Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 121
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Blood ; 139(20): 3018-3029, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-34601591

RESUMEN

Hemochromatosis (HC) is a genetically heterogeneous disorder in which uncontrolled intestinal iron absorption may lead to progressive iron overload (IO) responsible for disabling and life-threatening complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. The recent advances in the knowledge of pathophysiology and molecular basis of iron metabolism have highlighted that HC is caused by mutations in at least 5 genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. This has led to an HC classification based on different molecular subtypes, mainly reflecting successive gene discovery. This scheme was difficult to adopt in clinical practice and therefore needs revision. Here we present recommendations for unambiguous HC classification developed by a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society), including both clinicians and basic scientists during a meeting in Heidelberg, Germany. We propose to deemphasize the use of the molecular subtype criteria in favor of a classification addressing both clinical issues and molecular complexity. Ferroportin disease (former type 4a) has been excluded because of its distinct phenotype. The novel classification aims to be of practical help whenever a detailed molecular characterization of HC is not readily available.


Asunto(s)
Proteínas de Transporte de Catión , Hemocromatosis , Sobrecarga de Hierro , Proteínas de Transporte de Catión/metabolismo , Hemocromatosis/diagnóstico , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Hierro/metabolismo
2.
Am J Hematol ; 96(8): 1008-1016, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-33844865

RESUMEN

The role of iron in the formation and functioning of erythrocytes, and to a lesser degree of white blood cells, is well established, but the relationship between iron and platelets is less documented. Physiologically, iron plays an important role in hematopoiesis, including thrombopoiesis; iron levels direct, together with genetic factors, the lineage commitment of megakaryocytic/erythroid progenitors toward either megakaryocyte or erythroid progenitors. Megakaryocytic iron contributes to cellular machinery, especially energy production in platelet mitochondria. Thrombocytosis, possibly favoring vascular thrombosis, is a classical feature observed with abnormally low total body iron stores (mainly due to blood losses or decreased duodenal iron intake), but thrombocytopenia can also occur in severe iron deficiency anemia. Iron sequestration, as seen in inflammatory conditions, can be associated with early thrombocytopenia due to platelet consumption and followed by reactive replenishment of the platelet pool with possibility of thrombocytosis. Iron overload of genetic origin (hemochromatosis), despite expected mitochondrial damage related to ferroptosis, has not been reported to cause thrombocytopenia (except in case of high degree of hepatic fibrosis), and iron-related alteration of platelet function is still a matter of debate. In acquired iron overload (of transfusional and/or dyserythropoiesis origin), quantitative or qualitative platelet changes are difficult to attribute to iron alone due to the interference of the underlying hematological conditions; likewise, hematological improvement, including increased blood platelet counts, observed under iron oral chelation is likely to reflect mechanisms other than the sole beneficial impact of iron depletion.


Asunto(s)
Plaquetas/metabolismo , Hierro/sangre , Humanos
3.
Blood Cells Mol Dis ; 84: 102444, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32464486

RESUMEN

BACKGROUND: Five main genes are associated with hemochromatosis; however, current studies show that, in addition to these genes, others may be associated with primary iron overload (IO). One of these is the bone morphogenetic protein 6 (BMP6), which encodes a protein that modulates hepcidin synthesis and, consequently, iron homeostasis. AIM: To identify BMP6 gene pathogenic variants in patients with IO and non-homozygous genotype for the HFE p.Cys282Tyr mutation. MATERIALS AND METHODS: Fifty-three patients with primary IO and non-homozygous genotype for the HFE p.Cys282Tyr were selected. Subsequent bidirectional DNA sequencing of BMP6 exons was performed. RESULTS: Two novel variants were found. One at homozygous state p.Gln158Ter (c.472C>T) was pathogenic, the other one at heterozygous state p.Val394Met (c.1180G>A) was of uncertain significance (VUS); the third variant at heterozygous state p.Arg257His (c.770G>A) has already been described and associated with IO. No BMP6 pathogenic variants that would explain iron overload phenotypes were detected in 94% of the studied patients. CONCLUSION: Identification of the BMP6 pathogenic variants in Brazilian patients with primary IO might contribute to the genetic understanding of this phenotype.


