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Wang X, Wang B, Cheng M, Yu L, Liu W, Nie X, Wang M, Zhou M, Chen W. Lipid peroxidation mediates the association between iron overload and liver injury: cross-sectional and longitudinal analyses in general Chinese urban adults. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:60343-60353. [PMID: 37022540 DOI: 10.1007/s11356-023-26702-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 03/24/2023] [Indexed: 05/10/2023]
Abstract
Iron overload has been associated with acute/chronic organ failure, but whether iron overload induces liver injury remains unclear. The objectives of this study were to assess the relationship between urinary iron and serum alanine aminotransferase (ALT, a biomarker for liver injury), and investigate the potential mediating roles of lipid peroxidation and oxidative DNA damage in such association. Levels of urinary iron, serum ALT, and urinary biomarkers of lipid peroxidation (8-iso-prostaglandin-F2α [8-iso-PGF2α]) and oxidative DNA damage (8-hydroxy-deoxyguano-sine [8-OHdG]) were measured among 5386 observations of 4220 participants from the Wuhan-Zhuhai cohort. The relationships of urinary iron with serum ALT and risk of hyperALT were evaluated by linear mixed model and logistic regression model, respectively. The mediating roles of 8-iso-PGF2α and 8-OHdG were assessed by mediation analyses. This cross-sectional analysis found that urinary iron was positively associated with ALT (β = 0.032; 95% CI: 0.020, 0.044) and hyperALT prevalence (OR = 1.127; 95% CI: 1.065, 1.192). After 3 years of follow-up, participants with persistent high iron levels had increased risk of developing hyperALT (RR = 3.800; 95% CI: 1.464, 9.972) when compared with those with persistent low iron levels. In addition, each 1% increase in urinary iron was associated with a 0.146% (95% CI: 0.128%, 0.164%) increase and a 0.192% (95% CI: 0.154%, 0.229%) increase in 8-iso-PGF2α and 8-OHdG, respectively. Urinary 8-iso-PGF2α (β = 0.056; 95% CI: 0.039, 0.074) was positively associated with ALT, while the association between 8-OHdG and ALT was insignificant. Furthermore, increased 8-iso-PGF2α significantly mediated 22.48% of the urinary iron-associated ALT increment. Our study demonstrated that iron overload was significantly associated with liver injury, which was partly mediated by lipid peroxidation. Controlling iron intake and regulating lipid peroxidation may help in preventing liver injury.
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Affiliation(s)
- Xing Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Bin Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Man Cheng
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Linling Yu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Wei Liu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Xiuquan Nie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Mengyi Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Min Zhou
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China.
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Liu Z, Suo C, Jiang Y, Zhao R, Zhang T, Jin L, Chen X. Phenome-Wide Association Analysis Reveals Novel Links Between Genetically Determined Levels of Liver Enzymes and Disease Phenotypes. PHENOMICS (CHAM, SWITZERLAND) 2022; 2:295-311. [PMID: 36939802 PMCID: PMC9590558 DOI: 10.1007/s43657-021-00033-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/10/2021] [Accepted: 10/15/2021] [Indexed: 11/26/2022]
Abstract
Serum liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], λ-glutamyl transferase [GGT] and alkaline phosphatase [ALP]) are the leading biomarkers to measure liver injury, and they have been reported to be associated with several intrahepatic and extrahepatic diseases in observational studies. We conducted a phenome-wide association study (PheWAS) to identify disease phenotypes associated with genetically predicted liver enzymes based on the UK Biobank cohort. Univariable and multivariable Mendelian randomization (MR) analyses were performed to obtain the causal estimates of associations that detected in PheWAS. Our PheWAS identified 40 out of 1,376 pairs (16, 17, three and four pairs for ALT, AST, GGT and ALP, respectively) of genotype-phenotype associations reaching statistical significance at the 5% false discovery rate threshold. A total of 34 links were further validated in Mendelian randomization analyses. Most of the disease phenotypes that associated with genetically determined ALT level were liver-related, including primary liver cancer and alcoholic liver damage. The disease outcomes associated with genetically determined AST involved a wide range of phenotypic categories including endocrine/metabolic diseases, digestive diseases, and neurological disorder. Genetically predicted GGT level was associated with the risk of other chronic non-alcoholic liver disease, abnormal results of function study of liver, and cholelithiasis. Genetically determined ALP level was associated with pulmonary heart disease, phlebitis and thrombophlebitis of lower extremities, and hypercholesterolemia. Our findings reveal novel links between liver enzymes and disease phenotypes providing insights into the full understanding of the biological roles of liver enzymes. Supplementary Information The online version contains supplementary material available at 10.1007/s43657-021-00033-y.
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Affiliation(s)
- Zhenqiu Liu
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, 200438 China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225316 China
| | - Chen Suo
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225316 China
- Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Shanghai, 200032 China
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032 China
| | - Yanfeng Jiang
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, 200438 China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225316 China
| | - Renjia Zhao
- Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Shanghai, 200032 China
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032 China
| | - Tiejun Zhang
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225316 China
- Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Shanghai, 200032 China
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032 China
| | - Li Jin
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, 200438 China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225316 China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, 200438 China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225316 China
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Rollins MR, Chou ST. Adverse events of red blood cell transfusions in patients with sickle cell disease. Transfus Apher Sci 2022; 61:103557. [PMID: 36064527 PMCID: PMC10149091 DOI: 10.1016/j.transci.2022.103557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Blood transfusion is a common medical intervention for patients with sickle cell disease (SCD) and disease related complications. While patients with SCD are at risk for all transfusion related adverse events defined by the National Healthcare Safety Network (NHSN) Biovigilance Component Hemovigilance Module Surveillance Protocol, they are uniquely susceptible to certain adverse events. This review discusses risk factors, mitigation strategies, and management recommendations for alloimmunization, hemolytic transfusion reactions, hyperviscosity and transfusion-associated iron overload in the context of SCD.
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Affiliation(s)
- Margo R Rollins
- Children's Healthcare of Atlanta, Department of Pathology and Laboratory Medicine, 1405 Clifton Rd NE, 1st Floor, Atlanta, GA 30322, USA; Emory University School of Medicine, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, 1405 Clifton Rd NE, Atlanta, GA 30322, USA
| | - Stella T Chou
- The Children's Hospital of Philadelphia, Departments of Pediatrics and Pathology and Laboratory Medicine, The School of Medicine at the University of Pennsylvania, 3615 Civic Center Boulevard, Abramson Research Building Room 316D, Philadelphia, PA 19104, USA.
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Biopsy-based optimization and calibration of a signal-intensity-ratio-based MRI method (1.5 Tesla) in a dextran-iron loaded mini-pig model, enabling estimation of very high liver iron concentrations. MAGNETIC RESONANCE MATERIALS IN PHYSICS, BIOLOGY AND MEDICINE 2022; 35:843-859. [PMID: 35038062 PMCID: PMC9463247 DOI: 10.1007/s10334-021-00998-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 12/26/2021] [Accepted: 12/28/2021] [Indexed: 11/15/2022]
Abstract
Objective Magnetic resonance imaging (MRI)-based techniques for non-invasive assessing liver iron concentration (LIC) in patients with iron overload have a limited upper measuring range around 35 mg/g dry weight, caused by signal loss from accelerated T1-, T2-, T2* shortening with increasing LIC. Expansion of this range is necessary to allow evaluation of patients with very high LIC. Aim To assess measuring range of a gradient-echo R2* method and a T1-weighted spin-echo (SE), signal intensity ratio (SIR)-based method (TE = 25 ms, TR = 560 ms), and to extend the upper measuring range of the SIR method by optimizing echo time (TE) and repetition time (TR) in iron-loaded minipigs. Methods Thirteen mini pigs were followed up during dextran-iron loading with repeated percutaneous liver biopsies for chemical LIC measurement and MRIs for parallel non-invasive estimation of LIC (81 examinations) using different TEs and TRs. Results SIR and R2* method had similar upper measuring range around 34 mg/g and similar method agreement. Using TE = 12 ms and TR = 1200 ms extended the upper measuring range to 115 mg/g and yielded good method of agreement. Discussion The wider measuring range is likely caused by lesser sensitivity of the SE sequence to iron, due to shorter TE, leading to later signal loss at high LIC, allowing evaluation of most severe hepatic iron overload. Validation in iron-loaded patients is necessary.
