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Cao S, Pang Y, Wei Y, Wang D, Xiong A, Yan J, Zeng H. Bibliometric and graphical analysis of ferroptosis and aging research: Trends, gaps, and future directions. Pathol Res Pract 2025; 269:155949. [PMID: 40174280 DOI: 10.1016/j.prp.2025.155949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/11/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
Over the past 12 years, a significant body of evidence derived from extensive research has underscored the pivotal involvement of ferroptosis in the mechanisms underlying aging. Despite the growing body of literature on this topic, there remains a paucity of analytical and descriptive studies that explore its trajectory, key research directions, current trends, primary focal points, and future outlooks. This research endeavors to provide an exhaustive overview of the advancements in understanding the relationship between ferroptosis and aging over the past 12 years. The dataset utilized in this study was extracted from the Web of Science, encompassing records from January 1, 2012, through June 19, 2024. We conducted comprehensive bibliometric and visual analyses using advanced analytical tools. The results highlight China's dominant contribution, which accounts for 48.52 % of total publications, positioning it as a key player in this research area. Leading institutions, including Columbia University, Southern Medical University, and the Salk Institute for Biological Studies, demonstrate high research productivity. Pamela Maher and Gu Wei are identified as the most prolific researchers in this field. Free Radical Biology and Medicine is the leading journal, publishing the most articles in this field. This study identifies mitochondrial diseases, arrhythmias, Parkinson's disease, hepatocellular carcinoma, and iron-refractory iron deficiency anemia as the key diseases investigated in this field. This bibliometric evaluation offers critical perspectives for both experienced scholars and early-career researchers, enabling the identification of novel ideas and advancements within this domain.
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Affiliation(s)
- Siyang Cao
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China
| | - Yingchen Pang
- Department of Pulmonary and Critical Care Medicine, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Department of Pulmonary and Critical Care Medicine, Shenzhen Xinhua Hospital, Shenzhen, Guangdong, PR China
| | - Yihao Wei
- Department of Rehabilitation Science, The Hong Kong Polytechnic University, Hong Kong; Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, Guangdong, PR China; Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, PR China
| | - Deli Wang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China
| | - Ao Xiong
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China.
| | - Jun Yan
- Department of Radiology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China.
| | - Hui Zeng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, PR China; Department of Orthopedics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, PR China.
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Parlak G, Aksu MD, Gümrük F, Ünal Ş. Single-center experience of four cases with iron-refractory iron deficiency anemia (IRIDA). Turk J Pediatr 2024; 66:658-665. [PMID: 39582459 DOI: 10.24953/turkjpediatr.2024.4522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 09/30/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND Iron refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive type of anemia characterized by unresponsiveness to oral iron therapy and partial response to parenteral iron therapy. In this article, we report the clinical presentation of four patients with IRIDA admitted to our clinic, including their laboratory values at admission and after oral and parenteral iron treatment, and the analysis of their mutation(s) in TMPRSS6 gene. CASE Four patients from different families, aged between 3 and 14 years, two girls and two boys, two of whom were from consanguineous marriages, who were diagnosed with iron deficiency anemia in primary health care institutions and referred to our clinic because of inadequate response to oral iron treatment were included. Patients were evaluated for the differential diagnosis of microcytic, hypochromic anemia and investigated for the etiology of IDA. Homozygous or compound heterozygous mutations causing defective matriptase-2 protein expression were detected in the TMPRSS6 gene; these mutations included four frameshift mutations-two of which were the same in two cases and causing premature terminal stop codons-and a nonsense mutation, all of which were previously demonstrated in the literature. The response to parental iron therapy ranged from complete non-response to mild to good response in hemoglobin levels, but none of the patients showed improvement in iron parameters. CONCLUSIONS Increased awareness of IRIDA and keeping it in mind in the differential diagnosis in the presence of hypochromic microcytic anemia that does not respond to iron treatment will be crucial in improving the diagnosis and treatment of the disease and ultimately enhancing the quality of care for affected individuals.
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Affiliation(s)
- Gülin Parlak
- Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Türkiye
| | - Muhammed Doğukan Aksu
- Faculty of Medicine, Hacettepe University, Ankara, Türkiye
- Department of Basic Oncology, Cancer Institute, Hacettepe University, Ankara, Türkiye
| | - Fatma Gümrük
- Department of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Ankara, Türkiye
| | - Şule Ünal
- Department of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Ankara, Türkiye
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Dentand AL, Schubert MG, Krayenbuehl PA. Current iron therapy in the light of regulation, intestinal microbiome, and toxicity: are we prescribing too much iron? Crit Rev Clin Lab Sci 2024; 61:546-558. [PMID: 38606523 DOI: 10.1080/10408363.2024.2331477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/26/2024] [Accepted: 03/13/2024] [Indexed: 04/13/2024]
Abstract
Iron deficiency is a widespread global health concern with varying prevalence rates across different regions. In developing countries, scarcity of food and chronic infections contribute to iron deficiency, while in industrialized nations, reduced food intake and dietary preferences affect iron status. Other causes that can lead to iron deficiency are conditions and diseases that result in reduced intestinal iron absorption and blood loss. In addition, iron absorption and its bioavailability are influenced by the composition of the diet. Individuals with increased iron needs, including infants, adolescents, and athletes, are particularly vulnerable to deficiency. Severe iron deficiency can lead to anemia with performance intolerance or shortness of breath. In addition, even without anemia, iron deficiency leads to mental and physical fatigue, which points to the fundamental biological importance of iron, especially in mitochondrial function and the respiratory chain. Standard oral iron supplementation often results in gastrointestinal side effects and poor compliance. Low-dose iron therapy seems to be a valid and reasonable therapeutic option due to reduced hepatic hepcidin formation, facilitating efficient iron resorption, replenishment of iron storage, and causing significantly fewer side effects. Elevated iron levels influence gut microbiota composition, favoring pathogenic bacteria and potentially disrupting metabolic and immune functions. Protective bacteria, such as bifidobacteria and lactobacilli, are particularly susceptible to increased iron levels. Dysbiosis resulting from iron supplementation may contribute to gastrointestinal disorders, inflammatory bowel disease, and metabolic disturbances. Furthermore, gut microbiota alterations have been linked to mental health issues. Future iron therapy should consider low-dose supplementation to mitigate adverse effects and the impact on the gut microbiome. A comprehensive understanding of the interplay between iron intake, gut microbiota, and human health is crucial for optimizing therapeutic approaches and minimizing potential risks associated with iron supplementation.
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Affiliation(s)
- Anaëlle L Dentand
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland
| | - Morton G Schubert
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland
| | - Pierre-Alexandre Krayenbuehl
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland
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Correnti M, Gammella E, Cairo G, Recalcati S. Iron Absorption: Molecular and Pathophysiological Aspects. Metabolites 2024; 14:228. [PMID: 38668356 PMCID: PMC11052485 DOI: 10.3390/metabo14040228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/12/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Iron is an essential nutrient for growth among all branches of life, but while iron is among the most common elements, bioavailable iron is a relatively scarce nutrient. Since iron is fundamental for several biological processes, iron deficiency can be deleterious. On the other hand, excess iron may lead to cell and tissue damage. Consequently, iron balance is strictly regulated. As iron excretion is not physiologically controlled, systemic iron homeostasis is maintained at the level of absorption, which is mainly influenced by the amount of iron stores and the level of erythropoietic activity, the major iron consumer. Here, we outline recent advances that increased our understanding of the molecular aspects of iron absorption. Moreover, we examine the impact of these recent insights on dietary strategies for maintaining iron balance.
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Affiliation(s)
| | | | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy; (M.C.); (E.G.); (S.R.)
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Sharma A, Kumar A, Saha PK, Saha L. The role of TMPRSS6 gene polymorphism in iron resistance iron deficiency anaemia (IRIDA): a systematic review. Ann Hematol 2024; 103:1085-1102. [PMID: 38072851 DOI: 10.1007/s00277-023-05576-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/30/2023] [Indexed: 03/16/2024]
Abstract
Iron resistance iron deficiency anaemia is a rare autosomal recessive disorder characterized by hypochromic microcytic anaemia, low transferrin saturation and inappropriately high hepcidin levels. The aetiology of this condition is rooted in genetic variations within the transmembrane serine protease 6 (TMPRSS6) genes, responsible for encoding matriptase-2, a pivotal negative regulator of hepcidin. We conducted a systematic search across four electronic databases, yielding 538 articles in total out of which 25 were finally included and were preceded further, aiming to prognosticate prevalent single nucleotide polymorphisms (SNPs) and detrimental genetic alterations. This review aims to elucidate the effects of various SNPs and pathogenic mutations on both haematological and biochemical parameters, as well as their potential interethnic correlation. Employing bioinformatics tools, we subjected over 100 SNPs to scrutiny, discerning their potential functional ramifications. We found rs1373272804, rs1430692214 and rs855791 variants to be most frequent and were having a significant impact on haematological and biochemical profile. We found that individuals of European ancestry were more prone to have these variants compared to other ethnic groups. In conclusion, this review not only sheds light on the association of TMPRSS6 polymorphism in iron resistance iron deficiency anaemia (IRIDA), but also highlights the critical need for further investigations involving larger sample size and more diverse ethnic groups around the globe. These future studies will be vital for gaining a stronger and more reliable understanding of how these genetic differences are linked to the development of IRIDA.
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Affiliation(s)
- Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), 4Th Floor, Research Block B, Chandigarh, India, 160012
| | - Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), 4Th Floor, Research Block B, Chandigarh, India, 160012
| | - Pradip Kumar Saha
- Department of Obstetrics and Gynaecology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India, 160012
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), 4Th Floor, Research Block B, Chandigarh, India, 160012.