Asunto(s)
Proteína Morfogenética Ósea 6/genética , Sobrecarga de Hierro/genética , Mutación Puntual , Adulto , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad
4.
FASEB J ; 33(10): 11072-11081, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31298936

RESUMEN

Iron excess increases the hepatic expression of hepcidin, the systemic iron metabolism regulator that favors iron sequestration in the spleen. Genetic iron overload related to hepcidin insufficiency decreases the spleen iron concentration and increases hepatic iron concentration, whereas during secondary iron overload, the hepcidin expression increases together with spleen iron concentration in addition to hepatic iron concentrations increase. Links between iron metabolism and other metals being suggested, our aim was to investigate, during iron overload, the relationships between the hepatic hepcidin expression level and the hepatic and splenic concentrations of iron, manganese, copper, zinc, and molybdenum, determined using inductively coupled plasma mass spectrometry. Hepcidin-deficient mice, secondary iron overload mice models, and their respective controls were studied. Spleen molybdenum and manganese concentrations paralleled the modulation of both spleen iron concentrations, increasing in secondary iron overload and decreasing in hepcidin deficiency related iron overload, as well as hepatic hepcidin mRNA expression. Our data suggest that iron, manganese, and molybdenum metabolisms could share mechanisms controlling their distribution that are associated to hepcidin modulation. In diseases with abnormal hepcidin levels, including chronic inflammation, special attention should be paid to those metals that can participate with the phenotype.-Cavey, T., Latour, C., Island, M.-L., Leroyer, P., Guggenbuhl, P., Coppin, H., Roth, M.-P., Bendavid, C., Brissot, P., Ropert, M., Loréal, O. Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin-deficient and secondary iron overload models in mice.


Asunto(s)
Hepcidinas/genética , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Manganeso/metabolismo , Molibdeno/metabolismo , Animales , Hepcidinas/deficiencia , Hepcidinas/metabolismo , Sobrecarga de Hierro/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/metabolismo
5.
FASEB J ; 33(12): 13492-13502, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31560858

RESUMEN

Hereditary aceruloplasminemia (HA), related to mutations in the ceruloplasmin (Cp) gene, leads to iron accumulation. Ceruloplasmin ferroxidase activity being considered essential for macrophage iron release, macrophage iron overload is expected, but it is not found in hepatic and splenic macrophages in humans. Our objective was to get a better understanding of the mechanisms leading to iron excess in HA. A clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) knockout of the Cp gene was performed on Sprague-Dawley rats. We evaluated the iron status in plasma, the expression of iron metabolism genes, and the status of other metals whose interactions with iron are increasingly recognized. In Cp-/- rats, plasma ceruloplasmin and ferroxidase activity were absent, together with decreased iron concentration and transferrin saturation. Similarly as in humans, the hepatocytes were iron overloaded conversely to hepatic and splenic macrophages. Despite a relative hepcidin deficiency in Cp-/- rats and the loss of ferroxidase activity, potentially expected to limit the interaction of iron with transferrin, no increase of plasma non-transferrin-bound iron level was found. Copper was decreased in the spleen, whereas manganese was increased in the plasma. These data suggest that the reported role of ceruloplasmin cannot fully explain the iron hepatosplenic phenotype in HA, encouraging the search for additional mechanisms.-Kenawi, M., Rouger, E., Island, M.-L., Leroyer, P., Robin, F., Remy, S., Tesson, L., Anegon, I., Nay, K., Derbré, F., Brissot, P., Ropert, M., Cavey, T., Loréal, O. Ceruloplasmin deficiency does not induce macrophagic iron overload: lessons from a new rat model of hereditary aceruloplasminemia.


Asunto(s)
Ceruloplasmina/deficiencia , Modelos Animales de Enfermedad , Trastornos del Metabolismo del Hierro/complicaciones , Sobrecarga de Hierro/patología , Hierro/metabolismo , Macrófagos/patología , Enfermedades Neurodegenerativas/complicaciones , Animales , Secuencia de Bases , Sistemas CRISPR-Cas , Ceruloplasmina/antagonistas & inhibidores , Ceruloplasmina/genética , Femenino , Hierro/análisis , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/patología , Sobrecarga de Hierro/etiología , Hígado/metabolismo , Hígado/patología , Macrófagos/metabolismo , Masculino , Mutación , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Ratas , Ratas Sprague-Dawley , Homología de Secuencia , Bazo/metabolismo , Bazo/patología
6.
BMC Med Genet ; 19(1): 3, 2018 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-29301508

