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1.
Medicina (Kaunas) ; 55(7)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269687

RESUMO

Background and objectives: The etiology of anemia associated with heart failure is not fully understood, but there are data suggesting the involvement of multiple mechanisms, including various drug therapies used in patients with heart failure. Our primary objective was to evaluate the impact of beta blockers, angiotensin-converting enzyme inhibitors, and calcium-channel blockers on iron metabolism in patients with heart failure. Materials and Methods: This was a prospective observational study that included patients diagnosed with heart failure and iron deficiency (defined by ferritin <100 µg/L, or 100-300 µg/L with transferrin saturation <20%). Patients with anemia secondary to a known cause were excluded. Results: We found a statistically significant correlation between beta-blocker treatment and ferritin values (p = 0.02). Iron, hemoglobin, and hematocrit levels were significantly lower in the patients using calcium-channel blockers than those who were not. We also found a statistically significant indirect correlation (p = 0.04) between the use of angiotensin-converting enzyme inhibitors and hematocrit levels. Conclusion: The contribution of our study arises from the additional data regarding the drug-induced etiology of iron deficiency. Practitioners should be aware of the potential impact of therapeutic recommendations and this should imply a close monitoring of the biochemical parameters of iron deficiency in this category of patients.


Assuntos
Anemia/etiologia , Insuficiência Cardíaca/tratamento farmacológico , Distúrbios do Metabolismo do Ferro/etiologia , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Anemia/sangue , Anemia/complicações , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Feminino , Insuficiência Cardíaca/sangue , Humanos , Ferro/análise , Ferro/sangue , Distúrbios do Metabolismo do Ferro/sangue , Masculino , Pessoa de Meia-Idade
2.
Nutrients ; 11(5)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137583

RESUMO

BACKGROUND: Since haemodialysis is a lifesaving therapy, adequate control measures are necessary to evaluate its adequacy and to constantly adjust the dose to reduce hospitalisation and prolong patient survival. Malnutrition is common in haemodialysis patients and closely related to morbidity and mortality. Patients undergoing haemodialysis have a high prevalence of protein-energy malnutrition and inflammation, along with abnormal iron status. The haemodialysis dose delivered is an important predictor of patient outcome. AIM: To evaluate through haemodialysis adequacy, which parameter(s), if any, better predict Kt/V, among those used to assess nutritional status, inflammation response, and iron status. METHODS: We retrospectively studied 78 patients undergoing haemodialysis due to end-stage renal disease. As parameters of nutritional status, geriatric nutritional risk index (GNRI), transferrin levels, lymphocyte count, and albumin concentration were analysed. As signs of inflammation, C reactive protein (CRP) levels and ferritin concentrations were studied as well. Iron status was evaluated by both transferrin and ferritin levels, as well as by haemoglobin (Hb) concentration. RESULTS: The core finding of our retrospective study is that transferrin levels predict the adequacy of haemodialysis expressed as Kt/V; the latter is the only predictor (P = 0.001) when adjusting for CRP concentrations, a solid marker of inflammation, and for ferritin levels considered an iron-storage protein, but also a parameter of inflammatory response. DISCUSSION AND CONCLUSION: In keeping with the results of this study, we underline that the use of transferrin levels to assess haemodialysis quality combine into a single test the evaluation of the three most important factors of protein-energy wasting.


Assuntos
Inflamação/sangue , Distúrbios do Metabolismo do Ferro/sangue , Falência Renal Crônica/terapia , Desnutrição Proteico-Calórica/sangue , Diálise Renal , Transferrina/metabolismo , Idoso , Biomarcadores/sangue , Feminino , Avaliação Geriátrica , Humanos , Inflamação/diagnóstico , Inflamação/etiologia , Mediadores da Inflamação/sangue , Ferro/sangue , Ferro/deficiência , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Valor Preditivo dos Testes , Desnutrição Proteico-Calórica/diagnóstico , Desnutrição Proteico-Calórica/etiologia , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
4.
Blood ; 133(1): 51-58, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30401707

RESUMO

ß-Thalassemia (BT) is an inherited genetic disorder that is characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by BT suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of ≥1 erythroid factor with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contribute to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. Understanding the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed; clinical trials are underway that have the potential to improve erythrocyte production, as well as to reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE.


