Iron Overload In Patients Research Articles

Genotype in Patients with Thalassemia Major Has No Impact on Risk of Liver Fibrosis

Introduction and Objectives: Patients with Thalassemia Major (TM) develop various complications related to iron overload and transfusion associated infections. It is unknown as yet if the specific genotype leading to TM has further impact on the development of liver fibrosis. Therefore, we planned to assess the impact of genotypes in patients with TM on the risk of liver fibrosis.Methods: We included 88 patients with TM with available genotyping data in this study. These patients were followed and transfused in a single tertiary academic center. All those patients had their liver fibrosis assessed by ultrasound elastography (FibroScan device) with a cut off value of 7.8 kPa. The genotyping was done using Amplification Refractory Mutation System (ARMS)-hot start-polymerase chain reaction (PCR) technique. Iron overload was assessed using the average serum ferritin in the 5 years prior to the liver fibrosis assessment. Association was assessed using Chi-squared test and adjustment using multivariable logistic regression.Results: A total of 88 patients were included with a median age of 27 years (Interquartile range [IQR]: 23-31). Females constituted 54% of patients and 34% of patients were splenectomised. The median alanine transaminase, aspartate transaminase, albumin and total bilirubin were 31 U/L (IQR: 20-58), 30 U/L (IQR: 18-46), 46 g/L (IQR: 43-48) and 23 µmol/L (IQR: 15-34) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1472 µg/L (IQR: 741-2760) and 7.0 mg/gdw (IQR: 3.5-15.9) respectively. Thirty seven percent of patients had positive serology for HCV while 1% of patients had positive serology for HBV. The genotypes seen in this study included homozygous IVS-I, 5 (G-C) in 39 patients, homozygous codon 44 (-C) in 19 patients, double heterozygous IVS-I, 5 (G-C)/25 bp deletion in 5 patients and others (≤ 3 patients each) in 25 patients. The proportion of patients with fibrosis was 55%. The proportion of patients with fibrosis in the homozygous IVS-I, 5 (G-C) group was 58% compared to 52% in all other genotypes and the difference was not statistically significant (odds ratio of 1.3 with a p value of 0.6652). The impact of the genotype remained non-significant after adjustment of iron overload in the multivariable logistic regression model. The only statistically significant factor was the iron overload (p values: iron overload 0.006, genotype 0.966).Conclusion: The risk of liver fibrosis is associated with the iron overload in patients with TM. There is no additional independent impact of the genotype. Further studies with larger sample size to study the impact of various genotypes are required to confirm these results. DisclosuresNo relevant conflicts of interest to declare.

The Safety and Efficacy of Deferasirox for the Transplant Patients with Iron Overload