RESUMEN

BACKGROUND: Hereditary hemochromatosis (HH) encompasses a group of autosomal recessive disorders mainly characterized by enhanced intestinal absorption of iron and its accumulation in parenchymal organs. HH diagnosis is based on iron biochemical and magnetic resonance imaging (MRI) assessment, and genetic testing. Questionnaires, such as SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient's quality of life (QL). In addition, different genotypes are identified as results of genetic tests in patients with suspected primary iron overload. In the present study, our aim was to evaluate whether domains of QL are different according to genotypic groups in patients suspected of HH. METHODS: Seventy-nine patients with primary iron overload were included and two genotypic groups were formed (group 1: homozygous genotype for the HFE p.Cys282Tyr mutation; group 2: other genotypes). RESULTS: Group 1 had higher means of plasma transferrin saturation (86 ± 19%) and serum ferritin (1669 ± 1209 ng/mL) compared to group 2 (71 ± 12%, 1252 ± 750 ng/mL, respectively; p = 0.001). Four domains were significantly different among groups 1 and 2: physical functioning (p = 0.03), bodily pain (p = 0.03), vitality (p = 0.02) and social functioning (p = 0.01). CONCLUSIONS: Our main finding was that patients with p.Cys282Tyr homozygosity had a worse QL scenario assessed by SF-36, compared with patients with iron overload without the same genotype. Being aware of this relationship between genotypes and QL might be helpful in the overall management of patients suspected of hereditary hemochromatosis.


Asunto(s)
Predisposición Genética a la Enfermedad , Hemocromatosis/diagnóstico , Hemocromatosis/genética , Calidad de Vida , Adulto , Femenino , Ferritinas/sangre , Pruebas Genéticas , Genotipo , Homocigoto , Humanos , Hierro/sangre , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/genética , Masculino , Persona de Mediana Edad , Mutación , Factores Socioeconómicos , Encuestas y Cuestionarios , Transferrina/metabolismo
7.
Gastroenterology ; 150(3): 672-683.e4, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26582087

RESUMEN

BACKGROUND & AIMS: Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals. METHODS: We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses. RESULTS: We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production. CONCLUSIONS: We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload.


Asunto(s)
Proteína Morfogenética Ósea 6/genética , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hepcidinas/biosíntesis , Heterocigoto , Hierro/metabolismo , Hígado/metabolismo , Mutación Missense , Anciano , Animales , Biopsia , Proteína Morfogenética Ósea 6/metabolismo , Estudios de Casos y Controles , Línea Celular , Cromatografía Liquida , Análisis Mutacional de ADN , Femenino , Ferritinas/sangre , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hemocromatosis/sangre , Hepcidinas/sangre , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Zarigüeyas , Fenotipo , Proteínas Smad Reguladas por Receptores/metabolismo , Espectrometría de Masas en Tándem , Transfección
8.
J Hepatol ; 64(2): 505-515, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26596411

RESUMEN

Body iron has a very close relationship with the liver. Physiologically, the liver synthesizes transferrin, in charge of blood iron transport; ceruloplasmin, acting through its ferroxidase activity; and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron. The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor 2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease. It is less involved in the usual (type A) form of ferroportin disease which targets primarily the macrophagic system. Hereditary aceruloplasminemia raises important pathophysiological issues in light of its peculiar organ iron distribution.


Asunto(s)
Trastornos del Metabolismo del Hierro , Hierro/metabolismo , Hígado/metabolismo , Errores Innatos del Metabolismo , Humanos , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/metabolismo , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Especificidad de Órganos
10.
Am J Hematol ; 91(12): 1202-1205, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27518069

