HFE hemochromatosis: an overview about therapeutic recommendations

Abstract Hemochromatosis is currently characterized by the iron overload caused by hepcidin deficiency. Large advances in the knowledge on the hemochromatosis pathophysiology have occurred due to a better understanding of the protein of the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype. In the present review, the main aims are to show updates on hemochromatosis and to report a practical set of therapeutic recommendations for the human factors engineering protein (HFE) hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, elaborated by the Haemochromatosis International Taskforce.

Urine hepcidin, netrin-1, neutrophil gelatinase-associated lipocalin and C-C motif chemokine ligand 2 levels in multicystic dysplastic kidney / Níveis de hepcidina, netrina-1, lipocalina associada a gelatinase neutrofílica e ligante de quimiocina C-C motif na urina do rim displásico multicístico

ABSTRACT Introduction: Glomerular hyperfiltration may lead to proteinuria and chronic kidney disease in unilateral multicystic dysplastic kidney (MCDK). We aimed to investigate the urine neutrophil-gelatinase-associated lipocalin (NGAL), netrin-1, hepcidin, and C-C motif chemokine ligand-2 (MCP-1/CCL-2) levels in patients with MCDK. Methods: Thirty-two patients and 25 controls were included. The urine hepcidin, netrin-1, NGAL, and MCP-1/CCL-2 levels were determined by ELISA. Results: The patients had higher serum creatinine (Cr) levels, urine albumin, and netrin-1/Cr ratio with lower GFR. There were positive correlations between urine protein/Cr, MCP-1/CCL-2/Cr, and netrin-1 with NGAL (r = 0.397, p = 0.031; r = 0.437, p = 0.041, r = 0.323, p = 0.042, respectively). Urine netrin-1/Cr was positively correlated with MCP-1/CCL-2/Cr (r = 0.356, p = 0.045). There were positive associations between the presence of proteinuria and netrin-1/Cr, MCP-1/CCL-2/Cr, and NGAL/Cr [Odds ratio (OR): 1.423, p = 0.037, OR: 1.553, p = 0.033, OR: 2.112, p = 0.027, respectively)]. ROC curve analysis showed that netrin-1/Cr, MCP-1/CCL-2/Cr, and NGAL/Cr had high predictive values for determining proteinuria p = 0.027, p = 0.041, p = 0.035, respectively). Urine hepcidin/Cr was negatively correlated with tubular phosphorus reabsorption and was positively correlated with urine NGAL/Cr (r = -0.418, p = 0.019; r = 0.682, p = 0.000; respectively). Conclusions: MCP-1/CCL-2 may play a role in the development of proteinuria in MCDK. Netrin-1 may be a protective factor against proteinuria-induced renal injury. Urine hepcidin/Cr may reflect proximal tubule damage in MCDK. Urine NGAL/Cr may be a predictor of tubule damage by proteinuria.

Resumo Introdução: A hiperfiltração glomerular pode causar proteinúria e doença renal crônica no rim displásico multicístico unilateral (RDM). Nosso objetivo foi investigar os níveis de lipocalina associada à gelatinase neutrofílica na urina (NGAL), netrina-1, hepcidina e quimiocina C-C com ligante-2 (MCP-1/CCL-2) em pacientes com RDM. Métodos: Trinta e dois pacientes e 25 controles foram incluídos. Os níveis urinários de hepcidina, netrin-1, NGAL e MCP-1/CCL-2 foram determinados por ELISA. Resultados: Os pacientes apresentaram níveis séricos mais elevados de creatinina (Cr), albumina na urina e relação netrina-1/Cr com menor TFG. Houve correlação positiva entre proteína na urina/Cr, MCP-1/CCL-2/Cr e netrina-1 com NGAL (r = 0,397, p = 0,031; r = 0,437, p = 0,041, r = 0,323, p = 0,042, respectivamente). A netrina-1/Cr na urina foi correlacionada positivamente com MCP-1/CCL-2/Cr (r = 0,356, p = 0,045). Houve associações positivas entre a presença de proteinúria e netrina-1/Cr, MCP-1/CCL-2/Cr e NGAL/Cr [Odds ratio (OR): 1,423, p = 0,037, OR: 1,553, p = 0,033, OR: 2,112, p = 0,027, respectivamente) ]. A análise da curva ROC mostrou que netrina-1/Cr, MCP-1/CCL-2/Cr e NGAL/Cr apresentaram altos valores preditivos para determinar a proteinúria p = 0,027, p = 0,041, p = 0,035, respectivamente). A hepcidina/Cr na urina foi correlacionada negativamente com a reabsorção tubular de fósforo e positivamente com a NGAL/Cr na urina (r = -0,418, p = 0,019; r = 0,682, p = 0,000; respectivamente). Conclusões: MCP-1/CCL-2 pode ter participação no desenvolvimento de proteinúria no RDM. A Netrina-1 pode ser um fator protetor contra lesão renal induzida por proteinúria. Hepcidina/Cr na urina pode refletir danos em túbulos proximais no RDM. O valor de NGAL/Cr urinário pode ser um preditor de danos nos túbulos por proteinúria.

