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Valenti L, Corradini E, Adams LA, Aigner E, Alqahtani S, Arrese M, Bardou-Jacquet E, Bugianesi E, Fernandez-Real JM, Girelli D, Hagström H, Henninger B, Kowdley K, Ligabue G, McClain D, Lainé F, Miyanishi K, Muckenthaler MU, Pagani A, Pedrotti P, Pietrangelo A, Prati D, Ryan JD, Silvestri L, Spearman CW, Stål P, Tsochatzis EA, Vinchi F, Zheng MH, Zoller H. Consensus Statement on the definition and classification of metabolic hyperferritinaemia. Nat Rev Endocrinol 2023; 19:299-310. [PMID: 36805052 PMCID: PMC9936492 DOI: 10.1038/s41574-023-00807-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2023] [Indexed: 02/19/2023]
Abstract
Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.
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Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
- Biological Resource Center and Precision Medicine Lab, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
- Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
| | - Elena Corradini
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, Modena, Italy.
| | - Leon A Adams
- Medical School, University of Western Australia, Perth, Australia
| | - Elmar Aigner
- First Department of Medicine, University Clinic Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Saleh Alqahtani
- Royal Clinics and Gastroenterology and Hepatology, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Edouard Bardou-Jacquet
- University of Rennes, UMR1241, CHU Rennes, National Reference Center for Hemochromatosis and iron metabolism disorder, INSERM CIC1414, Rennes, France
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology, University of Turin, Turin, Italy
| | - Jose-Manuel Fernandez-Real
- Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain
- Department of Medical Sciences, Faculty of Medicine, Girona University, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Domenico Girelli
- Section of Internal Medicine, Department of Medicine, University of Verona, Policlinico Giambattista Rossi, Verona, Italy
| | - Hannes Hagström
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Benjamin Henninger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Kris Kowdley
- Liver Institute Northwest, Seattle, WA, USA
- Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA
| | - Guido Ligabue
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
- Division of Radiology, Ospedale di Sassuolo S.p.A, Sassuolo, Modena, Italy
| | - Donald McClain
- Wake Forest School of Medicine, Winston Salem, NC, USA
- Department of Veterans Affairs, Salisbury, NC, USA
| | - Fabrice Lainé
- INSERM CIC1414, Liver Unit, CHU Rennes, Rennes, France
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Martina U Muckenthaler
- Department of Paediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany
- Center for Molecular Translational Iron Research, Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
- German Centre for Cardiovascular Research, Partner Site Heidelberg, Heidelberg, Germany
| | - Alessia Pagani
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Patrizia Pedrotti
- Laboratorio di RM Cardiaca Cardiologia 4, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Antonello Pietrangelo
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, Modena, Italy
| | - Daniele Prati
- Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - John D Ryan
- Hepatology Unit, Beaumont Hospital, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Laura Silvestri
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Per Stål
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
| | - Francesca Vinchi
- Iron Research Laboratory, Lindsley F.Kimball Research Institute, New York Blood Center, New York, NY, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Heinz Zoller
- Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
- Doppler Laboratory on Iron and Phosphate Biology, Innsbruck, Austria
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Barbalho SM, Laurindo LF, Tofano RJ, Flato UAP, Mendes CG, de Alvares Goulart R, Briguezi AMGM, Bechara MD. Dysmetabolic Iron Overload Syndrome: Going beyond the Traditional Risk Factors Associated with Metabolic Syndrome. ENDOCRINES 2023; 4:18-37. [DOI: 10.3390/endocrines4010002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Dysmetabolic iron overload syndrome (DIOS) corresponds to the increase in iron stores associated with components of metabolic syndrome (MtS) and in the absence of an identifiable cause of iron excess. The objective of this work was to review the main aspects of DIOS. PUBMED and EMBASE were consulted, and PRISMA guidelines were followed. DIOS is usually asymptomatic and can be diagnosed by investigating MtS and steatosis. About 50% of the patients present altered hepatic biochemical tests (increased levels of γ-glutamyl transpeptidase itself or associated with increased levels of alanine aminotransferase). The liver may present parenchymal and mesenchymal iron overload, but the excess of iron is commonly mild. Steatosis or steatohepatitis is observed in half of the patients. Fibrosis is observed in about 15% of patients. Hyperferritinemia may damage the myocardium, liver, and several other tissues, increasing morbidity and mortality. Furthermore, DIOS is closely related to oxidative stress, which is closely associated with several pathological conditions such as inflammatory diseases, hypertension, diabetes, heart failure, and cancer. DIOS is becoming a relevant finding in the general population and can be associated with high morbidity/mortality. For these reasons, investigation of this condition could be an additional requirement for the early prevention of cardiovascular diseases.
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Affiliation(s)
- Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília, São Paulo 17500-000, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Ricardo José Tofano
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Department of Cardiology, Associação Beneficente Hospital Universitário (ABHU), Rua Dr. Próspero Cecílio Coimbra, 80, Marília, São Paulo 17525-160, Brazil
| | - Uri Adrian Prync Flato
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília, São Paulo 17500-000, Brazil
| | - Claudemir G. Mendes
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Ricardo de Alvares Goulart
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Ana Maria Gonçalves Milla Briguezi
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Marcelo Dib Bechara
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
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Fujiwara S, Izawa T, Mori M, Atarashi M, Yamate J, Kuwamura M. Dietary iron overload enhances Western diet induced hepatic inflammation and alters lipid metabolism in rats sharing similarity with human DIOS. Sci Rep 2022; 12:21414. [PMID: 36496443 PMCID: PMC9741655 DOI: 10.1038/s41598-022-25838-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Hepatic iron overload is often concurrent with nonalcoholic fatty liver disease (NAFLD). Dysmetabolic iron overload syndrome (DIOS) is characterized by an increase in the liver and body iron stores and metabolic syndrome components. Increasing evidences suggest an overlap between NAFLD with iron overload and DIOS; however, the mechanism how iron is involved in their pathogenesis remains unclear. Here we investigated the role of iron in the pathology of a rat model of NAFLD with iron overload. Rats fed a Western (high-fat and high-fructose) diet for 26 weeks represented hepatic steatosis with an increased body weight and dyslipidemia. Addition of dietary iron overload to the Western diet feeding further increased serum triglyceride and cholesterol, and enhanced hepatic inflammation; the affected liver had intense iron deposition in the sinusoidal macrophages/Kupffer cells, associated with nuclear translocation of NFκB and upregulation of Th1/M1-related cytokines. The present model would be useful to investigate the mechanism underlying the development and progression of NAFLD as well as DIOS, and to elucidate an important role of iron as one of the "multiple hits" factors.
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Affiliation(s)
- Sakura Fujiwara
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Takeshi Izawa
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Mutsuki Mori
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Machi Atarashi
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Jyoji Yamate
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Mitsuru Kuwamura
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
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Tickell AM, Rohleder C, Ho N, McHugh C, Jones G, Song YJC, Hickie IB, Scott EM. Identifying pathways to early-onset metabolic dysfunction, insulin resistance and inflammation in young adult inpatients with emerging affective and major mood disorders. Early Interv Psychiatry 2022; 16:1121-1129. [PMID: 34852406 DOI: 10.1111/eip.13260] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 09/09/2021] [Accepted: 11/07/2021] [Indexed: 12/17/2022]
Abstract
AIM Young people with common mood disorders face the prospect of shortened life expectancy largely due to premature cardiovascular disease. Metabolic dysfunction is a risk factor for premature cardiovascular disease. There is an ongoing debate whether metabolic dysfunction can be simply explained by weight gain secondary to psychotropic medications or whether shared genetic vulnerability, intrinsic immune-metabolic disturbances or other system perturbations (e.g. dysregulated sympathetic nervous system, circadian dysfunction) are more relevant determinants of premature cardiovascular disease. Thus, we aimed to investigate underlying drivers of metabolic dysfunction and premature cardiovascular disease in young people in the early phases of common mood disorders. METHODS We evaluated the relationships between insulin resistance (assessed by HOMA2-IR) and body mass index (BMI), sex, diagnosis, medication, inflammatory markers and hormonal factors in 327 inpatients with emerging affective and major mood disorders admitted to the Young Adult Mental Health Unit, St Vincent's Private Hospital, Sydney. RESULTS While HOMA2-IR scores were positively associated with BMI (rs = 0.465, p < .001), they were also higher in those prescribed mood stabilizers (p = .044) but were not associated with specific diagnoses, other medication types or the number of prescribed medications. Further, high-sensitivity C-reactive protein levels (but not thyroid-stimulating hormone and ferritin levels) were positively associated with HOMA2-IR (rs = 0. 272, p < .001) and BMI (rs = . 409, p < .001). CONCLUSIONS In addition to BMI, other non-specific markers of inflammation are associated with early metabolic dysfunction in young people with emerging affective and major mood disorders.