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Lewis R, Bewersdorf JP, Zeidan AM. Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options. Cancer Manag Res 2021; 13:645-657. [PMID: 33531837 PMCID: PMC7846829 DOI: 10.2147/cmar.s240600] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 01/13/2021] [Indexed: 12/18/2022] Open
Abstract
For the majority of patients with lower-risk myelodysplastic syndrome (LR-MDS), one of the primary clinical goals is to alleviate the symptoms associated with the resultant cytopenias and to minimize the transfusion burden. While supportive red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs) may lead to clinical improvement, frequent transfusions are often complicated by iron overload and decreased quality of life; furthermore, most patients either do not respond to ESAs or will eventually develop resistance. As such, there is a great need for further therapeutic options in the management of anemia related to MDS. Several additional therapeutics are now available in select patients with LR-MDS and symptomatic anemia including luspatercept, lenalidomide, and immunosuppressive therapy. Furthermore, several novel agents are currently in development to address this area of clinical need such as imetelstat and roxadustat. In this article, we review the currently available therapeutic options for symptomatic anemia in LR-MDS as well as review the therapeutic agents in development.
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Affiliation(s)
- Russell Lewis
- Department of Medicine, Section of Hematology, Yale University, New Haven, CT, USA
| | | | - Amer M Zeidan
- Department of Medicine, Section of Hematology, Yale University, New Haven, CT, USA
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Consequences of parenteral iron-dextran loading investigated in minipigs. A new model of transfusional iron overload. Blood Cells Mol Dis 2020; 83:102440. [PMID: 32353700 DOI: 10.1016/j.bcmd.2020.102440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/18/2020] [Accepted: 04/16/2020] [Indexed: 11/21/2022]
Abstract
Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections. Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads. It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO. Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients.
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Al-Moshary M, Imtiaz N, Al-Mussaed E, Khan A, Ahmad S, Albqami S. Clinical and Biochemical Assessment of Liver Function Test and Its Correlation with Serum Ferritin Levels in Transfusion-dependent Thalassemia Patients. Cureus 2020; 12:e7574. [PMID: 32391223 PMCID: PMC7205361 DOI: 10.7759/cureus.7574] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aims The aim of our study was to correlate liver function tests with serum ferritin levels in multi-transfused thalassemia patients. Methods This was a descriptive cross-sectional study conducted in the department of hematology, Khyber Medical University, from January 2018 to December 2018. Thalassemia patients of either sex dependent on transfusion ≥ 1 year and having a confirmatory report of the disease were included in our study. The nonprobability convenience sampling technique was used. The Pearson correlation coefficient was applied to observe the correlation between serum ferritin level and liver function tests. A p-value of ≤0.05 was considered statistically significant. SPSS version 23 (SPSS Inc., Chicago, Illinois) was used for data analysis. Results A total of 138 subjects of age range 2-23 years, with a mean age of 12.08 ± 6.02 years, were included in our study. The mean serum ferritin of patients in our study was 3278.64 ng/ml with the lowest of 285.2 ng/mL and the highest of 10940.2 ng/ml. With the increase in serum ferritin levels, a rapid increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels was seen. When serum ferritin levels were correlated with total bilirubin level, the bilirubin level remains static with a further increase in serum ferritin levels. Conclusion It was deduced that iron deposition is the ultimate reason for increased liver enzymes. There was a positive correlation between serum ferritin and ALT, AST, and ALP while a weak connection was found between serum ferritin and bilirubin levels.
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Affiliation(s)
- May Al-Moshary
- Pathology, Princess Nourah Bint Abdul Rahman University, Riyadh, SAU
| | - Nayab Imtiaz
- Pathology, Institute of Kidney Disease, Peshawar, PAK
| | - Eman Al-Mussaed
- Pathology, Princess Nourah Bint Abdul Rahman University, Riyadh, SAU
| | - Adnan Khan
- Pediatrics, Rehman Medical Institute, Peshawar, PAK
| | | | - Sara Albqami
- Internal Medicine, King Saud University, Riyadh, SAU
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Evolving therapies for lower-risk myelodysplastic syndromes. Ann Hematol 2020; 99:677-692. [PMID: 32078008 DOI: 10.1007/s00277-020-03963-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/10/2020] [Indexed: 12/16/2022]
Abstract
The development in the therapeutic landscape of myelodysplastic syndromes (MDS) has substantially lagged behind other hematologic malignancies with no new drug approvals for MDS for 13 years since the approval of decitabine in the United States in 2006. While therapeutic concepts for MDS patients continue to be primarily defined by clinical-pathologic risk stratification tools such as the International Prognostic Scoring System (IPSS) and its revised version IPSS-R, our understanding of the genetic landscape and the molecular pathogenesis of MDS has greatly evolved over the last decade. It is expected that the therapeutic approach to MDS patients will become increasingly individualized based on prognostic and predictive genetic features and other biomarkers. Herein, we review the current treatment of lower-risk MDS patients and discuss promising agents in advanced clinical testing for the treatment of symptomatic anemia in lower-risk MDS patients such as luspatercept and imetelstat. Lastly, we review the clinical development of new agents and the implications of the wider availability of mutational analysis for the management of individual MDS patients.
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Tavares AHJ, Benites BD, Fertrin KY. Myocardial Iron Overload in Sickle Cell Disease: A Rare But Potentially Fatal Complication of Transfusion. Transfus Med Rev 2019; 33:170-175. [PMID: 31153715 DOI: 10.1016/j.tmrv.2019.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/09/2019] [Accepted: 04/18/2019] [Indexed: 02/02/2023]
Abstract
Sickle cell disease (SCD) is a frequent indication for chronic transfusion, which can cause iron overload. Excess iron often affects the liver, but not the heart in SCD. Magnetic resonance (MR) is recommended to detect myocardial iron overload (MIO) but its elevated cost requires optimized indication. We aimed to compile all published data on MIO in SCD upon the description of a fatal case of severe MIO in our institution, and to determine associated risk factors. We performed a systematic review using the PRISMA guidelines in two databases (PubMed and Web of Science). Inclusion criteria were publication in English, patients diagnosed with SCD, and reporting ferritin and MIO by MR. Twenty publications reported on 865 SCD adult and pediatric patients, with at least 10 other cases of MIO. The prevalence of MIO in chronically transfused SCD patients can be estimated to be 3% or less, and is associated with high transfusion burden, top-up transfusions, and low adherence to iron chelation. Cardiac siderosis in SCD is rarely reported, and increased awareness with better use of the available screening tools are necessary. Prospective studies should define the recommended chelation regimens depending on the severity of MIO.
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Affiliation(s)
| | | | - Kleber Yotsumoto Fertrin
- Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Campinas, Brazil; Division of Hematology, University of Washington, Seattle, WA.
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El-Beshlawy A, Inusa B, Beneitez Pastor D, Xicoy B, Soledada Duran Nieto M, Bruederle A, Azmon A, Gilotti G, Elalfy M. International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting. ACTA ACUST UNITED AC 2019; 24:238-246. [PMID: 30558524 DOI: 10.1080/16078454.2018.1558758] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE The study evaluates the long-term deferasirox treatment of adult and pediatric patients with chronic transfusional iron overload in clinical practice. METHODS In this non-interventional study, patients were observed for up to 3 years from initiation of deferasirox treatment both prospectively and retrospectively for up to 1 year prior to enrollment. The primary end points were the proportion of patients with ≥1 notable increase in serum creatinine (SCr), and ≥1 notable increase in alanine aminotransferase (ALT). RESULTS Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-year dropout rate of 12.5% due to adverse events (AEs). Increase in SCr > 33% above baseline and the age-adjusted ULN (upper limit of normal) was observed in 14 patients (95%CI, 7.1-19.2). The ALT levels >5 × ULN was observed in 1 patient. Most frequent AEs reported during treatment with deferasirox include gastrointestinal disturbances. CONCLUSIONS The long-term treatment with deferasirox was manageable in most transfusion-dependent patients with no unexpected safety findings. Regular monitoring and an adjusted deferasirox dosing strategy per local labels allowed continued iron chelation treatment and control of transfusional iron in the majority of patients on study.
