CI 3.1 to 5.4 ms) without any significant differences (p = 0.71). In the liver, the mean difference was 0.036 ms (95% CI -0.1609 to 0.2329 ms) with a regression correlation coefficient of 0.97. For the heart, the automated T2(*) value was 26.0 ms (95% CI 22.9 to 29.0 ms) vs 25.3 ms (95% CI 22.3 to 28.3 ms), p = 0.28. The mean difference was 0.72 ms (95% CI 0.08191 to 1.3621 ms) with a correlation coefficient of 0.96. The automated online tool provides similar T2(*) values for the liver and myocardial iron concentrations as compared with a standard reference software. The online program provides an open-source tool for the calculation of T2(*) values, incorporating an automated correction algorithm in a simple and easy-to-use interface.

MR relaxometry in chronic liver diseases: Comparison of T1 mapping, T2 mapping, and diffusion-weighted imaging for assessing cirrhosis diagnosis and severity

BackgroundMR relaxometry has been extensively studied in the field of cardiac diseases, but its contribution to liver imaging is unclear. We aimed to compare liver and spleen T1 mapping, T2 mapping, and diffusion-weighted MR imaging (DWI) for assessing the diagnosis and severity of cirrhosis. MethodsWe prospectively included 129 patients with normal (n=40) and cirrhotic livers (n=89) from May to September 2014. Non-enhanced liver T1 mapping, splenic T2 mapping, and liver and splenic DWI were measured and compared for assessing cirrhosis severity using Child-Pugh score, MELD score, and presence or not of large esophageal varices (EVs) and liver stiffness measurements using Fibroscan® as reference. ResultsLiver T1 mapping was the only variable demonstrating significant differences between normal patients (500±79ms), Child-Pugh A patients (574±84ms) and Child-Pugh B/C patients (690±147ms; all p-values <0.00001). Liver T1 mapping had a significant correlation with Child-Pugh score (Pearson's correlation coefficient of 0.46), MEDL score (0.30), and liver stiffness measurement (0.52). Areas under the receiver operating characteristic curves of liver T1 mapping for the diagnosis of cirrhosis (O.85; 95% confidence intervals (CI), 0.77–0.91), Child-Pugh B/C cirrhosis (0.87; 95%CI, 0.76–0.93), and large EVs (0.75; 95%CI, 0.63–0.83) were greater than that of spleen T2 mapping, liver and spleen DWI (all p-values<0.01). ConclusionLiver T1 mapping is a promising new diagnostic tool for assessing cirrhosis diagnosis and severity, showing higher diagnostic accuracy than liver and spleen DWI, while T2 mapping is not reliable.

Improved T1, contrast concentration, and pharmacokinetic parameter quantification in the presence of fat with two-point Dixon for dynamic contrast-enhanced magnetic resonance imaging.

To evaluate the impact of fat and fat-suppression on the quantification of T1, gadolinium concentration, and pharmacokinetic parameters in DCE-MRI. T1 values were measured in fat-free phantoms using variable flip angle with no fat suppression, quick or interleaved fat saturation (QFS), or two-point Dixon and were compared with reference values measured with inversion recovery-prepared turbo spin echo. Relaxivity of gadolinium-benzyloxypropionictetraacetate (Gd-BOPTA) was measured in emulsions of Gd-BOPTA solution and fat using Dixon in-phase and water-only images. Liver T1 and pharmacokinetic parameters of 15 patients were calculated from Dixon in-phase and water-only images and were correlated with liver fat signal fraction. T1 values measured using Dixon water-only and non-fat-suppressed images matched the reference values; while T1 values measured using QFS showed large deviations. Relaxivities and Gd measured in the Dixon water-only images were less affected by the fat than those measured in the in-phase images. The correlation between liver fat fraction and the differences in measured pharmacokinetic parameters using Dixon in-phase and water-only images were significant (P < 0.05) for T1, K(trans), and incremental area under the curve, but not Ve (P = 0.1). Dixon water-only images provided more reliable estimation of T1, Gd, and pharmacokinetic parameters when fat was present.