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Hamed HM, Bostany EE, Motawie AA, Abd Al-Aziz AM, Mourad AA, Salama HM, Kamel S, Hassan EM, Helmy NA, El-Saeed GS, Elghoroury EA. The association of TMPRSS6 gene polymorphism with iron status in Egyptian children (a pilot study). BMC Pediatr 2024; 24:105. [PMID: 38341535 PMCID: PMC10858485 DOI: 10.1186/s12887-024-04573-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 01/18/2024] [Indexed: 02/12/2024] Open
Abstract
Several studies have shown association of single nucleotide polymorphisms (SNPs) of hepcidin regulatory pathways genes with impaired iron status. The most common is in the TMPRSS6 gene. In Africa, very few studies have been reported. We aimed to investigate the correlation between the common SNPs in the transmembrane protease, serine 6 (TMPRSS6) gene and iron indicators in a sample of Egyptian children for identifying the suitable candidate for iron supplementation.Patients and methods One hundred and sixty children aged 5-13 years were included & classified into iron deficient, iron deficient anemia and normal healthy controls. All were subjected to assessment of serum iron, serum ferritin, total iron binding capacity, complete blood count, reticulocyte count, serum soluble transferrin receptor and serum hepcidin. Molecular study of TMPRSS6 genotyping polymorphisms (rs4820268, rs855791 and rs11704654) were also evaluated.Results There was an association of iron deficiency with AG of rs855791 SNP, (P = 0.01). The minor allele frequency for included children were 0.43, 0.45 & 0.17 for rs4820268, rs855791 & rs11704654 respectively. Genotype GG of rs4820268 expressed the highest hepcidin gene expression fold, the lowest serum ferroportin & iron store compared to AA and AG genotypes (p = 0.05, p = 0.05, p = 0.03 respectively). GG of rs855791 had lower serum ferritin than AA (p = 0.04), lowest iron store & highest serum hepcidin compared to AA and AG genotypes (p = 0.04, p = 0.01 respectively). Children having CC of rs11704654 had lower level of hemoglobin, serum ferritin and serum hepcidin compared with CT genotype (p = 0.01, p = 0.01, p = 0.02) respectively.Conclusion Possible contribution of SNPs (rs855791, rs4820268 and rs11704654) to low iron status.
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Grants
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- 11010150 National Research Centre, Egypt
- National Research Centre Egypt
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Affiliation(s)
- Hanan M Hamed
- Pediatrics Department, National Research Centre, Dokki, Cairo, 12622, Egypt.
| | - Eman El Bostany
- Pediatrics Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Ayat A Motawie
- Pediatrics Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | | | - Abbass A Mourad
- Pediatrics Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Hassan M Salama
- Pediatrics Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Solaf Kamel
- Clinical and Chemical Pathology Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Eman M Hassan
- Clinical and Chemical Pathology Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Neveen A Helmy
- Clinical and Chemical Pathology Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Gamila S El-Saeed
- Medical Biochemistry Department, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Eman A Elghoroury
- Clinical and Chemical Pathology Department, National Research Centre, Dokki, Cairo, 12622, Egypt
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Duminuco A, Chifotides HT, Giallongo S, Giallongo C, Tibullo D, Palumbo GA. ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis. Cancers (Basel) 2023; 16:154. [PMID: 38201581 PMCID: PMC10778144 DOI: 10.3390/cancers16010154] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.
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Affiliation(s)
- Andrea Duminuco
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy;
| | - Helen T. Chifotides
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd., Houston, TX 77030, USA;
| | - Sebastiano Giallongo
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (S.G.); (C.G.)
| | - Cesarina Giallongo
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (S.G.); (C.G.)
| | - Daniele Tibullo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
| | - Giuseppe A. Palumbo
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy;
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy; (S.G.); (C.G.)
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Dunlea E, Crushell E, Cotter M, Blau N, Ferreira CR. Clinical and biochemical footprints of inherited metabolic disease. XVI. Hematological abnormalities. Mol Genet Metab 2023; 140:107735. [PMID: 37989003 PMCID: PMC11752444 DOI: 10.1016/j.ymgme.2023.107735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/08/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Many classical inherited metabolic diseases (IMDs) are associated with significant hematological complications such as anemia or thrombosis. While these may not be the prominent presenting feature of these conditions, management of these issues is important for optimal outcomes in people with IMDs. Some disorders that are included in the nosology of inherited metabolic disorders, such as inherited disorders of red cell energy metabolism, have purely hematological features, and have typically been cared for by a hematologist. In the 16th issue of the Footprints series, we identified 265 IMDs associated with hematological abnormalities. We review the major hematological manifestations of IMDs, suggest further investigation of hematological findings, and discuss treatment options available for specific hematological complications of IMDs.
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Affiliation(s)
- Eoghan Dunlea
- Dept of Haematology, Children's Health Ireland, Temple Street, Dublin, Ireland; School of Medicine, Trinity College, Dublin, Ireland.
| | - Ellen Crushell
- National Centre for Inherited Metabolic Disorders, Children's Health Ireland, Temple Street, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland
| | - Melanie Cotter
- Dept of Haematology, Children's Health Ireland, Temple Street, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland.
| | - Nenad Blau
- Division of Metabolism, University Children's Hospital, Zürich, Switzerland.
| | - Carlos R Ferreira
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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Scaramellini N, Fischer D, Agarvas AR, Motta I, Muckenthaler MU, Mertens C. Interpreting Iron Homeostasis in Congenital and Acquired Disorders. Pharmaceuticals (Basel) 2023; 16:ph16030329. [PMID: 36986429 PMCID: PMC10054723 DOI: 10.3390/ph16030329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
Mammalian cells require iron to satisfy their metabolic needs and to accomplish specialized functions, such as hematopoiesis, mitochondrial biogenesis, energy metabolism, or oxygen transport. Iron homeostasis is balanced by the interplay of proteins responsible for iron import, storage, and export. A misbalance of iron homeostasis may cause either iron deficiencies or iron overload diseases. The clinical work-up of iron dysregulation is highly important, as severe symptoms and pathologies may arise. Treating iron overload or iron deficiency is important to avoid cellular damage and severe symptoms and improve patient outcomes. The impressive progress made in the past years in understanding mechanisms that maintain iron homeostasis has already changed clinical practice for treating iron-related diseases and is expected to improve patient management even further in the future.
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Affiliation(s)
- Natalia Scaramellini
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Dania Fischer
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Anand R. Agarvas
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
| | - Irene Motta
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Martina U. Muckenthaler
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Side, 69120 Heidelberg, Germany
| | - Christina Mertens
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- Correspondence: ; Tel.: +49-6221564582; Fax: +49-6221564580
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The Incidence and Risk Factors for Allogeneic Blood Transfusions in Pediatric Spine Surgery: National Data. Healthcare (Basel) 2023; 11:healthcare11040533. [PMID: 36833065 PMCID: PMC9956304 DOI: 10.3390/healthcare11040533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/29/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
(1) Background: Pediatric spinal surgery is a blood-intensive procedure. In order to introduce a rational blood management program, identifying the risk factors for transfusions is mandatory. (2) Methods: Data from the national database covering the period from January 2015 to July 2017 were analyzed. The available data included the demographics, characteristics of the surgeries performed, length of stay, and in-house mortality. (3) Results: The total number of patients used for the analysis was 2302. The primary diagnosis was a spinal deformity (88.75%). Most fusions were long, with four levels or more (89.57%). A total of 938 patients received a transfusion; thus, the transfusion rate was 40.75%. The present study identified several risk factors; the most significant was a number of levels fused greater than 4 (RR 5.51; CI95% 3.72-8.15; p < 0.0001), followed by the deformity as the main diagnosis (RR 2.69; CI95% 1.98-3.65; p < 0.0001). These were the two most significant factors increasing the odds of a transfusion. Other factors associated with an increased risk of transfusion were elective surgery, the female sex, and an anterior approach. The mean length of stay in days was 11.42 (SD 9.93); this was greater in the transfused group (14.20 vs. 9.50; p < 0.0001). (4) Conclusions: The rate of transfusions in pediatric spinal surgery remains high. A new patient blood management program is necessary to improve this situation.
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Fan S, Zhao T, Sun L. The global prevalence and ethnic heterogeneity of iron-refractory iron deficiency anaemia. Orphanet J Rare Dis 2023; 18:2. [PMID: 36604716 PMCID: PMC9814447 DOI: 10.1186/s13023-022-02612-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Iron-refractory iron deficiency anaemia (IRIDA) is an autosomal recessive iron deficiency anaemia caused by mutations in the TMPRSS6 gene. Iron deficiency anaemia is common, whereas IRIDA is rare. The prevalence of IRIDA is unclear. This study aimed to estimate the carrier frequency and genetic prevalence of IRIDA using Genome Aggregation Database (gnomAD) data. METHODS The pathogenicity of TMPRSS6 variants was interpreted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines. The minor allele frequency (MAF) of TMPRSS6 gene disease-causing variants in 141,456 unique individuals was examined to estimate the global prevalence of IRIDA in seven ethnicities: African/African American (afr), American Admixed/Latino (amr), Ashkenazi Jewish (asj), East Asian (eas), Finnish (fin), Non-Finnish European (nfe) and South Asian (sas). The global and population-specific carrier frequencies and genetic prevalence of IRIDA were calculated using the Hardy-Weinberg equation. RESULTS In total, 86 pathogenic/likely pathogenic variants (PV/LPV) were identified according to ACMG/AMP guideline. The global carrier frequency and genetic prevalence of IRIDA were 2.02 per thousand and 1.02 per million, respectively. CONCLUSIONS The prevalence of IRIDA is greater than previous estimates.
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Affiliation(s)
- Shanghua Fan
- grid.412632.00000 0004 1758 2270Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060 China
| | - Ting Zhao
- grid.414011.10000 0004 1808 090XDepartment of Neurology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003 China
| | - Liu Sun
- Department of Information Technology, School of Mathematics and Information Technology, Yuxi Normal University, Yuxi, 653100, China.