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Affiliation(s)
| | - Baba Inusa
- b Evelina Children's Hospital, Guy's and St Thomas' Hospital NHS Trust , London , UK
| | | | - Blanca Xicoy
- d ICO-Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute , Barcelona , Spain
| | | | | | - Amin Azmon
- f Novartis Pharma AG , Basel , Switzerland
| | - Geralyn Gilotti
- g Novartis Pharmaceuticals Corporation , East Hanover , NJ , USA
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Abstract
The relationship between blood transfusion intensity, chelatable iron pools, and extrahepatic iron distribution is described in thalassemia. Risk factors for cardiosiderosis are discussed with particular reference to the balance of transfusional iron loading rate and transferrin-iron utilization rate as marked by plasma levels of soluble transferrin receptors. Low transfusion regimens increase residual erythropoiesis allowing for apotransferrin-dependent clearance of non-transferrin-bound iron species otherwise destined for myocardium. The impact of transfusion rates on chelation dosing required for iron balance is also shown.
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Affiliation(s)
- John B Porter
- Haematology Department, University College London, UCLH and Whittington Hospitals, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
| | - Maciej W Garbowski
- Haematology Department, University College London, Cancer Institute, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
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Leitch HA, Buckstein R, Zhu N, Nevill TJ, Yee KWL, Leber B, Keating MM, St Hilaire E, Kumar R, Delage R, Geddes M, Storring JM, Shamy A, Elemary M, Wells RA. Iron overload in myelodysplastic syndromes: Evidence based guidelines from the Canadian consortium on MDS. Leuk Res 2018; 74:21-41. [PMID: 30286330 DOI: 10.1016/j.leukres.2018.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 08/08/2018] [Accepted: 09/15/2018] [Indexed: 01/19/2023]
Abstract
In 2008 the first evidence-based Canadian consensus guideline addressing the diagnosis, monitoring and management of transfusional iron overload in patients with myelodysplastic syndromes (MDS) was published. The Canadian Consortium on MDS, comprised of hematologists from across Canada with a clinical and academic interest in MDS, reconvened to update these guidelines. A literature search was updated in 2017; topics reviewed include mechanisms of iron overload induced cellular damage, evidence for clinical endpoints impacted by iron overload including organ dysfunction, infections, marrow failure, overall survival, acute myeloid leukemia progression, and endpoints around hematopoietic stem-cell transplant. Evidence for an impact of iron reduction on the same endpoints is discussed, guidelines are updated, and areas identified where evidence is suboptimal. The guidelines address common questions around the diagnosis, workup and management of iron overload in clinical practice, and take the approach of who, when, why and how to treat iron overload in MDS. Practical recommendations for treatment and monitoring are made. Evidence levels and grading of recommendations are provided for all clinical endpoints examined.
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Affiliation(s)
- Heather A Leitch
- Hematology, St. Paul's Hospital and the University of British Columbia, Vancouver, BC, Canada.
| | - Rena Buckstein
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Nancy Zhu
- Hematology/Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Thomas J Nevill
- Leukemia/BMT Program of British Columbia, Division of Hematology, Vancouver, BC, Canada
| | - Karen W L Yee
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Brian Leber
- McMaster University, Hamilton, Ontario, Canada
| | | | - Eve St Hilaire
- Centre d'Oncologie, Dr-Leon-Richard, Moncton, New Brunswick, Canada
| | - Rajat Kumar
- Hematology/Oncology, CancerCare Manitoba, Winnipeg, Manitoba, Canada
| | - Robert Delage
- Hematology Department, Centre Hospitalier Universitaire, Laval University, Quebec, QC, Canada
| | - Michelle Geddes
- Department of Medicine/Hematology, Foothills Medical Centre, Calgary, Alberta, Canada
| | | | - April Shamy
- Sir Mortimer B Davis Hospital, McGill University, Montreal, Quebec, Canada
| | - Mohamed Elemary
- Saskatoon Cancer Center, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Richard A Wells
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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Bou-Fakhredin R, Elias J, Taher AT. Iron Overload and Chelation Therapy in Hemoglobinopathies. THALASSEMIA REPORTS 2018. [DOI: 10.4081/thal.2018.7478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Iron overload (IOL) is highly prevalent among patients with hemoglobinopathies; both transfusion dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT). Whether IOL is secondary to regular transfusions like in TDT, or develops from increased intestinal absorption like in NTDT, it can cause significant morbidity and mortality. In TDT patients, iron accumulation in organ tissues is highly evident, and leads to organ toxicity and dysfunction. IOL in NTDT patients is cumulative with advancing age, and concern with secondary morbidity starts beyond the age of 10 years, as shown by the OPTIMAL CARE study. Several modalities are available for the diagnosis and monitoring of IOL. Serum ferritin (SF) assessment is widely available and heavily relied on in resource-poor countries. Non-invasive iron monitoring using MRI has become the gold standard to diagnose IOL. Three iron chelators are currently available for the treatment of IOL: deferoxamine (DFO) in subcutaneous or intravenous injection, oral deferiprone (DFP) in tablet or solution form, and oral deferasirox (DFX) in dispersible tablet (DT) and film-coated tablet (FCT). Today, the goal of ICT is to maintain safe levels of body iron at all times. Appropriate tailoring ICT with chelator choices and dose adjustment must be implemented in a timely manner. Clinical decision to initiate, adjust and stop ICT is based on SF, MRI-LIC and cardiac T2*. In this article, we review the mechanism of IOL in both TDT and NTDT, the pathophysiology behind it, its complications, and the different ways to assess and quantify it. We will also discuss the different ICT modalities available, and the emergence of novel therapies.
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Abstract
BACKGROUND β-thalassemia major (BTM) is an inherited blood disorder leading to severe anemia. A better understanding of BTM complications can be considered an important factor in developing effective health care provision. METHOD A descriptive exploratory design was used to identify the clinical burden of BTM from affected children's perspective. A convenience sample of 45 patients with BTM, accompanied by a family member, was recruited from a governmental hospital during April-May 2015. RESULTS The most reported clinical burden was facial deformity 86.9%, followed by systematic infection (48.8%), growth delay (44.4%), and liver problems (39.9%). Patient age was significantly associated with clinical burdens such as bone pain and facial deformity. The number of blood transfusions received was associated with growth delay and bone pain. CONCLUSION This study highlights the clinical burdens of thalassemia on affected children, in terms of physical appearance, growth delay and other burdens.
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Nakatani S, Nakatani A, Ishimura E, Toi N, Tsuda A, Mori K, Emoto M, Hirayama Y, Saito A, Inaba M. Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease. Kidney Blood Press Res 2018; 43:458-470. [PMID: 29590662 DOI: 10.1159/000488470] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 03/16/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Megalin mediates the uptake of glomerular-filtered iron in the proximal tubules. Urinary full length megalin (C-megalin) excretion has been found to be increased in association with megalin-mediated metabolic load to the endo-lysosomal system in proximal tubular epithelial cells (PTECs) of residual nephrons. In the present study, we investigated the association between urinary iron and C-megalin in chronic kidney disease (CKD) patients, and the possible harmful effect of iron in renal tubules. METHODS Urinary levels of iron and C-megalin were measured in 63 CKD patients using automatic absorption spectrometry and a recently-established sandwich ELISA, respectively. RESULTS Although both urinary C-megalin and urinary total protein levels were correlated with urinary iron (C-megalin: ρ = 0.574, p <0.001; total protein: ρ = 0.500, p <0.001, respectively), urinary C-megalin alone emerged as an independent factor positively associated with urinary iron (β = 0.520, p <0.001) (R2 = 0.75, p <0.001). Furthermore, urinary iron was significantly and positively associated with urinary 8-hydroxydeoxyguanosine, an oxidative stress marker, while no association with other markers of renal tubular injury, i.e., β2-microglobulin and N-acetyl-β-D-glucosaminidase, was noted. CONCLUSIONS Our findings suggest that renal iron handling may be associated with megalin-mediated endo-lysosomal metabolic load in PTECs of residual nephrons and oxidative stress in renal tubules.