Serum Ferritin Levels Correlation With Heart and Liver MRI and LIC in Patients With Transfusion-Dependent Thalassemia.

Background:Iron-loaded cardiac complication is the essential cause of mortality in patients with thalassemia. Early detection and treatment of cardiac over-load can reduce mortality.Objectives:The current study aimed to evaluate the relationship between serum ferritin levels and T2* magnetic resonance imaging (MRI) of heart and liver and liver iron concentration (LIC) to diagnose iron over load in countries with limited access.Patients and Methods:In the current cross-sectional study, 85 Iranian patients with thalassemia with the mean age of 22.7 ± 7 years were randomly selected. All patients were on regular blood transfusion. Echocardiography of heart and liver T2* MRI, determination of serum ferritin levels, and LIC were performed in all subjects at the same time. The correlation of serum ferritin levels with T2*MRI of heart and liver, and LIC was assessed. P value < 0.05 was considered statistically significant.Results:Abnormal myocardial iron load (T2* MRI < 20 ms) was detected in 58% of the patients and among whom, 36% had severe myocardial iron load (T2* MRI < 10 ms). Median and interquartile range of serum ferritin levels were 1434 and 2702 respectively in patients with thalassemia. Serum ferritin levels showed a statistically significant positive correlation with LIC (rs = 0.718, P < 0.001) and significant negative correlation with T2* Heart (rs = -0.329, P = 0.002), and T2* Liver (rs = -0.698, P < 0.001). However, Ejection fraction was not significantly correlated with serum ferritin levels in the patients (P = 0.399).Conclusions:Serum ferritin levels can be used to diagnose iron over-load in patients with thalassemiaas an alternative method in areas where T2* MRI is not available.

A study of T₁ relaxation time as a measure of liver fibrosis and the influence of confounding histological factors.

Liver biopsy is the standard test for the assessment of fibrosis in liver tissue of patients with chronic liver disease. Recent studies have used a non-invasive measure of T1 relaxation time to estimate the degree of fibrosis in a single slice of the liver. Here, we extend this work to measure T1 of the whole liver and investigate the effects of additional histological factors such as steatosis, inflammation and iron accumulation on the relationship between liver T1 and fibrosis. We prospectively enrolled patients who had previously undergone liver biopsy to have MR scans. A non-breath-holding, fast scanning protocol was used to acquire MR relaxation time data (T1 and T2*), and blood serum was used to determine the enhanced liver fibrosis (ELF) score. Areas under the receiver operator curves (AUROCs) for T1 to detect advanced fibrosis and cirrhosis were derived in a training cohort and then validated in a second cohort. Combining the cohorts, the influence of various histology factors on liver T1 relaxation time was investigated. The AUROCs (95% confidence interval (CI)) for detecting advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) for the training cohort were 0.81 (0.65-0.96) and 0.92 (0.81-1.0) respectively (p < 0.01). Inflammation and iron accumulation were shown to significantly alter T1 in opposing directions in the absence of advanced fibrosis; inflammation increasing T1 and iron decreasing T1. A decision tree model was developed to allow the assessment of early liver disease based on relaxation times and ELF, and to screen for the need for biopsy. T1 relaxation time increases with advanced fibrosis in liver patients, but is also influenced by iron accumulation and inflammation. Together with ELF, relaxation time measures provide a marker to stratify patients with suspected liver disease for biopsy.