Introduction: Iron overload in patients who received hematopoietic cell transplantation (HCT) is one of the major clinical issues. Although deferasirox is well known to be an iron chelating agent, its safety for the patients who received HCT is unknown. Then, we designed a multicenter prospective study (phase 1) to evaluate the safety and efficacy of deferasirox in patients with iron overload after HCT.Methods: The eligibility criteria includes the duration at least 6 month after HCT, serum ferritin more than 1,000 ng/ml, red blood cell (RBC) transfusions more than 20 units, disease remission, normal renal function, performance status of 0 or 1, and the unfit of phlebotomy. The exclusion criteria were history of iron chelating therapy after HCT, presence of moderate or severe chronic graft-versus-host disease (GVHD), uncontrollable complications, and the history of hepatitis B or C virus infection. A registration target was set at 20 patients including 5 ineligibles. Safety of deferasirox was assessed by the dose escalation methods in the individual. After the registration, deferasirox was started at a dose of 5 mg/kg for four weeks. Then, the dose was increased to 7.5 mg/kg and 10 mg/kg. The patient attended every two weeks for the safety evaluation. Cessation criteria were any grade 2 to 4 of adverse event or early disease relapse. Namely, 4 weeks medication within grade 1 of adverse events was defined as tolerable and successful medication for the identical dose. Primary endpoint was the maximum tolerate dose of deferasirox and defined from the dose in which 50 to 80% of the eligible patients were tolerable.Results: A total of 16 patients were enrolled to the study from March 2013 to January 2016. One case was excluded out of analysis due to the early relapse and 15 were eligible. Median age was 42 years old (range: 22-68). Disease included acute myeloid leukemia (n=6), acute lymphoblastic leukemia (n=2), aplastic anemia (n=2), non-Hodgkin's lymphoma (n=2), and others (n=3). Median duration from HCT to deferasirox administration was 9 months (range: 6-84). Median amount of RBC transfusions was 54 units (range: 20-156). Median value of serum ferritin was 1,537 ng/ml (range: 1,027-7,655). Regarding to the dose escalation test, 9 cases succeeded in taking from the initial 5mg/kg to the final 10mg/kg and 6 resulted in withdrawal during the treatment: abnormality of clinical test in 5 mg/kg (n=3), late relapse in 7.5 mg/kg (n=1), self-cessation and gastrointestinal event in 10 mg/kg (n=2). Achievement rates of successful medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in10 mg/kg (9 of 15), respectively. Among 10 evaluable cases, mean value of ferritin decreased from 1,605 ng/ml at pre-treatment to 1,303 ng/ml at post-treatment. The change of other markers were as follows: hemoglobin from 12.0 g/dl to 12.6 g/dl, aspartate aminotransferase (AST) from 24.9 IU/L to 28.3 IU/L, alanine aminotransferase (ALT) from 25.8 IU/L to 28.4 IU/L, creatinine (Cr) from 0.80 mg/dl to 1.05 mg/dl. Liver iron content (LIC) was examined only in 3 cases and the mean LIC was did not change before and after the treatment at 200 μmol/g. Main of grade 1 of adverse events were elevation of clinical test including Cr (60%), AST (40%), ALT (40%), and alkaline phosphatase (33%), diarrhea (27%), abdominal pain (20%), skin rash (20%), constipation (20%), nausea (13%). None of the patients developed the exacerbation of GVHD.Conclusion: This dose escalating method of deferasirox treatment for transplant patients may be feasible. Ten mg/kg of deferasirox may be maximum tolerated dose when given after HCT. The efficacy of iron chelation would be inadequate due to the low dose and short term of deferasirox. Validation of phase 2 study is warrant. DisclosuresMorita:Bristol-Myers Squibb: Speakers Bureau. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding. Okamoto:Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Selective Death of Leukemia Initiating Cells Induced By Deferasirox

Despite high remission rate after therapy, only 30-40% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. The main cause of treatment failure is thought to be insufficient eradication of leukemia initiating cells (LIC). Identifying drugs that can efficiently eradicate LICs is therefore imperative. HIF1α is essential for LIC maintenance and targeting HIF1α selectively eliminates LIC. Deferasirox is an iron chelator used to reduce chronic iron overload in patients receiving long-term blood transfusions. Our aim is to study the ability ofdeferasirox to induce apoptosis and to target HIF1α in AML LICs.CD34+CD38- LIC-like cells, sorted from the KG1a cell line, exhibited increased sensitivity to deferasirox with an IC50 of 1.3μM compared to 8.9μM calculated for the more mature CD34+CD38+ cells. The LIC-like cells, which were more sensitive to deferasirox, were less sensitive to ARA-C compared to the CD34+CD38+ cells. Deferasirox was >2-fold more efficient in inducing apoptosis in the CD34+CD38− cells, compared to the CD34+CD38+ cells (74±7.2% & 32±6.2% apoptosis, respectively). Deferasirox demonstrated a synergistic cytotoxic effect with ARA-C on both the CD34+CD38− and CD34+CD38+ KG1a cell fractions. Similar results were observed with CD34+CD38-CD123+ LICs and CD34+CD38+ CD123+ progenitor cells isolated from AML patients. As shown with the cell line, AML patient LICs were 2-fold more sensitive to deferasirox treatment showing a 62±15% induction of cell death compared to only a 34±9% induction in leukemic progenitor cell death (p<0.01). The increase in cell death was accompanied by an increment of reactive oxygen species (ROS) levels which was more prominent in the LICs compared to the progenitor cells. Furthermore, deferasirox enhanced the cytotoxic effects of ARA-C on both the LSCs and the leukemic progenitor cells. These data indicate that deferasirox is highly cytotoxic to AML cells; however, it is significantly more specific to AML initiating cells. In addition, deferasirox exhibited significant inhibitory effect on the proliferation of both the CD34+CD38− and CD34+CD38+ KG1a cell fractions accompanying by an S-phase arrest. The inhibition of proliferation was also demonstrated using proliferation dye and colony assay on both the LIC-like cells and the LICs isolated from AML patient (p<0.001). Since deferasirox is an NFkB inhibitor which regulates HIF1α levels, and since HIF1α is selectively activated in AML stem cells and is essential for maintenance of these cells, we studied the effect of deferasirox on this pathway. We found that NFkB translocation to the nucleus was reduced by over 80% and as a result the binding of NFkB to the HIF1α promoter was decreased in the LIC-like cells treated with deferasirox. HIF1α was downregulated transcriptionally (~45% reduction) and translationally (~55% reduction) in the LIC-like cells while it was upregulated in the CD34+CD38+KG1a cells following deferasirox treatment. In order to understand which of deferasirox’s properties is crucial for its apoptotic effect, we used the iron chelator, deferipron, which does not effect on NFkB or HIF1α and siHIF1α. Each one of these treatments alone did not lead to an apoptotic effect in LIC-like cells or in the CD34+CD38+ kg1a cells. Conversely, the combination of the two lead to an increase in apoptosis in the LIC-like cells suggesting that only a combination of iron chelation and HIF1α reduction is sufficient to result in an apoptotic response. The apoptotic effect wasn’t observed in the CD34+CD38+ fraction. These data hint that AML-LICs are selectively targeted by deferasirox.We describe a novel and unique anti-LIC property of deferasirox, which was originally developed as an iron chelator. We found clinically relevant concentrations of deferasirox to be cytotoxic in vitro to AML progenitor cells but even more potent against LICs. We believe that deferasirox exerts its cytotoxic effect, at least in part, by downregulating HIF1α levels in the LIC population. Pending further characterization, deferasirox can be considered as a potential therapeutic agent for eradicating LICs. DisclosuresNo relevant conflicts of interest to declare.

Male Gender Increases the Risk of Liver Fibrosis in Patients with Thalassemia Major Independent of Iron Overload

Introduction and Objectives: Iron overload in patients with Thalassemia Major (TM) leads to various complications including liver fibrosis. The independent impact of gender on this risk has been previously investigated but not yet confirmed. We, therefore, planned to assess the independent impact of gender in patients with TM on the risk of liver fibrosis.Methods: We included 96 patients with TM followed and transfused in one academic tertiary hospital. Patients underwent assessment of liver fibrosis using ultrasound elastography (FibroScan device) with a cut off value of 7.8 kPa. The mean ferritin in the 5 years prior to elastography assessment was used to represent iron overload. Association was tested using Chi-squared and the independent impact of gender was confirmed in the multivariable logistic regression with a model that included mean ferritin and gender.Results: The median age of the 96 included patients was 26 years (Interquartile range [IQR]: 22-30). Males constituted 45% of patients and 33% of patients were splenectomised. The median alanine transaminase, aspartate transaminase, albumin and total bilirubin were 30 U/L (IQR: 18-64), 30 U/L (IQR: 18-46), 46 g/L (IQR: 44-48) and 21 µmol/L (IQR: 14-32) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1293 µg/L (IQR: 753-2715) and 6.7 mg/gdw (IQR: 3.5-16.1) respectively. Thirty seven percent of patients had positive serology for HCV while 1% of patients had positive serology for HBV. The proportion of patients with fibrosis as assessed by elastography was 59%. The proportion of male patients with fibrosis was 70% compared to 51% in female patients with a trend towards statistical significance (odds ratio [OR] of 2.2 with a p value of 0.094). In the multivariable logistic regression model, both gender (OR of 3.0, P value of 0.0188) and ferritin (OR of 1.0004, p value of 0.0036) were statistically significant independent predictors of liver fibrosis.Conclusion: Male gender increases the risk of liver fibrosis independent from iron overload. Our study confirms the previously suspected but unproven association. Follow up and therapy may be tailored to include gender as a decision factor. Larger studies are needed to further confirm these results. DisclosuresNo relevant conflicts of interest to declare.

Iron overload patients with unknown etiology from national survey in Japan.

Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

The ICET-A Recommendations for the Diagnosis and Management of Disturbances of Glucose Homeostasis in Thalassemia Major Patients.

Iron overload in patients with thalassemia major (TM) affects glucose regulation and is mediated by several mechanisms. The pathogenesis of glycaemic abnormalities in TM is complex and multifactorial. It has been predominantly attributed to a combination of reduced insulin secretory capacity and insulin resistance. The exact mechanisms responsible for progression from norm glycaemia to overt diabetes in these patients are still poorly understood but are attributed mainly to insulin deficiency resulting from the toxic effects of iron deposited in the pancreas and insulin resistance. A group of endocrinologists, haematologists and paediatricians, members of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) convened to formulate recommendations for the diagnosis and management of abnormalities of glucose homeostasis in thalassemia major patients on the basis of available evidence from clinical and laboratory data and consensus practice. The results of their work and discussions are described in this article.

Study of abnormal iron metabolism parameters and iron overload in patients with myelodysplastic syndromes

目的研究骨髓增生异常综合征(MDS)患者铁代谢参数和临床特征。方法对2015年6月至2016年3月间初诊未经祛铁治疗的94例MDS患者的铁代谢参数和临床特征进行回顾性调查。结果94例初治MDS患者中，71例(75.53%)贫血，56例(59.57%)存在输血依赖，52例(55.32%)存在铁过载。IPSS低危／中危-1较中危-2/高危铁过载多见(P<0.01)。铁过载组和非铁过载组比较，血清铁(SI)升高[36.5(8.5~64.7)µmol/L对25.2(3.7~45.3)µmol/L，P<0.01]，转铁蛋白饱和度(TSAT)降低[43.5%(12.2%~77.2%)对53.4%(14.8%~97.5%)，P<0.01]，不稳定细胞铁(LCI)及细胞内活性氧簇(ROS)差异无统计学意义。靶器官(心、肝、胰岛等)功能临床资料比较中，铁过载组ALT及B型钠尿肽前体分别为25(3~158)U/L及190(6~4 281)ng/L，均明显高于非铁过载组的16(5~80)U/L及84(12~2 275)ng/L(P=0.03及P=0.05)。难治性贫血伴环状铁粒幼红细胞(RARS)患者与非RARS患者铁代谢参数差异均无统计学意义(P>0.05)，输血依赖程度和输血量显著影响SI、TSAT及SF(P值均<0.01)，但LCI及ROS组间差异无统计学意义。无输血依赖、非铁过载的38例患者中，骨髓红系病态造血、幼红细胞比例增高组LCI水平显著增高。结论初治MDS患者贫血及输血依赖现象较为常见，输血频率和输血量显著影响铁代谢参数。而无输血依赖的非铁过载患者骨髓红系病态造血、幼红细胞比例增高影响LCI水平，LCI可以作为衡量铁过载和铁分布重要的早期指标。

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo.

BackgroundIron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer.MethodsThe effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts.ResultsDFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm3 for controls vs. 327 mm3 for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm3 for controls vs. 274 mm3 for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX.ConclusionsDFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling.