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12
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Response to Prolonged Duration of Therapeutic Dose Oral Iron Therapy in a Girl With Novel TMPRSS6 Gene Variants: A Case Report and Review Literature. J Pediatr Hematol Oncol 2023; 45:e109-e118. [PMID: 36598965 DOI: 10.1097/mph.0000000000002573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 09/18/2022] [Indexed: 01/05/2023]
Abstract
Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in the TMPRSS6 gene, which impair iron homeostasis. We reported a 4-year-old girl who presented with a 1-year history of iron deficiency anemia. Her hemoglobin level increased from 6.5 g/dL to 12.6 g/dL with a prolonged duration of therapeutic dose oral iron therapy (5 mg/kg/d), and the level remained quite stable during the therapy. Genetic analysis of the TMPRSS6 gene revealed compound heterozygotes of 2 novel pathogenic variants: c.811C> T (NM_153609.3) in exon 7 (NP_705837: p.R271Ter) and c.1254C> G in exon 11 (p.Y418Ter). The results highlight the significance of genetic investigation and long-term iron therapy in iron-refractory iron deficiency anemia patients.
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13
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Al-Jamea LH, Woodman A, M. Heiba N, Elshazly SA, Ben Khalaf N, Al-Yami FS, Bilal Waheed K, Al Mutair A, Alsedi A, Quiambao JV, Alzahrani FM, Albaqami WF, Al Qahtani FH, Mohammed Aljarah N, Fathallah DM, Halim Deifalla A. TMPRSS6 gene mutations in six Saudi families with iron refractory iron deficiency anemia. Gene 2023; 851:146977. [DOI: 10.1016/j.gene.2022.146977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/07/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022]
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14
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Świątczak M, Młodziński K, Sikorska K, Raczak A, Lipiński P, Daniłowicz-Szymanowicz L. Chronic Fatigue Syndrome in Patients with Deteriorated Iron Metabolism. Diagnostics (Basel) 2022; 12:diagnostics12092057. [PMID: 36140459 PMCID: PMC9498000 DOI: 10.3390/diagnostics12092057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/11/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Fatigue is a common, non-specific symptom that often impairs patients’ quality of life. Even though fatigue may be the first symptom of many serious diseases, it is often underestimated due to its non-specific nature. Iron metabolism disorders are a prominent example of conditions where fatigue is a leading symptom. Whether it is an iron deficiency or overload, tiredness is one of the most common features. Despite significant progress in diagnosing and treating iron pathologies, the approach to chronic fatigue syndrome in such patients is not precisely determined. Our study aims to present the current state of knowledge on fatigue in patients with deteriorated iron metabolism.
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Affiliation(s)
- Michał Świątczak
- II Department of Cardiology and Electrotherapy, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
| | - Krzysztof Młodziński
- II Department of Cardiology and Electrotherapy, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
| | - Katarzyna Sikorska
- Department of Tropical Medicine and Epidemiology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
| | - Alicja Raczak
- Clinical Psychology Department, Faculty of Health Sciences, Medical University of Gdańsk, 80-210 Gdańsk, Poland
| | - Paweł Lipiński
- Department of Molecular Biology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Wólka Kosowska, 05-552 Jastrzębiec, Poland
| | - Ludmiła Daniłowicz-Szymanowicz
- II Department of Cardiology and Electrotherapy, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
- Correspondence:
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15
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Zulfiqar A, Naseer S, Saleem A, Ahmed S, Sardar R. Genetic diversity studies for grain iron and zinc content analysis for Elite rice (Oryza sativa L.) genotype by using SSR markers. J Food Compost Anal 2022. [DOI: 10.1016/j.jfca.2022.104816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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16
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Hoving V, Korman SE, Antonopoulos P, Donker AE, Schols SEM, Swinkels DW. IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology. Genes (Basel) 2022; 13:genes13081309. [PMID: 35893046 PMCID: PMC9331965 DOI: 10.3390/genes13081309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 12/19/2022] Open
Abstract
Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant.
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Affiliation(s)
- Vera Hoving
- Department of Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands;
| | - Scott E. Korman
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands; (S.E.K.); (P.A.); (D.W.S.)
| | - Petros Antonopoulos
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands; (S.E.K.); (P.A.); (D.W.S.)
| | - Albertine E. Donker
- Department of Pediatrics, Máxima Medical Center, De Run 4600, 5504 NB Veldhoven, The Netherlands;
| | - Saskia E. M. Schols
- Department of Hematology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands;
- Correspondence:
| | - Dorine W. Swinkels
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GE Nijmegen, The Netherlands; (S.E.K.); (P.A.); (D.W.S.)
- Sanquin Blood Bank, Sanquin Diagnostics BV, Plesmanlaan 125, 1066 NH Amsterdam, The Netherlands
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17
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The mutual crosstalk between iron and erythropoiesis. Int J Hematol 2022; 116:182-191. [PMID: 35618957 DOI: 10.1007/s12185-022-03384-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 04/26/2022] [Accepted: 05/06/2022] [Indexed: 02/08/2023]
Abstract
Iron homeostasis and erythropoiesis are strongly interconnected. On one side iron is essential to terminal erythropoiesis for hemoglobin production, on the other erythropoiesis may increase iron absorption through the production of erythroferrone, the erythroid hormone that suppresses hepcidin expression Also erythropoietin production is modulated by iron through the iron regulatory proteins-iron responsive elements that control the hypoxia inducible factor 2-α. The second transferrin receptor, an iron sensor both in the liver and in erythroid cells modulates erythropoietin sensitivity and is a further link between hepcidin and erythropoiesis. When erythropoietin is decreased in iron deficiency the erythropoietin sensitivity is increased because the second transferrin receptor is removed from cell surface. A deranged balance between erythropoiesis and iron/hepcidin may lead to anemia, as in the case of iron deficiency, defective iron uptake and erythroid utilization or subnormal recycling. Defective control of hepcidin production may cause iron deficiency, as in the recessive disorder iron refractory iron deficiency anemia or in anemia of inflammation, or in iron loading anemias, which are characterized by excessive but ineffective erythropoiesis. The elucidation of the mechanisms that regulates iron homeostasis and erythropoiesis is leading to the development of drugs for the benefit of both iron and erythropoiesis disorders.
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18
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Evaluation of liver specific ionizable lipid nanocarrierin the delivery of siRNA. Chem Phys Lipids 2022; 246:105207. [PMID: 35623403 DOI: 10.1016/j.chemphyslip.2022.105207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 05/08/2022] [Accepted: 05/11/2022] [Indexed: 11/23/2022]
Abstract
Hepcidin, a key regulator of iron homeostasis, has been implicated in the pathogenesis of various iron-related diseases. Although small interfering RNA (siRNA) are potent to modulate the expression of hepcidin, their bioavailability remains a major issue. The β-galactopyranoside-conjugated liposomes (GAL-liposome) targeting liver synthesized hepcidin were prepared by thin lipid film hydration method to encapsulate siRNA and the conjugation of β-galactopyranoside to the lipid nanocarrier was achieved by covalent chemistry. The prepared siRNA loaded GAL-lip were spherical with around 50 nm radius in size as observed by HR-TEM. The zeta potential and polydispersity index of the prepared liposomes were -19.9±0.96 mV and 0.44±0.05, respectively. The encapsulation efficiency as determined by dialysis bag method was around 91.76±1.74%. The cell viability and cellular uptake analysis was examined in HepG2 cells by MTT assay and flow cytometry, respectively. The stability and cumulative release of siRNA was also assessed. The hepcidin mRNA expression on administration of siRNA loaded GAL-lip was determined in HepG2 cells and in lipopolysaccharide-induced mice model followed by examining itsin vivo biodistribution by fluorescence microscopy. The results suggested thatsiRNA loaded GAL-lip reduced the hepcidin levels, thus, highlighting a novel ligand conjugated ionizable lipid-based nanocarrier for inducing RNA interference.
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19
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Correnti M, Gammella E, Cairo G, Recalcati S. Iron Mining for Erythropoiesis. Int J Mol Sci 2022; 23:ijms23105341. [PMID: 35628152 PMCID: PMC9140467 DOI: 10.3390/ijms23105341] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/05/2022] [Accepted: 05/09/2022] [Indexed: 01/27/2023] Open
Abstract
Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis.
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20
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van der Staaij H, Donker AE, Bakkeren DL, Salemans JMJI, Mignot-Evers LAA, Bongers MY, Dieleman JP, Galesloot TE, Laarakkers CM, Klaver SM, Swinkels DW. Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia. Int J Mol Sci 2022; 23:ijms23031917. [PMID: 35163840 PMCID: PMC8836508 DOI: 10.3390/ijms23031917] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/30/2022] [Accepted: 02/03/2022] [Indexed: 02/04/2023] Open
Abstract
Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population.
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Affiliation(s)
- Hilde van der Staaij
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center (Radboudumc), 6525 GA Nijmegen, The Netherlands; (H.v.d.S.); (A.E.D.); (C.M.L.); (S.M.K.)
- Máxima Medical Center (MMC), Department of Pediatrics, 5504 DB Veldhoven, The Netherlands
| | - Albertine E. Donker
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center (Radboudumc), 6525 GA Nijmegen, The Netherlands; (H.v.d.S.); (A.E.D.); (C.M.L.); (S.M.K.)
- Máxima Medical Center (MMC), Department of Pediatrics, 5504 DB Veldhoven, The Netherlands
| | - Dirk L. Bakkeren
- Máxima Medical Center (MMC), Department of Clinical Chemistry, 5504 DB Veldhoven, The Netherlands;
| | - Jan M. J. I. Salemans
- Máxima Medical Center (MMC), Department of Gastroenterology, 5504 DB Veldhoven, The Netherlands;
| | | | - Marlies Y. Bongers
- Máxima Medical Center (MMC), Department of Gynecology, 5504 DB Veldhoven, The Netherlands;
- Maastricht University Medical Center, Department of Gynecology, 6229 HX Maastricht, The Netherlands
| | - Jeanne P. Dieleman
- Máxima Medical Center Academy, Máxima Medical Center (MMC), 5504 DB Veldhoven, The Netherlands;
| | - Tessel E. Galesloot
- Department for Health Evidence, Radboud Institute for Health Sciences, 6500 HB Nijmegen, The Netherlands;
| | - Coby M. Laarakkers
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center (Radboudumc), 6525 GA Nijmegen, The Netherlands; (H.v.d.S.); (A.E.D.); (C.M.L.); (S.M.K.)
- Hepcidinanalysis, Translational Metabolic Laboratory, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands
| | - Siem M. Klaver
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center (Radboudumc), 6525 GA Nijmegen, The Netherlands; (H.v.d.S.); (A.E.D.); (C.M.L.); (S.M.K.)
- Hepcidinanalysis, Translational Metabolic Laboratory, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands
| | - Dorine W. Swinkels
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center (Radboudumc), 6525 GA Nijmegen, The Netherlands; (H.v.d.S.); (A.E.D.); (C.M.L.); (S.M.K.)
- Hepcidinanalysis, Translational Metabolic Laboratory, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands
- Correspondence: ; Tel.: +31-(0)2-4361-8957
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21
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Anemia feriprivă – manifestare de debut al unei boli celiace oculte. ONCOLOG-HEMATOLOG.RO 2022. [DOI: 10.26416/onhe.60.3.2022.7153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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22
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Rana S, Prabhakar N. Iron disorders and hepcidin. Clin Chim Acta 2021; 523:454-468. [PMID: 34755647 DOI: 10.1016/j.cca.2021.10.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022]
Abstract
Iron is an essential element due to its role in a wide variety of physiological processes. Iron homeostasis is crucial to prevent iron overload disorders as well as iron deficiency anemia. The liver synthesized peptide hormone hepcidin is a master regulator of systemic iron metabolism. Given its role in overall health, measurement of hepcidin can be used as a predictive marker in disease states. In addition, hepcidin-targeting drugs appear beneficial as therapeutic agents. This review emphasizes recent development on analytical techniques (immunochemical, mass spectrometry and biosensors) and therapeutic approaches (hepcidin agonists, stimulators and antagonists). These insights highlight hepcidin as a potential biomarker as well as an aid in the development of new drugs for iron disorders.
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Affiliation(s)
- Shilpa Rana
- Department of Biochemistry, Sector-25, Panjab University, Chandigarh 160014, India
| | - Nirmal Prabhakar
- Department of Biochemistry, Sector-25, Panjab University, Chandigarh 160014, India.
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23
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Snook J, Bhala N, Beales ILP, Cannings D, Kightley C, Logan RP, Pritchard DM, Sidhu R, Surgenor S, Thomas W, Verma AM, Goddard AF. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut 2021; 70:2030-2051. [PMID: 34497146 PMCID: PMC8515119 DOI: 10.1136/gutjnl-2021-325210] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.
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Affiliation(s)
- Jonathon Snook
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Neeraj Bhala
- Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust and Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Ian L P Beales
- Gastroenterology, University of East Anglia, Norwich, UK
| | - David Cannings
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Chris Kightley
- Digestive Diseases, Kettering General Hospital NHS Foundation Trust, Kettering, UK
| | | | - D Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool and Department of Gastroenterology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Reena Sidhu
- Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Sue Surgenor
- Gastroenterology, University Hospitals Dorset NHS Foundation Trust, Poole, UK
| | - Wayne Thomas
- Haematology, Plymouth Hospitals NHS Foundation Trust, Plymouth, Plymouth, UK
| | - Ajay M Verma
- Digestive Diseases, Kettering General Hospital NHS Foundation Trust, Kettering, UK
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McVey MJ, Lau W, Naraine N, Zaarour C, Zeller R. Perioperative blood conservation strategies for pediatric scoliosis surgery. Spine Deform 2021; 9:1289-1302. [PMID: 33900586 DOI: 10.1007/s43390-021-00351-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 04/10/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Many pediatric patients with severe scoliosis requiring surgery have baseline anemia. Pediatric scoliosis fusion surgery is associated with perioperative blood loss requiring transfusion. As such, many patients in this surgical population could benefit from a perioperative blood conservation program. METHODS Here we present a narrative review of perioperative blood conservation strategies for pediatric scoliosis surgery involving nurses, transfusion medicine physicians, anesthesiologists, surgeons, dieticians, perfusionists and neurophysiologists spanning the pre-, intra- and postoperative phases of care. RESULTS The review highlights how perioperative blood conservation strategies, have the potential to minimize exposures to exogenous blood products. Further, we describe a relevant example of blood conservation related to the care of a Jehovah's Witness patient undergoing staged scoliosis repair. Lastly, we outline areas which would benefit from clinical studies to further elucidate perioperative blood conservation interventions and their outcomes relevant to pediatric scoliosis surgery patients. CONCLUSION Interdisciplinary communication and meticulous blood conservation strategies are proving to be a means of reducing if not eliminating the need for allogeneic blood products for surgical correction of pediatric scoliosis.
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Affiliation(s)
- Mark J McVey
- Departments of Anesthesia, University of Toronto, Toronto, ON, Canada. .,Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. .,Department of Physics, Ryerson University, Toronto, ON, Canada.
| | - W Lau
- Transfusion Medicine SickKids Hospital, Toronto, ON, Canada
| | - N Naraine
- Transfusion Medicine SickKids Hospital, Toronto, ON, Canada
| | - C Zaarour
- Departments of Anesthesia, University of Toronto, Toronto, ON, Canada.,Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada
| | - R Zeller
- Department of Pediatric Orthopedic Surgery, The Hospital for Sick Children, 555 Univesity Avenue, Toronto, ON, M5G 1X8, Canada
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Colucci S, Marques O, Altamura S. 20 years of Hepcidin: How far we have come. Semin Hematol 2021; 58:132-144. [PMID: 34389105 DOI: 10.1053/j.seminhematol.2021.05.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/12/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022]
Abstract
Twenty years ago the discovery of hepcidin deeply changed our understanding of the regulation of systemic iron homeostasis. It is now clear that hepcidin orchestrates systemic iron levels by controlling the amount of iron exported into the bloodstream through ferroportin. Hepcidin expression is increased in situations where systemic iron levels should be reduced, such as in iron overload and infection. Conversely, hepcidin is repressed during iron deficiency, hypoxia or expanded erythropoiesis, to increase systemic iron availability and sustain erythropoiesis. In this review, we will focus on molecular mechanisms of hepcidin regulation and on the pathological consequences of their disruption.
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Affiliation(s)
- Silvia Colucci
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany
| | - Oriana Marques
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany
| | - Sandro Altamura
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany..
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26
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Camaschella C, Pagani A. Mendelian inheritance of anemia due to disturbed iron homeostasis. Semin Hematol 2021; 58:175-181. [PMID: 34389109 DOI: 10.1053/j.seminhematol.2021.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/16/2021] [Accepted: 05/31/2021] [Indexed: 02/01/2023]
Abstract
Genetic disorders that affect proteins involved in maintaining iron balance may lead to Mendelian anemias. They may be classified as defects of intestinal iron absorption, iron transport in the circulation, iron uptake and utilization by maturing erythroid cells, iron recycling by macrophages and systemic regulation of iron homeostasis. All these Mendelian anemias are rare disorders, prevalently recessive, characterized by microcytic and hypochromic red blood cells. Advances in our knowledge of iron metabolism and its systemic regulation on one side have facilitated the identification of novel iron related anemias, while on the other the study of the affected patients and of the corresponding animal models have contributed to our understanding of iron trafficking and regulation.
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Affiliation(s)
- Clara Camaschella
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
| | - Alessia Pagani
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
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Xu Y, Alfaro-Magallanes VM, Babitt JL. Physiological and pathophysiological mechanisms of hepcidin regulation: clinical implications for iron disorders. Br J Haematol 2021; 193:882-893. [PMID: 33316086 PMCID: PMC8164969 DOI: 10.1111/bjh.17252] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/04/2020] [Indexed: 02/06/2023]
Abstract
The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin assures the balance of circulating and stored iron levels for multiple physiological processes including oxygen transport and erythropoiesis, while limiting the toxicity of excess iron. The liver is the major site where regulatory signals from iron, erythropoietic drive and inflammation are integrated to control hepcidin production. Pathologically, hepcidin dysregulation by genetic inactivation, ineffective erythropoiesis, or inflammation leads to diseases of iron deficiency or overload such as iron-refractory iron-deficiency anaemia, anaemia of inflammation, iron-loading anaemias and hereditary haemochromatosis. In the present review, we discuss recent insights into the molecular mechanisms governing hepcidin regulation, how these pathways are disrupted in iron disorders, and how this knowledge is being used to develop novel diagnostic and therapeutic strategies.
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Affiliation(s)
- Yang Xu
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Víctor M. Alfaro-Magallanes
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- LFE Research Group, Department of Health and Human Performance, Faculty of Physical Activity and Sport Sciences, Universidad Politécnica de Madrid (UPM), Madrid, Spain
| | - Jodie L. Babitt
- Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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28
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Delivery systems for improving iron uptake in anemia. Int J Pharm 2021; 601:120590. [PMID: 33845149 DOI: 10.1016/j.ijpharm.2021.120590] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/30/2021] [Accepted: 04/05/2021] [Indexed: 01/01/2023]
Abstract
Anemia poses a threat to a broad population globally as depleted hemoglobin leads to a plethora of conditions, and the most common cause includes iron deficiency. Iron is an essential element important for erythropoiesis, DNA synthesis, protection of the immune system, energy production, and cognitive function and hence should be maintained at appropriate levels. Various proteins are involved in transporting and absorption of iron, activation of heme synthesis, and RBC production that could be possible targets to improve iron delivery. Oral supplementation of iron either from dietary or synthetic sources has been the frontline therapy for treating iron deficiency in anemia. At the same time, intravenous administration is provided in chronic anemia, such as chronic kidney diseases (CKD). This review focuses on the strategies developed to overcome the disadvantages of available iron therapies and increase iron absorption and uptake in the body to restore iron content. Nanotechnology combined with the food fortification processes gained attention as they help develop new delivery systems to improve iron uptake by enterocytes. Furthermore, naturally obtained products such as polysaccharides, peptides, proteins, and new synthetic molecules have been used in fabrication of iron-carrier systems. The establishment of transdermal iron delivery systems such as microneedle arrays or iontophoresis, or the discovery of new molecules also proved to be an effective way for delivering iron in patients non-compliant to oral therapy.
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Hu Y, Stilp AM, McHugh CP, Rao S, Jain D, Zheng X, Lane J, Méric de Bellefon S, Raffield LM, Chen MH, Yanek LR, Wheeler M, Yao Y, Ren C, Broome J, Moon JY, de Vries PS, Hobbs BD, Sun Q, Surendran P, Brody JA, Blackwell TW, Choquet H, Ryan K, Duggirala R, Heard-Costa N, Wang Z, Chami N, Preuss MH, Min N, Ekunwe L, Lange LA, Cushman M, Faraday N, Curran JE, Almasy L, Kundu K, Smith AV, Gabriel S, Rotter JI, Fornage M, Lloyd-Jones DM, Vasan RS, Smith NL, North KE, Boerwinkle E, Becker LC, Lewis JP, Abecasis GR, Hou L, O'Connell JR, Morrison AC, Beaty TH, Kaplan R, Correa A, Blangero J, Jorgenson E, Psaty BM, Kooperberg C, Walton RT, Kleinstiver BP, Tang H, Loos RJF, Soranzo N, Butterworth AS, Nickerson D, Rich SS, Mitchell BD, Johnson AD, Auer PL, Li Y, Mathias RA, Lettre G, Pankratz N, Laurie CC, Laurie CA, Bauer DE, Conomos MP, Reiner AP. Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. Am J Hum Genet 2021; 108:874-893. [PMID: 33887194 DOI: 10.1016/j.ajhg.2021.04.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
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Affiliation(s)
- Yao Hu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA
| | - Adrienne M Stilp
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Caitlin P McHugh
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Shuquan Rao
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA
| | - Deepti Jain
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Xiuwen Zheng
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - John Lane
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | | | - Laura M Raffield
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Ming-Huei Chen
- Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA; National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA
| | - Lisa R Yanek
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Marsha Wheeler
- Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA
| | - Yao Yao
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA
| | - Chunyan Ren
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA
| | - Jai Broome
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Jee-Young Moon
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Paul S de Vries
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Brian D Hobbs
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Quan Sun
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Praveen Surendran
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK; Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98105, USA
| | - Thomas W Blackwell
- TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA
| | - Hélène Choquet
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA
| | - Kathleen Ryan
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Ravindranath Duggirala
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA
| | - Nancy Heard-Costa
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Zhe Wang
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Nathalie Chami
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Michael H Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Nancy Min
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Lynette Ekunwe
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Leslie A Lange
- Division of Biomedical Informatics and Personalized Medicine, School of Medicine University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Mary Cushman
- Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT 05405, USA
| | - Nauder Faraday
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Joanne E Curran
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA
| | - Laura Almasy
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia and Department of Genetics University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Kousik Kundu
- Department of Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK
| | - Albert V Smith
- TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA
| | | | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Myriam Fornage
- University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | | | - Ramachandran S Vasan
- National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA; Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Nicholas L Smith
- Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA 98105, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA 98105, USA
| | - Kari E North
- Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Eric Boerwinkle
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Lewis C Becker
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Joshua P Lewis
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Goncalo R Abecasis
- TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA
| | - Lifang Hou
- Northwestern University, Chicago, IL 60208, USA
| | - Jeffrey R O'Connell
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Alanna C Morrison
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Terri H Beaty
- School of Public Health, John Hopkins University, Baltimore, MD 21205, USA
| | - Robert Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78539, USA
| | - Eric Jorgenson
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94601, USA
| | - Bruce M Psaty
- Department of Epidemiology, University of Washington, Seattle, WA 98105, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA 98105, USA; Department of Medicine, University of Washington, Seattle, WA 98105, USA
| | - Charles Kooperberg
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98105, USA
| | - Russell T Walton
- Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Benjamin P Kleinstiver
- Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
| | - Hua Tang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Nicole Soranzo
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Department of Human Genetics, Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK
| | - Adam S Butterworth
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge CB1 8RN, UK
| | - Debbie Nickerson
- Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA
| | - Stephen S Rich
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Braxton D Mitchell
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Andrew D Johnson
- Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA; National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01701, USA
| | - Paul L Auer
- Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA
| | - Yun Li
- Departments of Biostatistics, Genetics, Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Rasika A Mathias
- Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MA 21205, USA
| | - Guillaume Lettre
- Montreal Heart Institute, Montréal, QC H1T 1C8, Canada; Faculté de Médecine, Université de Montréal, Montréal, QC H1T 1C8, Canada
| | - Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Cathy C Laurie
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Cecelia A Laurie
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Daniel E Bauer
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA
| | - Matthew P Conomos
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Alexander P Reiner
- Department of Epidemiology, University of Washington, Seattle, WA 98105, USA.
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Acquired Refractory Iron Deficiency Anemia. Mediterr J Hematol Infect Dis 2021; 13:e2021028. [PMID: 34007416 PMCID: PMC8114894 DOI: 10.4084/mjhid.2021.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 04/06/2021] [Indexed: 12/17/2022] Open
Abstract
Anemia is a global health problem affecting one-third of the world population, and half of the cases are due to iron deficiency (ID). Iron deficiency anemia (IDA) is the leading cause of disability in several countries. Although multiple mechanisms may coexist, ID and IDA causes can be classified as i) insufficient iron intake for the body requirement, ii) reduced absorption, and iii) blood losses. Oral iron represents the mainstay of IDA treatment. IDA is defined as "refractory" when the hematologic response after 4 to 6 weeks of treatment with oral iron (an increase of >=1 g/dL of Hb) is absent. The cause of iron-refractory anemia is usually acquired and frequently related to gastrointestinal pathologies, although a rare genetic form called iron-refractory iron deficiency anemia (IRIDA) exists. In some pathological circumstances, either genetic or acquired, hepcidin increases, limiting the absorption in the gut, remobilization, and recycling of iron, thereby reducing iron plasma levels. Indeed, conditions with high hepcidin levels are often under-recognized as iron refractory, leading to inappropriate and unsuccessful treatments. This review provides an overview of the iron refractory anemia underlying conditions, from gastrointestinal pathologies to hepcidin dysregulation and iatrogenic or provoked conditions, and the specific diagnostic and treatment approach.
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Kang W, Barad A, Clark AG, Wang Y, Lin X, Gu Z, O'Brien KO. Ethnic Differences in Iron Status. Adv Nutr 2021; 12:1838-1853. [PMID: 34009254 PMCID: PMC8483971 DOI: 10.1093/advances/nmab035] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
Iron is unique among all minerals in that humans have no regulatable excretory pathway to eliminate excess iron after it is absorbed. Iron deficiency anemia occurs when absorbed iron is not sufficient to meet body iron demands, whereas iron overload and subsequent deposition of iron in key organs occur when absorbed iron exceeds body iron demands. Over time, iron accumulation in the body can increase risk of chronic diseases, including cirrhosis, diabetes, and heart failure. To date, only ∼30% of the interindividual variability in iron absorption can be captured by iron status biomarkers or iron regulatory hormones. Much of the regulation of iron absorption may be under genetic control, but these pathways have yet to be fully elucidated. Genome-wide and candidate gene association studies have identified several genetic variants that are associated with variations in iron status, but the majority of these data were generated in European populations. The purpose of this review is to summarize genetic variants that have been associated with alterations in iron status and to highlight the influence of ethnicity on the risk of iron deficiency or overload. Using extant data in the literature, linear mixed-effects models were constructed to explore ethnic differences in iron status biomarkers. This approach found that East Asians had significantly higher concentrations of iron status indicators (serum ferritin, transferrin saturation, and hemoglobin) than Europeans, African Americans, or South Asians. African Americans exhibited significantly lower hemoglobin concentrations compared with other ethnic groups. Further studies of the genetic basis for ethnic differences in iron metabolism and on how it affects disease susceptibility among different ethnic groups are needed to inform population-specific recommendations and personalized nutrition interventions for iron-related disorders.