RESUMEN

p.Cys282Tyr (C282Y) homozygosity explains most cases of HFE-related hemochromatosis, but a significant number of patients presenting with typical type I hemochromatosis phenotype remain unexplained. We sought to describe the clinical relevance of rare HFE variants in non-C282Y homozygotes. Patients referred for hemochromatosis to the National Reference Centre for Rare Iron Overload Diseases from 2004 to 2010 were studied. Sequencing was performed for coding region and intronic flanking sequences of HFE, HAMP, HFE2, TFR2, and SLC40A1. Nine private HFE variants were identified in 13 of 206 unrelated patients. Among those, five have not been previously described: p.Leu270Argfs*4, p.Ala271Valfs*25, p.Tyr52*, p.Lys166Asn, and p.Asp141Tyr. Our results show that rare HFE variants are identified more frequently than variants in the other genes associated with iron overload. Rare HFE variants are therefore the most frequent cause of hemochromatosis in non-C282Y homozygote HFE patients. Am. J. Hematol. 91:1202-1205, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Variación Genética , Proteína de la Hemocromatosis/genética , Hemocromatosis/genética , Adulto , Anciano , Femenino , Homocigoto , Humanos , Sobrecarga de Hierro/genética , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN
11.
Bull Acad Natl Med ; 200(2): 309-325, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29898327

RESUMEN

Due to major advances in the understanding of iron metabolism as well as in the bioche- iuical, imaging, and genetic domains: i) The nosologicalframework of hemochromatosis (HC) encompasses not only HFE-HC, by far the most frequent HC form, but also non-HFE HC diseases which comprise essentially juvenile HC and the ferroportin disease. ii) The diagnostic approach has become totally non invasive, based on clinical, imaging and biological data. iii) The treatment remains, for most forms, based on venesections, but the innovative emerging therapeutic approach is represented by hepcidin supplementation.


Asunto(s)
Hemocromatosis/diagnóstico , Hemocromatosis/terapia , Proteínas de Transporte de Catión/metabolismo , Hemocromatosis/clasificación , Hemocromatosis/genética , Hepcidinas/administración & dosificación , Humanos
12.
Blood Cells Mol Dis ; 54(2): 151-4, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25486930

RESUMEN

As our understanding of iron metabolism improves through the more accurate description of iron metabolism actors, new causes of iron overload are identified. We, here, report 16 cases of hereditary hypotransferrinemia related to 4 previously undescribed TF (transferrin) mutations (p.Val221Gly, p.Arg609Trp, p.Glu370Lys, p.Tyr533X and p.Cys421Arg). We show that, besides increasing serum transferrin saturation without iron overload, hypotransferrinemia, when associated to mutations in HFE or HAMP or to acquired factors, can lead to clinically relevant iron burden. These cases emphasize the usefulness of serum transferrin determination in the diagnostic evaluation of iron overload and the importance for clinicians to be aware of this syndrome.


Asunto(s)
Hepcidinas/genética , Antígenos de Histocompatibilidad Clase I/genética , Sobrecarga de Hierro/genética , Hierro/metabolismo , Proteínas de la Membrana/genética , Errores Innatos del Metabolismo de los Metales/genética , Mutación , Transferrina/deficiencia , Transferrina/genética , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Expresión Génica , Genotipo , Proteína de la Hemocromatosis , Hepcidinas/metabolismo , Heterocigoto , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/patología , Masculino , Proteínas de la Membrana/metabolismo , Errores Innatos del Metabolismo de los Metales/sangre , Errores Innatos del Metabolismo de los Metales/complicaciones , Errores Innatos del Metabolismo de los Metales/patología , Persona de Mediana Edad , Linaje , Transferrina/metabolismo
13.
Hepatology ; 59(3): 839-47, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23775519

RESUMEN

UNLABELLED: Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE-related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (± 99) µg/L. Magnetic resonance imaging showed that iron overload was absent in nine patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis discovered after LT. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. CONCLUSION: In HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients who received LTs for other liver diseases.


Asunto(s)
Hemocromatosis/cirugía , Hepcidinas/sangre , Antígenos de Histocompatibilidad Clase I/genética , Hierro/metabolismo , Hepatopatías/cirugía , Trasplante de Hígado , Proteínas de la Membrana/genética , Adulto , Anciano , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Estimación de Kaplan-Meier , Hepatopatías/metabolismo , Hepatopatías/mortalidad , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/mortalidad , Hepatopatías Alcohólicas/cirugía , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad
14.
Liver Int ; 35(6): 1731-8, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25495562