Room-temperature susceptometry detects mostly hepatocyte iron in iron overload patients

Room-temperature susceptometry detects mostly hepatocyte iron in iron overload patients

Correlation between liver iron concentration determined by magnetic resonance imaging and serum ferritin in adolescents with thalassaemia disease

Background:MRI imaging is an alternative to serum ferritin for assessing iron overload in patients with thalassaemia disease.Aims:To correlate liver iron concentration (LIC) determined by MRI and clinical and biochemical parameters.Methods:An MRI study using cardiovascular magnetic resonance (CMR) tools to determine cardiac and liver iron was undertaken in adolescents with thalassaemia disease.Results:Eighty-nine patients (48 males) with thalassaemia disease were enrolled. Seventy patients had been transfusion-dependent since a mean (SD) age of 3.8 (3.0) years, and 19 patients were not transfusiondependent. Mean (SD) haematocrit was 27.3 (2.9)%. Twenty-eight patients were splenectomized. Mean (SD) serum ferritin was 1673 (1506) μg/L. All transfusion-dependent patients received iron chelation at the mean (SD) age of 8.4 (3.5) years with either monotherapy of desferrioxamine, deferiprone, deferasirox or combined therapy of desferrioxamine and deferiprone, while only 5 of 19 patients who were not transfusion-dependent received oral chelation. The 89 patients underwent an MRI scan at the mean (SD) age of 14.8 (3.2) years. No patients had myocardial iron overload, but nine had severe liver iron overload, 27 had moderate liver iron overload, and 36 had mild liver iron overload. A significant correlation between liver T2* and serum ferritin was expressed as the equation: T2* (ms) = 28.080–7.629 log ferritin (μg/L) (r2 0.424, P = 0.0001). Patients with serum ferritin of >1000 to >2500 μg/L risked moderate and severe liver iron loading with the odds ratio ranging from 6.8 to 13.3 (95% CI 2.5–50.8).Conclusion:In thalassaemia, MRI is an alternative means of assessing iron stores, but when it is not available serum ferritin can be used to estimate liver T2*.

Haemochromatosis and gastrointestinal cancer.

Iron overload in patients with haemochromatosis is a strong risk factor for liver cancer, but its influence on other gastrointestinal cancer risk is unclear. The aim was to assess the relative risk of luminal gastrointestinal cancer among patients diagnosed with haemochromatosis. This population-based, nationwide Swedish cohort study included patients with haemochromatosis in Sweden in 1965-2013. The incidence of gastrointestinal cancers was assessed through the Swedish Cancer Registry. The measure of relative risk was the standardised incidence ratio (SIR) with 95% confidence interval (CI), that is, the ratio of the observed number of gastrointestinal cancers in the haemochromatosis cohort divided by the expected number of such cancers, calculated from the entire corresponding background population of Sweden. Among 6,849 patients in the haemochromatosis cohort with up to 48 years of follow-up, the SIRs were 3-fold increased for oesophageal squamous cell carcinoma (SIR = 3.2, 95% CI 1.3-6.6; n = 7) and 40% increased for colon adenocarcinoma (SIR = 1.4, 95% CI 1.1-1.9; n = 54). No associations were found between haemochromatosis and the risk of adenocarcinoma of the oesophagus (SIR = 0.5, 95% CI 0.0-2.5; n = 1), stomach (SIR = 0.7, 95% CI 0.3-1.4; n = 8), small bowel (SIR = 1.2, 95% CI 0.0-6.7; n = 1) or rectum (SIR = 1.0, 95% CI 0.6-1.6; n = 21). These findings indicate that haemochromatosis increases the risk of oesophageal squamous cell carcinoma and colon adenocarcinoma, but might not influence the risk of other types of luminal gastrointestinal cancer. These findings should encourage further research examining the role of iron overload in cancer aetiology.