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Affiliation(s)
- Wanhui Kang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Alexa Barad
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Andrew G Clark
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA,Department of Computational Biology, Cornell University, Ithaca, NY, USA
| | - Yiqin Wang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Xu Lin
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
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Jallow MW, Campino S, Prentice AM, Cerami C. Association of common TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians. Sci Rep 2021; 11:8075. [PMID: 33850216 PMCID: PMC8044158 DOI: 10.1038/s41598-021-87565-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/25/2021] [Indexed: 11/08/2022] Open
Abstract
Genome-wide association studies in Europeans and Asians have identified numerous variants in the transmembrane protease serine 6 (TMPRSS6) and transferrin (TF) genes that are associated with changes in iron status. We sought to investigate the effects of common TMPRSS6 and TF gene SNPs on iron status indicators in a cohort of healthy Africans from rural Gambia. We measured iron biomarkers and haematology traits on individuals participating in the Keneba Biobank with genotype data on TMPRSS6 (rs2235321, rs855791, rs4820268, rs2235324, rs2413450 and rs5756506) and TF (rs3811647 and rs1799852), n = 1316. After controlling for inflammation, age and sex, we analysed the effects of carrying either single or multiple iron-lowering alleles on iron status. TMPRSS6 rs2235321 significantly affected plasma hepcidin concentrations (AA genotypes having lower hepcidin levels; F ratio 3.7, P = 0.014) with greater impact in individuals with low haemoglobin or ferritin. No other TMPRSS6 variant affected hepcidin. None of the TMPRSS6 variants nor a TMPRSS6 allele risk score affected other iron biomarkers or haematological traits. TF rs3811647 AA carriers had 21% higher transferrin (F ratio 16.0, P < 0.0001), 24% higher unsaturated iron-binding capacity (F ratio 12.8, P < 0.0001) and 25% lower transferrin saturation (F ratio 4.3, P < 0.0001) compared to GG carriers. TF rs3811647 was strongly associated with transferrin, unsaturated iron-binding capacity (UIBC) and transferrin saturation (TSAT) with a single allele effect of 8-12%. There was no association between either TF SNP and any haematological traits or iron biomarkers. We identified meaningful associations between TMPRSS6 rs2235321 and hepcidin and replicated the previous findings on the effects of TF rs3811647 on transferrin and iron binding capacity. However, the effects are subtle and contribute little to population variance. Further genetic and functional studies, including polymorphisms frequent in Africa populations, are needed to identify markers for genetically stratified approaches to prevention or treatment of iron deficiency anaemia.
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Affiliation(s)
- Momodou W Jallow
- Nutrition Theme, MRC Unit, The Gambia at London School of Hygiene & Tropical Medicine, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, The Gambia
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Susana Campino
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Andrew M Prentice
- Nutrition Theme, MRC Unit, The Gambia at London School of Hygiene & Tropical Medicine, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, The Gambia
| | - Carla Cerami
- Nutrition Theme, MRC Unit, The Gambia at London School of Hygiene & Tropical Medicine, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, The Gambia.
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Tański W, Chabowski M, Jankowska-Polańska B, Jankowska EA. Anaemia and iron deficiency in patients with
rheumatoid arthritis and other chronic diseases. POSTEP HIG MED DOSW 2021. [DOI: 10.5604/01.3001.0014.7838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Anaemia is one of the most common symptoms accompanying many chronic diseases, e.g.
collagenases, neoplasms, and chronic inflammations (inflammatory bowel disease, chronic
kidney disease and heart failure). Iron deficiency anaemia is the most common type of anaemia
(80%). It affects 1% to 2% of the population. Iron deficiency (ID) – absolute or functional
– is characterised by reduced ferritin levels and transferrin saturation (TSAT) of less than
20%. Iron deficiency is the most common dietary deficiency. However, iron deficiency might
be one of the common causes of anaemia of chronic disease (ACD). Anaemia affects 33%
to 60% of patients with RA. Rheumatoid arthritis (RA) is a chronic immune-mediated systemic
connective tissue disease, in which chronic inflammation of the synovial tissue of the
joints damages articular cartilages, bones and other joint structures. The prevalence of RA is
approximately 0.3% to 2%. Low haemoglobin levels in RA patients are significantly correlated
with disability, activity and duration of the disease as well as damage to joints and joint pain.
Treatment of anaemia in RA patients includes iron supplementation, blood transfusions, the
use of erythropoiesis-stimulating agents, and treatment of the underlying condition. Biological
treatments used in RA patients, such as e.g. infliximab, tocilizumab and anakinra, not only
slow the progression of joint involvement but also prevent anaemia.
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Affiliation(s)
- Wojciech Tański
- Department of Internal Medicine, 4th Military Teaching Hospital, Wrocław, Poland
| | - Mariusz Chabowski
- Division of Oncology and Palliative Care, Department of Clinical Nursing, Faculty of Health Science, Wrocław Medical University, Wrocław, Poland
| | - Beata Jankowska-Polańska
- Division of Nursing in Internal Medicine, Department of Clinical Nursing, Faculty of Health Science, Wrocław Medical University, Wrocław, Poland
| | - Ewa Anita Jankowska
- Dept of Cardiology, Wrocław Medical University, Faculty of Medicine, Wrocław, Poland
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Affiliation(s)
- Schuyler Tong
- Department of Pediatrics and Pediatric Hematology Oncology, University of California at San Francisco Benioff Children's Hospital Oakland, Oakland, CA
| | - Elliott Vichinsky
- Department of Pediatrics and Pediatric Hematology Oncology, University of California at San Francisco Benioff Children's Hospital Oakland, Oakland, CA.,Pediatric Hematology Oncology, University of California, San Francisco, CA
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Maciak K, Adamowicz-Salach A, Poznanski J, Gora M, Fronk J, Burzynska B. A Family Affected by a Life-Threatening Erythrocyte Defect Caused by Pyruvate Kinase Deficiency With Normal Iron Status: A Case Report. Front Genet 2020; 11:560248. [PMID: 33193643 PMCID: PMC7655982 DOI: 10.3389/fgene.2020.560248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/09/2020] [Indexed: 01/19/2023] Open
Abstract
Background Red cell pyruvate kinase deficiency (PKD) is a defect of glycolysis causing congenital non-spherocytic hemolytic anemia. PKD is transmitted as an autosomal recessive trait. The clinical features of PKD are highly variable, from mild to life-threatening anemia which can lead to death in the neonatal period. Most patients with PKD must receive regular transfusions in early childhood and as a consequence suffer from iron overloading. Patient Here, we report a Polish family with life-threatening hemolytic anemia of unknown etiology. Whole exome sequencing identified two heterozygous mutations, c.1529 G > A (p.R510Q) and c.1495 T > C (p.S499P) in the PKLR gene. Molecular modeling showed that the both PKLR mutations are responsible for major disturbance of the protein structure and functioning. Despite frequent transfusions the patients do not show any signs of iron overload and hepcidin, a major regulator of iron uptake, is undetectable in their serum. The patients were homozygous for the rs855791 variant of the TMPRSS6 gene which has earlier been shown to down-regulate iron absorption and accumulation. Conclusion The lack of iron overload despite a reduced level of hepcidin in two transfusion-dependent PKD patients suggests the existence of a hepcidin-independent mechanism of iron regulation preventing iron overloading.
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Affiliation(s)
- Karolina Maciak
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Anna Adamowicz-Salach
- Department of Pediatrics, Hematology and Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Jaroslaw Poznanski
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Monika Gora
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Jan Fronk
- Faculty of Biology, Institute of Biochemistry, University of Warsaw, Warsaw, Poland
| | - Beata Burzynska
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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36
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Affiliation(s)
- Na Hee Lee
- Department of Pediatrics, Cha Bundang Medical Center, Cha University, Seongnam, Korea
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37
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Jallow MW, Cerami C, Clark TG, Prentice AM, Campino S. Differences in the frequency of genetic variants associated with iron imbalance among global populations. PLoS One 2020; 15:e0235141. [PMID: 32609760 PMCID: PMC7329092 DOI: 10.1371/journal.pone.0235141] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/09/2020] [Indexed: 02/08/2023] Open
Abstract
Iron deficiency anaemia is a major health problem affecting approximately 1.2 billion people worldwide. Young children, women of reproductive age and pregnant women living in sub-Saharan Africa are the most vulnerable. It is estimated that iron deficiency accounts for half of anaemia cases. Apart from nutritional deficiency, infection, inflammation and genetic factors are the major drivers of anaemia. However, the role of genetic risk factors has not been thoroughly investigated. This is particularly relevant in African populations, as they carry high genetic diversity and have a high prevalence of anaemia. Multiple genetic variations in iron regulatory genes have been linked to impaired iron status. Here we conducted a literature review to identify genetic variants associated with iron imbalance among global populations. We compare their allele frequencies and risk scores and we investigated population-specific selection among populations of varying geographic origin using data from the Keneba Biobank representing individuals in rural Gambia and the 1000 Genomes Project. We identified a significant lack of data on the genetic determinants of iron status in sub-Saharan Africa. Most of the studies on genetic determinants of iron status have been conducted in Europeans. Also, we identified population differences in allele frequencies in candidate putative genetic risk factors. Given the disproportionately high genetic diversity in African populations coupled with their high prevalence of iron deficiency, there is need to investigate the genetic influences of low iron status in Sub-Saharan Africa. The resulting insights may inform the future implementation of iron intervention strategies.
