Significant Iron Overload Research Articles

Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload

Osteoporosis is one of the leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin-ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1(-/-)) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1(-/-) mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1(-/-) mice relative to wildtype (WT) mice. Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1(-/-) mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis.

Spatial Repolarization Heterogeneity Detected by Magnetocardiography Correlates with Cardiac Iron Overload and Adverse Cardiac Events in Beta-Thalassemia Major

BackgroundPatients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events.Methods and ResultsFifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values<0.001). Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20) compared to those with normal T2* (all p values<0.001). Loge cardiac T2* correlated with SI-QTc (r = −0.609, p<0.001), SD-QTc (r = −0.572, p<0.001), and QTc dispersion (r = −0.622, p<0.001), while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86), similar to that of cardiac T2*.ConclusionsMultichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events.

Sobrecarga de ferro em adolescente com xerocitose: a importância da ressonância nuclear magnética

ABSTRACTTo report a case of iron overload secondary to xerocytosis, a rare disease in a teenager, diagnosed, by T2* magnetic resonance imaging. We report the case of a symptomatic patient with xerocytosis, a ferritin level of 350ng/mL and a significant cardiac iron overload. She was diagnosed by T2* magnetic resonance imaging and received chelation therapy Ektacytometric analysis confirmed the diagnosis of hereditary xerocytosis. Subsequent T2* magnetic resonance imaging demonstrated complete resolution of the iron overload in various organs, as a new echocardiography revealed a complete resolution of previous cardiac alterations. The patient remains in chelation therapy. Xerocytosis is a rare autosomal dominant genetic disorder characterized by dehydrated stomatocytosis. The patient may present with intense fatigue and iron overload. We suggest the regular use of T2* magnetic resonance imaging for the diagnosis and control of the response to iron chelation in xerocytosis, and we believe it can be used also in other hemolytic anemia requiring transfusions.

Significance of magnetic resonance imaging in the detection of iron overload

To evaluate the significance of magnetic resonance imaging (MRI) T2(*) value analysis in patients with iron overload and compare it with other clinical parameters. A total of 53 patients with suspected iron overload were recruited from four Beijing hospitals from December 2010 to December 2012. Their liver and heart T2(*) values were calculated and their serum ferritin (SF), transferrin saturation, blood transfusion volume and other clinical parameters were recorded and analyzed. There were 37 males and 16 females with a medium age of 50 years(15-72 years). Their etiologies included myelodysplastic syndromes (MDS, n = 25), aplastic anemia (AA, n = 16), myelofibrosis (n = 5), hemochromatosis (n = 2) and β thalassaemia (n = 2), and 3 patients with high SF values were found on regular health examinations. Among them, there were transfusion history (n = 45), SF>1000 µg/L (n = 49), sign of iron overload (n = 10), abnormal liver function (n = 38) and hyperglycemia (n = 32). T2(*) value analysis showed that 10 patients had no evidence of iron overload, 43 patients had liver iron overload (14 mild, 22 moderate and 7 severe) and 2 patients had heart iron overload (1 MDS with heavy transfusion history and 1 AA with heart failure). No relations existed between T2(*) value and SF (P = 0.050) , T2(*) value and transfusion volume (P = 0.820) , and liver T2(*) value and heart T2(*) value (P = 0.129) . MRI T2(*) value is an accurate way of quantitative detection of iron overload. It provides a comprehensive understanding of patients with iron overload in conjunctions with MRI T2(*) value and other clinical parameters.