Assuntos
Eritropoese , Distúrbios do Metabolismo do Ferro/etiologia , Distúrbios do Metabolismo do Ferro/patologia , Ferro/metabolismo , Talassemia beta/complicações , Animais , Humanos , Talassemia beta/patologia
5.
Biochim Biophys Acta Mol Basis Dis ; 1864(3): 967-973, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29317336

RESUMO

Understandings of the disturbed iron metabolism in Parkinson's disease (PD) are largely from the perspectives of neurons. Neurodegenerative processes in PD trigger universal and conserved astroglial dysfunction and microglial activation. In this review, we start with astroglia and microglia in PD with an emphasis on their roles in spreading α-synuclein pathology, and then focus on their contributions in iron metabolism under normal conditions and the diseased state of PD. Elevated iron in the brain regions affects glial features, meanwhile, glial effects on neuronal iron metabolism are largely dependent on their releasing factors. These advances might be valuable for better understanding and modulating iron metabolism disturbance in PD.


Assuntos
Astrócitos/fisiologia , Distúrbios do Metabolismo do Ferro/etiologia , Ferro/metabolismo , Microglia/fisiologia , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Animais , Astrócitos/patologia , Humanos , Distúrbios do Metabolismo do Ferro/metabolismo , Microglia/patologia
6.
Liver Int ; 38(1): 164-173, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28679028

RESUMO

BACKGROUND AND AIMS: Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinaemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinaemia in NAFLD. METHODS: Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation. RESULTS: Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin. CONCLUSIONS: While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial.


Assuntos
Ferritinas/sangue , Distúrbios do Metabolismo do Ferro/sangue , Ferro/análise , Fígado/química , Hepatopatia Gordurosa não Alcoólica/sangue , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Hepcidinas/análise , Humanos , Resistência à Insulina , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Estudos Prospectivos , Regulação para Cima
7.
Mutat Res ; 774: 25-32, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29173496

RESUMO

Iron, as an essential nutrient, and the DNA, as the carrier of genetic information which is physically compacted into chromosomes, are both needed for normal life and well-being. Therefore, it is not surprising that close interactions exist between iron and the genome. On the one hand, iron, especially when present in excess, may alter genome stability through oxidative stress, and may favor cell cycle abnormalities and the development of malignant diseases. The genome also receives a feedback signal from the systemic iron status, leading to promotion of expression of genes that regulate iron metabolism. Conversely, on the other hand, DNA mutations may cause genetic iron-related diseases such as hemochromatosis, archetype of iron-overload diseases, or refractory iron deficiency anemia (IRIDA).


Assuntos
Instabilidade Genômica , Distúrbios do Metabolismo do Ferro/etiologia , Sobrecarga de Ferro/etiologia , Ferro/metabolismo , Mutação , Humanos , Distúrbios do Metabolismo do Ferro/metabolismo , Sobrecarga de Ferro/metabolismo
8.
Am J Hematol ; 92(4): 338-343, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28052375

RESUMO

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.


Assuntos
Ferritinas/sangue , Distúrbios do Metabolismo do Ferro/etiologia , Adulto , Estudos de Casos e Controles , Feminino , Glicosilação , Humanos , Sobrecarga de Ferro , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , RNA Mensageiro/sangue , Irmãos , Adulto Jovem
9.
Med Clin (Barc) ; 148(5): 218-224, 2017 Mar 03.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28073521

RESUMO

Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesised has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders.


Assuntos
Hepcidinas/metabolismo , Distúrbios do Metabolismo do Ferro/metabolismo , Ferro/metabolismo , Biomarcadores/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Homeostase , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/etiologia , Distúrbios do Metabolismo do Ferro/terapia
12.
Medicine (Baltimore) ; 95(14): e3150, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27057839

RESUMO

Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and ß-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and ß-thalassemia), hepatic hepcidin concentration is significantly reduced.Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin.Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated.Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve ß-thalassemia phenotypes by improving ineffective erythropoiesis. Relative to the current conventional therapies, such as phlebotomy and blood transfusion, therapeutics targeting hepcidin would open a new avenue for treatment of iron-related diseases.