MRI monitoring in diagnosis and follow-up of iron overload

目的探索磁共振成像技术（MRI）在铁过载患者诊断和随访中的应用。方法回顾性分析北京协和医院2011年7月至2014年3月临床上怀疑有铁过载的患者107例，通过MRI技术测定其肝脏、心脏及胰腺T2*值，同时检测了血清铁蛋白（SF)、转铁蛋白饱和度、输血量及其他实验室指标，比较脏器T2*值与SF、输血量的关系；对其中10例经过祛铁治疗的患者进行随访，探索治疗后SF及T2*值的改变。结果①男65例，女42例，中位年龄51(8~77)岁。诊断为骨髓增生异常综合征50例，再生障碍性贫血36例，骨髓纤维化10例，血色病7例，β地中海贫血携带者4例。②肝脏T2*值和SF之间呈低度相关(r=0.120，P=0.001)，心脏T2*值与SF无相关性(r=0.012，P=0.289)；肝脏和心脏T2*值均与输血量无相关性（分别为r=0.019，P=0.175；r=0.000，P=0.845）；肝脏T2*值与心脏T2*值之间无相关性(r=0.015,P=0.235)。③70例患者同时接受肝脏、心脏和胰腺T2*值检测，胰腺T2*值与SF呈低度相关(r=0.061,P=0.039)，与输血量无相关性(r=0.000，P=0.960)；胰腺T2*值与肝脏T2*值无相关性(r=0.047，P=0.071)，而与心脏T2*值呈低度相关(r=0.110，P=0.005)。④其中10例患者进行了规律足量祛铁治疗，治疗前、后SF水平明显下降，分别为（2 566.5±1 152.2)µg/L、(1 473.4±803.0)µg/L(P=0.001)；治疗前、后肝脏T2*值变化不大，分别为（6.0±5.1) ms、(6.3±6.0)ms(P=0.629)。结论各脏器铁过载的程度明显不同，MRI定量检测较SF更好地反映脏器间铁过载程度的差异；规律的祛铁治疗在半年内对SF的变化有显著影响，但对肝脏T2*值影响不大，可能需要更长时间的祛铁治疗才能观察到脏器铁沉积的改善。

Reference method for measurement of the hepatic iron concentration.

Reference method for measurement of the hepatic iron concentration.

Free-breathing myocardial T2* mapping using GRE-EPI and automatic non-rigid motion correction.

BackgroundMeasurement of myocardial T2* is becoming widely used in the assessment of patients at risk for cardiac iron overload. The conventional breath-hold, ECG-triggered, segmented, multi-echo gradient echo (MGRE) sequence used for myocardial T2* quantification is very sensitive to respiratory motion and may not be feasible in patients who are unable to breath-hold. We propose a free-breathing myocardial T2* mapping approach that combines a single-shot gradient-echo echo-planar imaging (GRE-EPI) sequence for T2*-weighted image acquisition with automatic non-rigid motion correction (MOCO) of respiratory motion between single-shot images.MethodsECG-triggered T2*-weighted images at different echo times were acquired by a black-blood, single-shot GRE-EPI sequence during free-breathing. A single image at a single TE is acquired in each heartbeat. Automatic non-rigid MOCO was applied to correct for in-plane respiratory motion before pixel-wise T2* mapping. In a total of 117 patients referred for clinical cardiac magnetic resonance exams, the free-breathing MOCO GRE-EPI sequence was compared to the breath-hold segmented MGRE approach. Image quality was scored independently by 2 experienced observers blinded to the particular image acquisition strategy. T2* measurements in the interventricular septum and in the liver were compared for the two methods in all cases with adequate image quality.ResultsT2* maps were acquired in all 117 patients using the breath-hold MGRE and the free-breathing MOCO GRE-EPI approaches, including 8 patients with myocardial iron overload and 25 patients with hepatic iron overload. The mean image quality of the free-breathing MOCO GRE-EPI images was scored significantly higher than that of the breath-hold MGRE images by both reviewers. Out of the 117 studies, 21 breath-hold MGRE studies (17.9 % of all the patients) were scored to be less than adequate or very poor by both reviewers, while only 2 free-breathing MOCO GRE-EPI studies were scored to be less than adequate image quality. In a comparative evaluation of the images with at least adequate quality, the intra-class correlation coefficients for myocardial and liver T2* were 0.868 and 0.986 respectively (p < 0.001), indicating that the T2* measured by breath-hold MGRE and free-breathing MOCO GRE-EPI were in close agreement. The coefficient of variation between the breath-hold and free-breathing approaches for myocardial and liver T2* were 9.88 % and 9.38 % respectively. Bland-Altman plots demonstrated good absolute agreement of T2* in the interventricular septum and the liver from the free-breathing and breath-hold approaches (mean differences -0.03 and 0.16 ms, respectively).ConclusionThe free-breathing approach described for T2* mapping using MOCO GRE-EPI enables accurate myocardial and liver T2* measurements and is insensitive to respiratory motion.