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Affiliation(s)
| | - Cathrin Rohleder
- Brain and Mind Centre, University of Sydney, Camperdown, Australia
| | - Nicholas Ho
- Brain and Mind Centre, University of Sydney, Camperdown, Australia
| | - Catherine McHugh
- Brain and Mind Centre, University of Sydney, Camperdown, Australia
| | - Graham Jones
- SydPath, St Vincent's Hospital, Sydney, Australia.,St Vincent's Clinical School, University of NSW, Australia
| | | | - Ian B Hickie
- Brain and Mind Centre, University of Sydney, Camperdown, Australia
| | - Elizabeth M Scott
- Brain and Mind Centre, University of Sydney, Camperdown, Australia.,Young Adult Mental Health Unit, St Vincent's Private Hospital, Sydney, Australia
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Branisso PPF, de Oliveira CPMS, Filho HML, Lima FR, Santos AS, Mancini MC, de Melo ME, Carrilho FJ, Rocha MDS, Clark P, Branisso HJP, Cercato C. Non-invasive methods for iron overload evaluation in dysmetabolic patients. Ann Hepatol 2022; 27:100707. [PMID: 35477031 DOI: 10.1016/j.aohep.2022.100707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/04/2022] [Accepted: 03/22/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Although hyperferritinemia may reflect the inflammatory status of patients with non-alcoholic fatty liver disease (NAFLD), approximately 33% of hyperferritinemia cases reflect real hepatic iron overload. AIM To evaluate a non-invasive method for assessing mild iron overload in patients with NAFLD using 3T magnetic resonance imaging (MRI) relaxometry, serum hepcidin, and the expression of ferritin subunits. METHODS This cross-sectional study assessed patients with biopsy-proven NAFLD. MRI relaxometry was performed using a 3T scanner in all patients, and the results were compared with iron content determined by liver biopsy. Ferritin, hepcidin, and ferritin subunits were assessed and classified according to ferritin levels and to siderosis identified by liver biopsy. RESULTS A total of 67 patients with NAFLD were included in the study. MRI revealed mild iron overload in all patients (sensitivity, 73.5%; specificity, 70%). For mild (grade 1) siderosis, the transverse relaxation rate (R2*) threshold was 58.9 s-1 and the mean value was 72.5 s-1 (SD, 33.9), while for grades 2/3 it was 88.2 s-1 (SD, 31.9) (p < 0.001). The hepcidin threshold for siderosis was > 30.2 ng/mL (sensitivity, 87%; specificity, 82%). Ferritin H and ferritin L subunits were expressed similarly in patients with NAFLD, regardless of siderosis. There were no significant differences in laboratory test results between the groups, including glucose parameters and liver function tests. CONCLUSIONS MRI relaxometry and serum hepcidin accurately assessed mild iron overload in patients with dysmetabolic iron overload syndrome.
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Affiliation(s)
- Paula Pessin Fábrega Branisso
- Obesity and metabolic syndrome study group, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil.
| | | | - Hilton Muniz Leão Filho
- Radiology department, InRad, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Fabiana Roberto Lima
- Patology department, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Aritânia Sousa Santos
- Laboratory of Carbohydrates and Raioimmunoassay (LIM/18), Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Marcio Correa Mancini
- Obesity and metabolic syndrome study group, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Maria Edna de Melo
- Radiology department, InRad, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Flair José Carrilho
- Gastroenterology department, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Manoel de Souza Rocha
- Radiology department, InRad, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
| | - Paul Clark
- Magnepath digital health company, Perth, Australia
| | | | - Cintia Cercato
- Obesity and metabolic syndrome study group, Hospital das Clínicas de São Paulo, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil
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7
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Mariani R, Pelucchi S, Paolini V, Belingheri M, di Gennaro F, Faverio P, Riva M, Pesci A, Piperno A. Prolonged exposure to welding fumes as a novel cause of systemic iron overload. Liver Int 2021; 41:1600-1607. [PMID: 33713383 PMCID: PMC8252060 DOI: 10.1111/liv.14874] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/25/2021] [Accepted: 03/04/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Inhalation of welding fume may cause pulmonary disease known as welder's lung. At our centre we came across a number of welders with systemic iron overload and prolonged occupational history and we aimed at characterizing this novel clinical form of iron overload. METHODS After exclusion of other known causes of iron overload, 20 welders were fully evaluated for working history, hepatic, metabolic and iron status. MRI iron assessment was performed in 19 patients and liver biopsy in 12. We included 40 HFE-HH patients and 24 healthy controls for comparison. RESULTS 75% of patients showed lung HRCT alterations; 90% had s-FERR > 1000 ng/mL and 60% had TSAT > 45%. Liver iron overload was mild in 8 and moderate-severe in 12. The median iron removed was 7.8 g. Welders showed significantly lower TSAT and higher SIS and SIS/TIS ratio than HFE-HH patients. Serum hepcidin was significantly higher in welders than in HFE-HH patients and healthy controls. At liver biopsy, 50% showed liver fibrosis that was mild in four, and moderate-severe in two. Liver staging correlated with liver iron overload. CONCLUSIONS Welders with prolonged fume exposure can develop severe liver iron overload. The mechanism of liver iron accumulation is quite different to that of HFE-HH suggesting that reticuloendothelial cells may be the initial site of deposition. We recommend routine measurement of serum iron indices in welders to provide adequate diagnosis and therapy, and the inclusion of prolonged welding fume exposure in the list of acquired causes of hyperferritinemia and iron overload.
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Affiliation(s)
- Raffaella Mariani
- Centre for Rare Diseases ‐ Disorders of Iron Metabolism ‐ ASST‐MonzaCentre of European Reference Network (EuroBloodNet)San Gerardo Hospital MonzaMonzaItaly
| | - Sara Pelucchi
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly
| | | | - Michael Belingheri
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Unit of Occupational Medicine Unit‐ ASST‐MonzaSan Gerardo HospitalMonzaItaly
| | | | - Paola Faverio
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Respiratory Unit ‐ ASST‐MonzaSan Gerardo Hospital MonzaMonzaItaly
| | - Michele Riva
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Unit of Occupational Medicine Unit‐ ASST‐MonzaSan Gerardo HospitalMonzaItaly
| | - Alberto Pesci
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Respiratory Unit ‐ ASST‐MonzaSan Gerardo Hospital MonzaMonzaItaly
| | - Alberto Piperno
- Centre for Rare Diseases ‐ Disorders of Iron Metabolism ‐ ASST‐MonzaCentre of European Reference Network (EuroBloodNet)San Gerardo Hospital MonzaMonzaItaly,Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly,Medical Genetics ‐ ASST‐MonzaSan Gerardo Hospital MonzaMonzaItaly
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8
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Dietary iron to total energy intake ratio and type 2 diabetes incidence in a longitudinal 12-year analysis of the Korean Genome and Epidemiology Cohort Study. Eur J Nutr 2021; 60:4453-4461. [PMID: 34085096 DOI: 10.1007/s00394-021-02596-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 05/21/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Recent study found iron consumption has been associated with an increased risk of type 2 diabetes (T2DM). Even though, high iron intake is correlated with total caloric intake, most studies have evaluated the individual effect of iron and total caloric intake. The aim of this study was to investigate the effect of iron intake, in conjunction with total energy intake, on developing T2DM. We also investigated the interactions between dietary iron and energy ratios (IERs) and iron-related single nucleotide polymorphisms (SNPs) in the development of T2DM. METHODS The study was carried out in Ansan and Ansung, Korea, between March 2001 and December 2014. A total of 6413 participants (3073 men and 3340 women), aged 40-69 years, were enrolled in this study. The mean follow-up period was 8.4 years. The study population was divided into quartiles based on IERs with cut-off points at 4.54, 5.41, and 6.29. The odds ratios (ORs) for new-onset T2DM were calculated across each quartile of IERs and a random forest model was constructed using the default settings to predict new-onset T2DM. To confirm the interaction among IERs, SNPs, and the incidence of T2DM, we measured the predictive power of new-onset T2DM using IER and six SNPs in genes related to iron metabolism [rs855791 (TPMRSS6), rs38116479 (TF), rs1799852 (TF), rs2280673, rs1799945 (HFT), rs180562 (HFE)]. RESULTS The prevalence of T2DM was 762 (11.8%). IERs showed a positive association with T2DM. The ORs were 1.30 (95% CI 1.02-1.67), 1.20 (95% CI 0.94-1.56), and 1.43 (95% CI 1.11-1.86) across the IER quartiles after adjusting for non-dietary and dietary metabolic risk factors. When the IER was 1.89-fold higher than the reference group, the risk of developing T2DM increased by 43% (OR 1.43; 95% CI 1.11-1.86). CONCLUSION A higher IER was positively associated with developing T2DM independent of dietary or non-dietary risk factors. We also found the possible interactions between the identified SNPs and iron intake in relations to T2DM.
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Pelucchi S, Ravasi G, Arosio C, Mauri M, Piazza R, Mariani R, Piperno A. HIF1A: A Putative Modifier of Hemochromatosis. Int J Mol Sci 2021; 22:ijms22031245. [PMID: 33513852 PMCID: PMC7865586 DOI: 10.3390/ijms22031245] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 12/20/2022] Open
Abstract
HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression.
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Affiliation(s)
- Sara Pelucchi
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.P.); (G.R.); (M.M.); (R.P.)
| | - Giulia Ravasi
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.P.); (G.R.); (M.M.); (R.P.)
| | - Cristina Arosio
- Liceo Artistico Statale Amedeo Modigliani, 20833 Giussano, Italy;
| | - Mario Mauri
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.P.); (G.R.); (M.M.); (R.P.)
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.P.); (G.R.); (M.M.); (R.P.)
- Hematology and Clinical Research Unit, ASST-Monza, San Gerardo Hospital Monza, 20900 Monza, Italy
| | - Raffaella Mariani
- Centre of European Reference Network (EuroBloodNet) and Centre for Rare Diseases-Disorders of Iron Metabolism-ASST-Monza, San Gerardo Hospital Monza, 20900 Monza, Italy;
| | - Alberto Piperno
- Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.P.); (G.R.); (M.M.); (R.P.)
- Centre of European Reference Network (EuroBloodNet) and Centre for Rare Diseases-Disorders of Iron Metabolism-ASST-Monza, San Gerardo Hospital Monza, 20900 Monza, Italy;
- Medical Genetics-ASST-Monza, S. Gerardo Hospital Monza, 20900 Monza, Italy
- Correspondence: ; Tel.: +39-039-233-3461
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Abstract
Iron overload is a common clinical problem resulting from hereditary hemochromatosis or secondary hemosiderosis (mainly associated with transfusion therapy), being also associated with chronic liver diseases and metabolic disorders. Excess of iron accumulates in organs like the liver, pancreas and heart. Without treatment, patients with iron overload disorders will develop liver cirrhosis, diabetes and cardiomyopathy. Iron quantification is therefore crucial not only for diagnosis of iron overload but also to monitor iron-reducing therapies. Liver iron concentration is considered the surrogate marker of total body iron stores. Because liver biopsy is invasive and prone to high variability and sampling bias, MR imaging has emerged as a non-invasive method and gained wide acceptance, now being considered the standard of care for assessing iron overload. Nevertheless, there are different MR techniques for iron quantification and there is still no consensus about the best technique or postprocessing tool for hepatic iron quantification, with the choice of imaging technique depending mainly on the local expertise as well on the available equipment and software. Because different methods should not be used interchangeably, it is important to choose one method and use the same one when following up patients over time.
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Affiliation(s)
- Manuela França
- Radiology Department - Centro Hospitalar Universitário do Porto, Largo Prof Abel Salazar, 4099-001, Porto, Portugal.
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, I3S, Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
| | - João Gomes Carvalho
- Radiology Department - Centro Hospitalar Universitário do Porto, Largo Prof Abel Salazar, 4099-001, Porto, Portugal
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Marchi G, Nascimbeni F, Motta I, Busti F, Carubbi F, Cappellini MD, Pietrangelo A, Corradini E, Piperno A, Girelli D. Hyperferritinemia and diagnosis of type 1 Gaucher disease. Am J Hematol 2020; 95:570-576. [PMID: 32031266 DOI: 10.1002/ajh.25752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 01/28/2020] [Accepted: 02/03/2020] [Indexed: 12/21/2022]
Affiliation(s)
- Giacomo Marchi
- EuroBloodNet Referral Center for Iron Disorders and Gruppo Interdisciplinare Malattie del Ferro, Internal Medicine Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Fabio Nascimbeni
- Regional Referral Center for Lysosomal Storage Diseases, Division of Internal Medicine and Metabolism, Azienda Ospedaliero-Universitaria di Modena - Ospedale Civile, University of Modena and Reggio Emilia, Modena, Italy
| | - Irene Motta
- Department of Medicine and Medical Specialities, Fondazione IRCSS Cà Granda, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Fabiana Busti
- EuroBloodNet Referral Center for Iron Disorders and Gruppo Interdisciplinare Malattie del Ferro, Internal Medicine Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Francesca Carubbi
- Regional Referral Center for Lysosomal Storage Diseases, Division of Internal Medicine and Metabolism, Azienda Ospedaliero-Universitaria di Modena - Ospedale Civile, University of Modena and Reggio Emilia, Modena, Italy
| | - Maria Domenica Cappellini
- Department of Medicine and Medical Specialities, Fondazione IRCSS Cà Granda, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Antonello Pietrangelo
- Division of Internal Medicine and Center for Hemochromatosis and Heredometabolic Liver Diseases, EuroBloodNet Referral Center for Iron Disorders, Azienda Ospedaliero-Universitaria di Modena - Policlinico, Modena, Italy
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Elena Corradini
- Division of Internal Medicine and Center for Hemochromatosis and Heredometabolic Liver Diseases, EuroBloodNet Referral Center for Iron Disorders, Azienda Ospedaliero-Universitaria di Modena - Policlinico, Modena, Italy
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Alberto Piperno
- EuroBloodNet and MetabERN Referral Center, Department of Medicine and Surgery, University of Milano-Bicocca, Medical Genetics, ASST Monza - S. Gerardo Hospital, Monza, Italy
| | - Domenico Girelli
- EuroBloodNet Referral Center for Iron Disorders and Gruppo Interdisciplinare Malattie del Ferro, Internal Medicine Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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Piperno A, Pelucchi S, Mariani R. Inherited iron overload disorders. Transl Gastroenterol Hepatol 2020; 5:25. [PMID: 32258529 DOI: 10.21037/tgh.2019.11.15] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/12/2019] [Indexed: 12/21/2022] Open
Abstract
Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.
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Affiliation(s)
- Alberto Piperno
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy
| | - Sara Pelucchi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Raffaella Mariani
- Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy
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Castiella A, Urreta I, Zapata E, Zubiaurre L, Alústiza JM, Otazua P, Salvador E, Letamendi G, Arrizabalaga B, Rincón ML, Emparanza JI. Liver iron concentration in dysmetabolic hyperferritinemia: Results from a prospective cohort of 276 patients. Ann Hepatol 2020; 19:31-35. [PMID: 31587985 DOI: 10.1016/j.aohep.2019.07.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/30/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION AND OBJECTIVES We aimed to study the liver iron concentration in patients referred for hyperferritinemia to six hospitals in the Basque Country and to determine if there were differences between patients with or without metabolic syndrome. PATIENTS AND METHODS Metabolic syndrome was defined by accepted criteria. Liver iron concentration was determined by magnetic resonance imaging. RESULTS We obtained the data needed to diagnose metabolic syndrome in 276 patients; a total of 135 patients (49%), 115/240 men (48%), and 20/36 women (55.6%) presented metabolic syndrome. In all 276 patients, an MRI for the determination of liver iron concentration (mean±SD) was performed. The mean liver iron concentration was 30.83±19.38 for women with metabolic syndrome, 38.84±25.50 for men with metabolic syndrome, and 37.66±24.79 (CI 95%; 33.44-41.88) for the whole metabolic syndrome group. In 141 patients (51%), metabolic syndrome was not diagnosed: 125/240 were men (52%) and 16/36 were women (44.4%). The mean liver iron concentration was 34.88±16.18 for women without metabolic syndrome, 44.48±38.16 for men without metabolic syndrome, and 43.39±36.43 (CI 95%, 37.32-49.46) for the whole non-metabolic syndrome group. Comparison of the mean liver iron concentration from both groups (metabolic syndrome vs non-metabolic syndrome) revealed no significant differences (p=0.12). CONCLUSIONS Patients with hyperferritinemia and metabolic syndrome presented a mildly increased mean liver iron concentration that was not significantly different to that of patients with hyperferritinemia and non-metabolic syndrome.
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Affiliation(s)
- Agustin Castiella
- Gastroenterology Service, Mendaro Hospital, Mendaro, Spain; Gastroenterology Service, Donostia University Hospital, Donostia, Spain.
| | - Iratxe Urreta
- Clinical Epidemiology Unit, CASPe, CIBER-ESP, Donostia University Hospital, Donostia, Spain
| | - Eva Zapata
- Gastroenterology Service, Mendaro Hospital, Mendaro, Spain; Gastroenterology Service, Donostia University Hospital, Donostia, Spain
| | | | | | - Pedro Otazua
- Gastroenterology Service, Mondragon Hospital, Mondragon, Spain
| | | | | | | | | | - José I Emparanza
- Clinical Epidemiology Unit, CASPe, CIBER-ESP, Donostia University Hospital, Donostia, Spain
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Czaja AJ. Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications. Aliment Pharmacol Ther 2019; 49:681-701. [PMID: 30761559 DOI: 10.1111/apt.15173] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. AIMS To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. CONCLUSIONS Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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15
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Lynch S, Pfeiffer CM, Georgieff MK, Brittenham G, Fairweather-Tait S, Hurrell RF, McArdle HJ, Raiten DJ. Biomarkers of Nutrition for Development (BOND)-Iron Review. J Nutr 2018; 148:1001S-1067S. [PMID: 29878148 PMCID: PMC6297556 DOI: 10.1093/jn/nxx036] [Citation(s) in RCA: 193] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/27/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
This is the fifth in the series of reviews developed as part of the Biomarkers of Nutrition for Development (BOND) program. The BOND Iron Expert Panel (I-EP) reviewed the extant knowledge regarding iron biology, public health implications, and the relative usefulness of currently available biomarkers of iron status from deficiency to overload. Approaches to assessing intake, including bioavailability, are also covered. The report also covers technical and laboratory considerations for the use of available biomarkers of iron status, and concludes with a description of research priorities along with a brief discussion of new biomarkers with potential for use across the spectrum of activities related to the study of iron in human health.The I-EP concluded that current iron biomarkers are reliable for accurately assessing many aspects of iron nutrition. However, a clear distinction is made between the relative strengths of biomarkers to assess hematological consequences of iron deficiency versus other putative functional outcomes, particularly the relationship between maternal and fetal iron status during pregnancy, birth outcomes, and infant cognitive, motor and emotional development. The I-EP also highlighted the importance of considering the confounding effects of inflammation and infection on the interpretation of iron biomarker results, as well as the impact of life stage. Finally, alternative approaches to the evaluation of the risk for nutritional iron overload at the population level are presented, because the currently designated upper limits for the biomarker generally employed (serum ferritin) may not differentiate between true iron overload and the effects of subclinical inflammation.
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Affiliation(s)
| | - Christine M Pfeiffer
- National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA
| | - Michael K Georgieff
- Division of Neonatology, Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN
| | - Gary Brittenham
- Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY
| | - Susan Fairweather-Tait
- Department of Nutrition, Norwich Medical School, Norwich Research Park, University of East Anglia, Norwich NR4 7JT, UK
| | - Richard F Hurrell
- Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Harry J McArdle
- Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, UK
| | - Daniel J Raiten
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)
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Ravasi G, Pelucchi S, Mariani R, Casati M, Greni F, Arosio C, Pelloni I, Majore S, Santambrogio P, Levi S, Piperno A. Unexplained isolated hyperferritinemia without iron overload. Am J Hematol 2017; 92:338-343. [PMID: 28052375 DOI: 10.1002/ajh.24641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/21/2016] [Accepted: 12/31/2016] [Indexed: 02/06/2023]
Abstract
Although hyperferritinemia may be reflective of elevated total body iron stores, there are conditions in which ferritin levels are disproportionately elevated relative to iron status. Autosomal dominant forms of hyperferritinemia due to mutations in the L-ferritin IRE or in A helix of L-ferritin gene have been described, however cases of isolated hyperferritinemia still remain unsolved. We describe 12 Italian subjects with unexplained isolated hyperferritinemia (UIH). Four probands have affected siblings, but no affected parents or offspring. Sequencing analyses did not identify casual mutations in ferritin gene or IRE regions. These patients had normal levels of intracellular ferritin protein and mRNA in peripheral blood cells excluding pathological ferritin production at transcriptional and post-transcriptional level. In contrast with individuals with benign hyperferritinemia caused by mutations affecting the ferritin A helix, low rather than high glycosylation of serum ferritin was observed in our UIH subjects compared with controls. These findings suggest that subjects with UIH have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance. The cause remains to be defined and we can only speculate the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin turnover including ferritin secretion.
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Affiliation(s)
- Giulia Ravasi
- School of Medicine and Surgery; University of Milano-Bicocca; Monza Italy
| | - Sara Pelucchi
- School of Medicine and Surgery; University of Milano-Bicocca; Monza Italy
| | - Raffaella Mariani
- ASST-Monza - S.Gerardo Hospital; Centre for Disorder of Iron Metabolism; Monza Italy
| | - Marco Casati
- ASST-Monza - S.Gerardo Hospital; Unit of Clinical Chemistry; Monza Italy
| | - Federico Greni
- School of Medicine and Surgery; University of Milano-Bicocca; Monza Italy
| | | | - Irene Pelloni
- ASST-Monza - S.Gerardo Hospital; Centre for Disorder of Iron Metabolism; Monza Italy
| | - Silvia Majore
- Medical Genetics, Molecular Medicine Department; Sapienza University of Rome, San Camillo-Forlanini Hospital; Roma Italy
| | - Paolo Santambrogio
- Division of Neuroscience; San Raffaele Scientific Institute; Milano Italy
| | - Sonia Levi
- Division of Neuroscience; San Raffaele Scientific Institute; Milano Italy
- University Vita-Salute San Raffaele; Milano Italy
| | - Alberto Piperno
- School of Medicine and Surgery; University of Milano-Bicocca; Monza Italy
- ASST-Monza - S.Gerardo Hospital; Centre for Disorder of Iron Metabolism; Monza Italy
- Consortium of Human Molecular Genetics; Monza Italy
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Rametta R, Dongiovanni P, Pelusi S, Francione P, Iuculano F, Borroni V, Fatta E, Castagna A, Girelli D, Fargion S, Valenti L. Hepcidin resistance in dysmetabolic iron overload. Liver Int 2016; 36:1540-8. [PMID: 26998752 DOI: 10.1111/liv.13124] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 03/12/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Dysmetabolic iron overload syndrome (DIOS) is a frequent condition predisposing to metabolic, cardiovascular and hepatic damage, whose pathogenesis remains poorly defined. Aim of this study was to characterize iron metabolism in DIOS. METHODS We evaluated 18 patients with DIOS, compared to 18 with nonalcoholic fatty liver and 23 healthy individuals with normal iron status, and 10 patients with hereditary haemochromatosis by a 24-h oral iron tolerance test with hepcidin measurement and iron metabolism modelling under normal iron stores. RESULTS Dysmetabolic iron overload syndrome patients had higher peak transferrin saturation and area under the-curve of transferrin saturation than subjects with normal iron status, but lower values than haemochromatosis patients (P < 0.05 for all). Conversely, they had higher peak circulating hepcidin levels and area under the curve of hepcidin than the other groups (P < 0.05 for all). This was independent age, sex, haemoglobin, ferritin, and transferrin saturation levels (P = 0.0002). Hepcidin increase in response to the rise in transferrin saturation (hepcidin release index) was not impaired in DIOS patients. Viceversa, the ability of the hepcidin spike to control the rise in transferrin saturation at the beginning of the test (hepcidin resistance index) was impaired in DIOS (P = 0.0002). In DIOS patients, the hepcidin resistance index was correlated with ferritin levels at diagnosis (P = 0.016). CONCLUSIONS Dysmetabolic iron overload syndrome is associated with a subtle impairment in the ability of the iron hormone hepcidin to restrain iron absorption following an iron challenge, suggesting a hepcidin resistance state. Further studies are required to better characterize the molecular mechanism underpinning this new iron metabolism alteration.
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Affiliation(s)
- Raffaela Rametta
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Paolo Francione
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Federica Iuculano
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Vittorio Borroni
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Erika Fatta
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Annalisa Castagna
- Policlinico G.B. Rossi, Department of Medicine, Università di Verona, Verona, Italy
| | - Domenico Girelli
- Policlinico G.B. Rossi, Department of Medicine, Università di Verona, Verona, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.,Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. .,Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
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Milic S, Mikolasevic I, Orlic L, Devcic E, Starcevic-Cizmarevic N, Stimac D, Kapovic M, Ristic S. The Role of Iron and Iron Overload in Chronic Liver Disease. Med Sci Monit 2016; 22:2144-2151. [PMID: 27332079 PMCID: PMC4922827 DOI: 10.12659/msm.896494] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/24/2015] [Indexed: 12/13/2022] Open
Abstract
The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models.
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Affiliation(s)
- Sandra Milic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
| | - Ivana Mikolasevic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
- Department of Nephrology, Dialysis and Kidney Transplantation, UHC Rijeka, Rijeka, Croatia
| | - Lidija Orlic
- Department of Nephrology, Dialysis and Kidney Transplantation, UHC Rijeka, Rijeka, Croatia
| | - Edita Devcic
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
| | | | - Davor Stimac
- Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia
| | - Miljenko Kapovic
- Department of Biology and Medical Genetics, Faculty of Medicine, Rijeka, Croatia
| | - Smiljana Ristic
- Department of Biology and Medical Genetics, Faculty of Medicine, Rijeka, Croatia
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Badar S, Busti F, Ferrarini A, Xumerle L, Bozzini P, Capelli P, Pozzi-Mucelli R, Campostrini N, De Matteis G, Marin Vargas S, Giorgetti A, Delledonne M, Olivieri O, Girelli D. Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload. Am J Hematol 2016; 91:420-5. [PMID: 26799139 DOI: 10.1002/ajh.24304] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 01/08/2016] [Accepted: 01/13/2016] [Indexed: 12/14/2022]
Abstract
Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available "first level" molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non-diagnostic (i.e. simple heterozygosity) test, because of a known heterogeneity involving at least four other genes (HAMP, HJV, TFR2, and SLC40A1). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of "non-HFE" HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)-based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non-diagnostic first level genetic test. We identified several mutations, some of which were novel (i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of "non-HFE" HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS-based "second level" genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations.
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Affiliation(s)
- Sadaf Badar
- Department of Medicine; Section of Internal Medicine, University of Verona; Verona Italy
| | - Fabiana Busti
- Department of Medicine; Section of Internal Medicine, University of Verona; Verona Italy
| | | | - Luciano Xumerle
- Department of Biotechnology; University of Verona; Verona Italy
| | - Paolo Bozzini
- Department of Medicine; Section of Internal Medicine, University of Verona; Verona Italy
| | - Paola Capelli
- Unit of Pathology, Azienda Ospedaliera Universitaria Integrata Verona; Verona Italy
| | - Roberto Pozzi-Mucelli
- Department of Diagnostics and Public Health; Section of Radiology, University of Verona; Verona Italy
| | - Natascia Campostrini
- Department of Medicine; Section of Internal Medicine, University of Verona; Verona Italy
| | - Giovanna De Matteis
- Unit of Clinical Chemistry, Azienda Ospedaliera Universitaria Integrata Verona; Verona Italy
| | | | | | | | - Oliviero Olivieri
- Department of Medicine; Section of Internal Medicine, University of Verona; Verona Italy
| | - Domenico Girelli
- Department of Medicine; Section of Internal Medicine, University of Verona; Verona Italy
- Veneto Regional Referral Center for Iron Metabolism Disorders, GIMFer (Gruppo Interdisciplinare Sulle Malattie Del Ferro); Azienda Ospedaliera Uiversitaria Integrata Verona; Verona Italy
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20
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Homocysteine upregulates hepcidin expression through BMP6/SMAD signaling pathway in hepatocytes. Biochem Biophys Res Commun 2016; 471:303-8. [PMID: 26855134 DOI: 10.1016/j.bbrc.2016.02.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 02/01/2016] [Indexed: 12/25/2022]
Abstract
Subjects with severe hyperhomocysteinemia have hypoferric anemia and excessive iron deposition in the liver. Hepcidin, the central regulator of iron homeostasis, plays a key role in iron metabolism. However, the regulation of homocysteine (Hcy) on hepcidin is largely unclear. We conducted experiments in HepG2 cells to identify the mechanisms with which Hcy modulates hepcidin expression. We found that treatment with Hcy dose-dependently increased both hepcidin transcript levels and protein levels, as assessed by quantitative real-time reverse-transcriptase polymerase chain reaction and western blotting, respectively. Hcy also activated BMP6 signaling and increased the phosphorylation of SMAD1/5/8 in HepG2 cells. We found that Hcy's effect on hepcidin expression was impaired by the knockdown of BMP6 and its receptors ALK2/3/6 with siRNAs. These results demonstrated that Hcy up-regulated hepcidin expression through the BMP6/SMAD pathway, suggesting a novel mechanism underlying the hyperhomocysteinemia-associated perturbation of iron homeostasis.
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21
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Vetro C, Rosso R, Palmucci S, Russello M, Colletta G, Romeo MA, Ximenes B, Romano A, Palumbo GA, Di Raimondo F. Erythrocytapheresis is a valid and safe therapeutic option in dysmetabolic iron overload syndrome. J Clin Apher 2015; 31:443-7. [PMID: 26411360 DOI: 10.1002/jca.21434] [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: 04/03/2015] [Accepted: 09/10/2015] [Indexed: 11/10/2022]
Abstract
Dysmetabolic iron overload syndrome is a rare event causing hepatic impairment with serious long-term side effects. Here, we describe a case of metabolic syndrome-related hepatic iron overload that showed a rapid, effective, and safe response to erythrocytapheresis. J. Clin. Apheresis 31:443-447, 2016. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Calogero Vetro
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy.
| | - Rosamaria Rosso
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Stefano Palmucci
- Radiodiagnostic and Radiotherapy Unit, University Hospital "Policlinico-Vittorio Emanuele", Catania, Catania, Italy
| | | | - Grazia Colletta
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Maria Anna Romeo
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Benedetta Ximenes
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Alessandra Romano
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Giuseppe Alberto Palumbo
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
| | - Francesco Di Raimondo
- Unit of Thalassemia, Division of Haematology, a.O. "Policlinico-Vittorio Emanuele", University of Catania, Catania, Italy
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Hb and dyslipidaemia as predicting markers of serum alanine aminotransferase elevation in Chinese adolescents. Public Health Nutr 2015; 19:1067-73. [PMID: 26328752 DOI: 10.1017/s1368980015002293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Fe is an essential element for erythropoiesis and Hb synthesis. High Hb levels affect the blood's viscosity and are associated with cardiovascular dysfunction. The aim of the present study was to examine relationships of Hb and cardiometabolic abnormalities with the risk of alanine aminotransferase (ALT) elevation in adolescents. DESIGN A population-based, cross-sectional study. SETTING National Nutrition and Health Survey in Taiwan (2010-2011, adolescents). SUBJECTS Healthy adolescents aged 13-18 years. RESULTS In total, 1941 adolescents (963 boys and 978 girls) were entered in the study. The mean age was 15·3 (sd 0·1) years (boys, 15·3 (sd 0·1) years; girls, 15·2 (sd 0·1) years). ALT tertile cut-off points for boys were 11 and 16 U/l, and for girls were 9 and 12 U/l. Girls without dyslipidaemia and presenting in the highest quartile (Q1) of Hb (>13·6 g/dl) were 1·89 and 3·76 times more likely to have raised serum ALT (9 and >12 U/l, respectively) than the reference (lowest quartile of Hb (Q1), 12 U/l) than the reference (Q1 of Hb, 15·4 g/dl), who were 7·40 times more likely to have elevated serum ALT of >16 U/l than the reference (Q1 of Hb, <14·1 g/dl). CONCLUSIONS Our findings suggest that an increased Hb level is a predictor of elevated serum ALT in adolescent girls with dyslipidaemia. Our study also highlights the importance of further research to establish cut-off points for Hb and its utility in diagnosing and preventing the onset of dyslipidaemia in adolescents.
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23
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Lückhoff HK, Kruger FC, Kotze MJ. Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries. World J Hepatol 2015; 7:1192-1208. [PMID: 26019735 PMCID: PMC4438494 DOI: 10.4254/wjh.v7.i9.1192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/18/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
Heterogeneity in clinical presentation, histological severity, prognosis and therapeutic outcomes characteristic of non-alcoholic fatty liver disease (NAFLD) necessitates the development of scientifically sound classification schemes to assist clinicians in stratifying patients into meaningful prognostic subgroups. The need for replacement of invasive liver biopsies as the standard method whereby NAFLD is diagnosed, graded and staged with biomarkers of histological severity injury led to the development of composite prognostic models as potentially viable surrogate alternatives. In the present article, we review existing scoring systems used to (1) confirm the presence of undiagnosed hepatosteatosis; (2) distinguish between simple steatosis and NASH; and (3) predict advanced hepatic fibrosis, with particular emphasis on the role of NAFLD as an independent cardio-metabolic risk factor. In addition, the incorporation of functional genomic markers and application of emerging imaging technologies are discussed as a means to improve the diagnostic accuracy and predictive performance of promising composite models found to be most appropriate for widespread clinical adoption.
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Galimberti S, Trombini P, Bernasconi DP, Redaelli I, Pelucchi S, Bovo G, Di Gennaro F, Zucchini N, Paruccini N, Piperno A. Simultaneous liver iron and fat measures by magnetic resonance imaging in patients with hyperferritinemia. Scand J Gastroenterol 2015; 50:429-38. [PMID: 25633726 DOI: 10.3109/00365521.2014.940380] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Hyperferritinemia is frequent in chronic liver diseases of any cause, but the extent to which ferritin truly reflects iron stores is variable. In these patients, both liver iron and fat are found in variable amount and association. Liver biopsy is often required to quantify liver fat and iron, but sampling variability and invasiveness limit its use. We aimed to assess single breath-hold multiecho magnetic resonance imaging (MRI) for the simultaneous lipid and iron quantification in patients with hyperferritinemia. MATERIAL AND METHODS We compared MRI results for both iron and fat with their respective gold standards - liver iron concentration and computer-assisted image analysis for steatosis on biopsy. We prospectively studied 67 patients with hyperferritinemia and other 10 consecutive patients were used for validation. We estimated two linear calibration equations for the prediction of iron and fat based on MRI. The agreement between MRI and biopsy was evaluated. RESULTS MRI showed good performances in both the training and validation samples. MRI information was almost completely in line with that obtained from liver biopsy. CONCLUSION Single breath-hold multiecho MRI is an accurate method to obtain a valuable measure of both liver iron and steatosis in patients with hyperferritinemia.
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Affiliation(s)
- Stefania Galimberti
- Department of Health Sciences, Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca , Monza , Italy
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Nikonorov AA, Skalnaya MG, Tinkov AA, Skalny AV. Mutual interaction between iron homeostasis and obesity pathogenesis. J Trace Elem Med Biol 2015; 30:207-14. [PMID: 24916791 DOI: 10.1016/j.jtemb.2014.05.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 04/15/2014] [Accepted: 05/14/2014] [Indexed: 02/08/2023]
Abstract
Obesity is identified as an important medical problem. One of the pathologic conditions observed in obesity is systemic iron deficiency and hypoferremia. Along with a large number of studies indicating disturbed iron homeostasis in obesity, recent data indicate a cause-effect relationship between iron status and obesity-related pathologies. The primary objective of the article is to consider two aspects of the iron-obesity interplay: (1) the mechanisms leading to impaired iron balance, and (2) the pathways of iron participation in obesity-related pathogenesis. While considering disturbance of iron homeostasis in obesity, a number of potential mechanisms of hypoferremia are proposed. At the same time, the inflammation of obesity and obesity-related hepcidin and lipocalin 2 hyperproduction seem to be the most probable reasons of obesity-related hypoferremia. Oversecretion of these proteins leads to iron sequestration in reticuloendothelial system cells. The latter also leads to increased adipose tissue iron content, thus producing preconditions for adverse effects of local iron overload. Being a redox-active metal, iron is capable of inducing oxidative stress as well as endoplasmic reticulum stress, inflammation and adipose tissue endocrine dysfunction. Iron-mediated mechanisms of toxicity may influence aspects of obesity pathogenesis possibly even leading to obesity aggravation. Thus, a mutual interaction between disturbance in iron homeostasis and obesity pathogenesis is proposed. All sides of this interaction should be considered to design new therapeutic approaches to the treatment of disturbed iron homeostasis in obesity.