A Multicenter Study On Hereditary Spherocytosis In Lebanon

Introduction Hereditary spherocytosis (HS), the most common cause of inherited chronic hemolysis in Northern Europe and North America, is characterized by a wide variety of clinical features, ranging from an asymptomatic condition to a fulminant hemolytic anemia. Guidelines regarding the management and diagnosis of HS have been updated in 2012. Few reports exist on HS prevalence and related molecular abnormalities in Mediterranean populations. The prevalence and features of HS in Lebanon have not yet been reported. The aim of this study is to determine demographic, clinical, hematological and therapeutic features as well as outcome of a group of Lebanese patients with HS. Methods This is a retrospective hospital-based surveillance study conducted at 4 centers in Northern Lebanon and Central Beirut. Data was collected from archived files on 31 patients between May 2012 and May 2013 and included patients’ demographics, clinical presentation, diagnostic laboratory tests, treatment modalities and outcome. Analysis was conducted using SPSS 19, and t-test was used to compare two groups. We also conducted an Analysis of Variances where we included demographic variables that were different between the two groups as covariates (ANCOVA) in order to look for group effect. Statistical significance was set at p&lt;0.05. Results Thirty one patients, median age at diagnosis 60 months, age range 11 -.180 months were included in this study. 58.1% and 41.9% were females and males. 54.8% (17/31) had a family history for HS and 32.3% (10/31) had one parent with HS. The predominant clinical manifestations at diagnosis were pallor in 27/31 (87.1%), splenomegaly in 23/31 (74.2%) and anemia in 20/31 (64.5%) patients respectively. The mean size of the spleen at diagnosis was 5.51±2.91 cms below the costal margin. 9.7 % of patients had symptomatic gallstones. The mean hemoglobin, MCV, MCHC and reticulocyte count at time of diagnosis were 8.7 ± 2.1 g/dL, 73.0 ± 9.9 fL/red cell, 34.13±2 g/dl and 6.58±4.2% respectively. 13/17 (68.4%) had spherocytes on baseline blood smear. Osmotic fragility test performed in 27/31 (87.1%) was compatible with diagnosis of HS in 88.24 % patients. HPLC performed in 17/31 (54.8%) showed a mean HbF of 3.82 % and sickle cell trait in 4/17(2,35%) patients. 5/19 (26.3%) had concomitant G6PD deficiency. Folic acid supplementation was provided to patients with moderate to severe disease. 23/31 patients (74.2%) required intermittent or regular blood transfusions and 10/31 patients (32.3%) underwent splenectomy as part of their treatment. All splenectomies were done after 5 years of age except in one patient who had recurrent severe hemolysis necessitating splenectomy at 3 years. There were no correlations between the need for splenectomy with age at diagnosis (p-value 0.97), MCHC level (p-value 0.43) and blood type (p-value 0.17). There was a positive correlation between the need for splenectomy and the need for blood transfusion (r=0.671; p=0.006) and between G6PD status and the need for transfusion (r=0.778; p=0.002). 30/31(96%) patients are alive and doing well while 1 patient died from acute splenic sequestration. Of the 30 surviving patients, 3 (10%) had had a complicated disease course characterized by very severe and early hemolysis in 2 patients and significant iron overload in a third patient. Conclusions This is the first study from Lebanon describing the demographic, clinical, hematological and therapeutic features as well as outcome of patients with HS. Data generated from this study suggest underreporting of the disease and over utilization of the osmotic fragility test underscoring the need to initiate more awareness amongst Lebanese health providers about this disease and its new diagnostic guidelines. Clinical features, therapeutic modalities and excellent patients’ outcome in this Lebanese group appear to be similar to modern published reports. Major limitations of this study include its retrospective design and the small sample size. Prospective studies with long term follow up and enrolling a larger sample size are needed to better assess the utility of newer diagnostic tests and the long term complications associated with splenectomy. Disclosures: No relevant conflicts of interest to declare.

Outcome Of Bone Marrow Transplantation In Lebanese Children With β-Thalassemia Major