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Affiliation(s)
- Momodou W. Jallow
- Nutrition Theme, MRC Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- * E-mail: (SC); (MWJ)
| | - Carla Cerami
- Nutrition Theme, MRC Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia
| | - Taane G. Clark
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Andrew M. Prentice
- Nutrition Theme, MRC Unit The Gambia at London School of Hygiene & Tropical Medicine, Banjul, The Gambia
| | - Susana Campino
- Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- * E-mail: (SC); (MWJ)
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Al-Jamea LH, Woodman A, Heiba NM, Elshazly SA, Khalaf NB, Fathallah DM, Al-Nashmi ME, Quiambao JV, Deifalla AH. Genetic analysis of TMPRSS6 gene in Saudi female patients with iron deficiency anemia. Hematol Oncol Stem Cell Ther 2020; 14:41-50. [PMID: 32446932 DOI: 10.1016/j.hemonc.2020.04.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/20/2020] [Accepted: 04/24/2020] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE/BACKGROUND Mutations in transmembrane protease serine 6 (TMPRSS6) gene induce high hepcidin level, which causes iron-refractory iron deficiency anemia (IRIDA) by preventing duodenal iron absorption. This study aims to identify the common genetic variations of the TMPRSS6 gene that affect iron levels among Saudi female patients with iron deficiency anemia (IDA). METHODS All study participants were Saudi females (12-49 years old): 32 patients with IDA, 32 patients with IRIDA, and 34 healthy individuals comprising the control group. Hematological investigations, iron profile, serum hepcidin level, and TMPRSS6 gene transcription were determined. The TMPRSS6 gene was amplified, sequenced, and analyzed among all study participants. RESULTS The mean hepcidin and TMPRSS6 RNA transcription levels in IDA and IRIDA groups were significantly lower than those in the control group. TMPRSS6 gene sequence analysis detected 41 variants: two in the 5' untranslated region (5'UTR), 17 in introns, and 22 in exons. Thirty-three variants were previously reported in the Single Nucleotide Polymorphism Database, and eight variants were novel; one novel variant was in 5'UTR (g.-2 T > G); five novel variants were detected in exons (p.W73X, p.D479N, p.E523K, p.L674L, and p.I799I). At the time of the sequence analysis of our samples, two variants-p.D479N and p.674L-were novel. However, these variants are present at a very low allele frequency in other populations (L674L, 0.00007761 and D479N, 0.000003980). CONCLUSION This is the first study to investigate the genetic variants of TMPRSS6 gene in Saudi female patients with IDA. The generated data will serve as a reference for future studies on IDA in the Arab population.
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Affiliation(s)
- Lamiaa H Al-Jamea
- Clinical Laboratory Sciences, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia.
| | - Alexander Woodman
- Postgraduate Studies and Research, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia
| | | | | | - Noureddine Ben Khalaf
- Department of Life Sciences, Health Biotechnology Program, College of Graduate Studies, Arabian Gulf University, Manama, Bahrain
| | - Dahmani M Fathallah
- Department of Life Sciences, Health Biotechnology Program, College of Graduate Studies, Arabian Gulf University, Manama, Bahrain
| | - Moudi E Al-Nashmi
- Department of Medical Laboratory Services, Ministry of Health, Kuwait
| | - Jenifer Vecina Quiambao
- Postgraduate Studies and Research, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia
| | - Abdel Halim Deifalla
- Anatomy Department, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
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Elstrott B, Khan L, Olson S, Raghunathan V, DeLoughery T, Shatzel JJ. The role of iron repletion in adult iron deficiency anemia and other diseases. Eur J Haematol 2020; 104:153-161. [PMID: 31715055 PMCID: PMC7031048 DOI: 10.1111/ejh.13345] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/26/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022]
Abstract
Iron deficiency anemia (IDA) is the most prevalent and treatable form of anemia worldwide. The clinical management of patients with IDA requires a comprehensive understanding of the many etiologies that can lead to iron deficiency including pregnancy, blood loss, renal disease, heavy menstrual bleeding, inflammatory bowel disease, bariatric surgery, or extremely rare genetic disorders. The treatment landscape for many causes of IDA is currently shifting toward more abundant use of intravenous (IV) iron due to its effectiveness and improved formulations that decrease the likelihood of adverse effects. IV iron has found applications beyond treatment of IDA, and there is accruing data about its efficacy in patients with heart failure, restless leg syndrome, fatigue, and prevention of acute mountain sickness. This review provides a framework to diagnose, manage, and treat patients presenting with IDA and discusses other conditions that benefit from iron supplementation.
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Affiliation(s)
- Benjamin Elstrott
- Division of Hematology-Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Lubna Khan
- Division of Hematology-Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Sven Olson
- Division of Hematology-Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Vikram Raghunathan
- Division of Hematology-Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Thomas DeLoughery
- Division of Hematology-Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Joseph J. Shatzel
- Division of Hematology-Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
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40
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Belot A, Gourbeyre O, Fay A, Palin A, Besson-Fournier C, Latour C, Hopkins CR, Tidmarsh GF, Coppin H, Roth MP, Ritter MR, Hong CC, Meynard D. LJ000328, a novel ALK2/3 kinase inhibitor, represses hepcidin and significantly improves the phenotype of IRIDA. Haematologica 2019; 105:e385-e388. [PMID: 31806689 DOI: 10.3324/haematol.2019.236133] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Audrey Belot
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Ophélie Gourbeyre
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Alexis Fay
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Anais Palin
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | | | - Chloé Latour
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Corey R Hopkins
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Hélène Coppin
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Marie-Paule Roth
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | | | - Charles C Hong
- Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, USA
| | - Delphine Meynard
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
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Vanlalsanga, Singh SP, Singh YT. Rice of Northeast India harbor rich genetic diversity as measured by SSR markers and Zn/Fe content. BMC Genet 2019; 20:79. [PMID: 31646978 PMCID: PMC6806518 DOI: 10.1186/s12863-019-0780-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/21/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Rice (Oryza sativa L.) is one of the most important crops of the world and a major staple food for half of the World's human population. The Northeastern (NE) region of India lies in the Indo-Burma biodiversity hotspot and about 45% of the total flora of the country is found in the region. Local rice cultivars from different states of NE India were analyzed for genetic diversity and population structure using microsatellite markers, and their zinc and iron content. RESULTS A total of 149 bands were detected using twenty-two microsatellite markers comprising both random and trait-linked markers, showing 100% polymorphism and high value of expected heterozygosity (0.6311) and the polymorphism information content (0.5895). Nali Dhan cultivar of Arunachal Pradesh possessed the highest genetic diversity (0.3545) among studied populations while Moirangphou Khonganbi of Manipur exhibited the lowest genetic diversity (0.0343). The model-based population structure revealed that all the studied 65 rice cultivars were grouped into two clusters. Cluster I was represented by 36 cultivars and cluster II by 29 cultivars. Badalsali cultivar of Assam possessed the highest Zn content (75.8 μg/g) and Kapongla from Manipur possessed the lowest (17.98 μg/g). The highest and the lowest Fe content was found in Fazu (215.62 μg/g) and Idaw (11.42 μg/g) of Mizoram. CONCLUSION The result suggested rice cultivars of NE India possessing high genetic diversity (Nali dhan), high Zn (Badalsali) and Fe (Fazu) content can be useful as a source of germplasm for future rice improvement programs.
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Affiliation(s)
- Vanlalsanga
- Department of Botany, Mizoram University, Aizawl, Mizoram, India
| | | | - Y Tunginba Singh
- Department of Botany, Mizoram University, Aizawl, Mizoram, India.
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Pagani A, Nai A, Silvestri L, Camaschella C. Hepcidin and Anemia: A Tight Relationship. Front Physiol 2019; 10:1294. [PMID: 31649559 PMCID: PMC6794341 DOI: 10.3389/fphys.2019.01294] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 09/25/2019] [Indexed: 12/13/2022] Open
Abstract
Hepcidin, the master regulator of systemic iron homeostasis, tightly influences erythrocyte production. High hepcidin levels block intestinal iron absorption and macrophage iron recycling, causing iron restricted erythropoiesis and anemia. Low hepcidin levels favor bone marrow iron supply for hemoglobin synthesis and red blood cells production. Expanded erythropoiesis, as after hemorrhage or erythropoietin treatment, blocks hepcidin through an acute reduction of transferrin saturation and the release of the erythroblast hormone and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis, limiting iron consumption, increases transferrin saturation and stimulates hepcidin transcription. Deregulation of hepcidin synthesis is associated with anemia in three conditions: iron refractory iron deficiency anemia (IRIDA), the common anemia of acute and chronic inflammatory disorders, and the extremely rare hepcidin-producing adenomas that may develop in the liver of children with an inborn error of glucose metabolism. Inappropriately high levels of hepcidin cause iron-restricted or even iron-deficient erythropoiesis in all these conditions. Patients with IRIDA or anemia of inflammation do not respond to oral iron supplementation and show a delayed or partial response to intravenous iron. In hepcidin-producing adenomas, anemia is reverted by surgery. Other hepcidin-related anemias are the “iron loading anemias” characterized by ineffective erythropoiesis and hepcidin suppression. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and some forms of hemolytic anemias as pyruvate kinase deficiency. The paradigm is non-transfusion-dependent thalassemia where the release of erythroferrone from the expanded pool of immature erythroid cells results in hepcidin suppression and secondary iron overload that in turn worsens ineffective erythropoiesis and anemia. In thalassemia murine models, approaches that induce iron restriction ameliorate both anemia and the iron phenotype. Manipulations of hepcidin might benefit all the above-described anemias. Compounds that antagonize hepcidin or its effect may be useful in inflammation and IRIDA, while hepcidin agonists may improve ineffective erythropoiesis. Correcting ineffective erythropoiesis in animal models ameliorates not only anemia but also iron homeostasis by reducing hepcidin inhibition. Some targeted approaches are now in clinical trials: hopefully they will result in novel treatments for a variety of anemias.
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Affiliation(s)
- Alessia Pagani
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | - Antonella Nai
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Laura Silvestri
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Clara Camaschella
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
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Vlasveld LT, Swinkels DW. Loss-of-function ferroportin disease: novel mechanistic insights and unanswered questions. Haematologica 2019; 103:1753-1755. [PMID: 30381414 DOI: 10.3324/haematol.2018.203315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- L Tom Vlasveld
- Department of Internal Medicine, Haaglanden Medical Center, Location Bronovo, The Hague
| | - Dorine W Swinkels
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
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Vlasveld LT, Janssen R, Bardou-Jacquet E, Venselaar H, Hamdi-Roze H, Drakesmith H, Swinkels DW. Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features. Pharmaceuticals (Basel) 2019; 12:ph12030132. [PMID: 31505869 PMCID: PMC6789780 DOI: 10.3390/ph12030132] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/14/2019] [Accepted: 08/20/2019] [Indexed: 12/14/2022] Open
Abstract
Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.
