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19 pages, 2762 KiB

Open AccessArticle

Induction of Hepcidin Expression in the Renal Cortex of Sickle Cell Disease Mice

by Asrar Ahmad, Namita Kumari, Nowah Afangbedji, Sergei Nekhai and Marina Jerebtsova

Int. J. Mol. Sci. 2023, 24(13), 10806; https://doi.org/10.3390/ijms241310806 - 28 Jun 2023

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In patients with sickle cell disease (SCD), chronic hemolysis and frequent blood transfusions cause iron overload and accumulation in the kidneys. The iron deposition is found in the renal cortex and correlates with the severity of hemolysis. In this study, we observed a [...] Read more.

In patients with sickle cell disease (SCD), chronic hemolysis and frequent blood transfusions cause iron overload and accumulation in the kidneys. The iron deposition is found in the renal cortex and correlates with the severity of hemolysis. In this study, we observed a significant accumulation of iron in the renal cortex of a mouse model of SCD, and assessed the expression of the proteins involved in maintaining renal iron homeostasis. Despite the intracellular iron accumulation, the levels of the transferrin receptor in the kidneys were increased, but the levels of the iron exporter ferroportin were not altered in SCD mice. Ferroportin is regulated by hepcidin, which binds to it and promotes its degradation. We found reduced serum hepcidin levels but increased renal hepcidin production in SCD mice. Furthermore, we observed significant macrophage infiltration and increased expression of intercellular adhesion molecule 1 in the endothelial cells of the kidneys in SCD mice. These observations correlated with elevated levels of proinflammatory cytokines IL-1β and IL-6, which can potentially stimulate hepcidin expression. Taken together, our results demonstrate that in individuals with SCD, a renal inflammation state induces renal hepcidin production that blocks the upregulation of ferroportin levels, resulting in dysregulation of iron homeostasis in the kidney and iron deposition in the renal cortex. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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25 pages, 5420 KiB

Open AccessArticle

The Role of Fractalkine in the Regulation of Endometrial Iron Metabolism in Iron Deficiency

by Edina Pandur, Ramóna Pap, Gergely Jánosa, Adrienn Horváth and Katalin Sipos

Int. J. Mol. Sci. 2023, 24(12), 9917; https://doi.org/10.3390/ijms24129917 - 08 Jun 2023

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Abstract

Iron is a crucial element in the human body. Endometrial iron metabolism is implicated in endometrium receptivity and embryo implantation. Disturbances of the maternal as well as the endometrial iron homeostasis, such as iron deficiency, can contribute to the reduced development of the [...] Read more.

Iron is a crucial element in the human body. Endometrial iron metabolism is implicated in endometrium receptivity and embryo implantation. Disturbances of the maternal as well as the endometrial iron homeostasis, such as iron deficiency, can contribute to the reduced development of the fetus and could cause an increased risk of adverse pregnancy outcomes. Fractalkine is a unique chemokine that plays a role in the communication between the mother and the fetus. It has been demonstrated that FKN is involved in the development of endometrial receptivity and embryo implantation, and it functions as a regulator of iron metabolism. In the present study, we examined the effect of FKN on the iron metabolism of HEC-1A endometrial cells in a state of iron deficiency mediated by desferrioxamine treatment. Based on the findings, FKN enhances the expression of iron metabolism-related genes in iron deficiency and modifies the iron uptake via transferrin receptor 1 and divalent metal transporter-1, and iron release via ferroportin. FKN can activate the release of iron from heme-containing proteins by elevating the level of heme oxygenase-1, contributing to the redistribution of intracellular iron content. It was revealed that the endometrium cells express both mitoferrin-1 and 2 and that their levels are not dependent on the iron availability of the cells. FKN may also contribute to maintaining mitochondrial iron homeostasis. FKN can improve the deteriorating effect of iron deficiency in HEC-1A endometrium cells, which may contribute to the development of receptivity and/or provide iron delivery towards the embryo. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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14 pages, 1545 KiB