The effect of hepcidin on components of metabolic syndrome in chronic kidney disease: a cross-sectional study

SUMMARY BACKGROUND Hepcidin is an important regulator of iron homeostasis. OBJECTIVES This cross-sectional study was conducted to evaluate the association between hepcidin and components of metabolic syndrome in patients with chronic kidney disease (CKD). DESIGN AND SETTING 103 CKD patients and 59 healthy volunteers were included in the study from the University Hospital. METHODS Serum hepcidin levels were measured by enyzme-linked immunosorbent assay (ELISA) test. As for the study parameters, age, sex, body mass index, renal diseases, serum biochemistry, complete blood count, iron and total iron-binding capacity, ferritin, high-sensitive C-reactive protein (hsCRP), C- reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were evaluated. RESULTS The mean age of the patients was 58.63 ± 11.8 years. Hepcidin level was significantly associated with hypertension and higher uric acid levels (P < 0.05). There was a positive correlation between hepcidin and urea, uric acid, creatinine, ferritin, CRP, ESR, phosphorus, triglyceride, low-density lipoprotein (LDL), proteinuria and albuminuria in 24-hour urine collection. A negative correlation was found between hepcidin and estimated glomerular filtration rate (eGFR), hemoglobin, hematocrit, calcium, 25 OH vitamin D, pH, and bicarbonate levels. CONCLUSION Hepcidin, a well-known hormone regulator of iron metabolism, may play an important role in the pathogenesis of metabolic syndrome in patients with CKD, and further studies might delineate in-depth its potential as a promising early marker in these patients.

RESUMO FUNDAMENTO A hepcidina é um importante regulador da homeostase do ferro. OBJETIVOS Este estudo transversal foi realizado para avaliar a associação entre hepcidina e componentes da síndrome metabólica em pacientes com doença renal crônica (DRC). PROJETO E LOCAL Cento e três pacientes com DRC e 59 voluntários saudáveis foram incluídos no estudo no Hospital Universitário. MÉTODOS Os níveis séricos de hepcidina foram medidos pelo teste imunoenzimático (Elisa). Quanto aos parâmetros do estudo, idade, sexo, índice de massa corporal, doenças renais, bioquímica sérica, hemograma completo, capacidade de ligação total de ferro e ferro, ferritina, proteína C reativa altamente sensível (hsCRP), proteína C reativa (PCR) e taxa de sedimentação de eritrócitos (VHS) foram avaliados. RESULTADOS A idade média dos pacientes foi de 58,63±11,8 anos. Número de pacientes em cada estágio da DRC, do estágio I ao estágio V (não em terapia renal substitutiva). O nível de hepcidina foi significativamente associado à hipertensão e níveis mais altos de ácido úrico (P <0,05). Houve correlação positiva entre hepcidina e ureia, ácido úrico, creatinina, ferritina, PCR, VHS, fósforo, triglicerídeo, lipoproteína de baixa densidade (LDL), proteinúria e albuminúria na coleta de urina de 24 horas. Foi encontrada correlação negativa entre hepcidina e taxa de filtração glomerular estimada (TFGe), hemoglobina, hematócrito, cálcio, 25 OH de vitamina D, pH e níveis de bicarbonato. CONCLUSÃO A hepcidina é um hormônio bem conhecido que regula o metabolismo do ferro, mas também pode ser um importante contribuinte para os componentes da síndrome metabólica em pacientes com DRC.