Twice Daily Use of Deferasirox Is More Effective in Decreasing Serum Ferritin

Patients with beta-thalassemia major (BTM) are prone to tissue iron overloading in case that not adequately chelated. Among the iron chelators, development of oral chelators have improved patients’adherence to treatment. Deferasirox is a tridentate iron chelator, used once daily with a half life of 8-16 hours. The negative chelation effect is achieved at doses above 30 mg/kg/day and the currently FDA-approved maximum dose for use in patients is 40 mg/kg/day. However, some of the deferasirox side effects are dose-dependent increasing the occurences of adverse events at high doses. Additionally, although there is data that non-transferrin bound iron is effectively decreased by once daily dosing, the iron chelation effects of the drug may increase since in some of the patients half-life of the drug has been reported to be even less than 7 hours. Herein, we compared the iron chelation effect and tolerability of deferasirox in the same patients who were using deferasirox at a dose of 40 mg/kg/day.The patients with BTM who were under iron chelation with deferasirox at a dose of median 40 mg/kg/day (38-41) once daily for at least 6 months were included (n=10). These patients were receiving deferasirox at a maximum dose in the enrollment to the study related to either serum ferritin levels above 1500 ng/ml or moderate to severe iron loading in cardiac or liver tissues. These patients were put on a twice daily regimen of the same dose and followed up at a median time period of 7 months (4-17). The serum ferritin, ALT, creatinine levels and T2* MRI of heart and liver were obtained at the beginning of the twice daily dosing and by the end of the follow-up time. Patients were given a questionairre to investigate the tolerability and satisfaction of once daily and twice daily use.The median age of the study group was 21 years (3-34), hal were males. The patients’ serum ferritin, cardiac and hepatic iron loading levels were summarized in Table 1. There was a statistically significant decrease in serum ferritin levels with twice daily use of deferasirox compared to once daily use of the same dose. The initial and follow-up ALT and serum creatinine levels did not differ significantly (p>0.05). None of the patient required a dose reduction or cessation of the drug related to a toxicity. The major tolerability concern of the patients in once daily dosing was nausea in 2 of the patients (20%). After twice daily dosing the major concern of the patients was twice daily use of the drug itself in 2 patients (20%). None of the patients reported nausea in twice-dosing. The patients’ satisfaction survey in the end of the study for once or twice daily use was for once daily use revealed preference for twice-use in 5 (50%) of the patients for either no nausea (n=2) with twice-use or better decrease in serum ferritin levels (n=3). Three (30%) preferred once daily use as a better way, related to lesser drug use. Two patients reported that there were no difference in terms of satisfaction.In conclusion, twice daily use of deferasirox at higher doses is much better tolerated and causes a better decline in serum ferritin levels of already high iron burden. Further studies in larger sample groups may be more definitive.Table 1The initial and follow-up iron overloading evaluationsMean ± SD (Range)pInitial SF (ng/ml) Follow-up SF2020±983 (1016-4128) 1533±1026 (521-4003)0.047Initial cardiac T2* MRI (ms) Follow-up cardiac T2* MRI25.4±8.6 (14.6-38) 21.5±7.8 (13.8-30)0.068Initial liver T2* MRI (ms) Follow-up liver T2* MRI3.6±1.9 (1.3-8) 6.7±5.1 (2.1-13.6)0.465 SFserum ferritin; SD: standard deviation DisclosuresNo relevant conflicts of interest to declare.