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Affiliation(s)
- Shinya Nakatani
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ayumi Nakatani
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Eiji Ishimura
- Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norikazu Toi
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akihiro Tsuda
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Katsuhito Mori
- Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masanori Emoto
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiaki Hirayama
- Reagent Research and Development Department, Denka Seiken Co., Ltd., Gosen, Japan
| | - Akihiko Saito
- Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan
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16
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Shah NR. Advances in iron chelation therapy: transitioning to a new oral formulation. Drugs Context 2017; 6:212502. [PMID: 28706555 PMCID: PMC5499896 DOI: 10.7573/dic.212502] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 05/02/2017] [Indexed: 01/19/2023] Open
Abstract
Iron overload is a concern for patients who require repeated red-blood-cell transfusions due to conditions such as sickle cell disease, thalassemia, or myelodysplastic syndromes. The recommended treatment for removing excess iron in these patients is iron chelation therapy. Currently available iron chelators include deferoxamine, which is administered by injection, and deferasirox and deferiprone, both of which are administered orally. Adherence to iron chelator therapy is an important consideration and may be affected by side effects. A new formulation of deferasirox, a film-coated tablet (FCT), has the potential to improve adherence by offering greater flexibility in administration compared with the original formulation of deferasirox, a dispersible tablet (DT) for oral suspension. This review provides an overview of the currently available iron chelator formulations, with a focus on a comparison between deferasirox DT for oral suspension and deferasirox FCT. The new formulation may be associated with fewer side effects and has increased bioavailability. In addition, alternative strategies for iron chelation, such as combining two different iron chelators, will be discussed.
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De Sanctis V, Soliman AT, Elsedfy H, Yaarubi SAL, Skordis N, Khater D, El Kholy M, Stoeva I, Fiscina B, Angastiniotis M, Daar S, Kattamis C. The ICET-A Recommendations for the Diagnosis and Management of Disturbances of Glucose Homeostasis in Thalassemia Major Patients. Mediterr J Hematol Infect Dis 2016; 8:e2016058. [PMID: 27872738 PMCID: PMC5111521 DOI: 10.4084/mjhid.2016.058] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 09/20/2016] [Indexed: 01/19/2023] Open
Abstract
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.
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Affiliation(s)
| | - Ashraf T. Soliman
- Department of Pediatrics, Division of Endocrinology, Alexandria University Children’s Hospital, Alexandria, Egypt
| | - Heba Elsedfy
- Department of Pediatrics, Ain Shams University, Cairo, Egypt
| | - Saif AL Yaarubi
- Pediatric Endocrine Unit, Department of Child Health, Sultan Qaboos University Hospital, Al-Khoud, Sultanate of Oman
| | - Nicos Skordis
- Division of Pediatric and Adolescent Endocrinology, Paedi Center for Specialized Pediatrics, St. George’s University Medical School at the University of Nicosia, Cyprus
| | - Doaa Khater
- Department of Pediatrics, Endocrinology Unit, Alexandria University Children’s Hospital, Egypt, and Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman
| | | | - Iva Stoeva
- Paediatric Endocrinologist,”Screening and Functional Endocrine Diagnostics” SBALDB. Professor Ivan Mitev, Medical University Sofia, Bulgaria
| | | | | | - Shahina Daar
- Department of Hematology, College of Medicine and Health Sciences Sultan Qaboos University Oman, Sultanate of Oman & Visiting Scholar, Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch 7600, South Africa
| | - Christos Kattamis
- First Department of Paediatrics, University of Athens, Athens, Greece
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18
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Ferraioli G, Lissandrin R, Tinelli C, Scudeller L, Bonetti F, Zicchetti M, Longo F, Murgia M, Bernuzzi S, Zecca M, Casula P, Piga A, Filice C. Liver stiffness assessed by transient elastography in patients with β thalassaemia major. Ann Hepatol 2016; 15:410-417. [PMID: 27049495 DOI: 10.5604/16652681.1198817] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
RATIONALE FOR THE STUDY This cross-sectional multicenter study was conducted to investigate any difference in liver stiffness measurements (LSM), evaluated by transient elastography, between patients affected by β thalassaemia major, with and without hepatitis C virus (HCV) infection, and healthy blood donors (controls). Secondary aim was to assess any correlation between transient elastography and serum ferritin, liver magnetic resonance imaging (MRI) T2* or superconductive quantum interference device (SQUID) liver susceptometry values. MATERIALS AND METHODS The study involved three centers. Transient elastography and MRI T2* examinations were performed in all centers. SQUID liver susceptometry was performed in center1 and center2. T-test for independent data or Mann-Whitney U test was used to analyse differences between two groups. Univariate Pearson's r coefficient was used to test correlations between liver stiffness measurements and all other variables. RESULTS In a study with 119 patients and 183 controls, patients who had never been infected with HCV showed significantly higher LSMs than controls [5.7 (95% CI, 5.2-6.2) kPa vs. 4.3 (95% CI, 4.1-4.4) kPa, p < 0.0001]. A moderate correlation between LSMs and ferritin values, adjusted for gender and age, was found in patients (r = 0.49, p < 0.0001) but not in controls (r = -0.22, p = 0.6). No correlation between LSMs and MRI T2* or SQUID liver susceptometry values was observed. In conclusion, compared to controls β thalassaemia major patients had a significant increase in LSMs independently from HCV infection.
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Affiliation(s)
- Giovanna Ferraioli
- Ultrasound Unit, Infectious Diseases Department, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
| | - Raffaella Lissandrin
- Ultrasound Unit, Infectious Diseases Department, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
| | - Carmine Tinelli
- Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Luigia Scudeller
- Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Federico Bonetti
- Pediatric Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mabel Zicchetti
- Ultrasound Unit, Infectious Diseases Department, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
| | - Filomena Longo
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Mauro Murgia
- Immuno-ematologia e Medicina Trasfusionale, Ospedale San Martino, Oristano, Italy
| | - Stefano Bernuzzi
- Department of "Medicina Diagnostica e dei Servizi", Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Marco Zecca
- Pediatric Haematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Paolo Casula
- Immuno-ematologia e Medicina Trasfusionale, Ospedale San Martino, Oristano, Italy
| | - Antonio Piga
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Carlo Filice
- Ultrasound Unit, Infectious Diseases Department, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
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Cagin YF, Sahin N, Polat A, Erdogan MA, Atayan Y, Eyol E, Bilgic Y, Seckin Y, Colak C. The Acute Effect of Humic Acid on Iron Accumulation in Rats. Biol Trace Elem Res 2016; 171:145-55. [PMID: 26380988 DOI: 10.1007/s12011-015-0507-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 08/18/2015] [Indexed: 01/03/2023]
Abstract
Free iron leads to the formation of pro-oxidant reactive oxygen species (ROS). Humic acids (HAs) enhance permeability of cellular wall and act as a chelator through electron transferring. This study was designed to test chelator effect of HA on iron as well as its anti-oxidant effect against the iron-induced hepatotoxicity and cardiotoxicity. The rats used were randomly divided into four groups (n = 8/group): group I (the control group); group II (the HA group), humic acid (562 mg/kg) was given over 10 days by oral gavage; group III (the iron group), iron III hydroxide polymaltose (250 mg/kg) was given over 10 days by intraperitoneal route; and group IV (the HA plus iron group), received the iron (similar to group II) plus humic acid (similar to those in groups II and III) group. Blood and two tissue samples both from liver and heart were obtained for biochemical and histopathological evaluations. Iron deposition, the iron-induced hepatotoxicity, and cardiotoxicity were demonstrated by histopathological and biochemical manner. However, no significant differences were observed in the serum biochemical values and the histopathological results among the iron and the HA plus iron groups in the liver tissue but not in the heart tissue. The protective effects of humic acid against iron-induced cardiotoxicity were shown but not against hepatotoxicity in our study.