RESUMEN

BACKGROUND & AIMS: C282Y homozygotes with serum ferritin (SF) levels >1000 µg/L and/or increased serum transaminase levels are at risk of severe F3/F4 fibrosis. Current practical guidelines recommend liver biopsy in such individuals. This prospective observational cohort study aimed to evaluate non-invasive alternative means such as hyaluronic acid (HA) and transient elastography (TE) for the assessment of severe fibrosis in patients with SF >1000 µg/L or elevated transaminases. METHODS: Between September 2005 and April 2013, 77 patients diagnosed C282Y homozygotes underwent a liver biopsy because of SF >1000 µg/L and/or increased transaminases according to current guidelines, with concomitant TE. All of them had clinical and biological evaluation, including HA measurement in 52 cases. RESULTS: A total of 19.5% of patients had F3-F4 severe fibrosis. HA was higher in patients with severe fibrosis, but did not accurately predict severe fibrosis. TE was significantly higher in patients with severe fibrosis (17.2 vs. 4.9 kPa; P < 0.05) and was able to accurately predict fibrosis stage in 47/61 (77%) patients with valid measurement using a lower threshold of 6.4 kPa and an upper threshold of 13.9 kPa. Efficient assessment of severe fibrosis was not possible in patients with intermediate TE values. CONCLUSION: An algorithm that successively employed SF and TE can accurately classify severe fibrosis in 61% of patients, restricting the need for liver biopsy to the 39% of patients with intermediate or unvalid TE values. This algorithm should be validated in independent cohorts before extended use.


Asunto(s)
Diagnóstico por Imagen de Elasticidad/métodos , Ferritinas/sangre , Hemocromatosis/complicaciones , Cirrosis Hepática/diagnóstico , Hígado/patología , Adulto , Biopsia , Femenino , Hemocromatosis/genética , Homocigoto , Humanos , Ácido Hialurónico/sangre , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Curva ROC , Transaminasas/sangre
15.
Biometals ; 28(4): 733-43, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26041486

RESUMEN

Iron is reported to interact with other metals. In addition, it has been shown that genetic background may impact iron metabolism. Our objective was to characterize, in mice of three genetic backgrounds, the links between iron and several non-iron metals. Thirty normal mice (C57BL/6, Balb/c and DBA/2; n = 10 for each group), fed with the same diet, were studied. Quantification of iron, zinc, cobalt, copper, manganese, magnesium and rubidium was performed by ICP/MS in plasma, erythrocytes, liver and spleen. Transferrin saturation was determined. Hepatic hepcidin1 mRNA level was evaluated by quantitative RT-PCR. As previously reported, iron parameters were modulated by genetic background with significantly higher values for plasma iron parameters and liver iron concentration in DBA/2 and Balb/c strains. Hepatic hepcidin1 mRNA level was lower in DBA/2 mice. No iron parameter was correlated with hepcidin1 mRNA levels. Principal component analysis of the data obtained for non-iron metals indicated that metals parameters stratified the mice according to their genetic background. Plasma and tissue metals parameters that are dependent or independent of genetic background were identified. Moreover, relationships were found between plasma and tissue content of iron and some other metals parameters. Our data: (i) confirms the impact of the genetic background on iron parameters, (ii) shows that genetic background may also play a role in the metabolism of non-iron metals, (iii) identifies links between iron and other metals parameters which may have implications in the understanding and, potentially, the modulation of iron metabolism.


Asunto(s)
Antecedentes Genéticos , Hierro/metabolismo , Animales , Cobalto/sangre , Cobalto/metabolismo , Cobre/sangre , Cobre/metabolismo , Hepcidinas/sangre , Hepcidinas/genética , Hepcidinas/metabolismo , Hierro/sangre , Magnesio/sangre , Magnesio/metabolismo , Masculino , Manganeso/sangre , Manganeso/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Análisis de Componente Principal , ARN Mensajero/sangre , ARN Mensajero/genética , ARN Mensajero/metabolismo , Rubidio/sangre , Rubidio/metabolismo , Zinc/sangre , Zinc/metabolismo
16.
Rev Prat ; 65(10): 1305-11, 2015 Dec.
Artículo en Francés | MEDLINE | ID: mdl-26979029

RESUMEN

Chronic iron overload, either of genetic (hemochromatoses) or acquired (transfusions) origin, leads to frequent disorders, affecting both the quality of life and life expectancy. Major recent advances in the knowledge of iron metabolism, together with advances in biology, imaging and drug design have already significantly improved the diagnostic and therapeutic approaches. These conceptual and technological ameliorations should, in the near future, continue to benefit the clinical management of iron overloaded patients.