Assuntos
Hepcidinas/efeitos dos fármacos , Distúrbios do Metabolismo do Ferro/tratamento farmacológico , Hepcidinas/fisiologia , Homeostase , Humanos , Ferro/fisiologia , Distúrbios do Metabolismo do Ferro/etiologia
13.
Bone Marrow Transplant ; 51(1): 89-95, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26367238

RESUMO

Elevated serum ferritin contributes to treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The multicenter DE02 trial assessed the safety, efficacy and impact of deferasirox on iron homeostasis after allogeneic HSCT. Deferasirox was administered at a starting dose of 10 mg/kg per day to 76 recipients of allogeneic HSCT, with subsequent dose adjustments based on efficacy and safety. Deferasirox was initiated at a median of 168 days after HSCT, with 84% of patients still on immunosuppression. Baseline serum ferritin declined from 2045 to 957 ng/mL. Deferasirox induced a negative iron balance in 84% of patients. Hemoglobin increased in the first 3 months, and trough serum cyclosporine levels were stable. Median exposure was 330 days, with a median compliance rate of >80%. The most common investigator-reported drug-related adverse events (AEs) were increased blood creatinine (26.5%), nausea (9.0%) and abdominal discomfort (8.3%). Fifty-four (71.1%) patients experienced drug-related AEs, which occasionally resulted in discontinuation (gastrointestinal (n=6), skin (n=3), elevated transaminases (n=1) and creatinine (n=1)). The incidence of AEs appeared to be dose related, with 7.5 mg/kg per day being the best-tolerated dose. Low-dose deferasirox is an effective chelation therapy after allogeneic HSCT, with a manageable safety profile, even in patients receiving cyclosporine.


Assuntos
Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Ferritinas/sangue , Transplante de Células-Tronco Hematopoéticas , Distúrbios do Metabolismo do Ferro , Ferro/sangue , Triazóis/administração & dosagem , Triazóis/farmacocinética , Adulto , Idoso , Aloenxertos , Benzoatos/efeitos adversos , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Ciclosporina/sangue , Deferasirox , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/sangue , Distúrbios do Metabolismo do Ferro/tratamento farmacológico , Distúrbios do Metabolismo do Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Triazóis/efeitos adversos
16.
Clin Rheumatol ; 34(11): 1989-92, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26233722

RESUMO

There are four medical conditions characterized by high levels of ferritin, the macrophage activation syndrome (MAS), adult onset Still' s disease (AOSD), catastrophic antiphospholipid syndrome (CAPS), and septic shock, that share similar clinical and laboratory features, suggesting a common pathogenic mechanism. This common syndrome entity is termed "the hyperferritinemic syndrome." Here, we describe two different cases of hyperferritinemic syndrome triggered by Chikungunya fever virus infection: a 21-year-old female with SLE and a 32-year-old male patient who developed AOSD after the coinfection of dengue and Chikungunya viruses.


Assuntos
Síndrome Antifosfolipídica/etiologia , Catarata/congênito , Febre de Chikungunya/complicações , Dengue/complicações , Distúrbios do Metabolismo do Ferro/congênito , Doença de Still de Início Tardio/etiologia , Adulto , Síndrome Antifosfolipídica/diagnóstico , Catarata/diagnóstico , Catarata/etiologia , Feminino , Ferritinas/sangue , Febre , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/etiologia , Lúpus Eritematoso Sistêmico , Masculino , Doença de Still de Início Tardio/diagnóstico , Adulto Jovem
17.
Neurobiol Dis ; 81: 93-107, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25724358

RESUMO

Iron accumulation occurs in the CNS in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying such iron accumulation are not fully understood. We studied the expression and cellular localization of molecules involved in cellular iron influx, storage, and efflux. This was assessed in two mouse models of EAE: relapsing-remitting (RR-EAE) and chronic (CH-EAE). The expression of molecules involved in iron homeostasis was assessed at the onset, peak, remission/progressive and late stages of the disease. We provide several lines of evidence for iron accumulation in the EAE spinal cord which increases with disease progression and duration, is worse in CH-EAE, and is localized in macrophages and microglia. We also provide evidence that there is a disruption of the iron efflux mechanism in macrophages/microglia that underlie the iron accumulation seen in these cells. Macrophages/microglia also lack expression of the ferroxidases (ceruloplasmin and hephaestin) which have antioxidant effects. In contrast, astrocytes which do not accumulate iron, show robust expression of several iron influx and efflux proteins and the ferroxidase ceruloplasmin which detoxifies ferrous iron. Astrocytes therefore are capable of efficiently recycling iron from sites of EAE lesions likely into the circulation. We also provide evidence of marked dysregulation of mitochondrial function and energy metabolism genes, as well as of NADPH oxidase genes in the EAE spinal cord. This data provides the basis for the selective iron accumulation in macrophage/microglia and further evidence of severe mitochondrial dysfunction in EAE. It may provide insights into processes underling iron accumulation in MS and other neurodegenerative diseases in which iron accumulation occurs.