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Affiliation(s)
- Yasir Furkan Cagin
- Department of Gastroenterology, Medical Faculty, Inonu University, 44280, Malatya, Turkey.
| | - N Sahin
- Department of Pathology, Medical Faculty, Inonu University, Malatya, Turkey
| | - A Polat
- Department of Physiology, Medical Faculty, Inonu University, Malatya, Turkey
| | - M A Erdogan
- Department of Gastroenterology, Medical Faculty, Inonu University, 44280, Malatya, Turkey
| | - Y Atayan
- Department of Gastroenterology, Medical Faculty, Inonu University, 44280, Malatya, Turkey
| | - E Eyol
- Department of Pharmaceutical Toxicology, Inonu University, Malatya, Turkey
| | - Y Bilgic
- Department of Gastroenterology, Medical Faculty, Inonu University, 44280, Malatya, Turkey
| | - Y Seckin
- Department of Gastroenterology, Medical Faculty, Inonu University, 44280, Malatya, Turkey
| | - C Colak
- Department of Biostatistics and Medical Informatics, Medical Faculty, Inonu University, Malatya, Turkey
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20
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Quinn CT, St Pierre TG. MRI Measurements of Iron Load in Transfusion-Dependent Patients: Implementation, Challenges, and Pitfalls. Pediatr Blood Cancer 2016; 63:773-80. [PMID: 26713769 PMCID: PMC5064750 DOI: 10.1002/pbc.25882] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 11/30/2015] [Accepted: 12/01/2015] [Indexed: 01/19/2023]
Abstract
Magnetic resonance imaging (MRI) has played a key role in studies of iron overload in transfusion-dependent patients, providing insights into the relations among liver and cardiac iron loading, iron chelator dose, and morbidity. Currently, there is rapid uptake of these methods into routine clinical practice as part of the management strategy for iron overload in regularly transfused patients. Given the manifold methods of data acquisition and analysis, there are several potential pitfalls that may result in inappropriate decision making. Herein, we review the challenges of establishing suitable MRI techniques for tissue iron measurement in regularly transfused patients.
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Affiliation(s)
- Charles T. Quinn
- Division of HematologyCincinnati Children's Hospital Medical CenterCincinnatiOhio
| | - Tim G. St Pierre
- School of PhysicsThe University of Western AustraliaCrawleyAustralia
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21
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Retrospective comparison of gradient recalled echo R2* and spin-echo R2 magnetic resonance analysis methods for estimating liver iron content in children and adolescents. Pediatr Radiol 2015; 45:1629-34. [PMID: 26008870 DOI: 10.1007/s00247-015-3378-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 03/23/2015] [Accepted: 04/22/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND Serial surveillance of liver iron concentration (LIC) provides guidance for chelation therapy in patients with iron overload. The diagnosis of iron overload traditionally relies on core liver biopsy, which is limited by invasiveness, sampling error, cost and general poor acceptance by pediatric patients and parents. Thus noninvasive diagnostic methods such as MRI are highly attractive for quantification of liver iron concentration. OBJECTIVE To compare two MRI-based methods for liver iron quantification in children. MATERIALS AND METHODS 64 studies on 48 children and young adults (age range 4-21 years) were examined by gradient recalled echo (GRE) R2* and spin-echo R2 MRI at 1.5T to evaluate liver iron concentration. Scatter plots and Bland-Altman difference plots were generated to display and assess the relationship between the methods. RESULTS With the protocols used in this investigation, Bland-Altman agreement between the methods is best when LIC is <20 mg/g dry tissue. Scatter plots show that all values with LIC <20 mg/g dry tissue fall within the 95% prediction limits. CONCLUSION Liver iron concentration as determined by the R2* and R2 MR methods is statistically comparable, with no statistical difference between these methods for LIC <20 mg/g.
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22
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Puliyel M, Mainous AG, Berdoukas V, Coates TD. Iron toxicity and its possible association with treatment of Cancer: lessons from hemoglobinopathies and rare, transfusion-dependent anemias. Free Radic Biol Med 2015; 79:343-51. [PMID: 25463277 DOI: 10.1016/j.freeradbiomed.2014.10.861] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 10/22/2014] [Accepted: 10/30/2014] [Indexed: 01/19/2023]
Abstract
Exposure to elevated levels of iron causes tissue damage and organ failure, and increases the risk of cancer. The toxicity of iron is mediated through generation of oxidants. There is also solid evidence indicating that oxidant stress plays a significant role in a variety of human disease states, including malignant transformation. Iron toxicity is the main focus when managing thalassemia. However, the short- and long-term toxicities of iron have not been extensively considered in children and adults treated for malignancy, and only recently have begun to draw oncologists' attention. The treatment of malignancy can markedly increase exposure of patients to elevated toxic iron species without the need for excess iron input from transfusion. This under-recognized exposure likely enhances organ toxicity and may contribute to long-term development of secondary malignancy and organ failure. This review discusses the current understanding of iron metabolism, the mechanisms of production of toxic free iron species in humans, and the relation of the clinical marker, transferrin saturation (TS), to the presence of toxic free iron. We will present epidemiological data showing that high TS is associated with poor outcomes and development of cancer, and that lowering free iron may improve outcomes. Finally, we will discuss the possible relation between some late complications seen in survivors of cancer and those due to iron toxicity.
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Affiliation(s)
- Mammen Puliyel
- Section of Hematology, Childrens Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles California, USA
| | - Arch G Mainous
- Department of Health Services Research, Management and Policy, University of Florida, Gainesville, Fla. USA
| | - Vasilios Berdoukas
- Section of Hematology, Childrens Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles California, USA
| | - Thomas D Coates
- Section of Hematology, Childrens Center for Cancer, Blood Disease and Bone Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles California, USA.
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Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 2014; 6:748-73. [PMID: 24549403 DOI: 10.1039/c3mt00347g] [Citation(s) in RCA: 411] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
"Serum ferritin" presents a paradox, as the iron storage protein ferritin is not synthesised in serum yet is to be found there. Serum ferritin is also a well known inflammatory marker, but it is unclear whether serum ferritin reflects or causes inflammation, or whether it is involved in an inflammatory cycle. We argue here that serum ferritin arises from damaged cells, and is thus a marker of cellular damage. The protein in serum ferritin is considered benign, but it has lost (i.e. dumped) most of its normal complement of iron which when unliganded is highly toxic. The facts that serum ferritin levels can correlate with both disease and with body iron stores are thus expected on simple chemical kinetic grounds. Serum ferritin levels also correlate with other phenotypic readouts such as erythrocyte morphology. Overall, this systems approach serves to explain a number of apparent paradoxes of serum ferritin, including (i) why it correlates with biomarkers of cell damage, (ii) why it correlates with biomarkers of hydroxyl radical formation (and oxidative stress) and (iii) therefore why it correlates with the presence and/or severity of numerous diseases. This leads to suggestions for how one might exploit the corollaries of the recognition that serum ferritin levels mainly represent a consequence of cell stress and damage.
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Affiliation(s)
- Douglas B Kell
- School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK.
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24
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Wu D, Coselli JS, Johnson ML, LeMaire SA. Hepatopancreaticobiliary Values after Thoracoabdominal Aneurysm Repair. AORTA (STAMFORD, CONN.) 2014; 2:135-42. [PMID: 26798731 DOI: 10.12945/j.aorta.2014.14-015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 07/16/2014] [Indexed: 11/18/2022]
Abstract
BACKGROUND After thoracoabdominal aortic aneurysm (TAAA) repair, blood tests assessing hepatopancreaticobiliary (HPB) organs commonly have abnormal results. The clinical significance of such abnormalities is difficult to determine because the expected postoperative levels have not been characterized. Therefore, we sought to establish expected trends in HPB laboratory values after TAAA repair. METHODS This 5-year study comprised 155 patients undergoing elective Crawford extent II TAAA repair. In accordance with a prospective study protocol, all repairs involved left-sided heart bypass, selective visceral perfusion, and cold renal perfusion. Blood levels of aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, amylase, and lipase were measured before TAAA repair and for 7 days afterward. Ratios between postoperative and baseline levels were compared for each time point with 95% confidence intervals. RESULTS Temporal patterns for the laboratory values varied greatly. Amylase, lipase, and AST underwent significant early increases before decreasing to preoperative levels. LDH increased immediately and remained significantly elevated, whereas ALT increased more gradually. GGT remained near baseline through postoperative day 4, and then increased to more than twice baseline. Total bilirubin never differed significantly from baseline. After adjusted analysis, the ischemic time predicted the maximum AST, lipase, GGT, and LDH values. CONCLUSIONS Although most HPB laboratory values increase significantly after elective TAAA repair, the temporal trends for different values vary substantially. The ischemic time predicts the maximum AST, lipase, GGT, and LDH levels. These trends should be considered when laboratory values are assessed after TAAA repair.
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Affiliation(s)
| | | | - Michael L Johnson
- University of Houston, College of Pharmacy, Department of Clinical Sciences and Administration, Division of Pharmacy Administration and Public Health, Houston, Texas
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Coates TD. Physiology and pathophysiology of iron in hemoglobin-associated diseases. Free Radic Biol Med 2014; 72:23-40. [PMID: 24726864 PMCID: PMC4940047 DOI: 10.1016/j.freeradbiomed.2014.03.039] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 03/26/2014] [Accepted: 03/27/2014] [Indexed: 01/19/2023]
Abstract
Iron overload and iron toxicity, whether because of increased absorption or iron loading from repeated transfusions, can be major causes of morbidity and mortality in a number of chronic anemias. Significant advances have been made in our understanding of iron homeostasis over the past decade. At the same time, advances in magnetic resonance imaging have allowed clinicians to monitor and quantify iron concentrations noninvasively in specific organs. Furthermore, effective iron chelators are now available, including preparations that can be taken orally. This has resulted in substantial improvement in mortality and morbidity for patients with severe chronic iron overload. This paper reviews the key points of iron homeostasis and attempts to place clinical observations in patients with transfusional iron overload in context with the current understanding of iron homeostasis in humans.
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Affiliation(s)
- Thomas D Coates
- Children׳s Center for Cancer and Blood Diseases, Children׳s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
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26
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Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome. Blood 2014; 124:873-81. [PMID: 24923296 DOI: 10.1182/blood-2014-03-563221] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.
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Gaweda AE, Ginzburg YZ, Chait Y, Germain MJ, Aronoff GR, Rachmilewitz E. Iron dosing in kidney disease: inconsistency of evidence and clinical practice. Nephrol Dial Transplant 2014; 30:187-96. [PMID: 24821751 DOI: 10.1093/ndt/gfu104] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The management of anemia in patients with chronic kidney disease (CKD) is difficult. The availability of erythropoiesis-stimulating agents (ESAs) has increased treatment options for previously transfusion-requiring patients, but the recent evidence of ESA side effects has prompted the search for complementary or alternative approaches. Next to ESA, parenteral iron supplementation is the second main form of anemia treatment. However, as of now, no systematic approach has been proposed to balance the concurrent administration of both agents according to individual patient's needs. Furthermore, the potential risks of excessive iron dosing remain a topic of controversy. How, when and whether to monitor CKD patients for potential iron overload remain to be elucidated. This review addresses the question of risk and benefit of iron administration in CKD, highlights the evidence supporting current practice, provides an overview of standard and potential new markers of iron status and outlines a new pharmacometric approach to physiologically compatible individualized dosing of ESA and iron in CKD patients.
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Affiliation(s)
| | | | - Yossi Chait
- University of Massachusetts, Amherst, MA, USA
| | - Michael J Germain
- Baystate Medical Center, Tufts University School of Medicine, Boston, MA, USA
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Wollmer E, Neubauer A. Komplikationen der allogenen Knochenmark- und Stammzelltransplantation. Internist (Berl) 2014; 55:547-60; quiz 561. [DOI: 10.1007/s00108-013-3432-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013; 122:2943-64. [PMID: 23980065 DOI: 10.1182/blood-2013-03-492884] [Citation(s) in RCA: 510] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.
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Voskaridou E, Komninaka V, Karavas A, Terpos E, Akianidis V, Christoulas D. Combination therapy of deferasirox and deferoxamine shows significant improvements in markers of iron overload in a patient with β-thalassemia major and severe iron burden. Transfusion 2013; 54:646-9. [PMID: 23834310 DOI: 10.1111/trf.12335] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 06/02/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Iron overload is a common complication of patients with β-thalassemia major (TM). Despite the availability of three iron chelators, deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), some patients fail to respond adequately to monotherapy with any of them. We report a case of TM who had refractory severe iron overload and was successfully and safely chelated with the combination of DFX with DFO. CASE REPORT A 40-year-old male with β-TM, who had been regularly transfused from the age of 2, had been administered in the past iron chelation with DFO, DFP, and DFX monotherapy, without major improvement on his iron overload status. Liver and cardiac magnetic resonance imaging (MRI) revealed severe iron overload, while serum ferritin was persistently greater than 2500 μg/L. After the patient gave informed consent, he was administered combination therapy of DFX at 30 mg/kg/day for 7 days per week and DFO at 2500 mg/day for 4 days every week and routinely followed up for compliance. RESULTS Eighteen months later, serum ferritin was reduced to 680 μg/L, while both liver and cardiac MRI T2* values improved, reflecting lower iron overload. The combination regimen was well tolerated and no adverse events were documented. CONCLUSION This is the first official report of simultaneous daily administration of the two iron chelators DFX and DFO that demonstrates the beneficial effect of the combination on heart and liver hemosiderosis. If our observation is confirmed in more patients, this combination could constitute a useful option in tailoring individual chelation therapy for β-TM patients with iron overload.
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Affiliation(s)
- Ersi Voskaridou
- Thalassaemia and Sickle Cell Disease Reference Centre, Laikon General Hospital; Thalassaemia Unit, Korgialeneio Benakeio Hospital; Department of Clinical Therapeutics, University of Athens School of Medicine; Medical Advisor of Novartis Hellas SACI; Department of Hematology, 251 General Air Force Hospital, Athens, Greece
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Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, Hoffman TM, Kiernan MS, Lerakis S, Piga A, Porter JB, Walker JM, Wood J. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation 2013; 128:281-308. [PMID: 23775258 DOI: 10.1161/cir.0b013e31829b2be6] [Citation(s) in RCA: 285] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.
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Lee JW, Kang HJ, Choi JY, Kim NH, Jang MK, Yeo CW, Lee SS, Kim H, Park JD, Park KD, Shin HY, Shin JG, Ahn HS. Pharmacogenetic study of deferasirox, an iron chelating agent. PLoS One 2013; 8:e64114. [PMID: 23737969 PMCID: PMC3667856 DOI: 10.1371/journal.pone.0064114] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Accepted: 04/10/2013] [Indexed: 11/19/2022] Open
Abstract
Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing −1774 del and/or −24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79–28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7–43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34–150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.