Predicting hepcidin level using inflammation markers and iron indicators in patients with anemia of chronic disease

ABSTRACT Background: Recently, a small peptide called Hepcidin, was found to have an important role in regulating the iron metabolism in anemia of chronic disease (ACD) patients. Hepcidin is regulated by a variety of conditions at the transcriptional level. Therefore, our study aims to predict the level of hepcidin serum using inflammation markers and iron indicators in patients afflicted with ACD and observe how this severity of inflammation separated the level of interleukin-6 (IL-6), as well the as hepcidin level. Methods: A cross-sectional data analysis was conducted on 80 ACD adult patients treated at the Sanglah Teaching Hospital in Bali, Indonesia. We used hepcidin serum and several markers, such as the hemoglobin level, inflammation markers, renal function tests, IL-6, and iron indicators, to predict the hepcidin level. Results: This study recruited 80 ACD patients, comprising 45 men (56.3%) and 35 women (43.7%). The mean age of the participants was 43 ± 16.5 years. Only IL-6, ferritin and serum creatinine correlate significantly with serum hepcidin from seven variables that were previously eligible to enter the analysis. This study found the model to predict the hepcidin level using IL-6 ferritin and the creatinine level as the hepcidin level (predicted) = −23.76 + 0.396 (IL 6) + 0.448 (ferritin) + 0.310 (creatinine). Conclusion: This study has revealed that the creatinine level, ferritin and IL-6 can be used to predict the hepcidin level in patients with anemia of chronic disease. It is to be hoped that further cohort studies can validate our formula to predict the hepcidin level.

The effect of nonsurgical periodontal therapy on hepcidin and on inflammatory and iron marker levels

Abstract Serum hepcidin levels may increase in response to infection and inflammation. The present study investigated the effect of nonsurgical periodontal therapy (NSPT) on levels of serum hepcidin, inflammatory markers, and iron markers. An interventional study was conducted on 67 patients (age 30-65 years) without other diseases, except for chronic periodontitis (CP). Patients were allocated to either CP or control groups. The CP group received supragingival and subgingival scaling and root planing procedures, whereas the control group received supragingival scaling. Probing depth (PD), bleeding on probing, clinical attachment level (CAL), visible plaque index (VPI), serum hepcidin and interleukin-6 (IL-6) levels, high-sensitivity C-reactive protein (hs-CRP), hematological markers, and iron markers were measured at baseline and at 90 days after NSPT. The CP group had statistically significant lower mean values for mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) (p ≤ 0.05). The control group had statistically significant reductions in hemoglobin, hematocrit, MCV, and MCH (p ≤ 0.05). Serum hepcidin, IL-6, and erythrocyte sedimentation rate (ESR) levels were significantly decreased in both groups after NSPT. Periodontal markers were more markedly reduced in the CP group compared with the control group (p ≤ 0.05). These findings suggest that NSPT may reduce the serum levels of IL-6, hepcidin, and periodontal parameters.

Hepcidin serum levels in HCV chronically mono-infected naïve patients, compared to healthy individuals

Introduction: Metabolism of iron is altered in patients infected with chronically Hepatitis C. The aim of this study is to compare compare the hepcidin levels in between individuais chronically infected with HCV and uninfected individuals. The aim of this study is to compare the hepcidin serum levels between individuals chronically infected with HCV and uninfected individuals. Methods: A cross-sectional study evaluating hepcidin serum levels of mono-infected HCV (n=29), naive, non-diabetic, non-cirrhotic and non-obese patients by means of ELISA, compared to uninfected patients (n=9) with the same characteristics. The degree of liver fibrosis, according to the METAVIR scale on liver biopsies, the lipid profile, the resistance insulin level, as calculated on HOMA-IR (homeostatic model assessment for insulin resistance), the interleukin-6 (IL-6) and the ferritin serum levels were also measured. Results: The levels of hepcidin were significantly lower in HCV patients compared to controls (8.4 pg/mL (±4.94) vs. 19.51 pg/mL (±5.51)) with p<0.001. The levels of ferritin and hepcidin did not show any relation. There was no difference between hepcidin levels in relation to viral genotype, viral load, IL-6 and degrees of fibrosis within HCV infected individuals. Conclusion: It is possible that hepatic iron overload in this population is explained by suppressed levels of hepcidin in patients with HCV. (AU)