AbstractAbstract 5505 IntroductionBone marrow transplantation (BMT) represents the only curative modality for β-Thalassemia Major (β–TM). Best results are achieved in regularly transfused and chelated pediatric patients. Outcome of BMT in 36 Lebanese children who received treatment in the Mediterranean Institute of Hematology (IME) centers in Italy is presented. Methods36 children with β–TM treated at Chronic Care Center, Lebanon underwent BMT from HLA compatible donors in IME centers. Each was assigned a Pesaro risk category and underwent a percutaneous liver biopsy before BMT. Conditioning regimen consisted of busulfan, cyclophosphamide ± Thiotepa and ATG. GvHD prophylaxis included cyclosporine A, methotrexate and prednisolone. Engraftment was evaluated by fluorescence in situ hybridization. Transplant related mortality (TRM) and other complications were calculated as cumulative incidence. Analyses were performed using R software. Results36 hepatitis B and C negative children with β –TM (M/F 1:l), median age 8.5 years, underwent BMT from HLA identical donors. The most common β-globin mutation was homozygous IVS1.110 (39.29%). 20.5%, 55.9% and 23.5% had Pesaro risk class 1, 2 and 3, respectively. Mean injected CD34+ cells, total nucleated cells and CD3+ cells/recipient were 10.9x106/Kg, 8.69x108/Kg and 66.3x106/Kg. Absolute neutrophil count >0.5 x109 and platelet count >20 x 109 were reached in all patients within a mean of +19.44±4 and +19.15 ±6.5 days. Regular chimerism surveillance showed complete engraftment in 35/36 children (97.3%) up till+ 4.2 years median follow up. 1/36 (2.7%) had partial engraftment but continued to be transfusion independent with a mean Hb of 9g/dcl for +1155 days. Immune reconstitution was seen in all patients by + 12 -18 months. At a median follow up of + 6.20 years, 32/36 (89%) of children are alive and transfusion independent. Among those who died (11%), 1 had multi organ failure, 2 had grade 4 acute GvHD and 1 had fulminant interstitial pneumonitis. 47% had acute GvHD which was not correlated with donor relation, conditioning regimen, and pre-BMT hepatomegaly, splenomegaly and transfusion frequency. 8/36 (22%) had grade 2 to 4 acute GvHD of which 75% resolved on treatment while 25% (all grade 4) were fatal. 9/32 (28%) surviving children had chronic GvHD completely resolved on treatment and not correlated with any recipient, donor or treatment feature. Other transplant related complications included CMV reactivation, sepsis, EBV and candida infections, hemorrhagic cystitis, cerebral toxoplasmosis, tuberculosis and transient cyclosporine related renal and neurotoxicity, all completely resolved on treatment. Late effects of transplant were monitored in 27 children. Iron overload data utilizing magnetic resonance imaging at + 3.1 year median follow up showed that mean baseline LIC for 27 patients was 11.3 mg Fe/g dw but ranged as high as 36.6 mg Fe/g dw. Median serum ferritin was 1255 ng/mL, with a maximum of 5884 ng/mL. 9/27 (33.3%) children had significant iron overload defined as SF >2500 ng/ml, or LIC >15 mg Fe/g dw, or T2* <20 msec, levels known to be associated with increased risk of progressive organ dysfunction and death. Median ejection fraction was 68 % (range 58-75%). Up till + 6.20 years median follow up, serum immunoglobulins, alanine and aspartate aminotransferases, BUN, creatinine and creatinine clearance were normal in all 27 children. Hypothyroidism, growth retardation and diffuse persistent vitiligo were seen in 3/25 (12%), 4/25 (16%) and 1/25 (4%) survivors respectively. SummaryOur results reflect an excellent outcome for Lebanese children with β –TM undergoing transplantation. TRM was low and associated complications were transient and manageable. Significant iron overload was, however, noted years after BMT underscoring the need for long term monitoring for iron overload and for iron removal to prevent associated negative outcomes. This study highlights the need for monitoring for late effects for years after transplant. It also demonstrates the effectiveness of international collaboration in facilitating cure for thalassemia in developing countries as Lebanon. Disclosures:No relevant conflicts of interest to declare.

Myocardial Iron overload In Thalassemia Major. how Early To Check?

Introduction It is still controversy in thalassemia major (TM) if Cardiovascular Magnetic Resonance (CMR) T2* screening should be initiated before the 10 years. To answer this question, we studied retrospectively the prevalence of cardiac iron and function and myocardial fibrosis by CMR in a consistent cohort of TM patients younger than 10 years. Methods From the 2171 patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we retrospectively selected the 35 TM patients aged less than 10 years who had undergone at least one MRI scan. Myocardial iron overload (MIO) was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated in a standard way by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired. Results Patients’ age ranged from 4.2 to 9.7 years. All MRI scans were performed without sedation. Nine patients (25.7%) showed no myocardial iron overload (MIO),22 patients (62.9%) showed an heterogeneous MIO with a T2* global value ≥ 20 ms; 2 patients (5.7%) showed an heterogeneous MIO and a T2* global value &lt; 20 ms and 2 patients (5.7%) had a homogeneous MIO. No patients showed myocardial fibrosis. Table 1 reports the data of the 4 patients (3 males and 1 female) with significant myocardial iron overload (global heart T2* &lt; 20 ms). The youngest was 6 years old, all showed no heart dysfunction and in all the iron transfused was less than 35 g. Conclusion The first cardiac T2* assessment should be performed as early as possible without sedation and it is mandatory whenever poor compliance is suspected or if chelation has been started late. The use of the contrast medium to detect myocardial fibrosis can be postponed until after 10 years of age. A more sensitive segmental approach to detected heart iron should be considered. Therapy can be modified on the basis of the MRI results and serious organ damage can be prevented. Disclosures: No relevant conflicts of interest to declare.