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Affiliation(s)
- Ji Won Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyoung Jin Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail:
| | - Ji-Yeob Choi
- Department of Biomedical Sciences, Graduate School of Seoul National University, Seoul, Republic of Korea
| | - Nam Hee Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Mi Kyung Jang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chang-Woo Yeo
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
| | - Sang Seop Lee
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
| | - Hyery Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - June Dong Park
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyung Duk Park
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Young Shin
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae-Gook Shin
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
| | - Hyo Seop Ahn
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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Anwar M, Wood J, Manwani D, Taragin B, Oyeku SO, Peng Q. Hepatic Iron Quantification on 3 Tesla (3 T) Magnetic Resonance (MR): Technical Challenges and Solutions. Radiol Res Pract 2013; 2013:628150. [PMID: 23766905 PMCID: PMC3674724 DOI: 10.1155/2013/628150] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 04/19/2013] [Accepted: 04/19/2013] [Indexed: 11/18/2022] Open
Abstract
MR has become a reliable and noninvasive method of hepatic iron quantification. Currently, most of the hepatic iron quantification is performed on 1.5 T MR, and the biopsy measurements have been paired with R 2 and R 2* values for 1.5 T MR. As the use of 3 T MR scanners is steadily increasing in clinical practice, it has become important to evaluate the practicality of calculating iron burden at 3 T MR. Hepatic iron quantification on 3 T MR requires a better understanding of the process and more stringent technical considerations. The purpose of this work is to focus on the technical challenges in establishing a relationship between T 2* values at 1.5 T MR and 3 T MR for hepatic iron concentration (HIC) and to develop an appropriately optimized MR protocol for the evaluation of T 2* values in the liver at 3 T magnetic field strength. We studied 22 sickle cell patients using multiecho fast gradient-echo sequence (MFGRE) 3 T MR and compared the results with serum ferritin and liver biopsy results. Our study showed that the quantification of hepatic iron on 3 T MRI in sickle cell disease patients correlates well with clinical blood test results and biopsy results. 3 T MR liver iron quantification based on MFGRE can be used for hepatic iron quantification in transfused patients.
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Affiliation(s)
- Muhammad Anwar
- Department of Pediatric Radiology, Children's Hospital at Montefiore, Bronx, NY, USA
| | - John Wood
- Department of Pediatric Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Division of Pediatric Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Deepa Manwani
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Bronx, NY, USA
| | - Benjamin Taragin
- Department of Pediatric Radiology, Children's Hospital at Montefiore, Bronx, NY, USA
| | - Suzette O. Oyeku
- Department of Pediatrics, Division of General Pediatrics, Children's Hospital at Montefiore, Bronx, NY, USA
| | - Qi Peng
- Department of Pediatric Radiology, Children's Hospital at Montefiore, Bronx, NY, USA
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Piga A, Longo F, Musallam KM, Cappellini MD, Forni GL, Quarta G, Chiavilli F, Commendatore F, Mulas S, Caruso V, Galanello R. Assessment and management of iron overload in β-thalassaemia major patients during the 21st century: a real-life experience from the Italian WEBTHAL project. Br J Haematol 2013; 161:872-83. [PMID: 23600689 DOI: 10.1111/bjh.12340] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 02/25/2013] [Indexed: 12/11/2022]
Abstract
We conducted a cross-sectional study on 924 β-thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the WEBTHAL software, to evaluate real-life application of iron overload assessment and management standards. Serum ferritin <2500 ng/ml was a risk factor for never having liver iron concentration (LIC) measurement, while absence of cardiac disease and siderosis were risk factors for a delay in LIC measurement >2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were <18 years, had iron intake ≤0·4 mg/kg per day, or a serum ferritin <2500 ng/ml. A history of normal CMR T2* was the main risk factor for a delay in subsequent assessment of >2 years. Deferoxamine (22·8%) was more commonly used in patients with Hepatitis C Virus or high serum creatinine. Deferiprone (20·6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a deferoxamine + deferiprone combination (17·9%) was more commonly used in patients with serum ferritin >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38·3%) was more commonly prescribed in patients <18 years, but less commonly used in those with heart disease or high iron intake. These observations largely echoed guidelines at the time, although some practices are expected to change in light of evolving evidence.
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Affiliation(s)
- Antonio Piga
- Department of Clinical and Biological Sciences, University of Turin, 10 Regione Gonzole, Orbassano, Turin, Italy.
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Goto T, Ikuta K, Inamoto Y, Kamoshita S, Yokohata E, Koyama D, Onodera K, Seto A, Watanabe K, Imahashi N, Tsukamoto S, Ozawa Y, Sasaki K, Ito M, Kohgo Y, Miyamura K. Hyperferritinemia after adult allogeneic hematopoietic cell transplantation: quantification of iron burden by determining non-transferrin-bound iron. Int J Hematol 2012; 97:125-34. [DOI: 10.1007/s12185-012-1252-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 12/06/2012] [Accepted: 12/06/2012] [Indexed: 12/28/2022]
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Abstract
Patients with β-thalassemia major (TM) and other refractory anemias requiring regular blood transfusions accumulate iron that damages the liver, endocrine system, and most importantly the heart. The prognosis in TM has improved remarkably over the past 10 years. This improvement has resulted from the development of magnetic resonance imaging (MRI) techniques, especially T2*, to accurately measure cardiac and liver iron, and from the availability of 3 iron-chelating drugs. In this article we describe the use of MRI to determine which adult and pediatric patients need to begin iron chelation therapy and to monitor their progress. We summarize the properties of each of the 3 drugs, deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), including their efficacy, patient acceptability, and side effects. We describe when to initiate or intensify therapy, switch to another drug, or use combined therapy. We also discuss the management of refractory anemias other than TM that may require multiple blood transfusions, including sickle cell anemia and myelodysplasia. The development of a potential fourth chelator FBS 0701 and the combined use of oral chelators may further improve the quality of life and survival in patients with TM and other transfusion-dependent patients.
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Deng J, Rigsby CK, Schoeneman S, Boylan E. A semiautomatic postprocessing of liver R2* measurement for assessment of liver iron overload. Magn Reson Imaging 2012; 30:799-806. [PMID: 22464453 DOI: 10.1016/j.mri.2012.02.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Revised: 10/25/2011] [Accepted: 02/14/2012] [Indexed: 01/28/2023]
Affiliation(s)
- Jie Deng
- Department of Medical Imaging, Children's Memorial Hospital, Chicago, IL 60614, USA.
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Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 2012; 18:1851-60. [PMID: 22563164 PMCID: PMC3337559 DOI: 10.3748/wjg.v18.i16.1851] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Revised: 11/15/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
Recognition and management of gastrointestinal and hepatic complications of hematopoietic stem cell transplantation has gained increasing importance as indications and techniques of transplantation have expanded in the last few years. The transplant recipient is at risk for several complications including conditioning chemotherapy related toxicities, infections, bleeding, sinusoidal obstruction syndrome, acute and chronic graft-versus-host disease (GVHD) as well as other long-term problems. The severity and the incidence of many complications have improved in the past several years as the intensity of conditioning regimens has diminished and better supportive care and GVHD prevention strategies have been implemented. Transplant clinicians, however, continue to be challenged with problems arising from human leukocyte antigen-mismatched and unrelated donor transplants, expanding transplant indications and age-limit. This review describes the most commonly seen transplant related complications, focusing on their pathogenesis, differential diagnosis and management.
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Bae SJ, Kang C, Sung KW, Chueh HW, Son MH, Lee SH, Yoo KH, Koo HH. Iron overload during follow-up after tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma. J Korean Med Sci 2012; 27:363-9. [PMID: 22468098 PMCID: PMC3314847 DOI: 10.3346/jkms.2012.27.4.363] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 01/17/2012] [Indexed: 01/28/2023] Open
Abstract
Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34(+) cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34(+) cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34(+) cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.