The Use of Biochemical Parameters Instead of MRI for the Prediction of Pancreatic Iron Loading Among Patients with β-Thalassemia Major

▪Patients with β-thalassemia major (BTM) are prone to morbidities and mortalities of iron accumulation as a consequence of transfusional iron overload and increased intestinal iron absorption. The use of cardiac and hepatic T2* measurements to pr edict the amount of iron accumulation in these organs have been studied extensively and was suggested to be used reliably. However, although the use of MRI for the assessment of iron status in other organs such as pancreas is possible, it may not be practical to screen all organs with MRI related to economical issues and also the prolonged imaging durations. Herein, we studied fasting glucose, fasting insulin, HOMA-IR, HOMA-B and oral glucose tolerance results among patients with BTM, to detect the correlations of these measurements with pancreas, cardiac and hepatic T2* or R2* MRI values.Patients with BTM from a single center were included in the study between February 2013 and January 2014. All patients were above seven years of age, and were on regular erythrocyte transfusion programme. Only the patients who were compliant to iron chelation treatments were included in the study. Patients with hepatitis B or C, and/or cirrhosis were excluded. The study included a total of 37 patients who fulfilled the inclusion and exclusion criteria. Cardiac, hepatic T2* and pancreas T2* and R2* MRI was applied with 1.5 T (Siemens, Symphony, Erlangen, Germany) device. Simultaneous to MRI, fasting glucose, fasting insulin, HOMA-IR, HOMA-B and oral glucose tolerance results were obtained. HOMA-B was calculated as: insulin (μU/ml) x 20/glucose (mg/dl) - 3.5 and the normal range is 130-400. HOMA-IR was calculated as: insulin (μU/ml) x glucose (mg/dl) / 22,5 and the normal range is 0.8-1.6. Insulin resistance is defined as HOMA-IR value above 1.6. Two patients had a diagnosis of diabetes mellitus.The mean age of patients participating in the study was 20.8 ± 6.3 years (7.1-36.8). Of the study group, 43.3 % was above 20 years of age. According to BMI assessments, 32 (86.5%) of the patients had normal BMI, whereas 5 (13.5%) were underweight.Insulin resistance was found in 7.4% of the patients. Fasting blood glucose has been shown to increase with decreases of pancreatic T2* values, which was indicative of increase in fasting glucose levels in parallel to increased pancreatic iron accumulation (r= -0,55, p=0.016). Also there was a statistically significant positive correlation between fasting insulin and pancreatic R2* values. (r= 0.59, p= 0.01). A positive correlation was found between fasting insulin levels and pancreas R2* measeures, indicating increase in fasting insulin levels, paralleling the pancreatic iron accumulation. Correlation analysis was perfromed for cardiac and hepatic T2*, pancreas T2*, R2* and simultaneously calculated HOMA-IR and HOMA-B values and a negative correlation was found between liver T2* and HOMA-IR values (r=-0.54, p=0.004). A negative correlation was found between pancreas R2* ile cardiac T2* (r=-0.67, p=0.02), indicating increased pancreatic iron loading in parallel with cardiac iron accumulation.In centers where T2*/R2* MRI fascilities are unavailable, fasting insulin, fasting glucose, HOMA-IR measurements may be used to predict pancreatic iron overload. Since hepatic iron loading correlated with insulin resistance development, the insulin resistance among patients with BTM may partially be explained with decreased hepatic insulin clearance from heavily iron loaded liver. Additionally, disorders of glucose metabolism should be taken as a sign for the need to exercise caution in terms of cardiac iron overload and just vice versa patients with cardiac iron loading should be examined thoroughly for consequences of pancreatic iron loading. These biochemical tests may be used dynamically and more frequently throughout the control visits, whereas MRI is ordered at most once or twice a year which may cause a delay for the earlier diagnosis. DisclosuresNo relevant conflicts of interest to declare.