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Affiliation(s)
- L Tom Vlasveld
- Department of Internal Medicine, Haaglanden MC-Bronovo, 2597AX The Hague, The Netherlands
| | - Roel Janssen
- Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Edouard Bardou-Jacquet
- Liver Diseases Department, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, University Hospital Pontchaillou, 35033 Rennes, France
| | - Hanka Venselaar
- Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud, University Medical Center, P.O. Box 9191, 6500 HB Nijmegen, The Netherlands
| | - Houda Hamdi-Roze
- Molecular Genetics Department, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, University Hospital Pontchaillou, 35033 Rennes, France
| | - Hal Drakesmith
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX39DS, UK
| | - Dorine W Swinkels
- Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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Daher R, Lefebvre T, Puy H, Karim Z. Extrahepatic hepcidin production: The intriguing outcomes of recent years. World J Clin Cases 2019; 7:1926-1936. [PMID: 31423425 PMCID: PMC6695539 DOI: 10.12998/wjcc.v7.i15.1926] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.
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Affiliation(s)
- Raêd Daher
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Thibaud Lefebvre
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Hervé Puy
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
| | - Zoubida Karim
- Université Paris Diderot, Bichat site, Paris 75018, France
- Inflammation Research Center (CRI), INSERM U1149/ERL CNRS 8252, Paris 75018, France
- Laboratory of Excellence, GR-Ex, Paris 75018, France
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46
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Armitage AE, Agbla SC, Betts M, Sise EA, Jallow MW, Sambou E, Darboe B, Worwui A, Weinstock GM, Antonio M, Pasricha SR, Prentice AM, Drakesmith H, Darboe MK, Kwambana-Adams BA. Rapid growth is a dominant predictor of hepcidin suppression and declining ferritin in Gambian infants. Haematologica 2019; 104:1542-1553. [PMID: 30733275 PMCID: PMC6669141 DOI: 10.3324/haematol.2018.210146] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/31/2019] [Indexed: 12/18/2022] Open
Abstract
Iron deficiency and iron deficiency anemia are highly prevalent in low-income countries, especially among young children. Hepcidin is the major regulator of systemic iron homeostasis. It controls dietary iron absorption, dictates whether absorbed iron is made available in circulation for erythropoiesis and other iron-demanding processes, and predicts response to oral iron supplementation. Understanding how hepcidin is itself regulated is therefore important, especially in young children. We investigated how changes in iron-related parameters, inflammation and infection status, seasonality, and growth influenced plasma hepcidin and ferritin concentrations during infancy using longitudinal data from two birth cohorts of infants in rural Gambia (n=114 and n=193). This setting is characterized by extreme seasonality, prevalent childhood anemia, undernutrition, and frequent infection. Plasma was collected from infants at birth and at regular intervals, up to 12 months of age. Hepcidin, ferritin and plasma iron concentrations declined markedly during infancy, with reciprocal increases in soluble transferrin receptor and transferrin concentrations, indicating declining iron stores and increasing tissue iron demand. In cross-sectional analyses at 5 and 12 months of age, we identified expected relationships of hepcidin with iron and inflammatory markers, but also observed significant negative associations between hepcidin and antecedent weight gain. Correspondingly, longitudinal fixed effects modeling demonstrated weight gain to be the most notable dynamic predictor of decreasing hepcidin and ferritin through infancy across both cohorts. Infants who grow rapidly in this setting are at particular risk of depletion of iron stores, but since hepcidin concentrations decrease with weight gain, they may also be the most responsive to oral iron interventions.
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Affiliation(s)
- Andrew E Armitage
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Schadrac C Agbla
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Modupeh Betts
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Ebrima A Sise
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Momodou W Jallow
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Ellen Sambou
- WHO Collaborating Center for New Vaccines Surveillance, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Bakary Darboe
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Archibald Worwui
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | | | - Martin Antonio
- WHO Collaborating Center for New Vaccines Surveillance, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Sant-Rayn Pasricha
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, The University of Melbourne, VIC, Melbourne, Australia
| | - Andrew M Prentice
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Hal Drakesmith
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Haematology Theme, Oxford Biomedical Research Centre, Oxford, UK
| | - Momodou K Darboe
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
| | - Brenda Anna Kwambana-Adams
- WHO Collaborating Center for New Vaccines Surveillance, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa
- NIHR Global Health Research Unit on Mucosal Pathogens, Division of Infection and Immunity, University College London, London, UK
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47
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Rostoker G, Vaziri ND. Risk of iron overload with chronic indiscriminate use of intravenous iron products in ESRD and IBD populations. Heliyon 2019; 5:e02045. [PMID: 31338466 PMCID: PMC6627982 DOI: 10.1016/j.heliyon.2019.e02045] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 03/14/2019] [Accepted: 07/03/2019] [Indexed: 01/19/2023] Open
Abstract
The routine use of recombinant erythropoiesis-stimulating agents (ESA) over the past three decades has enabled the partial correction of anaemia in most patients with end-stage renal disease (ESRD). Since ESA use frequently leads to iron deficiency, almost all ESA-treated haemodialysis patients worldwide receive intravenous iron (IV) to ensure sufficient available iron during ESA therapy. Patients with inflammatory bowel disease (IBD) are also often treated with IV iron preparations, as anaemia is common in IBD. Over the past few years, liver magnetic resonance imaging (MRI) has become the gold standard method for non-invasive diagnosis and follow-up of iron overload diseases. Studies using MRI to quantify liver iron concentration in ESRD have shown a link between high infused iron dose and risk of haemosiderosis in dialysis patients. In September 2017, the Pharmacovigilance Committee (PRAC) of the European Medicines Agency (EMA) considered convergent publications over the last few years on iatrogenic haemosiderosis in dialysis patients and requested that companies holding marketing authorization for iron products should investigate the risk of iron overload, particularly in patients with end-stage renal disease on dialysis and, by analogy, patients with IBD. We present a narrative review of data supporting the views and decision of the EMA, and then give our expert opinion on this controversial field of anaemia therapeutics.
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Affiliation(s)
- Guy Rostoker
- Division of Nephrology and Dialysis, Hôpital Privé Claude Galien, Ramsay-Générale de Santé, Quincy-sous-Sénart, France
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, University of California, Irvine, USA
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48
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Abstract
Iron refractory iron deficiency anemia is an autosomal recessive disorder arising from defects in iron metabolism that cause microcytic anemia to grow resistant to treatment. The patients usually do not respond to orally administered iron treatment and partially respond to intravenous iron administration. Mutations of TMPRSS6 gene which encodes matriptase-2 are the main cause of the disorder. Here, we describe the case of a 6-month-old Syrian boy who had hypochromic-microcytic anemia and normal ferritin levels at presentation. The patient did not respond to 1 month of iron therapy and his hemoglobin levels increased only after red blood cell transfusion. Mutation analysis demonstrated a novel 374 base pairs homozygote deletion spanning exon 15 of TMPRSS6 gene. Our results expand the mutation spectrum of TMPRSS6 gene in iron refractory iron deficiency anemia.
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Jallow MW, Campino S, Prentice AM, Cerami C. A recall-by-genotype study on polymorphisms in the TMPRSS6 gene and oral iron absorption: a study protocol. F1000Res 2019. [DOI: 10.12688/f1000research.19080.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: Oral iron supplementation is commonly used to treat and prevent anaemia. The transmembrane protease serine 6 gene (TMPRSS6), which encodes matriptase 2, is a negative regulator of hepcidin, the key controller of iron homeostasis. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene that are associated with an increased risk of iron-deficiency anaemia. We will investigate the in vivo effects of three previously reported TMPRSS6 variants (rs855791, rs4820268 and rs2235321) on oral iron absorption in non-anaemic volunteers in The Gambia. Methods: A recall-by-genotype study design will be employed. Pre-genotyped participants will be recruited from the West African BioResouce (WABR), which currently contains over 3000 genotyped individuals. Male and female volunteers will be selected based on polymorphisms (rs855791, rs4820268 and rs2235321) in the TMPRSS6 gene in the Gambian population. The effects of a single variant allele at one SNP and the additive effect of two or three variant alleles from either two or all three SNPs will be investigated. Study participants will be given a single oral dose of 400mg ferrous sulfate, and blood samples will be collected at baseline, two hours and five hours post supplementation. Differences in iron absorption between genotype groups will be assessed by measuring the increase in serum iron concentration at five hours post iron ingestion. Discussion: This study will increase understanding of the role of genetic variations in TMPRSS6 on oral iron absorption in subjects of West African origin. This will test for the biological basis for the association of each of the three TMPRSS6 variants with iron absorption. This may help in guiding future iron intervention strategies, particularly in populations with a high frequency of these SNPs and a high frequency of anaemia. Study registration: ClinicalTrials.gov NCT03341338 14/11/17.
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50
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Shokrgozar N, Golafshan HA. Molecular perspective of iron uptake, related diseases, and treatments. Blood Res 2019; 54:10-16. [PMID: 30956958 PMCID: PMC6439303 DOI: 10.5045/br.2019.54.1.10] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/01/2018] [Accepted: 10/01/2018] [Indexed: 12/20/2022] Open
Abstract
Iron deficiency anemia and anemia of chronic disorders are the most common types of anemia. Disorders of iron metabolism lead to different clinical scenarios such as iron deficiency anemia, iron overload, iron overload with cataract and neurocognitive disorders. Regulation of iron in the body is a complex process and different regulatory proteins are involved in iron absorption and release from macrophages into hematopoietic tissues. Mutation in these regulatory genes is the most important cause of iron refractory iron deficiency anemia (IRIDA). This review provides a glance into the iron regulation process, diseases related to iron metabolism, and appropriate treatments at the molecular level.
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Affiliation(s)
- Negin Shokrgozar
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Habib Allah Golafshan
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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