CHOP‐mediated hepcidin suppression modulates hepatic iron load

The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron-regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl(4)) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild-type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA-, but not CCl(4) - injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long-lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild-types) displayed significantly attenuated hepcidin down-regulation in response to acute TAA administration. CHOP mRNA levels increased 5-fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease.

Early Identification of Cardiovascular Involvement in Patients With β-Thalassemia Major

The aim of the present study was to evaluate left ventricular myocardial deformation and carotid arterial stiffness using 2-dimensional strain and echo-tracking in patients with asymptomatic β-thalassemia major (β-TM) without significant myocardial iron overload to determine whether early subclinical cardiovascular abnormalities would be detectable. We enrolled 32 patients with β-TM (23 women, mean age 35 ± 8years) and 33 healthy volunteers (20 women, mean age 35 ± 6years). All subjects underwent echocardiography with 2-dimensional strain analysis (XStrain) and ultrasonography of the carotid arteries with measurement of the stiffness parameters (ProSound Alpha 10). Cardiac magnetic resonance imaging using a T2* algorithm (37.7 ± 5.6ms) for the assessment of myocardial iron overload was performed in each patient. The clinical and standard echocardiographic parameters were comparable between the patients and healthy subjects. The global left ventricular longitudinal strain was significantly impaired in the patients compared with the controls (-17.9 ± 3.5% vs-24.3 ± 3.4%, p= 0.002), although the radial and circumferential strain values were similar between the 2 groups (p= NS for both). The carotid intima-media thickness was comparable between the patients and healthy subjects (0.67 ± 0.20mm vs 0.66 ± 0.15mm, p= NS). In contrast, the arterial stiffness was significantly increased in the patients compared with the controls (stiffness index 6.16 ± 1.31 vs 4.65 ± 0.82, p <0.001; arterial compliance 1.10 ± 0.26vs 1.28 ± 0.30cm(2)/mm Hg, p= 0.027; elastic modulus 74.1 ± 19.5vs 59.1 ± 12.1mm Hg, p= 0.001). In conclusion, cardiovascular abnormalities, although often subclinical, occur at an early stage of β-TM and also in the absence of significant iron overload. Thus, 2-dimensional strain and echo-tracking might be more accurate than standard echocardiography and vascular parameters in the early identification of cardiovascular involvement.

Incidence and natural history of pure red cell aplasia in major ABO‐mismatched haematopoietic cell transplantation

Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.

Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines

The current management of thalassemia includes regular transfusion programs and chelation therapy. It is important that physicians be aware that endocrine abnormalities frequently develop mainly in those patients with significant iron overload due to poor compliance to treatment, particularly after the age of 10 years. Since the quality of life of thalassemia patients is a fundamental aim, it is vital to monitor carefully their growth and pubertal development in order to detect abnormalities and to initiate appropriate and early treatment. Abnormalities should be identified and treatment initiated in consultation with a pediatric or an adult endocrinologist and managed accordingly. Appropriate management shall put in consideration many factors such as age, severity of iron overload, presence of chronic liver disease, thrombophilia status, and the presence of psychological problems. All these issues must be discussed by the physician in charge of the patient's care, the endocrinologist and the patient himself. Because any progress in research in the field of early diagnosis and management of growth disorders and endocrine complications in thalassemia should be passed on to and applied adequately to all those suffering from the disease, on the 8 May 2009 in Ferrara, the International Network on Endocrine Complications in Thalassemia (I-CET) was founded in order to transmit the latest information on these disorders to the treating physicians. The I-CET position statement outlined in this document applies to patients with transfusion-dependent thalassemia major to help physicians to anticipate, diagnose, and manage these complications properly.

Iron chelation therapy for a case of transfusion-independent MDS-RARS with significant iron overload

A 60-year-old man was referred to our institution for evaluation of anemia. He had not received medical examination or treatment for years and had no family history of hematological disorders. He used a moderate amount of alcohol daily (75–100 g ethanol per day) for more than a decade. Laboratory examination at the first visit showed white blood cells, 2,900/mm (71 % neutrophils, 20 % lymphocytes, 6 % monocytes, 3 % eosinophils, 1 % basophils); hemoglobin concentration, 7.6 g/dl; platelet count, 301,000/mm, MCV, 106 fl; MCH, 36.2 pg; MCHC, 34.2 %; reticulocyte count, 3.4 %; AST, 60 IU/l; ALT, 84 IU/l; LDH, 225 IU/l; direct bilirubin, 0.15 mg/dl; indirect bilirubin, 2.31 mg/dl; C-reactive protein 0.31 mg/dl; serum iron, 232 lg/dl; UIBC, 16 lg/dl; ferritin, 3,278 ng/ ml; and haptoglobin, 16 mg/dl. Serum concentrations of vitamins B6 and B12 and of folic acid were normal, and HBs antigen, HBs antibody, and HCV antibody were negative. Bone marrow (BM) examination revealed hypercellular marrow (245,000/mm) dominated by erythroblasts with megaloblastic changes. Myeloblasts included 1 % nucleated cells, and there was no apparent myeloid or megakaryocytic dysplasia. On iron staining, most erythroblasts were ringed sideroblasts (Fig. 1a). Chromosomal analysis found normal male karyotype. A tentative diagnosis of refractory anemia with ringed sideroblasts subtype of myelodysplastic syndrome (MDSRARS) was made. Metenolone acetate (10 mg/day) was initiated, but hemoglobin levels did not improve (Fig. 1b). The possibility of X-linked sideroblastic anemia (XLSA), a congenital disorder that is occasionally diagnosed later in life [1], was considered, and pyridoxal phosphate hydrate (90 mg/day) was administered orally, but was ineffective (Fig. 1b). In addition to very high serum ferritin (3.278 ng/ ml) and elevated serum transferrin saturation (93.5 %), mild hepatic dysfunction (AST 60 IU/l, ALT 84 IU/l) and mild hepatosplenomegaly with markedly high density of the liver on CT was observed at presentation (Fig. 1c). Thus, this patient was considered to have iron overload (IO), despite the fact that he had never been transfused, was negative for HCV infection, and had no signs of chronic inflammation. Neither glucose intolerance nor decreased cardiac function was observed. After 1 year from the first visit, despite significant reduction of alcohol intake, serum ferritin levels remained high, and the abnormalities in liver function remained unchanged (Fig. 1b). Considering the possibility that sustained IO in the liver may lead to hepatic cirrhosis and/or hepatocellular carcinoma [2], we initiated administration of an oral iron chelating agent (deferasirox 1,000 mg/day). Serum ferritin decreased steadily, falling to less than 500 ng/ ml in 19 months (Fig. 1b). AST and ALT also normalized, and the density of the liver on CT decreased from 100 to 70 HU. No hematological improvement was observed, either in the peripheral blood (PB) or in the BM. Thus, the clinical picture of this patient consisted of an unusual combination of sideroblastic anemia and clinically H. Ohashi H. Nagai Division of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

Combination Therapy of Deferasirox and Deferoxamine As Paregoric Treatment of Severe Iron Overload in Patients with Thalassemia Major