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Affiliation(s)
- Soo Jin Bae
- Faculty of Human Medicine, Hannover Medical School, Hannover, Germany
| | - Christine Kang
- Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Ki Woong Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Won Chueh
- Department of Pediatrics, Dong-A Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Meong Hi Son
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Hyun Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hong Hoe Koo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Deugnier Y, Turlin B, Ropert M, Cappellini MD, Porter JB, Giannone V, Zhang Y, Griffel L, Brissot P. Improvement in liver pathology of patients with β-thalassemia treated with deferasirox for at least 3 years. Gastroenterology 2011; 141:1202-11, 1211.e1-3. [PMID: 21741344 DOI: 10.1053/j.gastro.2011.06.065] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 05/27/2011] [Accepted: 06/09/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Most data on the effects of iron chelation therapy for patients with liver fibrosis come from small studies. We studied the effects of the oral iron chelator deferasirox on liver fibrosis and necroinflammation in a large population of patients with iron overload β-thalassemia. METHODS We studied data from 219 patients with β-thalassemia, collected from histologic analyses of biopsy samples taken at baseline and after at least 3 years of treatment with deferasirox. Treatment response was assessed from liver iron concentrations at baseline and the end of the study. Liver fibrosis, necroinflammation, and markers of iron overload and liver enzymes were recorded. Patients were also assessed, by serologic analysis at baseline, for hepatitis C virus infection. RESULTS By the end of the study, stability of Ishak fibrosis staging scores (change of -1, 0, or +1) or improvements (change of ≤-2) were observed in 82.6% of patients; Ishak necroinflammatory scores improved by a mean value of -1.3 (P<.001). Improvements in fibrosis stage and necroinflammation were independent of hepatitis C virus exposure or reduction in liver iron concentration defined by the response criteria. Absolute changes in concentrations of liver iron by the end of the study did not correlate with improved Ishak fibrosis or necroinflammatory scores. CONCLUSIONS Deferasirox treatment for 3 or more years reversed or stabilized liver fibrosis in 83% of patients with iron-overloaded β-thalassemia. This therapeutic effect was independent of reduced concentration of liver iron (defined by the response criteria) or previous exposure to hepatitis C virus.
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Affiliation(s)
- Yves Deugnier
- Liver Disease Unit and Inserm U-991, Department of Pathology, University Hospital Pontchaillou, Rennes, France.
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Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamim H, Taher AT. Elevated liver iron concentration is a marker of increased morbidity in patients with β thalassemia intermedia. Haematologica 2011; 96:1605-12. [PMID: 21791471 DOI: 10.3324/haematol.2011.047852] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Patients with β thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether iron overload in patients with β thalassemia intermedia is associated with morbidity. DESIGN AND METHODS This was a cross-sectional study of 168 patients with β thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co-morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity. RESULTS The mean age of the patients was 35.2 ± 12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4 ± 6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease. CONCLUSIONS Elevated liver iron concentration in patients with β thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease.
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Affiliation(s)
- Khaled M Musallam
- Department of Internal Medicine, Division of Hematology & Oncology, American University of Beirut Medical Center, Beirut, Lebanon
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Roy NBA, Myerson S, Schuh AH, Bignell P, Patel R, Wainscoat JS, McGowan S, Marchi E, Atoyebi W, Littlewood T, Chacko J, Vyas P, Killick SB. Cardiac iron overload in transfusion-dependent patients with myelodysplastic syndromes. Br J Haematol 2011; 154:521-4. [DOI: 10.1111/j.1365-2141.2011.08749.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood 2011; 118:884-93. [PMID: 21628399 DOI: 10.1182/blood-2010-11-316646] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.
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Inati A, Khoriaty E, Musallam KM. Iron in sickle-cell disease: what have we learned over the years? Pediatr Blood Cancer 2011; 56:182-90. [PMID: 21157888 DOI: 10.1002/pbc.22721] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Accepted: 05/27/2010] [Indexed: 01/19/2023]
Abstract
Over the last four decades, monumental advances have been made in the understanding, assessment, and management of transfusion-dependent patients, which have translated into significant improvements in patient morbidity and mortality. Important lessons have been learned from extensive clinical experience of iron management in the thalassemias, but greater knowledge of key differences in the sickle-cell disease (SCD) population may impact on our approach to patient assessment and management. The unique pathophysiology of SCD is reflected in a distinct pattern of iron loading with minimal organ-specific injury. An appreciation and understanding of these differences should allow us to develop tailored management approaches that optimize patient outcomes.
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Affiliation(s)
- Adlette Inati
- Division of Paediatric Haematology and Oncology, Children's Centre for Cancer and Blood Diseases, Rafik Hariri University Hospital, Beirut, Lebanon.
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Wood JC. Impact of iron assessment by MRI. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2011; 2011:443-450. [PMID: 22160072 DOI: 10.1182/asheducation-2011.1.443] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.
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Affiliation(s)
- John C Wood
- Department of Pediatrics and Radiology, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
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Muñoz M, García-Erce JA, Remacha ÁF. Disorders of iron metabolism. Part II: iron deficiency and iron overload. J Clin Pathol 2010; 64:287-96. [DOI: 10.1136/jcp.2010.086991] [Citation(s) in RCA: 182] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Main disorders of iron metabolismIncreased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron deficiency anaemia. In chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, resulting in hypoferraemia and iron restricted erythropoiesis, despite normal iron stores (functional iron deficiency), and finally anaemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD+ID). In contrast, low hepcidin expression may lead to hereditary haemochromatosis (HH type I, mutations of the HFE gene) and type II (mutations of the hemojuvelin and hepcidin genes). Mutations of transferrin receptor 2 lead to HH type III, whereas those of the ferroportin gene lead to HH type IV. All these syndromes are characterised by iron overload. As transferrin becomes saturated in iron overload states, non-transferrin bound iron appears. Part of this iron is highly reactive (labile plasma iron), inducing free radical formation. Free radicals are responsible for the parenchymal cell injury associated with iron overload syndromes.Role of laboratory testing in diagnosisIn iron deficiency status, laboratory tests may provide evidence of iron depletion in the body or reflect iron deficient red cell production. Increased transferrin saturation and/or ferritin levels are the main cues for further investigation of iron overload. The appropriate combination of different laboratory tests with an integrated algorithm will help to establish a correct diagnosis of iron overload, iron deficiency and anaemia.Review of treatment optionsIndications, advantages and side effects of the different options for treating iron overload (phlebotomy and iron chelators) and iron deficiency (oral or intravenous iron formulations) will be discussed.
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Pullarkat V. Iron overload in patients undergoing hematopoietic stem cell transplantation. Adv Hematol 2010; 2010:345756. [PMID: 20871852 PMCID: PMC2943091 DOI: 10.1155/2010/345756] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 07/01/2010] [Indexed: 01/19/2023] Open
Abstract
Recipients of hematopoietic stem cell transplantation (HSCT) frequently have iron overload resulting from chronic transfusion therapy for anemia. In some cases, for example, in patients with myelodysplastic syndromes and thalassemia, this can be further exacerbated by increased absorption of iron from the gut as a result of ineffective erythropoiesis. Accumulating evidence has established the negative impact of elevated pretransplantation serum ferritin, a surrogate marker of iron overload, on overall survival and nonrelapse mortality after HSCT. Complications of HSCT associated with iron overload include increased bacterial and fungal infections as well as sinusoidal obstruction syndrome and possibly other regimen-related toxicities. Based on current evidence, particular attention should be paid to prevention and management of iron overload in allogeneic HSCT candidates, especially in patients with thalassemia and myelodysplastic syndromes. The pathophysiology of iron overload in the HSCT patient and optimum strategies to deal with iron overload during and after HSCT require further study.
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Affiliation(s)
- Vinod Pullarkat
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, 150 East Duarte Road, Duarte, CA 91010, USA
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Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study. Leuk Res 2010; 34:1143-50. [PMID: 20451251 DOI: 10.1016/j.leukres.2010.03.009] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2009] [Revised: 03/05/2010] [Accepted: 03/06/2010] [Indexed: 11/24/2022]
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Leitch HA. Delineating parameters of iron overload in MDS patients treated with deferasirox. Leuk Res 2010; 34:1556-7. [PMID: 20719382 DOI: 10.1016/j.leukres.2010.06.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2010] [Revised: 06/30/2010] [Accepted: 06/30/2010] [Indexed: 11/24/2022]
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Abstract
The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis in one or more cell lines, resulting in insufficient bone marrow function. For most patients with MDS, supportive care by blood transfusions is still the mainstay of treatment. Especially in low-risk patients, anemia represents the major clinical problem, and many of these patients develop transfusional iron overload. This paper reviews the literature on transfusional iron overload in patients with MDS, looking at pathophysiology, evaluation, and treatment of the transfusional iron burden with desferrioxamine and oral chelators.
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Affiliation(s)
- Peter-D Jensen
- Department of Hematology, Arhus University Hospital, Aalborg Hospital, Hobrovej 42A, DK-9100 Aalborg, Denmark.
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