Clinical and methodological factors affecting non-transferrin-bound iron values using a novel fluorescent bead assay

Nontransferrin-bound iron (NTBI) is a heterogeneously speciated plasma iron, typically detectable when transferrin saturation (TfSat) exceeds 75%. Here, we examine factors affecting NTBI levels by a recently discovered direct chelator-based (CP851) fluorescent bead-linked flow-cytometric assay (bead-NTBI), compared with the established indirect nitrilotriacetate (NTA) assay in 122 iron-overloaded patients, including 64 on recent iron chelation therapy and 13 healthy volunteers. Both methods correlated (r = 0.57, P < 0.0001) but with low agreement, attributable to 2 major factors: (1) the NTA method, unlike the bead method, is highly dependent on TfSat, with NTBI under-estimation at low TfSat and over-estimation once Tf is saturated, (2) the bead method detects <3-fold higher values than the NTA assay in patients on recent deferiprone-containing chelation due to greater detection of chelate complexes but lower values for patients on deferasirox. The optimal timing of sample collection relative to chelation dosing requires further study. Patients with splenectomy, high-storage iron, and increased erythropoiesis had greater discrepancy between assays, consistent with differential access by both methods to the NTBI pools associated with these clinical variables. The bead-NTBI assay has advantages over the NTA assay, being less dependent on TfSat, hence of less tendency for false-negative or false-positive values at low and high TfSat, respectively.

The Effects of Nutrition, Exercise, and a Praying Program on Reducing Iron Overload in Patients With Beta-Thalassemia Major: A Randomized Clinical Trial.

BackgroundExcessive iron accumulation in the visceral organs creates problems for patients with beta-thalassemia major. Despite chelation therapy, mortality rate from the complications of this disease is still quite high.ObjectivesThis study aimed to investigate the effectiveness of nutrition, exercise, and a praying program at reducing iron overload in patients with beta-thalassemia major.Patients and MethodsThis randomized clinical trial assessed the effect of the designed care program on iron overload. The study was conducted in 38 patients with beta-thalassemia major who ranged in age from 15 - 35 years and had been referred to the largest center for thalassemic patients in Shiraz. The patients were randomly assigned to an intervention (n = 18) and a control (n = 20) group. Blood samples were collected from the participants before and two months after the intervention. Then, the data were statistically analyzed using chi-square, Fisher’s exact test, Mann-Whitney U-test, Wilcoxon, independent samples t-test, and paired samples t-test.ResultsThe results showed that the mean level of serum ferritin significantly decreased in the intervention group two months after beginning the intervention. Also, the mean level of serum iron decreased in the intervention group, but the difference was not statistically significant.ConclusionsThe planned educational program could be used to reduce iron overload and ultimately improve the patients’ health status.

Effect of Combined versus Monotherapy with Deferoxamine and Deferiprone in Iron Overloaded Thalassemia Patients: a Randomized Clinical Trial

Background: Patients with transfusional iron overload have depended on iron chelation therapy and improving chelation regimens have been of the highest priority. The aim of this study was to compare effect of combined versus monotherapy with Deferoxamine (DFO) and Deferiprone (DFP) in iron overloaded beta thalassemia (BT) major patients Materials and Methods We studied 36 BT major patients (mean age 7.6±4.6; range 3–16 years) attending the Ormieh Motahari hospital for regular transfusional support. Patients were randomly allocated to receive one of the following two treatments: DFO in combination with DFP (n=12), DFO alone (n=12) and DFP alone (n=12). Serum ferritin level, liver enzymes, blood urea nitrogen, and creatinine and side effects were monitored over a 12 months period. Results: After one year, serum ferritin decreased more significantly in patients on DFO+DFP therapy compared to patients who only received DFO or DFP alone (P<0.01). Side effects of DFP, including gastrointestinal upset (nausea, vomiting and abdominal pain) and mild agranulocytosis occurred in five (41.7%) and two (8.3%) patients, respectively but none led to discontinuation of the treatment. Conclusion: In comparison to the standard chelation monotherapy of DFO, combination treatment with additional DFP reduced serum ferritin and is effective procedure in clinical management of iron overload in patients with BT major.

Study of Hepcidin Level in Samples of Iraqi Patients With Iron Overload and Iron Deficiency Disorders

Hepcidin, a regulator of iron recycling and absorption, is a small peptide created by the hepatocytes when there is an increase in body iron and inflammation. It is regarded as a master regulator for the metabolism of iron. Hepcidin decreases iron absorption from food by decreasing the transportation of iron across the enterocytes in the gut mucosa. Hepcidin decreases iron escape from macrophages, which are considered as the main site for storage of iron and decreases iron escape from the liver.&#x0D; The aim of the study is to determine the properties of hepcidin as a diagnostic test of iron deficiency and to focus on its properties as a diagnostic test in iron overload.&#x0D; Thirty-four patients with iron deficiency anemia (IDA) and thirty patients with beta - thalassemia major were collected randomly from the National center of Hematology and from thalassemia center in Al-Karama Hospital respectively. Together with thirty age and sex matched healthy volunteers were collected as a control.History was taken and physical examination was done. Blood samples were taken; hematological parameters were estimated for all three groups.&#x0D; High hepcidin level was detected in 30 out of 34 patients with iron deficiency anemia with a mean range of (205.3 ng/ml). High hepcidin level is due to inflammatory conditions. In four patients with iron deficiency anemia, hepcidin levels were low and this is due to anemia and hypoxia. These stimulations decrease hepcidin production. In 30 patients with iron overload, hepcidin concentration was of low level with a mean range of (6.7 ng/ml) and this is due to stress erythropoiesis.&#x0D; These results suggest that serum hepcidin in iron deficiency anemia patients is high in spite of that the patients were not receiving iron supplement while in iron overload (IOL) patients serum hepcidin level is low mainly because of stress erythropoiesis due to their poor management.

Role of Three-Dimensional Speckle Tracking Echocardiography in the Quantification of Myocardial Iron Overload in Patients with Beta-Thalassemia Major.

The new three-dimensional speckle tracking echocardiography (3DSTE) may enable comprehensive quantification of global left ventricular (LV) myocardial mechanics. Twenty-four patients aged 29.3 ± 5.2 years and 22 controls were studied. 3DSTE was performed to assess LV 3D global strain, twist and torsion, ejection fraction, and systolic dyssynchrony index (SDI). The LV SDI was calculated as % of SD of times-to-peak strain of 16 segments/RR interval. The global performance index (GPI) was calculated as (global 3D strain·torsion)/SDI. Area under the receiver operating characteristic curve (AUC) was calculated to determine the capability of 3DSTE parameters to discriminate between patients with (cardiac magnetic resonance T2* <20 ms) and those without myocardial iron overload. Compared with controls, patients had significantly lower LV global 3D strain (P < 0.001), twist (P = 0.01), torsion (P = 0.04), and ejection fraction (P < 0.001) and greater SDI (P < 0.001). The GPI was lower in patients than controls (P < 0.001). T2* value correlated positively with global 3D strain (r = 0.74, P < 0.001) and GPI (r = 0.63, P = 0.001), and negatively with SDI (r = -0.44, P = 0.03). The AUCs of GPI, global 3D strain, ejection fraction, torsion, and 1/SDI were 0.94, 0.90, 0.87, 0.82, and 0.70, respectively. The GPI cutoff of 2.7°/cm had a sensitivity of 94.9% and a specificity of 88.9% of differentiating patients with from those without myocardial iron overload. The LV composite index of strain, torsion, and dyssynchrony derived from 3DSTE enables sensitive detection of myocardial iron overload in patients with thalassemia.

In vivo behavior of NTBI revealed by automated quantification system.

Non-Tf-bound iron (NTBI), which appears in serum in iron overload, is thought to contribute to organ damage; the monitoring of serum NTBI levels may therefore be clinically useful in iron-overloaded patients. However, NTBI quantification methods remain complex, limiting their use in clinical practice. To overcome the technical difficulties often encountered, we recently developed a novel automated NTBI quantification system capable of measuring large numbers of samples. In the present study, we investigated the in vivo behavior of NTBI in human and animal serum using this newly established automated system. Average NTBI in healthy volunteers was 0.44±0.076μM (median 0.45μM, range 0.28-0.66μM), with no significant difference between sexes. Additionally, serum NTBI rapidly increased after iron loading, followed by a sudden disappearance. NTBI levels also decreased in inflammation. The results indicate that NTBI is a unique marker of iron metabolism, unlike other markers of iron metabolism, such as serum ferritin. Our new automated NTBI quantification method may help to reveal the clinical significance of NTBI and contribute to our understanding of iron overload.

MRI-based evaluation of the factors leading to pituitary iron overload in patients with thalassemia major

Given the lack of studies evaluating pituitary iron overload in patients with thalassemia major, we used magnetic resonance imaging (MRI) to evaluate these patients and the factors affecting the disease process. The 84 patients with β-thalassemia major who were included in this study were referred to our clinic for cardiac and hepatic T2(*) MRI. T2(*)-weighted images of the pituitary gland, heart, and liver were obtained using a 1.5-tesla MRI unit and a multi-echo gradient-echo sequence. Associations between pituitary T2(*), cardiac T2(*), hepatic T2(*), pituitary height, serum ferritin (SF) level, patient age, and other demographic findings were assessed. Pituitary T2(*) values correlated with hepatic T2(*) values, cardiac T2(*) values, SF level, and patient age (P≤0.001, 0.001, 0.001, 0.01, respectively) but not with pituitary height (P=0.76). Pituitary and cardiac T2(*) values were lower in the subset of patients who underwent splenectomy (P=0.046 and P=0.002, respectively). Pituitary iron overload rapidly increases during puberty and in this study correlated with cardiac and hepatic T2(*) values, patient age, SF level, and liver size, but not with the height of the pituitary. Pituitary iron overload also increases following splenectomy. Together, these findings indicate that numerous factors contribute to pituitary iron overload.

Iron overload in non-transfusion-dependent thalassemia: association with genotype and clinical risk factors.

In the present study, we sought to determine the prevalence of iron overload in patients with non-transfusion-dependent thalassemia (NTDT) and its association with genotype and other clinical risk factors, and to evaluate the correlation between serum ferritin (SF) and liver iron concentration (LIC). Myocardial and liver iron concentration was measured by MRI using a T2* gradient multi-echo sequence in NTDT patients, aged 10-50years. Of 91 patients, 54 (59%) had hepatic iron overload. None had cardiac iron overload. The clinical risk factors for hepatic iron overload were age >20years (adjusted OR 30.2, 95% CI 4.5-203, p<0.001), hemoglobin level <7g/dL (adjusted OR 6.3, 95% CI 1.01-39.5, p=0.049), and cumulative RBC transfusion >10 units (adjusted OR 53.6, 95% CI 3.2-884, p=0.005). Beta-thalassemia genotype was associated with higher risk of iron overload by univariate analysis, but the association was not significant when adjusted for other clinical factors. The correlation coefficient between SF and LIC was 0.60 (p<0.001). In conclusion, the prevalence of hepatic iron overload is high in NTDT. Older age, lower hemoglobin level, and higher cumulative RBC transfusion are significant risk factors. SF and LIC show a significant positive correlation.

Tu1720 Comparison of FibroScan With MRI R2* of Liver and Serum Ferritin in Predicting Iron Overload in Patients With Thalassemia Major

Tu1720 Comparison of FibroScan With MRI R2* of Liver and Serum Ferritin in Predicting Iron Overload in Patients With Thalassemia Major