Open AccessArticle

The Role of Inflammation in Age-Associated Changes in Red Blood System

by Eryk Wacka, Edyta Wawrzyniak-Gramacka, Anna Tylutka, Barbara Morawin, Marzena Gutowicz and Agnieszka Zembron-Lacny

Int. J. Mol. Sci. 2023, 24(10), 8944; https://doi.org/10.3390/ijms24108944 - 18 May 2023

Cited by 5 | Viewed by 1988

Abstract

Aging-related anemia contributes to frailty syndrome, cognitive decline and early mortality. The study aim was to evaluate inflammaging in relation to anemia as a prognostic indicator in affected older patients. The participants (73.0 ± 7.2 years) were allocated into anemic (n = [...] Read more.

Aging-related anemia contributes to frailty syndrome, cognitive decline and early mortality. The study aim was to evaluate inflammaging in relation to anemia as a prognostic indicator in affected older patients. The participants (73.0 ± 7.2 years) were allocated into anemic (n = 47) and non-anemic (n = 66) groups. The hematological variables RBC, MCV, MCH, RDW, iron and ferritin were significantly lower, whereas erythropoietin EPO and transferrin Tf tended toward higher values in the anemic group. Approx. 26% of individuals demonstrated transferrin saturation TfS < 20%, which clearly indicates age-related iron deficiency. The cut-off values for pro-inflammatory cytokine IL-1β, TNFα and hepcidin were 5.3 ng/mL, 97.7 ng/mL and 9.4 ng/mL, respectively. High IL-1β negatively affected Hb concentration (r_s = −0.581, p < 0.0001). Relatively high odds ratios were observed for IL-1β (OR = 72.374, 95%Cl 19.688–354.366) and peripheral blood mononuclear cells CD34 (OR = 3.264, 95%Cl 1.263–8.747) and CD38 (OR = 4.398, 95%Cl 1.701–11.906), which together indicates a higher probability of developing anemia. The results endorse the interplay between inflammatory status and iron metabolism and demonstrated a high usefulness of IL-1β in identification of the underlying causes of anemia, while CD34 and CD38 appeared useful in compensatory response assessment and, in the longer term, as part of a comprehensive approach to anemia monitoring in older adults. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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11 pages, 4151 KiB

Open AccessCommunication

Ferritin Metabolism Reflects Multiple Myeloma Microenvironment and Predicts Patient Outcome

by Federica Plano, Emilia Gigliotta, Anna Maria Corsale, Mojtaba Shekarkar Azgomi, Carlotta Santonocito, Manuela Ingrascì, Laura Di Carlo, Antonino Elia Augello, Maria Speciale, Candida Vullo, Cristina Rotolo, Giulia Maria Camarda, Nadia Caccamo, Serena Meraviglia, Francesco Dieli, Sergio Siragusa and Cirino Botta

Int. J. Mol. Sci. 2023, 24(10), 8852; https://doi.org/10.3390/ijms24108852 - 16 May 2023

Cited by 1 | Viewed by 2414

Abstract

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production [...] Read more.

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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12 pages, 1053 KiB

Open AccessArticle

Peripheral and Central Iron Measures in Alcohol Use Disorder and Aging: A Quantitative Susceptibility Mapping Pilot Study

by Aiden R. Adams, Xinyi Li, Juliana I. Byanyima, Sianneh A. Vesslee, Thanh D. Nguyen, Yi Wang, Brianna Moon, Timothy Pond, Henry R. Kranzler, Walter R. Witschey, Zhenhao Shi and Corinde E. Wiers

Int. J. Mol. Sci. 2023, 24(5), 4461; https://doi.org/10.3390/ijms24054461 - 24 Feb 2023

Cited by 1 | Viewed by 2016

Abstract

Chronic excessive alcohol use has neurotoxic effects, which may contribute to cognitive decline and the risk of early-onset dementia. Elevated peripheral iron levels have been reported in individuals with alcohol use disorder (AUD), but its association with brain iron loading has not been [...] Read more.

Chronic excessive alcohol use has neurotoxic effects, which may contribute to cognitive decline and the risk of early-onset dementia. Elevated peripheral iron levels have been reported in individuals with alcohol use disorder (AUD), but its association with brain iron loading has not been explored. We evaluated whether (1) serum and brain iron loading are higher in individuals with AUD than non-dependent healthy controls and (2) serum and brain iron loading increase with age. A fasting serum iron panel was obtained and a magnetic resonance imaging scan with quantitative susceptibility mapping (QSM) was used to quantify brain iron concentrations. Although serum ferritin levels were higher in the AUD group than in controls, whole-brain iron susceptibility did not differ between groups. Voxel-wise QSM analyses revealed higher susceptibility in a cluster in the left globus pallidus in individuals with AUD than controls. Whole-brain iron increased with age and voxel-wise QSM indicated higher susceptibility with age in various brain areas including the basal ganglia. This is the first study to analyze both serum and brain iron loading in individuals with AUD. Larger studies are needed to examine the effects of alcohol use on iron loading and its associations with alcohol use severity, structural and functional brain changes, and alcohol-induced cognitive impairments. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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17 pages, 12519 KiB

Open AccessArticle

Discovery-Based Proteomics Identify Skeletal Muscle Mitochondrial Alterations as an Early Metabolic Defect in a Mouse Model of β-Thalassemia

by Patricia Reboucas, Carine Fillebeen, Amy Botta, Riley Cleverdon, Alexandra P. Steele, Vincent Richard, René P. Zahedi, Christoph H. Borchers, Yan Burelle, Thomas J. Hawke, Kostas Pantopoulos and Gary Sweeney

Int. J. Mol. Sci. 2023, 24(5), 4402; https://doi.org/10.3390/ijms24054402 - 23 Feb 2023

Viewed by 1909

Abstract

Although metabolic complications are common in thalassemia patients, there is still an unmet need to better understand underlying mechanisms. We used unbiased global proteomics to reveal molecular differences between the th^3/+ mouse model of thalassemia and wild-type control animals focusing on skeletal [...] Read more.

Although metabolic complications are common in thalassemia patients, there is still an unmet need to better understand underlying mechanisms. We used unbiased global proteomics to reveal molecular differences between the th^3/+ mouse model of thalassemia and wild-type control animals focusing on skeletal muscles at 8 weeks of age. Our data point toward a significantly impaired mitochondrial oxidative phosphorylation. Furthermore, we observed a shift from oxidative fibre types toward more glycolytic fibre types in these animals, which was further supported by larger fibre-type cross-sectional areas in the more oxidative type fibres (type I/type IIa/type IIax hybrid). We also observed an increase in capillary density in th^3/+ mice, indicative of a compensatory response. Western blotting for mitochondrial oxidative phosphorylation complex proteins and PCR analysis of mitochondrial genes indicated reduced mitochondrial content in the skeletal muscle but not the hearts of th^3/+ mice. The phenotypic manifestation of these alterations was a small but significant reduction in glucose handling capacity. Overall, this study identified many important alterations in the proteome of th^3/+ mice, amongst which mitochondrial defects leading to skeletal muscle remodelling and metabolic dysfunction were paramount. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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19 pages, 2000 KiB

Open AccessArticle

Monocyte MRI Relaxation Rates Are Regulated by Extracellular Iron and Hepcidin

by Praveen S. B. Dassanayake, Rahil Prajapati, Neil Gelman, R. Terry Thompson, Frank S. Prato and Donna E. Goldhawk

Int. J. Mol. Sci. 2023, 24(4), 4036; https://doi.org/10.3390/ijms24044036 - 17 Feb 2023

Cited by 1 | Viewed by 1486

Abstract

Many chronic inflammatory conditions are mediated by an increase in the number of monocytes in peripheral circulation, differentiation of monocytes to macrophages, and different macrophage subpopulations during pro- and anti-inflammatory stages of tissue injury. When hepcidin secretion is stimulated during inflammation, the iron [...] Read more.

Many chronic inflammatory conditions are mediated by an increase in the number of monocytes in peripheral circulation, differentiation of monocytes to macrophages, and different macrophage subpopulations during pro- and anti-inflammatory stages of tissue injury. When hepcidin secretion is stimulated during inflammation, the iron export protein ferroportin is targeted for degradation on a limited number of cell types, including monocytes and macrophages. Such changes in monocyte iron metabolism raise the possibility of non-invasively tracking the activity of these immune cells using magnetic resonance imaging (MRI). We hypothesized that hepcidin-mediated changes in monocyte iron regulation influence both cellular iron content and MRI relaxation rates. In response to varying conditions of extracellular iron supplementation, ferroportin protein levels in human THP-1 monocytes decreased two- to eightfold, consistent with paracrine/autocrine regulation of iron export. Following hepcidin treatment, ferroportin protein levels further decreased two- to fourfold. This was accompanied by an approximately twofold increase in total transverse relaxation rate, R₂*, compared to non-supplemented cells. A positive correlation between total cellular iron content and R₂* improved from moderate to strong in the presence of hepcidin. These findings suggest that hepcidin-mediated changes detected in monocytes using MRI could be valuable for in vivo cell tracking of inflammatory responses. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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14 pages, 3429 KiB

Open AccessArticle

Genetic Iron Overload Hampers Development of Cutaneous Leishmaniasis in Mice

by Edouard Charlebois, Yupeng Li, Victoria Wagner, Kostas Pantopoulos and Martin Olivier

Int. J. Mol. Sci. 2023, 24(2), 1669; https://doi.org/10.3390/ijms24021669 - 14 Jan 2023

Cited by 2 | Viewed by 1844

Abstract

The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania’s host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter [...] Read more.

The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania’s host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv^−/− mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv^−/− mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv^−/− peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv^−/− and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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17 pages, 3226 KiB

Open AccessArticle

Upregulation of Nrf2 Signalling and the Inhibition of Erastin-Induced Ferroptosis by Ferulic Acid in MIN6 Cells

by Tugba Kose, Paul A. Sharp and Gladys O. Latunde-Dada

Int. J. Mol. Sci. 2022, 23(24), 15886; https://doi.org/10.3390/ijms232415886 - 14 Dec 2022

Cited by 11 | Viewed by 2731

Abstract

Ferroptosis is a regulated cell death process characterised by the iron-dependent accumulation of oxidised polyunsaturated fatty acid-containing phospholipids. Its initiation is complicated and involves reactive oxygen species (ROS) and a loss of the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). [...] Read more.

Ferroptosis is a regulated cell death process characterised by the iron-dependent accumulation of oxidised polyunsaturated fatty acid-containing phospholipids. Its initiation is complicated and involves reactive oxygen species (ROS) and a loss of the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). These play critical roles in the development of ferroptotic cell damage by lipid peroxidation. Antioxidant therapy is a promising therapeutic strategy to prevent or even reverse the progression of ferroptosis. This study was designed to demonstrate the protective effect of ferulic acid (FA) against oxidative stress and erastin-mediated ferroptosis in murine MIN6 cells. Cells were treated with FA or its metabolite ferulic acid 4-O-sulfate disodium salt (FAS) and 20 μM of erastin. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, iron levels were measured by inductively coupled plasma mass spectrometry (ICP-MS), ROS levels were determined by a dihydrodichlorofluorescein (H2DCF) cell-permeant probe, and glutathione and lipid peroxidation were assayed with commercially available kits. The phenolic acids enhanced cell viability in erastin-treated MIN6 cells in a dose-dependent manner. Furthermore, MIN6 cells exposed to erastin alone showed elevated levels of iron and ROS, glutathione (GSH) depletion, and lipid peroxidation (p < 0.05) compared to cells that were protected by co-treatment with FA or FAS. The treatment of MIN6 cells with FA or FAS following exposure to erastin increased the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) protein levels. Consequently, levels of its downstream antioxidant proteins, HO-1, NQO1, GCLC, and GPX4, increased. FA and FAS greatly decreased erastin-induced ferroptosis in the presence of the Nrf2 inhibitor, ML385, through the regulation of Nrf2 response genes. In conclusion, these results show that FA and FAS protect MIN6 cells from erastin-induced ferroptosis by the Nrf2 antioxidant protective mechanism. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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Review

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20 pages, 1236 KiB

Open AccessReview

Iron Deficiency and Iron Deficiency Anemia: Potential Risk Factors in Bone Loss

by Jiancheng Yang, Qingmei Li, Yan Feng and Yuhong Zeng

Int. J. Mol. Sci. 2023, 24(8), 6891; https://doi.org/10.3390/ijms24086891 - 07 Apr 2023

Cited by 6 | Viewed by 8689

Abstract

Iron is one of the essential mineral elements for the human body and this nutrient deficiency is a worldwide public health problem. Iron is essential in oxygen transport, participates in many enzyme systems in the body, and is an important trace element in [...] Read more.

Iron is one of the essential mineral elements for the human body and this nutrient deficiency is a worldwide public health problem. Iron is essential in oxygen transport, participates in many enzyme systems in the body, and is an important trace element in maintaining basic cellular life activities. Iron also plays an important role in collagen synthesis and vitamin D metabolism. Therefore, decrease in intracellular iron can lead to disturbance in the activity and function of osteoblasts and osteoclasts, resulting in imbalance in bone homeostasis and ultimately bone loss. Indeed, iron deficiency, with or without anemia, leads to osteopenia or osteoporosis, which has been revealed by numerous clinical observations and animal studies. This review presents current knowledge on iron metabolism under iron deficiency states and the diagnosis and prevention of iron deficiency and iron deficiency anemia (IDA). With emphasis, studies related to iron deficiency and bone loss are discussed, and the potential mechanisms of iron deficiency leading to bone loss are analyzed. Finally, several measures to promote complete recovery and prevention of iron deficiency are listed to improve quality of life, including bone health. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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24 pages, 2185 KiB

Open AccessReview

Advances in Ferritin Physiology and Possible Implications in Bacterial Infection

by Clemens M. Gehrer, Anna-Maria Mitterstiller, Philipp Grubwieser, Esther G. Meyron-Holtz, Günter Weiss and Manfred Nairz

Int. J. Mol. Sci. 2023, 24(5), 4659; https://doi.org/10.3390/ijms24054659 - 28 Feb 2023

Cited by 7 | Viewed by 3088

Abstract

Due to its advantageous redox properties, iron plays an important role in the metabolism of nearly all life. However, these properties are not only a boon but also the bane of such life forms. Since labile iron results in the generation of reactive [...] Read more.

Due to its advantageous redox properties, iron plays an important role in the metabolism of nearly all life. However, these properties are not only a boon but also the bane of such life forms. Since labile iron results in the generation of reactive oxygen species by Fenton chemistry, iron is stored in a relatively safe form inside of ferritin. Despite the fact that the iron storage protein ferritin has been extensively researched, many of its physiological functions are hitherto unresolved. However, research regarding ferritin’s functions is gaining momentum. For example, recent major discoveries on its secretion and distribution mechanisms have been made as well as the paradigm-changing finding of intracellular compartmentalization of ferritin via interaction with nuclear receptor coactivator 4 (NCOA4). In this review, we discuss established knowledge as well as these new findings and the implications they may have for host–pathogen interaction during bacterial infection. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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22 pages, 716 KiB

Open AccessReview

Hereditary Hyperferritinemia

by Alberto Piperno, Sara Pelucchi and Raffaella Mariani

Int. J. Mol. Sci. 2023, 24(3), 2560; https://doi.org/10.3390/ijms24032560 - 29 Jan 2023

Cited by 5 | Viewed by 2739

Abstract

Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe²⁺, oxidize it and sequester it in a safe form in the cell, and to release [...] Read more.

Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe²⁺, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy—all of which may elevate serum ferritin—complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia. Full article

(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research)

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