Hepcidina: la llave del metabolismo del hierro / Hepcidin: the key of iron metabolism / Hepcidina: a chave do metabolismo do ferro

En las últimas décadas se ha avanzado en el conocimiento de la regulación del metabolismo del Hierro (Fe). La Hepcidina (Hp), producida por los hepatocitos, regula la absorción de hierro desde el tubo digestivo y la liberación desde los depósitos del sistema macrofágico y del hígado. En caso de deficiencia de Fe, la Hp está disminuida entregando Fe a la transferrina (Tf). El aumento de Fe y de las citoquinas de la inflamación estimulan la producción de Hp. El ejecutor de la Hp es la Ferroportina (FP), único exportador de Fe. Hay reguladores naturales de la Hp, como la Matriptasa 2. Las mutaciones que limitan su expresión inducen dificultades en la disponibilidad de Fe (IRIDA, sobrecarga de Fe). En los últimos años se ha identificado la Eritroferrona, producida por los eritroblastos activos en la eritropoyesis. Inhibe la síntesis de Hp, permitiendo la liberación del hierro de los depósitos y su absorción por el tubo digestivo, para facilitar la disponibilidad de Fe para la eritropoyesis. Aún no está definido cómo se podrán utilizar estos elementos en el campo diagnóstico, su estandarización y su aplicación terapéutica, pero es probable que resulten de gran utilidad.

In the last decades, a lot of progress has been made on the knowledge of iron (Fe) metabolism regulation. Hepcidin (Hp) is produced by hepatocytes and it regulates the iron absorption from the duodenum and the liberation from macrophages and from the liver. When there is iron deficiency, Hp, which delivers iron to transferrin (Tf), is low. Iron overload and inflammation cytokines stimulate Hp production. The Hp natural executor is Ferroportin (FP), which is the only iron exporter from the cells. One of the natural regulators of Hp is Matriptasa 2, which down regulates Hp. Mutations that limit their expression induce iron overload and anemia (IRIDA). In the last few years, Erythroferrone (ERFE) was discovered. ERFE is produced by active erythroblasts: it inhibits Hp synthesis, allowing the iron liberation from deposits and its duodenal absorption, and also the iron release from macrophages facilitating the erythroid production. The erythroblastic activity, even ineffective, acts as a stimulus of ERFE synthesis. Until now, it has not been defined yethow these different variables could be used for diagnosis, its standardization, or for therapeutic applications, but it is highly probable that they will improve our knowledge and managements kills in this field.

Nas últimas décadas háavanços no conhecimento da regulação do metabolismo do Ferro (Fe). A Hepcidina (Hp), produzida pelos hepatócitos, regula a absorção do ferro desde o tubo digestivo e a liberação desde os depósitos do sistema macrofágico e do fígado. Em caso de deficiência de Fe, a Hp está diminuída entregando Fe à transferrina (Tf). O aumento de Fe e as citoquinas da inflamação estimulam a produção de Hp. O executor da Hp é a Ferroportina (Fp), único exportador de Fe. Há reguladores naturais da Hp, como a Matriptase 2. As mutações que limitam sua expressão induzem dificultades na disponibilidade de Fe (IRIDA, sobrecarga de Fe). Nos últimos anos se identificou que a Eritroferrona, produzida pelos eritroblastosativos na eritropoiese inibe a síntese de Hp, permitindo a liberação de ferro dos depósitos e a absorção pelo tubo digestivo, para facilitar a disponibilidade de Fe para a eritropoiese. Ain da não sedefiniu como poderãoser utilizadosestes elementos no campo diagnóstico, sua padronização e sua aplicação terapêutica, mas é provável que sejam de grande utilidade.