Assuntos
Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/patologia , Ferritinas/metabolismo , Distúrbios do Metabolismo do Ferro/etiologia , Ferro/metabolismo , Medula Espinal/metabolismo , Animais , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Ferritinas/genética , Adjuvante de Freund/toxicidade , Proteína Glial Fibrilar Ácida/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/toxicidade , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Fatores de Tempo
18.
Neurobiol Dis ; 81: 66-75, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25771171

RESUMO

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify the expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack the expression of one or both Irps and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout (Irp1(-/-)Irp2(-/-)) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1(-/-) mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2(-/-) mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1(-/-) mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1(-/-) mice and discuss the phenotypes observed for Irp2(-/-) mice in detail with a particular emphasis on the neurological problems of these mice.


Assuntos
Distúrbios do Metabolismo do Ferro/etiologia , Proteínas Reguladoras do Ferro/deficiência , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Distúrbios do Metabolismo do Ferro/genética , Proteínas Reguladoras do Ferro/genética , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/genética
19.
Rev Med Interne ; 36(8): 522-9, 2015 Aug.
Artigo em Francês | MEDLINE | ID: mdl-25640247

RESUMO

The discovery of a hyperferritinemia is most of the time fortuitous. The diagnostic approach aims at looking for the responsible etiology and at verifying if an iron hepatic overload is present or not. Three diagnostic steps are proposed. The clinical elements and a few straightforward biological tests are sufficient at first to identify one of the four main causes: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome. None of these causes is associated with a significant iron hepatic overload. If the transferring saturation coefficient is raised (>50%) a hereditary hemochromatosis should be discussed. Secondly, less common disorders will be discussed. Among these, only the chronic hematological disorders either acquired or congenital are at risk of iron hepatic overload. Thirdly, if a doubt persists in the etiologic research, and the serum ferritin level is very high or continues to rise, it is essential to verify that there is no iron hepatic overload. For that purpose, the MRI with study of the iron overload is the main test, which will guide the therapeutic attitude. Identification of more than a single etiology occurs in more than 40% of the cases.


Assuntos
Ferritinas/sangue , Distúrbios do Metabolismo do Ferro/sangue , Distúrbios do Metabolismo do Ferro/diagnóstico , Humanos , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/etiologia
20.
Neurobiol Dis ; 81: 119-33, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25447222

RESUMO

Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498-499InsTC mutation which causes the substitution of the last 9 amino acids and an elongation of extra 16 amino acids at the C-terminus of L-ferritin peptide. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. In order to analyze the impact of the mutation in vivo, we generated mouse models for the some pathogenic human FTL gene in FVB and C57BL/6J strains. Transgenic mice in the FVB background showed high accumulation of the mutated ferritin in brain where it correlated with increased iron deposition with age, as scored by magnetic resonance imaging. Notably, the accumulation of iron-ferritin bodies was accompanied by signs of oxidative damage. In the C57BL/6 background, both the expression of the mutant ferritin and the iron levels were lower than in the FVB strain. Nevertheless, also these mice showed oxidative alterations in the brain. Furthermore, post-natal hippocampal neurons obtained from these mice experienced a marked increased cell death in response to chronic iron overload and/or acute oxidative stress, in comparison to wild-type neurons. Ultrastructural analyses revealed an accumulation of lipofuscin granules associated with iron deposits, particularly enriched in the cerebellum and striatum of our transgenic mice. Finally, experimental subjects were tested throughout development and aging at 2-, 8- and 18-months for behavioral phenotype. Rotarod test revealed a progressive impaired motor coordination building up with age, FTL mutant old mice showing a shorter latency to fall from the apparatus, according to higher accumulation of iron aggregates in the striatum. Our data show that our 498-499InsTC mouse models recapitulate early pathological and clinical traits of the human neuroferritinopathy, thus providing a valuable model for the study of the disease. Finally, we propose a mechanistic model of lipofuscine formation that can account for the etiopathogenesis of human neuroferritinopathy.


Assuntos
Apoferritinas/genética , Encéfalo/patologia , Distúrbios do Metabolismo do Ferro/etiologia , Distrofias Neuroaxonais , Doenças Neurodegenerativas/etiologia , Transtornos Psicomotores/etiologia , Fatores Etários , Animais , Apoferritinas/metabolismo , Encéfalo/metabolismo , Morte Celular/genética , Células Cultivadas , Dano ao DNA/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hipocampo/citologia , Humanos , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Distrofias Neuroaxonais/complicações , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
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