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Affiliation(s)
- Alexandr A Nikonorov
- Department of Biochemistry, Orenburg State Medical Academy, Sovetskaya Street 6, Orenburg 460000, Russia.
| | - Margarita G Skalnaya
- Russian Society of Trace Elements in Medicine, Zemlyanoy Val Street 46, Moscow 105064, Russia
| | - Alexey A Tinkov
- Department of Biochemistry, Orenburg State Medical Academy, Sovetskaya Street 6, Orenburg 460000, Russia
| | - Anatoly V Skalny
- Russian Society of Trace Elements in Medicine, Zemlyanoy Val Street 46, Moscow 105064, Russia; Institute of Bioelementology (Russian Satellite Centre of Trace Element - Institute for UNESCO), Orenburg State University, Pobedy Avenue 13, Orenburg 460352, Russia
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26
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Dongiovanni P, Lanti C, Gatti S, Rametta R, Recalcati S, Maggioni M, Fracanzani AL, Riso P, Cairo G, Fargion S, Valenti L. High fat diet subverts hepatocellular iron uptake determining dysmetabolic iron overload. PLoS One 2015; 10:e0116855. [PMID: 25647178 PMCID: PMC4315491 DOI: 10.1371/journal.pone.0116855] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 12/15/2014] [Indexed: 02/06/2023] Open
Abstract
Increased serum ferritin associated with mild hepatic iron accumulation, despite preserved upregulation of the iron hormone hepcidin, is frequently observed in patients with dysmetabolic overload syndrome (DIOS). Genetic factors and Western diet represent predisposing conditions, but the mechanisms favoring iron accumulation in DIOS are still unclear. Aims of this study were to assess the effect a high-fat diet (HFD) on hepatic iron metabolism in an experimental model in rats, to further characterize the effect of free fatty acids on iron metabolism in HepG2 hepatocytes in vitro, and to assess the translational relevance in patients with fatty liver with and without iron accumulation. Despite decreased uptake of dietary iron, rats fed HFD accumulated more hepatic iron than those fed regular diet, which was associated with steatosis development. Hepatic iron accumulation was paralleled by induction of ferritin, in the presence of preserved upregulation of hepcidin, recapitulating the features of DIOS. HFD was associated with increased expression of the major iron uptake protein Transferrin receptor-1 (TfR-1), consistently with upregulation of the intracellular iron sensor Iron regulated protein-1 (IRP1). Supplementation with fatty acids induced TfR-1 and IRP1 in HepG2 hepatocytes, favoring intracellular iron accumulation following exposure to iron salts. IRP1 silencing completely abrogated TfR-1 induction and the facilitation of intracellular iron accumulation induced by fatty acids. Hepatic TfR-1 mRNA levels were upregulated in patients with fatty liver and DIOS, whereas they were not associated with liver fat nor with inflammation. In conclusion, increased exposure to fatty acids subverts hepatic iron metabolism, favoring the induction of an iron uptake program despite hepatocellular iron accumulation.
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Affiliation(s)
- Paola Dongiovanni
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy
| | - Claudia Lanti
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy
| | - Stefano Gatti
- Preclinical Surgical Research Center, and Surgery, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy
| | - Raffaela Rametta
- Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milano, Italy
| | - Marco Maggioni
- Pathology, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy
| | - Anna Ludovica Fracanzani
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy
| | - Patrizia Riso
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milano, Italy
| | - Silvia Fargion
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy
| | - Luca Valenti
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Milano, Italy
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López-Calderón C, Palacios R, Cobo A, Nuño E, Ruiz J, Márquez M, Santos J. Serum ferritin in HIV-positive patients is related to immune deficiency and inflammatory activity. Int J STD AIDS 2014; 26:393-7. [PMID: 24912540 DOI: 10.1177/0956462414539669] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 05/19/2014] [Indexed: 11/17/2022]
Abstract
To analyse the prevalence of high ferritin levels in asymptomatic HIV patients and its related factors we conducted a cross-sectional study of a cohort of HIV outpatients in regular follow-up. Epidemiological, clinical, analytical and therapeutic data were collected. Patients completed a questionnaire about cardiovascular risk factors and underwent a physical examination and a 12-h fasting blood analysis. High ferritin levels were defined as a plasma ferritin level >200 µg/L in women and >300 µg/L in men. A total of 571 patients (78.1% men) were included. Median age was 43.2 years, HIV sexual transmission 68.5%, median CD4 count 474 cells/µL, 36.3% AIDS cases, 86.2% on antiretroviral therapy and 74.8% of them with undetectable viral load; 14.6% metabolic syndrome criteria, and mean cardiovascular risk at 10 years 6.67%. High ferritin levels prevalence was 11%, and related factors were a CD4 count <350 cells/µL (odds ratio, OR 2.37 [1.3-4.1], p = 0.003), ultrasensitive C-reactive protein >3 mg/L (OR 2.67 [1.5-4.7], p = 0.001) and chronic hepatitis C virus infection (OR 2.77 [1.5-4.9], p = 0.001). High ferritin levels are not uncommon in HIV patients, and they correlate with immunosuppression defined as CD4 count <350 cells/µL, higher ultrasensitive C-reactive protein and hepatitis C virus infection, and in contrast to the general population, they are not related to increased cardiovascular risk or metabolic syndrome.
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Affiliation(s)
| | - Rosario Palacios
- UGC Enfermedades Infecciosas, Hospital Virgen de la Victoria, Málaga, Spain FIMABIS, Málaga, Spain
| | - Andrés Cobo
- UGC Análisis Clínicos, Hospital Virgen de la Victoria, Málaga, Spain
| | - Enrique Nuño
- UGC Enfermedades Infecciosas, Hospital Virgen de la Victoria, Málaga, Spain FIMABIS, Málaga, Spain
| | - Josefa Ruiz
- UGC Enfermedades Infecciosas, Hospital Virgen de la Victoria, Málaga, Spain FIMABIS, Málaga, Spain
| | - Manuel Márquez
- UGC Enfermedades Infecciosas, Hospital Virgen de la Victoria, Málaga, Spain FIMABIS, Málaga, Spain
| | - Jesús Santos
- UGC Enfermedades Infecciosas, Hospital Virgen de la Victoria, Málaga, Spain FIMABIS, Málaga, Spain
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Basuli D, Stevens RG, Torti FM, Torti SV. Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol 2014; 5:117. [PMID: 24904420 PMCID: PMC4033158 DOI: 10.3389/fphar.2014.00117] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/30/2014] [Indexed: 12/11/2022] Open
Abstract
Disruptions in iron homeostasis are linked to a broad spectrum of chronic conditions including cardiovascular, malignant, metabolic, and neurodegenerative disease. Evidence supporting this contention derives from a variety of analytical approaches, ranging from molecular to population-based studies. This review focuses on key epidemiological studies that assess the relationship between body iron status and chronic diseases, with particular emphasis on atherosclerosis ,metabolic syndrome and diabetes. Multiple surrogates have been used to measure body iron status, including serum ferritin, transferrin saturation, serum iron, and dietary iron intake. The lack of a uniform and standardized means of assessing body iron status has limited the precision of epidemiological associations. Intervention studies using depletion of iron to alter risk have been conducted. Genetic and molecular techniques have helped to explicate the biochemistry of iron metabolism at the molecular level. Plausible explanations for how iron contributes to the pathogenesis of these chronic diseases are beginning to be elucidated. Most evidence supports the hypothesis that excess iron contributes to chronic disease by fostering excess production of free radicals. Overall, epidemiological studies, reinforced by basic science experiments, provide a strong line of evidence supporting the association between iron and elevated risk of cardiovascular disease and diabetes. In this narrative review we attempt to condense the information from existing literature on this topic.
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Affiliation(s)
- Debargha Basuli
- Molecular Biology and Biophysicis, University of Connecticut Health Center, Farmington CT, USA
| | - Richard G Stevens
- Division of Epidemiology and Biostatistics, Department of Community Medicine and Health Care, University of Connecticut Health Center, Farmington CT, USA
| | - Frank M Torti
- Internal Medicine, University of Connecticut Health Center, Farmington CT, USA
| | - Suzy V Torti
- Molecular Biology and Biophysicis, University of Connecticut Health Center, Farmington CT, USA
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Abstract
INTRODUCTION The discovery of hemochromatosis genes and the availability of molecular-genetic tests considerably modified the knowledge of the disease relative to physiopathology, penetrance, and expression, and had major impact in the diagnostic settings. AREAS COVERED Hemochromatosis is a heterogenous disorder at both genetic and phenotypic level. The review discusses criteria to define patients' iron phenotype and to use molecular tests to diagnose HFE-related and non-HFE hemochromatosis. The material examined includes articles published in the journals covered by PubMed US National Library of Medicine. The author has been working in the field of iron overload diseases for several years and has contributed 18 of the papers cited in the references. EXPERT OPINION Hemochromatosis genotyping is inseparable from phenotype characterization. A full clinical assessment is needed and DNA test performed when data suggest a clear indication of suspicion of being at risk for HH. HFE testing for p.Cys282Tyr mutation and p.His63Asp variant is the first molecular diagnostic step. Genotyping for rare mutations can be offered to patients with negative first-level HFE testing who have iron overload with no other explanation and should be performed in referral centers for iron overload disorders that can provide genetic advice and in-house genotyping services.
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Affiliation(s)
- Alberto Piperno
- University of Milano-Bicocca, Centre for the Diagnosis and Treatment of Hemochromatosis and Iron Disorders, S.Gerardo Hospital, Department of Health Sciences, Monza, Italy.
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30
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Martinelli N, Traglia M, Campostrini N, Biino G, Corbella M, Sala C, Busti F, Masciullo C, Manna D, Previtali S, Castagna A, Pistis G, Olivieri O, Toniolo D, Camaschella C, Girelli D. Increased serum hepcidin levels in subjects with the metabolic syndrome: a population study. PLoS One 2012; 7:e48250. [PMID: 23144745 PMCID: PMC3483177 DOI: 10.1371/journal.pone.0048250] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 09/21/2012] [Indexed: 12/15/2022] Open
Abstract
The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS.
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Affiliation(s)
| | - Michela Traglia
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
| | | | - Ginevra Biino
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
| | | | - Cinzia Sala
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
| | - Fabiana Busti
- Department of Medicine, University of Verona, Verona, Italy
| | - Corrado Masciullo
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
| | - Daniele Manna
- Department of Medicine, University of Verona, Verona, Italy
| | | | | | - Giorgio Pistis
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
| | | | - Daniela Toniolo
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
| | - Clara Camaschella
- Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy
- Vita Salute San Raffaele University, Milan, Italy
| | - Domenico Girelli
- Department of Medicine, University of Verona, Verona, Italy
- * E-mail:
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31
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Millonig G, Ganzleben I, Peccerella T, Casanovas G, Brodziak-Jarosz L, Breitkopf-Heinlein K, Dick TP, Seitz HK, Muckenthaler MU, Mueller S. Sustained submicromolar H2O2 levels induce hepcidin via signal transducer and activator of transcription 3 (STAT3). J Biol Chem 2012; 287:37472-82. [PMID: 22932892 DOI: 10.1074/jbc.m112.358911] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The peptide hormone hepcidin regulates mammalian iron homeostasis by blocking ferroportin-mediated iron export from macrophages and the duodenum. During inflammation, hepcidin is strongly induced by interleukin 6, eventually leading to the anemia of chronic disease. Here we show that hepatoma cells and primary hepatocytes strongly up-regulate hepcidin when exposed to low concentrations of H(2)O(2) (0.3-6 μM), concentrations that are comparable with levels of H(2)O(2) released by inflammatory cells. In contrast, bolus treatment of H(2)O(2) has no effect at low concentrations and even suppresses hepcidin at concentrations of >50 μM. H(2)O(2) treatment synergistically stimulates hepcidin promoter activity in combination with recombinant interleukin-6 or bone morphogenetic protein-6 and in a manner that requires a functional STAT3-responsive element. The H(2)O(2)-mediated hepcidin induction requires STAT3 phosphorylation and is effectively blocked by siRNA-mediated STAT3 silencing, overexpression of SOCS3 (suppressor of cytokine signaling 3), and antioxidants such as N-acetylcysteine. Glycoprotein 130 (gp130) is required for H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas Janus kinase 2 (JAK2) is dispensable upstream of STAT3. Importantly, hepcidin levels are also increased by intracellular H(2)O(2) released from the respiratory chain in the presence of rotenone or antimycin A. Our results suggest a novel mechanism of hepcidin regulation by nanomolar levels of sustained H(2)O(2). Thus, similar to cytokines, H(2)O(2) provides an important regulatory link between inflammation and iron metabolism.
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Affiliation(s)
- Gunda Millonig
- Center for Alcohol Research, University of Heidelberg and Salem Medical Center, 69120 Heidelberg, Germany.
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Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis. Gene 2012; 508:15-20. [PMID: 22890139 DOI: 10.1016/j.gene.2012.07.069] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 07/30/2012] [Indexed: 01/29/2023]
Abstract
Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype.
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Ravasi G, Pelucchi S, Trombini P, Mariani R, Tomosugi N, Modignani GL, Pozzi M, Nemeth E, Ganz T, Hayashi H, Barisani D, Piperno A. Hepcidin expression in iron overload diseases is variably modulated by circulating factors. PLoS One 2012; 7:e36425. [PMID: 22586470 PMCID: PMC3346721 DOI: 10.1371/journal.pone.0036425] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Accepted: 04/01/2012] [Indexed: 12/12/2022] Open
Abstract
Hepcidin is a regulatory hormone that plays a major role in controlling body iron homeostasis. Circulating factors (holotransferrin, cytokines, erythroid regulators) might variably contribute to hepcidin modulation in different pathological conditions. There are few studies analysing the relationship between hepcidin transcript and related protein expression profiles in humans. Our aims were: a. to measure hepcidin expression at either hepatic, serum and urinary level in three paradigmatic iron overload conditions (hemochromatosis, thalassemia and dysmetabolic iron overload syndrome) and in controls; b. to measure mRNA hepcidin expression in two different hepatic cell lines (HepG2 and Huh-7) exposed to patients and controls sera to assess whether circulating factors could influence hepcidin transcription in different pathological conditions. Our findings suggest that hepcidin assays reflect hepatic hepcidin production, but also indicate that correlation is not ideal, likely due to methodological limits and to several post-trascriptional events. In vitro study showed that THAL sera down-regulated, HFE-HH and C-NAFLD sera up-regulated hepcidin synthesis. HAMP mRNA expression in Huh-7 cells exposed to sera form C-Donors, HFE-HH and THAL reproduced, at lower level, the results observed in HepG2, suggesting the important but not critical role of HFE in hepcidin regulation.
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Affiliation(s)
- Giulia Ravasi
- Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy
| | - Sara Pelucchi
- Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy
| | - Paola Trombini
- Centre for Diagnosis and Treatment of Hemochromatosis, S. Gerardo Hospital, Monza, Italy
| | - Raffaella Mariani
- Centre for Diagnosis and Treatment of Hemochromatosis, S. Gerardo Hospital, Monza, Italy
| | - Naohisa Tomosugi
- Division of Nephrology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan
| | - Giulia Litta Modignani
- Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy
| | - Matteo Pozzi
- Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy
| | - Elizabeth Nemeth
- Department of Medicine and Pathology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, United States of America
| | - Tomas Ganz
- Department of Medicine and Pathology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, United States of America
| | - Hisao Hayashi
- Division of Nephrology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan
| | - Donatella Barisani
- Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy
| | - Alberto Piperno
- Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy
- Centre for Diagnosis and Treatment of Hemochromatosis, S. Gerardo Hospital, Monza, Italy
- Consortium of Human Molecular Genetics, Monza, Italy
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Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol 2011; 55:920-32. [PMID: 21718726 DOI: 10.1016/j.jhep.2011.05.008] [Citation(s) in RCA: 265] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 05/29/2011] [Accepted: 05/31/2011] [Indexed: 12/17/2022]
Abstract
The dysmetabolic iron overload syndrome (DIOS) is now a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. The pathogenesis is related to altered regulation of iron transport associated with steatosis, insulin resistance, and subclinical inflammation, often in the presence of predisposing genetic factors. Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage. Based on these premises, the association among DIOS, metabolic syndrome, and NAFLD is being investigated as a new risk factor to predict the development of overt cardiovascular and hepatic diseases, and possibly hepatocellular carcinoma, but most importantly, represents also a treatable condition. Indeed, iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Additional studies are warranted to evaluate the potential of iron reductive therapy on hard clinical outcomes in patients with DIOS.
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Senates E, Yilmaz Y, Colak Y, Ozturk O, Altunoz ME, Kurt R, Ozkara S, Aksaray S, Tuncer I, Ovunc AOK. Serum Levels of Hepcidin in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease. Metab Syndr Relat Disord 2011; 9:287-90. [DOI: 10.1089/met.2010.0121] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Affiliation(s)
- Ebubekir Senates
- Department of Gastroenterology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey
| | - Yusuf Yilmaz
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
| | - Yasar Colak
- Department of Gastroenterology, Goztepe Education and Research Hospital, Istanbul, Turkey
| | - Oguzhan Ozturk
- Department of Gastroenterology, Goztepe Education and Research Hospital, Istanbul, Turkey
| | - Mustafa Erhan Altunoz
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
| | - Ramazan Kurt
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
| | - Selvinaz Ozkara
- Department of Pathology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey
| | - Sebahat Aksaray
- Department of Microbiology and Clinical Microbiology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey
| | - Ilyas Tuncer
- Department of Gastroenterology, Goztepe Education and Research Hospital, Istanbul, Turkey
| | - Ayse Oya Kurdas Ovunc
- Department of Gastroenterology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey
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Trombini P, Paolini V, Pelucchi S, Mariani R, Nemeth E, Ganz T, Piperno A. Hepcidin response to acute iron intake and chronic iron loading in dysmetabolic iron overload syndrome. Liver Int 2011; 31:994-1000. [PMID: 21733088 PMCID: PMC4048852 DOI: 10.1111/j.1478-3231.2011.02520.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The pathogenesis of dysmetabolic iron overload syndrome (DIOS) is still unclear. Hepcidin is the key regulator of iron homeostasis controlling iron absorption and macrophage release. AIM To investigate hepcidin regulation by iron in DIOS. METHODS We analysed urinary hepcidin at baseline and 24 h after a 65 mg oral iron dose in 24 patients at diagnosis and after iron depletion (n = 13) and compared data with those previously observed in 23 healthy controls. Serum iron indices, liver histology and metabolic data were available for all patients. RESULTS At diagnosis, hepcidin values were significantly higher than in controls (P < 0.001). After iron depletion, hepcidin levels decreased to normal values in all patients. At baseline, a significant response of hepcidin to iron challenge was observed only in the subgroup with lower basal hepcidin concentration (P = 0.007). In iron-depleted patients, urinary hepcidin significantly increased after oral iron test (P = 0 .006). CONCLUSIONS Ours findings suggest that in DIOS, the progression of iron accumulation is counteracted by the increase in hepcidin production and progressive reduction of iron absorption, explaining why these patients develop a mild-moderate iron overload that tends to a plateau.
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Affiliation(s)
- Paola Trombini
- Department of Clinical Medicine and Prevention, Centre for Diagnosis and Therapy of Hemochromatosis, S. Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Valentina Paolini
- Department of Clinical Medicine and Prevention, Centre for Diagnosis and Therapy of Hemochromatosis, S. Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Sara Pelucchi
- Department of Clinical Medicine and Prevention, Centre for Diagnosis and Therapy of Hemochromatosis, S. Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Raffaella Mariani
- Department of Clinical Medicine and Prevention, Centre for Diagnosis and Therapy of Hemochromatosis, S. Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Elizabeta Nemeth
- Department of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Tomas Ganz
- Department of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Alberto Piperno
- Department of Clinical Medicine and Prevention, Centre for Diagnosis and Therapy of Hemochromatosis, S. Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
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Meroño T, Gómez L, Sorroche P, Boero L, Arbelbide J, Brites F, Brites F. High risk of cardiovascular disease in iron overload patients. Eur J Clin Invest 2011; 41:479-86. [PMID: 21128934 DOI: 10.1111/j.1365-2362.2010.02429.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Iron overload (IO) is defined as an increase in storage iron, regardless of the presence or absence of tissue damage. Whether increased iron stores are involved in the pathogenesis of cardiovascular disease remains controversial. OBJECTIVES To study insulin resistance markers, lipoprotein profile, activities of anti and prooxidant enzymes and cholesteryl ester transfer protein (CETP) in patients with IO. METHODS Twenty male patients with IO were compared with 20 sex- and age-matched controls. General biochemical parameters, lipoprotein profile, and activities of paraoxonase 1, employing two substrates, paraoxon (PON) and phenylacetate (ARE), lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) and CETP were determined. RESULTS IO patients showed higher levels of HOMA-IR and triglycerides [median (Q1-Q3)] [128 (93-193) vs. 79(51-91) mg dL(-1) , P < 0·0005] while lower high-density lipoprotein (HDL) cholesterol (mean ± SD) (41 ± 9 vs. 52 ± 10 mg dL(-1) , P < 0·0005) in comparison with controls. Moreover, the triglycerides/HDL-cholesterol [3·2 (2·0-5·1) vs. 1·5 (1·0-1·9), P < 0·0005] ratio and oxidized low-density lipoprotein levels [94 (64-103) vs. 68 (59-70) IU L(-1) , P < 0·05] were increased in the patient group. Although no difference was observed in ARE activity, PON activity was decreased in IO patients [246 (127-410) vs. 428 (263-516) nmol mL(-1) min(-1) , P < 0·05]. In addition, CETP and Lp-PLA(2) activities were also increased in the patients (189 ± 31 vs. 155 ± 36% ml(-1) h(-1) , P < 0·005; and 10·1 ± 2·9 vs. 8·2 ± 2·4 μmol mL(-1) h(-1) , P < 0·05, respectively). Associations between ferritin concentration and the alterations in lipid metabolism were also found. Multiple regression analyses identified HOMA-IR as independent predictor of CETP activity (B = 65·9, P < 0·0001, r(2) = 0·35), as well as ferritin concentration of Lp-PLA(2) activity (B = 3·7, P < 0·0001, r(2) = 0·40) after adjusting for confounding variables. CONCLUSIONS IO patients presented not only insulin resistance but also metabolic alterations that were related to elevated iron stores and are associated with high risk of cardiovascular disease.
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Affiliation(s)
- Tomás Meroño
- Tomàs Meroño, Department of Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
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Camaschella C, Strati P. Recent advances in iron metabolism and related disorders. Intern Emerg Med 2010; 5:393-400. [PMID: 20424932 DOI: 10.1007/s11739-010-0387-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2009] [Accepted: 03/26/2010] [Indexed: 02/08/2023]
Abstract
Iron is essential for life, because it is indispensable for several biological reactions such as oxygen transport, DNA synthesis and cell proliferation, but is toxic if present in excess since it causes cellular damage through free radical formation. Either cellular or systemic iron regulation can be disrupted in disorders of iron metabolism. In the past few years, our understanding of iron metabolism and its regulation has dramatically changed. New disorders of iron metabolism have emerged and the role of iron has started to be recognized as a cofactor of other disorders. The study of genetic conditions such as hemochromatosis and iron-refractory-iron-deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited for a more effective treatment of both genetic and acquired iron disorders.
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Affiliation(s)
- Clara Camaschella
- Università Vita-Salute e IRCCS San Raffaele, Via Olgettina 60, Milan, Italy.
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39
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Dysmetabolic hyperferritinemia is associated with normal transferrin saturation, mild hepatic iron overload, and elevated hepcidin. Ann Hematol 2010; 90:139-43. [DOI: 10.1007/s00277-010-1050-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 08/08/2010] [Indexed: 10/19/2022]
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40
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Freixenet N, Moreno-Rosel MS, Barceló MJ, Serrano A, Payà M, Crespo L, Pérez-Lucena MJ, Altés A, Baiget M, Félez J. Detection of hereditary hemochromatosis and biochemical iron overload in primary care: a multicenter case finding study in Spain. Am J Hematol 2010; 85:294-6. [PMID: 20196172 DOI: 10.1002/ajh.21634] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Genetic and metabolic factors are associated with increased hepatic iron stores in a selected population of p.Cys282Tyr heterozygotes. Blood Cells Mol Dis 2010; 44:159-63. [DOI: 10.1016/j.bcmd.2010.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Revised: 11/30/2009] [Accepted: 12/18/2009] [Indexed: 12/31/2022]
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Lecube A, Hernández C, Simó R. Glucose abnormalities in non-alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload. Diabetes Metab Res Rev 2009; 25:403-10. [PMID: 19444865 DOI: 10.1002/dmrr.972] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection are major causes of liver disease frequently described in outpatient patients with glucose abnormalities. Hyperferritinemia, which suggests that iron overload plays a decisive role in the pathophysiology of insulin resistance and hyperglycemia, is a common finding in both disorders. However, the role of the hepatic iron deposition differs from one to the other. In NAFLD, a moderate liver iron accumulation has been observed and molecular mechanisms, including the downregulation of the liver iron exporter ferroportin-1, have been described. Iron overload will enhance intrahepatic oxidative stress that promotes hepatic fibrosis, interfere with insulin signalling at various levels and may hamper hepatic insulin extraction. Therefore, liver fibrosis, hyperglycemia and hyperinsulinemia will lead to increased levels of insulin resistance and the development of glucose abnormalities. Furthermore, iron depletion by phlebotomy removes liver iron content and reduces serum glucose and insulin resistance in NAFLD patients. Therefore, it seems that iron overload participates in those glucose abnormalities associated with NAFLD. Concerning chronic HCV infection, it has been classically assumed that iron overload contributes to insulin resistance associated with virus infection. However, recent evidence argues against the presence of iron overload in these patients and points to inflammation associated with diabetes as the main contributor to the elevated ferritin levels. Therefore, glucose abnormalities, and specially type 2 diabetes, should be taken into account when evaluating serum ferritin levels in patients with HCV infection.
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Affiliation(s)
- Albert Lecube
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Diabetes and Metabolism Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.
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Piperno A, Mariani R, Trombini P, Girelli D. Hepcidin modulation in human diseases: from research to clinic. World J Gastroenterol 2009; 15:538-51. [PMID: 19195055 PMCID: PMC2653344 DOI: 10.3748/wjg.15.538] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2008] [Revised: 01/04/2009] [Accepted: 01/11/2009] [Indexed: 02/06/2023] Open
Abstract
By modulating hepcidin production, an organism controls intestinal iron absorption, iron uptake and mobilization from stores to meet body iron need. In recent years there has been important advancement in our knowledge of hepcidin regulation that also has implications for understanding the physiopathology of some human disorders. Since the discovery of hepcidin and the demonstration of its pivotal role in iron homeostasis, there has been a substantial interest in developing a reliable assay of the hormone in biological fluids. Measurement of hepcidin in biological fluids can improve our understanding of iron diseases and be a useful tool for diagnosis and clinical management of these disorders. We reviewed the literature and our own research on hepcidin to give an updated status of the situation in this rapidly evolving field.
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