AbstractAbstract 5181 Background:Despite the recent availability of multiple therapeutic options for chelation therapy, severe iron overload remains a significant cause of morbidity and mortality in a small group of patients with thalassemia major (TM). Every effort to induce negative iron balance for these patients is warranted. In this context, combination of deferasirox (DFX) and deferoxamine (DFO) may be of significant value. In this report, we present the paregoric use of DFX and DFO in severely iron overloaded thalassemic patients. Patients and Methods:Five patients (3 Males, 2 females) have been treated with DFX and DFO as a last rescue measure. In these patients previous combined treatment with DFO and DFP had failed. Informed consent and approval for the use of this schema as paregoric therapy was obtained by patients and hospital. The main inclusion criteria for this treatment were: LIC>30 mg/gr d. w. and T2* cardiac <10 msec. Treatment consisted of daily DFX at 30–40 mg/kg/day and DFO at 40–50 mg/kg/day for 3–6 days/week. Results:Patients' characteristics, results and toxicity are shown in table 1 and 2. Improvement in iron load status ranged widely during a follow-up from 1 to 3 yrs. LIC reduced in 4/5 patients, cardiac T2* increased in 3/5 patients, while LVEF showed no significant changes. Ferritin levels improved in 2/5 patients. Deterioration of safety parameters necessitated not to discontinue treatment. Conclusions:These data in the use of combination therapy of DFX and DFO suggest a potential modality of chelation therapy in severely iron overloaded patients. Response was variable and seemed not to be always related to compliance or the duration of treatment. Increase of serum creatinin and AST in all patients is a considerable problem in patients with persistent significant iron overload and already impaired hepatic and renal function, despite having been treated with different schema of iron chelation. Longer and cautious follow-up is needed to come to reliable conclusions.Table 1EffectivenessMRI - LICMRI - T2* cardiacMRI - LVEFFerritinNo.Start Age/genderComplianceBase1st year2nd year3rd yearChangeBase1st year2nd year3rd yearChangeBase1st year2nd year3rd yearChangeBase1st year2nd year3rd yearChangeyears/m-fmg/gr d.w.%msec%%%ìg/L%132,4/fFair42,55142,533,6−20,965,35,67,22063,464,969,3698,8568281508600770035,5225,5/mFair36,536,525,6−29,82,72.65311,17165,969,1−2,75.40053003500−35,2326,5/mFair42,525,6−39,73,52,6−25,762,660,9−2,7320033003,1429,0/fPoor39,542,542,54411,47,14,23,93,2−54,9606261,11,8110001200012400115505529,47/mPoor42,536,519,711,7−72,544,55810055,455,7847,952,8−4,78500865060003350−60,6Table 2SafetyCreat. Clearance*Serum CreatinineASTNo.BaseMinBaseMaxBaseMaxml/minmg/dlIU/l1118,16116,60,590,651431482101,2194,71,010,9771983165,8774,90,631,326083485,868,80,841,42453175124,1379,90,771,047797*as astimated using the Cockgroft-Gault equation. Disclosures:Ladis:Novartis: Consultancy, Honoraria, Research Funding; Apopharma: Consultancy, Honoraria, Research Funding. Kattamis:Apopharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Identification and characterization of the first SLC11A2 isoform 1a mutation causing a defect in splicing process and an hypomorphic allele expression of the SLC11A2 gene

Identification and characterization of the first <scp>SLC</scp>11<scp>A</scp>2 isoform 1a mutation causing a defect in splicing process and an hypomorphic allele expression of the <i><scp>SLC</scp>11<scp>A</scp>2</i> gene

Iron homeostasis in osteoporosis and its clinical implications

Osteoporosis has until now been considered to be a disease associated with abnormal calcium metabolism. However, an increasing number of clinical observations strongly suggest the association of iron overload with bone diseases, particularly in osteoporosis in menopausal women. The recent identification of hepcidin sheds new light into the crucial role of iron homeostasis in bone metabolism. Decreasing iron overload in cell studies as well as in animal experiments has been shown to improve bone cell metabolism and growth in vitro and in vivo. In view of the significant iron overload found in the aging population, especially in females, the therapeutic potential of lowering iron overload for the treatment of osteoporosis is suggested.

Congenital dyserythropoietic anaemia and pregnancy

A 26 year-old primigravida booked with a known diagnosis of congenital dyserythropoietic anaemia type I (CDA I). This rare (less than 1 in 100 000 births) autosomal recessive red cell...

A Chinese family carrying novel mutations in SEC23B and HFE2, the genes responsible for congenital dyserythropoietic anaemia II (CDA II) and primary iron overload, respectively

A Chinese family carrying novel mutations in <scp><i>SEC23B</i></scp> and <scp><i>HFE2</i></scp>, the genes responsible for congenital dyserythropoietic anaemia <scp>II</scp> (<scp>CDA II</scp>) and primary iron overload, respectively

IronXS: high-school screening for hereditary haemochromatosis is acceptable and feasible

As the results of the Human Genome Project are realised, screening for genetic mutations that predispose to preventable disease is becoming increasingly possible. How and where such screening should best be offered are critical, unanswered questions. This study aimed to assess the acceptability and feasibility of genetic screening for preventable disease, using the model of hereditary haemochromatosis, in high-school students. Screening was offered for the HFE C282Y substitution to 17,638 students. Questionnaires were administered at the time of screening (Q1) and approximately 1 month after results were communicated (Q2). Outcomes assessed were uptake of screening, change in scores of validated anxiety, affect and health perception scales from Q1 to Q2, knowledge and iron indices in C282Y homozygous individuals. A total of 5757 (32.6%) students had screening and 28 C282Y-homozygous individuals (1 in 206) were identified, and none of the 27 individuals who had iron indices measures had significant iron overload. There was no significant change in measures of anxiety, affect or health perception in C282Y homozygous or non-homozygous individuals. Over 86% of students answered each of five knowledge questions correctly at Q1. Genetic population-based screening for a preventable disease can be offered in schools in a way that results in minimal morbidity for those identified at high risk of disease. The results of this study are not only relevant for haemochromatosis, but for other genetic markers of preventable disease such as those for cardiovascular disease and cancer.

Molecular Characterization of Hemoglobinopathies and Red Cell Enzymopathies in the Czech and Slovak Populations: An Update

Abstract 5307 Background:Thalassemias are rare disorders in Middle Europe. However, as a result of historical and recent migration, thalassemias became common cause of congenital anemia in the Czech and Slovak populations. Abnormal hemoglobin variants and red-cell enzymopathies are rare cause of congenital anemia in this region.The aim of this work was to update the original reports of this research published almost two decades ago (Indrak et al., Hum Genet 1992; 88:399–404, Xu et al., Blood 1995; 85:257–63, Lenzner et al., Blood 1997; 89:1793–9). We assessed the frequency and spectrum of β-globin gene mutations in the patients with clinical symptoms of β-thalassemia or δ,β-thalassemia, the α-globin gene status in the patients with clinical symptoms of α-thalassemia, and we characterized red cell enzymopathies on molecular level in the Czech and Slovak populations. Patients and methods:Nearly 390 cases with clinical symptoms of thalassemia or hereditary nonspherocytic hemolytic anemia from several centers of Czech and Slovak Republic were analyzed. Hematological parameters, hemoglobin electrophoresis and enzyme activities were measured by standard procedures. Genomic DNA was used for PCR-sequencing analysis. Results:We identified 22 β-thalassemia mutations in more than 260 heterozygotes; most of the mutations were of Mediterranean origin. The newly discovered insertion of transposable element L1 into the HBB gene represents a novel etiology of β-thalassemia due to a silencing effect of repressive chromatin associated with retrotransposon insertion. The list of abnormal hemoglobins now contains 14 β-globin variants, involving Heinz body hemolytic anemia variant Hb Hana (β63(E7) His-Asn), phenotype of which was worsened by concomitant partial glutathione reductase deficiency (Mojzikova et al., Blood Cells Mol Dis 2010; 45:219–22).Several G6PD and PK variants were described in the Czech and Slovak populations; the G6PD variants include G6PD Olomouc, G6PD Varnsdorf and G6PD Praha. Recently, we identified a new frameshift mutation c. 1553delG (p. Arg518fs) at the homozygous state in exon 11 of the PKLR gene of the pediatric patient who suffered from transfusion dependent hemolytic anemia with Hb=9.4 g/dL, Ret=4.5%. His red cells PK activity was 4.52 IU/gHb (normal range 13–17 IU/gHb). The mutation occurs in C domain of PK-R subunit containing the binding site for fructose-1,6-bisphosphate. The patient’s extremely elevated level of growth differentiation factor 15 (GDF15, 3577 pg/mL, healthy controls 231–345 pg/mL) could explain hereditary hemochromatosis and signs of iron overload in this patient. Conclusions:In the Czech and Slovak populations, hemoglobinopathies and red-cell enzymopathies appear to be an uncommon disorder, which, however, must be considered as the prevailing cause of congenital anemia. Most of the thalassemia patients were heterozygous, manifesting thalassemia minor. Most of the hemoglobin variants were described in single families, some of them originated locally. Among hemolytic anemias due to red-cell enzymopathies is the most frequent PK deficiency.This work was supported by grants NT11208, NS10281 (Ministry of Health Czech Republic), MSM6198959205 (Ministry of Education, Youth and Sports) and student projects LF_2011_006 and LF_2011_011 of the Palacky University. Disclosures:No relevant conflicts of interest to declare.