Asunto(s)
Suplementos Dietéticos , Hepcidinas/administración & dosificación , Quelantes del Hierro/administración & dosificación , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/tratamiento farmacológico , Calidad de Vida , Reacción a la Transfusión , Predisposición Genética a la Enfermedad , Hemocromatosis/genética , Humanos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/genética , Esperanza de Vida , Pronóstico , Factores de Riesgo , Resultado del Tratamiento
17.
Hum Mutat ; 34(11): 1529-36, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23943237

RESUMEN

Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression.


Asunto(s)
Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Estudios de Asociación Genética , Sobrecarga de Hierro/congénito , Proteínas de Transporte de Catión/química , Ferritinas/metabolismo , Expresión Génica , Células HEK293 , Humanos , Espacio Intracelular/metabolismo , Hierro/metabolismo , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Mutación , Transferrina/metabolismo
18.
Biochim Biophys Acta ; 1820(3): 403-10, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21855608

RESUMEN

BACKGROUND: Besides transferrin iron, which represents the normal form of circulating iron, non-transferrin bound iron (NTBI) has been identified in the plasma of patients with various pathological conditions in which transferrin saturation is significantly elevated. SCOPE OF THE REVIEW: To show that: i) NTBI is present not only during chronic iron overload disorders (hemochromatosis, transfusional iron overload) but also in miscellaneous diseases which are not primarily iron overloaded conditions; ii) this iron species represents a potentially toxic iron form due to its high propensity to induce reactive oxygen species and is responsible for cellular damage not only at the plasma membrane level but also towards different intracellular organelles; iii) the NTBI concept may be expanded to include intracytosolic iron forms which are not linked to ferritin, the major storage protein which exerts, at the cellular level, the same type of protective effect towards the intracellular environment as transferrin in the plasma. MAJOR CONCLUSIONS: Plasma NTBI and especially labile plasma iron determinations represent a new important biological tool since elimination of this toxic iron species is a major therapeutic goal. GENERAL SIGNIFICANCE: The NTBI approach represents an important mechanistic concept for explaining cellular iron excess and toxicity and provides new important biochemical diagnostic tools. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.


Asunto(s)
Sobrecarga de Hierro/sangre , Hierro/sangre , Hierro/metabolismo , Transferrina/metabolismo , Muerte Celular , Ferritinas/sangre , Hemocromatosis/sangre , Humanos , Transporte Iónico , Hígado/metabolismo , Especies Reactivas de Oxígeno/metabolismo
19.
Mol Cell Biochem ; 378(1-2): 205-15, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23494528

RESUMEN

Natural polyamines such as putrescine (Put), spermidine (Spd), and spermine (Spm), which are present in the human diet in large amounts, associated with their active transporter, are assumed to play a role in non-heme iron uptake and iron bioavailability from nutrients. Enterocytes and hepatocytes play pivotal roles in the regulation of body iron homeostasis. In this study, we report the effects of natural polyamines on iron transport in the Caco-2 cell line. In enterocyte-like Caco-2 cells, polyamines did not significantly modulate the transepithelial iron flux across the cell monolayer cultured on permeable membranes. In contrast, Spd, Spm, and to a lesser extent, Put were shown to activate Caco-2 cell iron uptake and to induce an increase in the ferritin level. This iron co-transport in enterocytes, which involved an interaction between iron and polyamine then cell uptake of the polyamine-iron complexes by the polyamine transport system, was more pronounced in proliferating than in differentiated Caco-2 cells. Moreover, it was observed at physiological concentrations of both polyamines and iron. It could thus play a role in the rapid renewal of enterocytes. These data suggest the involvement of polyamines as components of the pool of transferrin-independent iron-chelating vectors. Further investigations are needed to demonstrate their biological relevance in physiological situations.


Asunto(s)
Compuestos Férricos/metabolismo , Poliaminas/farmacología , Transporte Biológico , Células CACO-2 , Diferenciación Celular , Permeabilidad de la Membrana Celular , Proliferación Celular , Ferritinas/metabolismo , Humanos
20.
Nat Genet ; 36(1): 77-82, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14647275

RESUMEN

Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.


Asunto(s)
Cromosomas Humanos Par 1 , Hemocromatosis/genética , Proteínas de la Membrana/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Proteínas Ligadas a GPI , Proteína de la Hemocromatosis , Humanos , Sobrecarga de Hierro , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA