Pancreatic Iron Overload Research Articles

Quantification of pancreatic iron overload and fat infiltration and their correlation with glucose disturbance in pediatric thalassemia major patients.

Diabetes mellitus affects more than a quarter of patients with thalassemia major (TM) worldwide, and increases the risk for cardiac complications, contributing to significant morbidity. Pancreatic iron overload (IO) and fat infiltration have been correlated with this endocrinal complication in adult TM patients. It has been shown that in adult TM patients, iron accumulation and fat infiltration are found to be heterogeneous in the pancreatic head, body, and tail region. R2* and a fat fraction (FF) generated by gradient-echo imaging can be used as quantitative parameters to assess the iron and fat contents of the pancreas. This study aimed to determine the pattern of pancreatic iron accumulation and fat infiltration in pediatric TM patients with gradient-echo imaging and evaluate the association between pancreatic IO and fat infiltration and glucose disturbances. A total of 90 children with TM (10.7±3.1 years) were included. All patients underwent pancreatic magnetic resonance imaging (MRI) using multi-echo gradient-echo sequences. IO was measured by R2* relaxometry in 90 patients, and FF values were measured using iterative decomposition of water and fat with echo asymmetry and the least-squares estimation (IDEAL) method in 40 patients. R2* and FF were assessed in the pancreatic head, body, and tail. The global R2* and global FF values were obtained by averaging the respective values from the pancreatic head, body, and tail. The correlations between global R2*, global FF, and fasting glucose were determined using Spearman's correlation analysis. The Friedman test was used to compare R2* and FF among different pancreatic regions. Receiver operating characteristic (ROC) analysis was used to determine the performance of global R2* and global FF in discriminating impaired fasting glucose from normal fasting glucose patients. The global R2* was positively correlated with the global FF in the pancreas (r=0.895, P<0.001). No significant differences were found in R2* among the 3 regions of the pancreas (χ2=4.050, P=0.132), but significant differences were found in FF among the 3 pancreatic regions (χ2=16.350, P<0.001). Both global pancreatic R2* (r=0.408, P<0.001) and global FF (r=0.523, P=0.001) were positively correlated with fasting glucose. ROC analysis showed that global pancreatic R2* and global FF had an area under the curve of 0.769 and 0.931 (both P<0.001), respectively, in discriminating between impaired and normal glucose function patients. Pediatric TM patients can have homogeneous iron siderosis and heterogeneous fat infiltration in the pancreas as measured by gradient-echo imaging, both of which are risk factors for diabetes.

The relationships between pancreatic T2* values and pancreatic iron loading with cardiac dysfunctions, hepatic and cardiac iron siderosis among Egyptian children and young adults with β-thalassaemia major and sickle cell disease: a cross-sectional study

Background: Cardiac, hepatic and pancreatic T2* measured by magnetic resonance imaging (MRI) has been proven to be an accurate and non-invasive method for measuring iron overload in iron overload conditions. There is accumulating evidence that pancreatic iron can predict cardiac iron in young children because the pancreas loads earlier than the heart. The aim of our study was to assess the relationships between pancreatic T2* values and pancreatic iron loading with cardiac dysfunctions and liver and cardiac iron among patients with β-thalassaemia major (βTM) and sickle cell disease (SCD). Methods: 40 βTM and 20 transfusion-dependant SCD patients were included along with 60 healthy age and sex-matched controls. Echocardiography and Tissue Doppler Imaging were performed for all subjects as well as the control group. Hepatic, cardiac and pancreatic iron overload in cases were assessed by MRI T2*. Results: The mean age of our patients was 13.7 years with mean frequency of transfusion/year 12. Mean cardiac T2* was 32.9 ms and mean myocardial iron concentration was 0.7 mg/g; One patient had cardiac iron overload of moderate severity. Mean pancreatic T2* was 22.3 ms with 20 patients having mild pancreatic iron overload. Pancreatic T2* correlated positively peak late diastolic velocity at septal mitral annulus (r=0.269, p=0.038), peak early diastolic velocity at tricuspid annulus (r=0.430, p=0.001) and mitral annular plane systolic excursion (r=0.326, p=0.01); and negatively with end systolic pulmonary artery pressure (r=-0.343, p=0.007) and main pulmonary artery diameter (MPA) (r=-0.259, p=0.046). We couldn’t test the predictability of pancreatic T2* in relation to cardiac T2* as only one patient had cardiac T2*<20 ms. Conclusion: There was a relationship between pancreatic iron siderosis with cardiac dysfunction in multi-transfused patients with βTM and SCD. No direct relation between pancreatic iron and cardiac siderosis was detected.

Iron overload parameters and early detection of cardiac disease among Egyptian children and young adults with β-thalassaemia major and sickle cell disease: a cross-sectional study.

Background: Cardiac, hepatic and pancreatic T2* measured by magnetic resonance imaging (MRI) has been proven to be an accurate and non-invasive method for measuring iron overload in iron overload conditions. There is accumulating evidence that pancreatic iron can predict cardiac iron in young children because the pancreas loads earlier than the heart. The aim of our study was to investigate cardiac function and cardiac iron and their relation to pancreatic iron among patients with β-thalassaemia major (βTM) and sickle cell disease (SCD). Methods: 40 βTM and 20 transfusion-dependant SCD patients were included along with 60 healthy age-matched controls. Echocardiography and Tissue Doppler Imaging were performed for all subjects as well as the control group. Hepatic, cardiac and pancreatic iron overload in cases were assessed by MRI T2*. Results: The study group consisted of 40 βTM and 20 transfusion dependant SCD patients with mean age 13.7 years and mean frequency of transfusion/year 12. Mean cardiac T2* was 32.9 ms and mean myocardial iron concentration was 0.7 mg/g; One patient had cardiac iron overload of moderate severity. Mean pancreatic T2* was 22.3 ms with 20 patients having mild pancreatic iron overload. Pancreatic T2* correlated positively with main pulmonary artery diameter (p=0.046), peak late diastolic velocity at septal mitral annulus (p=0.038), peak early diastolic velocity at tricuspid annulus (p=0.001) and mitral annular plane systolic excursion (p=0.01); and negatively with end systolic pulmonary artery pressure (p=0.007). We couldn't test the predictability of pancreatic T2* in relation to cardiac T2* as only one patient had cardiac T2*<20 ms. Conclusion: Assessment of pancreatic T2* in multi-transfused patients with βTM and SCD can predict myocardial dysfunction. No direct relation between pancreatic iron and cardiac siderosis was detected.

Pancreatic Iron and Glucidic Metabolism in Thalassemia Major

Background. A preliminary study involving 59 patients demonstrated that pancreatic iron assessed by magnetic resonance imaging (MRI) was the strongest overall predictor of glucose dysregulation in thalassemia major (TM) patients. Aim. In the present multicenter study we explored systematically the link between pancreatic iron and glucidic metabolism in a large cohort of TM patients. Methods. We considered 705 TM patients (372 F, mean age 37.00±9.95 years) enrolled in the E-MIOT (Extension-Myocardial Iron Overload in Thalassemia) project. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. The pattern of disturbances of glucose metabolism was assessed by means of the oral glucose tolerance test (OGTT). Results. According to OGTT results, 546 patients (77.4%) had normal glucose tolerance (NGT), 14 (2.0%) had isolated impaired fasting glucose (IFG), 29 (4.1%) had impaired glucose tolerance (IGT), and 116 (16.5%) had diabetes mellitus (DM). None of the 85 patients (12.1%) without pancreatic iron overload (global pancreas T2*≥26 ms) had IGT or DM (Figure 1). The 84.6% of patients with NGT had pancreatic iron overload. The global pancreatic T2* values were significantly higher in patients with NGT than in patients with DM (13.58±11.08 ms versus 8.09±4.72 ms, P&amp;lt;0.0001). Receiver operator characteristic (ROC) analysis showed that a global pancreas T2*&amp;lt;13.73 ms was the optimal cutoff for predicting an abnormal OGTT, with an area under the curve (AUC) of 0.62. Global pancreas T2* values showed a weak significant correlation with insulin values (R=0.160; P=0.002) and homeostasis model assessment-insulin resistance (HOMA-IR) index (R=0.122; P=0.019). Conclusion. A normal global pancreas T2* value has a negative predictive value of 100% for IGT and DM. The low specificity of pancreatic iron overload for glucose dysregulation seems to support the hypothesis that a latency time is need before pancreatic iron burden could give impaired glucose tolerance and overt diabetes mellitus. Figure 1 Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Pancreatic Iron Deposition Following the Role of Iron Loading Among Transfusion Dependent Sickle Cell Disease Egyptian Children and Young Adults

Background: Transfusion in sickle cell disease (SCD) is uncommon but a well-defined practice; either as a replacement in severe anemia or as a prophylactic therapy for its major complications mainly stroke. Differential iron loading in SCD especially the extrahepatic organs is not fully studied. Primary objective is to measure pancreatic iron load among Egyptian transfusion-dependant SCD patients by using MRI T2* relaxometry method. Secondaryobjective is to correlate pancreatic iron load to transfusion iron input, both hepatic and cardiac iron load, trend of serum ferritin. Subjects and Methods: Sixty-six transfusion-dependant SCD child and young adults 8-25 years with more than twenty transfusions before enrollment, non was on regular exchange transfusion; they underwent clinical and laboratory assessments; complete hemogram, serum ferritin and serum amylase. All patients performed MRI examination on a 1.5- Tesla super conductive MR Philips scanner in MRI unit in Ain Shams University Hospital; the study takes about 10 -15 minutes. Radiological quantification of iron overload was performed via simple mathematical models using Microsoft Excel Spread Sheet for heart, pancreas, and kidneys. Results: The mean age of the studied SCD patients were 15.68 ± 7.02 years, they were 35 male (53.0%), 43 of them (65.2%) had positive family history of SCD. All were multiple transfusion; 22 for cardiopulmonary complication and acute chest syndrome (ASC), nine for stroke prevention and 35 for frequent sickling crisis and symptomatic anemia. Most of patients (80.3%) were on chelation therapies that were mainly (92.5%) oral mono-therapy. High frequencies of comorbidities were recorded in the studied cohort; delayed puberty (65.2%), hepatitis C infection (23.1%) and stroke (14.1%). The studied SCD patients had median transfusion index of 120ml/kg/year with mean iron overload per day 0.23 ± 0.15 mg/kg and half of them had serum ferritin &gt; 2500ug/L. Almost two-thirds had moderate to severe liver iron overload with median LIC 11.63 mg/g liver dry weight, none had cardiac iron overload with median cardiac T2* 31 msec and nearly half of them (42.2%) showed marked decrease in signal intensity of renal cortex with relative sparing of the renal medulla and pelvis. Most of them (86%) had normal to mild pancreatic iron overload with median pancreatic R2* 53.8 msec. Pancreatic R2 level was not significantly correlated to either transfused iron, liver iron or serum ferritin and amylase. Patients with moderate to severe pancreatic iron overload had lower pre-transfusion hemoglobin level (p=0.004), higher level of marker of hemolysis (total bilirubin (p=0.012) and indirect bilirubin (p=0.048) than those with normal pancreatic MRI. Radiological quantification of iron overload was performed via a simple cheap and quick method for analysis of data. Conclusion: Moderately heavy transfused patients with SCD had no iron overload in the heart; pancreas follow same pattern as heart with minimal or no pancreatic iron loading, however moderate to severe hepatic iron loading. Whether iron loading might be related only to frequency of transfusion or also to frequency of vaso-occlusive will be discussed. Disclosures No relevant conflicts of interest to declare.

Assessment of Pancreatic Iron Overload in Transfusion Dependent Thalassemic Patients

Advances in the management of transfusion dependent thalassemic patients have improved the survival of these patients. The most important consequence of repeated and frequent transfusions is iron accumulation in vital organs. The magnetic resonance imaging (MRI) is a non-invasive and valid technique for the estimation of iron stores. Despite multiple studies about cardiac and liver MRI T2*, there is limited experience about pancreatic MRI. Although there is a weak correlation between hepatic and pancreatic siderosis, MRI assessment of iron deposition in the pancreas can reduce cardiac morbidity. Pancreatic siderosis may be a predictor for the development of glucose dysregulation. Pancreatic R2* &gt; 100 Hz is a risk factor for glucose intolerance or even overt diabetes. Splenectomy can accentuate the pancreatic iron overload. Early intensive chelation therapy in thalassemia patients can reverse glucose metabolism impairment. In this review, the MRI assessment of pancreatic iron overload in transfusion dependent thalassemia, the correlation between pancreas with liver and myocardial hemosiderosis and the importance of pancreatic iron overload in pathogenesis of diabetes mellitus in these patients were discussed.

P601Heart disease and pancreatic iron in thalassemia major

Abstract Background Some preliminary data have postulated a correlation between pancreatic iron overload and heart iron and function in thalassemia major (TM) patients. Purpose In the present multicenter study we explored systematically the link between pancreatic iron and heart disease in a large cohort of TM patients. Methods We considered 880 TM patients (467 M, mean age 37.83±10.05 years) enrolled in the E-MIOT (Extension-Myocardial Iron Overload in Thalassemia) project. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. Myocardial iron overload (MIO) was quantified using a T2* segmental approach. Biventricular function parameters were assessed by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis. Results A significant correlation between pancreatic and cardiac iron was reconfirmed in this more numerous population and a normal pancreas T2* showed negative predictive value of 100% for cardiac iron. LGE sequences were acquired in 273 TM patients and 84 (30.77%) of them showed macroscopic myocardial fibrosis. Global pancreas T2* values were significantly lower in patients with fibrosis (7.38±6.19 ms vs 11.91±9.79 ms; P&lt;0.0001). Sixty-four patients had at least one cardiac complication (arrhythmias, heart failure, pulmonary hyperthension, vascular disease). Patients with cardiac complications showed a significant lower global pancreas T2* (7.83±5.61 ms vs 12.76±10.34 ms; P=0.024). Specifically, global pancreas T2* values were significantly lower in patients with heart failure as well as in patients with arrhythmias and all patients with one of these two diseases had a pathologic global pancreas T2* value (see Figure). Conclusion Pancreatic iron is a strong predictor not only for cardiac iron, but also for cardiac complications supporting a more profound link between pancreatic iron and heart disease in TM.

Glucose and Lipid Profiles in Adolescents with Thalassemia Major and Its Association with Iron Overload in Specific Organs

BACKGROUND: Organ damage due to iron toxicity is one factor that increases the risk of getting cardiovascular and metabolic diseases in thalassemia patient. This study aims to determine glucose and lipid profiles in adolescents with thalassemia major and its association with iron overload in pancreas and liver.METHODS: This was a cross sectional study. Subjects were thalassemia major adolescents without any confounding factors that may affect glucose and lipid levels. Blood samples were collected to measure the glucose level, lipid profiles, ferritin level and transferrin saturation. T2-Magnetic Resonance Imaging was used to evaluate the iron overload in organs.RESULTS: From a total of 60 subjects, diabetes mellitus was diagnosed in 1 subject and impaired fasting glucose was diagnosed in 3 subjects. All subjects had high triglycerides/ high density lipoprotein-cholesterol (HDL-C) ratio, 59 subjects (98%) had low HDL-C, 18 subjects (30%) had hypertriglyceridemia, and none had abnormal high level of low density lipoprotein-cholesterol (LDL-C). The majority of subjects had ferritin ≥2,500 ng/mL (70%), mild pancreatic iron overload (56.6%), and moderate hepatic iron overload (43.8%). Degree of hyperferritinemia was not associated with glucose and lipid profiles. Blood glucose profiles were not associated with various degree of pancreatic iron overload. Similar result was also observed between lipid profiles and hepatic iron overload.CONCLUSION: Abnormal glucose and lipid profiles in thalassemia major can be found in adolescence. Normal blood glucose level isn’t necessarily associated with normal pancreatic iron deposition. Hepatic iron overload may worsen dyslipidemia in thalassemia major patients.KEYWORDS: glucose profile, lipid profile, pancreatic iron overload, hepatic iron overload, thalassemia major

PS1572 HEART DISEASE AND PANCREATIC IRON IN THALASSEMIA MAJOR

Background:Some preliminary data have postulated a correlation between pancreatic iron overload and heart iron and function in thalassemia major (TM) patients.Aims:In the present multicenter study we explored systematically the link between pancreatic iron and heart disease in a large cohort of TM patients.Methods:We considered 880 TM patients (467 M, mean age 37.83 ± 10.05 years) enrolled in the E‐MIOT (Extension‐Myocardial Iron Overload in Thalassemia) project. T2∗ measurements were performed over pancreatic head, body and tail and global value was the mean. Myocardial iron overload (MIO) was quantified using a T2∗ segmental approach. Biventricular function parameters were assessed by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.Results:A significant correlation between pancreatic and cardiac iron was reconfirmed in this more numerous population and a normal pancreas T2∗ showed negative predictive value of 100% for cardiac iron.LGE sequences were acquired in 273 TM patients and 84 (30.77%) of them showed macroscopic myocardial fibrosis. Global pancreas T2∗ values were significantly lower in patients with fibrosis (7.38 ± 6.19 ms vs 11.91 ± 9.79 ms; P &lt; 0.0001).Sixty‐four patients had at least one cardiac complication (arrhythmias, heart failure, pulmonary hyperthension, vascular disease). Patients with cardiac complications showed a significant lower global pancreas T2∗ (7.83 ± 5.61 ms vs 12.76 ± 10.34 ms; P = 0.024). Specifically, global pancreas T2∗ values were significantly lower in patients with heart failure as well as in patients with arrhythmias and all patients with one of these two diseases had a pathologic global pancreas T2∗ value (see Figure).Summary/Conclusion:Pancreatic iron is a strong predictor not only for cardiac iron, but also for cardiac complications supporting a more profound link between pancreatic iron and heart disease in TM.image

Role of Magnetic Resonance Imaging in Assessment of Pancreatic Iron Overload in Pediatric Beta-Thalassemic Major Patients

AbstractBackground: Thalassemia patients have diabetes mellitus subaltern to hemosiderosis.Aim of Study: To asses iron overload in pancreas of pediatrics beta-thalassemia major patients by T2*-Gradient-echo Magnetic Resonance Imaging (MRI) and to study corre-lation of results of data of MRI with affection with diabetes, serum ferritin level, hepatic hemosiderosis, and spleen removal.Methods: 20 (3-thalassemia major patients with regular blood transfusion (11 males and 9 females) follow-up at the Hematology Clinic, Children's Hospital, Tanta University.Results: Striking reduction in hepatic and pancreatic Signal Intensity Ratio (SIR) was appeared in thalassemic patients contrasted with controls (p<0.001), Thalassemic patients with anomalous glucose tolerance; demonstrating a more level of secondary hemosiderosis in the form of low signal intensity of pancreas and liver tissue contrasted with thalassemics with typical glucose tolerance or controls (p<0.001). Thalassemic patients with surgically removed spleen had essentially bring down SIR of pancreas contrasted with intact spleen patients (p<0.047). A solid connection was available amongst hepatic and pancreatic siderosis in examined patients (p<0.003).Conclusions: T2* GRE MRI assume a vital part in detec-tion of iron over-burden in B thalassemic patients, and was more obvious in patients with unusual glucose tolerance. After spleen removed, iron deposition might be more out of control in the pancreas. We prescribe serious chelation system to thalassemic patients generally and more in thalassemic patients with IGT with regular follow-up by susceptibility weighted sequences of magnetic resonance imaging.

Relation of Pancreatic Iron Overload Detected By MRI with Disorders of Glucose Metabolism and Results of Liver, Cardiac and Pitutiary MRI Among Transfusion Dependent Thalassemia (TDT) Patients in Turkey

The relationship between pancreatic iron overload and glucose dysregulation has not been well defined and need further investigation. Pancreas iron load measurements are also necessary to understand how hepatic, pancreatic, and cardiac iron burden prospectively modulate the evolution of diabetes in transfusion dependent thalassemia (TDT).Aim: This study aims to evaluate the presence of pancreatic iron overload among TDT patients in Turkey based on the MRI R2* and T2* results as well as to determine its association to Fasting blood glucose (FBG), insulin, fructosamine, Homa-IR, C-peptide, ferritin, liver, cardiac and hypophysis MRI R2* results.Material and Methods: This study was conducted at the Thalassemia Center in Istanbul University, Istanbul Medical Faculty. Forty-one TDT patients included the study with a mean age of 29.9±9,9 (median 29) years old, ranging from 11 to 45 years old. Pancreatic, liver, cardiac and hypophsis MRI's were conducted using 1.5 Tesla Philips MRI machine in the Department of Radiology.Pancreatic MRI R2* results < 30 Hz were considered normal, 30-100 Hz as mild, and > 100 Hz as moderate to severe pancreatic siderosis. Pancreatic MRI T2 results >26 ms were is normal, < 10 ms is severe iron overload as presented at literature. Correlations between pancreatic MRI R2* results and FBG, insulin, fructosamine, Homa-IR, C-peptide, ferritin, cardiac and hypophysis MRI R2* were evaluated using the Pearson correlation, Man Whitney U test.Results: Laboratory findings of glucose metabolism and MRI's of liver, pancreas, hypophsis and cardiac iron are shown at Table 1. There were no significant relationship between fasting blood glucose, insülin, C-peptid level, fructosamine, Homa-IR, ferritin and Pancreas T2* and R2* results (p>0.05). There was significant correlation between liver and pancreas MRI T2* and R2* results. (p<0.01). There was no significant correlation between hypophysis global R2, cardiac R2*, Pancreas T2* and, Pancreas R2* measurements (p>0.05). Fourteen patients were found to have normal pancreatic MRI R2* (34,1%) while 19 patients have normal pancreatic MRI T2 (46.3%). It is reported that T2 is irrelevant to age and sex, and R2 can be related to age-related fatty degeneration.There was significant pancreatic iron burden in 31.7% of patients (R2*>100 Hz), of whom only 1 patient was under 18 years of age.There were 22 (53.6%) patients with T2* <26 ms and had iron overload, 13 (31.7%) had T2 <10 ms and had significant iron overload. Almost three-quarters of patients (n:13, 31.7%) had moderate to severe pancreatic iron load on both T2* and R2* measurements. Thirteen patients with significant pancreatic iron overload had 3 severe hypophysis, 1 moderate, 2 severe cardiac siderosis. and had no serious liver iron burden. This shows that the treatment of chelation first led to liver, then heart and pituitary, respectively, and finally pancreatic iron burden and demonstrates the importance of pancreas MR in assessing the body iron load.Discussion:The lack of correlation between pancreatic and cardiac MRI R2* are in contrast to another demonstrating that pancreatic iron load are good predictors of cardiac iron load. This is due to the fact that our patients are followed up with cardiac MR and taken to the intensive chelation programs of the patients who detect iron in the heart.Previous studies also report that while pancreatic R2* may be sensitive for glucose dysregulation, most patients may still have no symptoms and normal blood glucose, indicating the presence of a preclinical iron burden. Pancreatic MRI R2* can detect pancreatic iron accumulation at a much earlier stage. Lack of excessive iron load in liver of our patient can be explain low glucose metabolism disorder despite high pancreatic iron overload. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Characterization of a Novel Mutation in SLC25A38 Resulting in Congenital Sideroblastic Anemia in a Canadian First Nations Population

Introduction: Congenital sideroblastic anemia (CSA) is an uncommon cause of inherited anemia characterized by pathologic iron accumulation. Severity of anemia and blood transfusion requirements are variable. Aberrations in iron-heme metabolism that underpin CSA result in iron overload, often preceding transfusion. The only curative therapy for CSA is hematopoietic stem cell transplantation (HSCT), offered to select patients with severe transfusion dependent anemia. Mutations in several genes have been identified to be responsible for CSA. Mutations in SLC25A38, encoding a mitochondrial glycine transporter required for heme biosynthesis, are a rare cause of CSA. Homozygosity for a novel founder missense mutation in SLC25A38 (c.560G>A) has been detected in a Canadian First Nations Northern Cree population. The associated phenotype is a severe anemia presenting in infancy and characterized by ineffective erythropoiesis and iron loading. The natural history and treatment outcomes of CSA caused by the c.560G>A mutation have not been described.Objectives: (1) To characterize the clinical features in patients homozygous for this founder mutation, including propensity to iron loading and (2) to describe the treatment course and outcomes for red cell transfusion, iron chelation, pyridoxine supplementation and HSCT.Methods: A retrospective chart review was conducted at the Winnipeg Health Sciences Centre and CancerCare Manitoba of all affected individuals homozygous for the c.560G>A mutation in SLC25A38.Results: Seven affected individuals (three females and four males) were identified. Comorbidities including dextrocardia, hypertrophic cardiomyopathy, rheumatoid arthritis and global developmental delay were noted in three members of the kindred, but there was no evidence of a syndromic form of CSA. The median age of presentation with anemia was 6 months (24 days - 4.4 years). The median age of CSA diagnosis was 1.5 years (6 months - 22 years). Alternative causes of anemia were initially suspected in five of the seven patients: iron deficiency, resulting in oral iron supplementation, and alpha thalassemia. Uniformly, individuals presented with a microcytic, hypochromic anemia, with elevated ferritin prior to first red cell transfusion. All affected individuals required red cell transfusion support, with six of seven patients requiring chronic transfusions at a median frequency of every four weeks. One individual, though chronically anemic, did not require regular transfusion support until the age of 20 years. One patient carried a successful pregnancy with transfusion support, but delivered prematurely. For all individuals, iron chelation was recommended, with six individuals starting chelation within three years of initiation of transfusions. Hepatic, cardiac, pituitary and pancreatic iron overload, and resultant organ dysfunction were noted in two subjects who did not adhere to chelation; one died of neutropenic sepsis after starting deferiprone for cardiac iron overload. Six individuals were given trials of pyridoxine supplementation, with two demonstrating a transient partial response with a rise in reticulocyte count and decrease in transfusion frequency. Three individuals underwent allogeneic HSCT (two from matched sibling donors, and one from a matched unrelated donor), at 5.5 years, 7.2 years, and 28 years. The oldest and most iron-loaded of the three died in the post-transplant period due to complications of sepsis. The other two individuals remain transfusion free, at 9 months and 15.6 years post-HSCT.Conclusions: A novel founder mutation in SLC25A38 causing CSA among individuals of Canadian First Nations Northern Cree descent results in a severe transfusion-dependent anemia. Despite a common genetic etiology, phenotypic variability was noted, with one individual having marked tolerance to anemia. A partial transient response to pyridoxine was noted in two individuals, raising the question of an alternative role for SLC25A38 in heme biosynthesis. HSCT, when performed before significant iron overloading, was beneficial. Characterization of this phenotype and evidence of successful HSCT may assist clinicians in identifying affected individuals with CSA and initiating timely and effective treatment. DisclosuresNo relevant conflicts of interest to declare.

Multicenter Validation of the Magnetic Resonance T2* Technique for Quantification of Pancreatic Iron

Introduction. The gradient echo multiecho T2* MRI technique is the most robust method for the non invasive, sensitive, and fast quantification of organ-specific iron overload. A crucial aspect is the transferability of the T2* technique among different MRI scanners, in order to expand the availability of high-quality monitoring of iron accumulation to a large population. The intra- and inter-operator reproducibility, inter-study reproducibility, and inter-scanner reproducibility of the T2* MRI method for measuring iron concentrations in the heart and liver have already been demonstrated. However, the transferability of the MRI multislice multiecho T2* technique for pancreatic iron overload assessment has not been evaluated. Thus, the aim of our study was to assess the transferability of this approach among ten MRI sites.Methods. All subjects underwent MRI using conventional clinical 1.5T scanners of three main vendors. Fifty healthy subjects, five for each site, including the reference centre, were scanned. Five patients with thalassemia were scanned locally at each site and were rescanned at the reference site in Pisa within 1 month.T2* image analysis was performed using custom-written, previously validated software (HIPPO MIOT®). T2* values over pancreatic head, body and tail were calculated and the global pancreatic T2* value was obtained as the mean. The lowest threshold of normal T2* value was 26 ms6.Results. On healthy subjects the global pancreas T2* values ranged from 28.93 to 48.89 ms (mean 37.88 ms, SD 5.08 ms). No significant difference was detected among the sites (P=0.334).Table 1 shows the global pancreas T2* values measured at the different MRI sites. The global pancreas T2* values ranged from 2.08 to 38.39 ms. There was not a significant difference between the T2* values measured in the MRI sites and the correspondent values observed in Pisa (12.02±10.20 ms vs 11.98±10.47 ms; P=0.808). All patients categorized as having pancreatic iron overload in the MRI sites, fell in the same category after the MRI executed in Pisa.There was a strong correlation between the global pancreas T2* values calculated from images obtained in Pisa and at the other MRI sites (R=0.978, P<0.0001).Figure 1 shows the global pancreas T2* values calculated from images obtained at the 9 MRI sites as a function of global pancreas T2* calculated from images obtained in Pisa. The line of best fit had a slope of 0.965 ± 0.021 and an intercept of 0.459 ± 0.328 ms. The R-squared value for the fit was 0.981. Neither constant bias (intercept did not significantly differs from zero) nor proportional bias (angular coefficient did not significantly differ from 1) affected the measurements.CoVs for all MRI sites are provided in Table 2; they ranged from 4.22 to 9.77%. The CoV for all the T2* values independently from the sites was 8.55%.The ICC considering all the T2* values, independently from the sites, was 0.995. The ICC for each MRI site is provided in Table 2 and it was always excellent.The comparison between Pisa and the other MRI sites by Bland-Altman analysis showed a mean absolute difference of -0.04 ± 1.47 ms for the global pancreas T2* values (Figure 2). No bias was present and no greater differences for higher T2* values were detected.The mean absolute difference in patients with pancreatic iron (N=39) was -0.15 ± 1.38 ms.Conclusion. The gradient-echo T2* MRI technique is an accurate and reproducible means for the calculation of pancreatic iron and may be transferred between MRI scanners in different centers from different manufacturers. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Multicenter validation of the magnetic resonance T2* technique for quantification of pancreatic iron.

To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for pancreatic iron overload assessment. Multiecho T2* sequences were installed on ten 1.5-T MRI scanners of the three main vendors. Five healthy subjects (n= 50) were scanned at each site. Five patients with thalassemia (n= 45) were scanned locally at each site and were rescanned at the reference site within 1month. T2* images were analyzed using a previously validated software and the global pancreatic T2* value was calculated as the mean of T2* values over the head, body, and tail. T2* values of healthy subjects were above 26ms and showed inter-site homogeneity. The T2* values measured in the MRI sites were comparable to the correspondent values observed in the reference site (12.02 ± 10.20ms vs 11.98 ± 10.47ms; p = 0.808), and the correlation coefficient was 0.978 (p < 0.0001). Coefficients of variation (CoVs) ranged from 4.22 to 9.77%, and the CoV for all the T2* values independently from the sites was 8.55%. The intraclass correlation coefficient (ICC) for each MRI site was always excellent and the global ICC was 0.995, independently from the sites. The mean absolute difference in patients with pancreatic iron (n = 39) was -0.15 ± 1.38ms. The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron and may be transferred among MRI scanners by different vendors in several centers. • The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron. • The gradient-echo T2* MRI technique for the quantification of pancreatic iron may be transferred among MRI scanners by different vendors in several centers. • Pancreatic iron might serve as an early predictor of cardiac siderosis and is the strongest overall predictor of glucose dysregulation.

Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation.

Whereas many studies have addressed the risk of organ dysfunction following hematopoietic stem cell transplantation (HSCT), little is known about pancreatic susceptibility in this setting. We aimed to investigate the effect of iron overload (IO) and total body irradiation (TBI) on pancreatic function of children undergoing HSCT.We retrospectively evaluated children admitted between 2012-2016 fulfilling the following criteria: normal pancreatic iron concentration (PIC), regular pancreatic function before HSCT, availability of abdominal magnetic resonance imaging with gradient-recalled-echo sequences and a full set of biochemical markers of IO and pancreatic function performed before HSCT and at discharge. We divided the patients according to the use of TBI or myeloablative chemotherapy (MCHT) in the conditioning regimen. All patients with severe IO or moderate IO with a high risk of engraftment delay or transplantation-related complications underwent chelation therapy with deferoxamine (DFO) from the first day of conditioning to discharge.63 patients had a HSCT in the study period, 13 did not fulfill the inclusion criteria; 50 (25 in each group) are included in the analysis, and did not show differences at baseline evaluation. At follow up testing the TBI group showed a significantly higher PIC (107,8±100,3 μmol/g vs 28,4±37,9 in MCHT group, p<0,0001). In the TBI group the patients who had DFO treatment had higher PIC (223,2±48,8 μmol/g vs 55,7±10,5 without DFO treatment, p<0,0001), and all patients having PIC >100 μmol/g at follow up had DFO-based chelation therapy, versus 26% of those with lower PIC (p<0,0001). The number of patients presenting exocrine pancreatic dysfunctions one month after transplantation was significantly higher in the TBI group (48% vs 4%; p<0.0001). The mean pancreatic volume reduction was significantly greater in the TBI group (39,1% vs 0,9% in the MCHT group; p<0,05), and was significantly worse on those who received DFO therapy.Based on our data, we suggest that TBI is detrimental for pancreatic functions, and speculate that DFO may contribute to the rapid pancreatic IO observed in these patients.

Quantification of pancreatic fat with dual-echo imaging at 3.0-T MR in clinical application: how do the corrections for T1 and T2* relaxation effect work and simplified correction strategy.

Background Dual-echo imaging is a routine clinical magnetic resonance (MR) sequence affected by T1 and T2* relaxation effect in fat quantification. The separate impacts of T1 and T2* relaxation effect in pancreatic fat quantification using dual-echo imaging at 3.0-T MR have not been reported in detail. Purpose To demonstrate the separate T1 and T2* relaxation effect on pancreatic fat quantification by dual-echo imaging at 3.0-T MR and the simplified correction strategy is discussed for convenient clinical application. Material and Methods Twenty-one non-alcoholic fatty liver disease (NAFLD) participants with high risk of pancreatic steatosis were included. Pancreatic fat fractions (FF) by dual-echo imaging with different corrections were compared to that of proton magnetic resonance spectroscopy (1H-MRS). Correlation analysis and Bland-Altman analysis were applied. Results The FF by 1H-MRS was 5.9 ± 1.7%. Significant positive correlation (all P < 0.01) was found between FF by 1H-MRS and each dual-echo imaging, in which T1 and T2* correction showed the best correlation (r = 0.95, FF = 6.2 ± 1.7%) and no correction showed the worst correlation (r = 0.86, FF = 5.2 ± 2.0%), and the simplified T1 and T2* correction manifested as r = 0.93 and FF = 6.3 ± 1.8%. FF by T1 and T2* correction showed the best agreement, while T1 correction showed the worst agreement as compared to that of 1H-MRS. Conclusion T1 and T2* correction shows the best performance while no correction dual-echo imaging remains clinical available which may benefit from prior OP echo. Simplified correction using single T2* (32.6 ms) of water and fat is recommended for convenient clinical application in absence of obvious pancreatic iron overload.

T2* Magnetic Resonance Imaging Study of Pancreatic Iron Overload and its Relation With the Diabetic State in Thalassemic Patients.

The present study was performed to evaluate pancreatic hemosiderosis by means of magnetic resonance imaging (MRI) T2* and its relation to the diabetic state in thalassemic patients. One hundred thirty transfusion-dependent thalassemic patients from Zafar adult thalassemia clinic, Tehran, Iran, were enrolled in the study. Data such as age, type of thalassemia, age at diagnosis, transfusion duration, ferritin level, and fasting blood sugar results were gathered. Pancreatic MRI T2* was performed for all patients. One hundred four thalassemic patients with no sign of diabetes mellitus and 26 thalassemic patients with diabetes mellitus entered the study. Out of a total of 130 patients, 102 had pancreatic hemosiderosis. Among them, 23 of 26 diabetic patients (88.5%) and 79 of 104 nondiabetic patients (76%) showed pancreatic hemosiderosis, indicating no statistically significant difference between the 2 groups. The mean pancreatic MRI T2* relaxation time for all patients was 13.99±12.43 ms. The mean relaxation was 13.62±8.38 and 14.08±13.28 ms for diabetic and nondiabetic patients, respectively, showing no statistical difference (P=0.202). In conclusion, we did not find a significant difference between diabetic and nondiabetic thalassemic patients regarding the MRI T2* relaxation time readings or the rate of pancreatic hemosiderosis. We recommend performing studies with a higher sample size and including patients from different age groups to further evaluate the role of T2* MRI of pancreatic iron overload and its relation with the diabetic state in thalassemic patients.

Correlation of Pancreatic Iron Overload Measured by T2*-Weighted Magnetic Resonance Imaging in Diabetic Patients with β-Thalassemia Major

Diabetes mellitus (DM) is one of the potential complications in patients with transfusion-dependent β-thalassemia major (β-TM). In this case-controlled study, we examined the pancreatic iron levels in outpatients with β-TM. In this study, cases of patients with β-TM and DM were gender- and age-matched with control subjects, who were non-diabetic and had normal blood glucose on standard oral glucose tolerance (OGTT) tests. One of four diagnoses [normal, pre-diabetes, impaired glucose tolerance (IGT), DM] was made according to the American Diabetes Association (ADA) criteria. The T2*-weighted magnetic resonance imaging (T2*-weighted MRI) of the heart, liver, and pancreas was performed using a 1.5 Tesla scanner. The study enrolled 26 diabetic cases, 17 non-diabetic cases, and eight cases of IGT or pre-diabetes cases. The severity of pancreatic and cardiac iron siderosis was significantly different between the groups. We found a statistically significant difference at 5.6 ms in the T2*-weighted MRI values for the pancreas between patients with normal vs. abnormal glucose metabolism [p < 0.009; odds ratio (OR): 11.2; 95% confidence interval (95% CI): 1.32-94.4)]. The receiver operating characteristic (ROC) curve for the 5.6 ms cutoff led to an area under the curve (AUC) of 0.69 (95% CI: 55.0-84.0; p < 0.02), with sensitivity and specificity of 94.0 and 42.0%, respectively. There was a moderate positive correlation between pancreatic and cardiac T2*-weighted MRI (r = 0.4; p < 0.001), and a weak correlation between the pancreas and the liver (r = 0.38; p < 0.005). To conclude, we have introduced a cutoff of 5.6 ms on T2*-weighted MRI of the pancreas for prediction of abnormal glucose metabolism in β-TM patients.

The Feasibility of Magnetic Resonance Imaging for Quantification of Liver, Pancreas, Spleen, Vertebral Bone Marrow, and Renal Cortex R2* and Proton Density Fat Fraction in Transfusion-Related Iron Overload.

Objective:We aimed to evaluate the feasibility of quantification of liver, pancreas, spleen, vertebral bone marrow, and renal cortex R2* and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and to evaluate the correlations among them in patients with transfusion-related iron overload.Materials and Methods:A total of 9 patients (5 boys, 4 girls) who were referred to our clinic with suspicion of hepatic iron overload were included in this study. All patients underwent T1-independent volumetric multi-echo gradient-echo imaging with T2* correction and spectral fat modeling. MRI examinations were performed on a 1.5 T MRI system.Results:All patients had hepatic iron overload. Severe hepatic iron overload was recorded in 5/9 patients (56%), and when we evaluated the PDFF maps of these patients, we observed an extensive patchy artifact in the liver in 4 of 5 patients (R2* greater than 671 Hz). When we performed MRI-PDFF measurements despite these artifacts, we observed artifactual high MRI-PDFF values. There was a close correlation between average pancreas R2* and average pancreas MRI-PDFF (p=0.003, r=0.860). There was a significant correlation between liver R2* and average pancreas R2* (p=0.021, r=0.747), liver R2* and renal cortex R2* (p=0.020, r=0.750), and average pancreas R2* and renal cortex R2* (p=0.003, r=0.858). There was a significant negative correlation between vertebral bone marrow R2* and age (p=0.018, r=-0.759).Conclusion:High iron content of the liver, especially with a T2* value shorter than the first echo time can spoil the efficacy of PDFF calculation. Fat deposition in the pancreas is accompanied by pancreatic iron overload. There is a significant correlation between hepatic siderosis and pancreatic siderosis. Renal cortical and pancreatic siderosis are correlated, too.

Accurate estimate of pancreatic T2* values: how to deal with fat infiltration.

We examined different approaches aimed to deal with the signal fluctuation of pancreatic T2* values due to fat infiltration in order to obtain accurate estimates of iron overload. Pancreatic T2* values were assessed in 20 patients (13 females, 37.24 ± 9.12 years) enrolled in the Myocardial Iron Overload in Thalassemia network without and with the application of fat suppression-FS (T2*-NoFS and T2*-FS). T2* values were assessed in three different ways: (1) from the immediate fit (original T2*); (2) discarding the echoes until the achievement of a good visual concordance between the signal and the model (final_vis T2*); (3) eliminating the echoes until the achievement of a fitting error (known) <5% (final_thres T2*). For the T2*-NoFS sequence the original T2* values were significantly higher than the final_vis T2* values (difference:4.8 ± 6.1 ms; P < 0.0001) and the final_thres T2* values (difference:4.3 ± 6.1 ms; P = 0.006). For the T2*-FS sequence the original T2* values were comparable to final_vis and final_thres T2* values. The original T2*-FS values were significantly different from the original T2*-NoFS values. The final_vis T2*-FS values were comparable to the final_vis T2*-NoFS values and the final_thresh T2*-FS values were comparable to the final_thresh T2*-NoFS values. For both T2*-FS and T2*-NoFS sequences, the final_thres T2* values were not significantly different from the final_vis T2* values and no bias was present. In the clinical practice, an accurate pancreatic iron overload assessment should be done by applying FS and, when needed, by discarding the TEs until the fitting error goes below 5%.