Liver and Cardiac Iron Measurements in Very Young Chronically Transfused Patients Show Dangerous Levels of Iron Loading

Abstract 1086Recurrent blood transfusion results in significant iron overload that can cause serious organ damage and death if not properly treated. Liver iron concentration (LIC) is the best indicator of total body iron status and can be measured non-invasively by magnetic resonance imaging (MRI). In the past, it was recommended that LIC assessments by liver biopsy begin after about 6 years of age (yo). MRI is also an excellent way to monitor iron cardiomyopathy, which remains a major cause of death in chronically transfused patients. To understand how rapidly iron overload develops, we reviewed the 1316 MRI iron studies we have performed since 2002 and summarized the LIC and cardiac R2* in a subset of 127 subjects who had their first MRI studies before 10 yo.Because of the known serious pitfalls in the assessment of total body iron by measurement of ferritin, LIC is measured by MRI in our center as standard of care in all patients on chronic transfusion soon after the start of iron chelation therapy. Most children less than 6 years of age require general anesthesia for this procedure. In some older children cooperation can be achieved by distraction techniques. Thirty three percent had sickle cell disease (SCD), 33% thalassemia major (TM), 11% Blackfan Diamond anemia (DBA), 3% congenital dyserythropoietic anemia (CDA), and 8.6% had other transfusion dependent anemias (OTRAN) and 11.4% had studies done not related to transfusion. This paper will focus on the 114 subjects whose MRI was done to evaluate transfusion related iron overload. The median age at first MRI was 6 years with 25% having their first study before 3.7and 10% before 2.1 yo. The median LIC was 9.8 mg/g dry weight (dw) and 10% of subjects had a first LIC > 22 mg/g dw. Only 2.5% had evidence of cardiac iron (T2* < 20ms). The median LICs (mg/g dw) were 8.9 for SCD, 11.8 for TM, 13 for DBA, 6.1 for CDA, and 8.7 OTRAN and were not statistically different. The minima ranged from 0.6 in OTRAN to 4.2 for CDA and the maxima ranged from 25 in CDA to 39.7 for SCD. There was significant iron loading even when we restricted the analysis to 27 subjects with a first MRI at < 3.5 yo; SCD (2.3 median (med), 2.8 maximum (max)), TM (14.6 med, 35 max), DBA (13 med, 15 max),CDA (6.6 med, 25 max) and OTRAN (5.8 med, 11 max). There were 4 subjects who had evidence of cardiac iron loading. Two had DBA with T2* of 18 ms and 16 ms at 2.5 and 3.7 years of age respectively. A third DBA subject had a T2* of 20 ms at only 4.6 yo. Two TM subjects had a T2* of 15 ms at 6.6 and 9.1 yo respectively.These data indicate that there is significant elevation in LIC by the age of 3.5 years with a median LIC of 11 mg/g dw and 25% of subjects having a LIC > 15 mg/g dw. These are very high levels of iron loading. Furthermore, 2.5% of subjects in this age already have evidence of cardiac iron loading.On the basis of such findings, direct measurement of liver iron by MRI is essential as soon as possible after the start of regular transfusions and cardiac iron should be measured early in high risk children with Diamond Blackfan anemia and thalassemia major. Disclosures:Berdoukas:ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coates:Novartis Inc: Speakers Bureau.