Prohepcidina y estado del hierro e inflamación en escolares sanos o H. pylori positivos asintomáticos / Prohepcidine iron status and inflammation in healthy and asymptomatic H. pylori school children / Pró-hepcidina estado de ferro e inflamação em estudantes saudáveis ou H. pylori positivos assintomáticos

El eje hepcidina-ferroportina es determinante en la homeostasis del hierro. Niveles elevados de hepcidina reducen la capacidad de absorción intestinal del hierro, así como su movilización entre tejidos. Una condición que produce valores séricos elevados de hepcidina es la infección. Como la infección con Helicobacter pylori (Hp) predispone a una deficiencia de hierro, en este estudio se evaluaron los niveles séricos de Pro-Hepcidina (PH), un precursor de la hepcidina, en un grupo de escolares asintomáticos, infectados con Hp (80 niños) y se los comparó con un grupo similar de niños sanos (59 niños). Los resultados mostraron que los niños infectados en los que se detectó la presencia de Hp (test de aire espirado) tenían valores de proteína C reactiva (PCR) significativamente más altos que los niños sanos. Ambos grupos presentaron valores similares de: adecuación de la ingesta de hierro, ferritina sérica (Fs), hemoglobina, hematocrito, receptores solubles de transferrina. La prevalencia de anemia y deficiencia subclínica de hierro en el grupo total (infectados + no infectados) fue de 10 y 60%, respectivamente sin diferencias entre los grupos. Sin embargo, en el grupo de niños sanos la PH sérica correlacionó significativamente (r=0,730/p<0,001) con los niveles de Fs, mientras que en los niños infectados, los niveles de PH no correlacionaron con la Fs, pero correlacionaron con la severidad de la infección (r=0,52/p<0,001). Esta tendencia de la PH a aumentar con la severidad de la infección podría explicar la mayor prevalencia de deficiencia de hierro en pacientes infectados con Hp.

The hepcidin-ferroportin axis is crucial in iron homeostasis. High serum hepcidine reduces iron intestinal absorption and tissue iron mobilization. Infection and inflammation increase serum hepcidin, predisposing to iron deficiency. Since Helicobacter pylori (Hp) infection has been associated to iron deficiency, the serum levels of prohepcidin PH (a precursor of hepcidin) were evaluated in 80 school children infected with Hp but without gastric symptoms. This was compared with PH levels in a group of 59 non Hp infected children. The results showed that infected children (exhaled air method) had higher levels of protein C reactive protein (CRP) than the non-infected group. Both groups had similar levels of iron consumption, serum ferritin (Fs), hemoglobin, hematocrit, soluble transferrin receptors and PH. The prevalence of anemia and of subclinical iron deficiency in the whole group (infected + non-infected) reached 10 and 60% respectively with no differences between groups. However, in the group of non-infected children, serum PH correlated (r=0.730/ p<0.001) with Fs levels whereas in the infected children, PH did not correlate with Fs but it correlated with the severity of the infection (r = 0.52/p<0.001). The tendency of PH to increase with the severity of infection could explain the higher prevalence of iron deficiency seen in Hp infection.

O eixo hepcidina-ferroportina é determinante na homeostase do ferro. Níveis elevados de hepcidina reduzem a capacidade de absorção intestinal do ferro, bem como sua mobilização entre tecidos. Uma condição que produz valores séricos elevados de hepcidina é a infecção. Como a infecção pelo Helicobacter pylori (Hp) predispõe a uma deficiência de ferro, neste estudo foram avaliados os níveis séricos de Pro-hepcidina (PH), um precursor da hepcidina em um grupo de estudantes assintomáticos infectados com Hp (80 crianças) e foram comparados com um grupo similar de crianças saudáveis (59 crianças). Os resultados mostraram que as crianças infectadas em que se detectou a presença de Hp (método de ar exalado) tinham valores de proteína C-reativa (PCR) significativamente mais elevada do que as crianças saudáveis. Ambos os grupos tiveram valores semelhantes de adequação da ingestão de ferro, ferritina sérica (Fs), hemoglobina, hematócrito, receptores solúveis de transferrina. A prevalência de anemia e deficiência subclínica de ferro no grupo total (infectados + não infectados) foi de 10 e 60%, respectivamente, sem diferenças entre os grupos. No entanto, no grupo de crianças saudáveis a PH sérica correlacionou significativamente (r=0,730/p<0,001) com os níveis de Fs, ao passo que em crianças infectadas, os níveis de PH não correlacionaram com a Fs, mas correlacionaram com a gravidade da infecção (r=0,52/p<0,001). Esta tendência da PH a aumentar com a gravidade da infecção poderia explicar a elevada prevalência de deficiência de ferro em pacientes infectados com Hp.

Differences in Hepatic Expression of Iron, Inflammation and Stress-Related Genes in Patients with Nonalcoholic Steatohepatitis

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. We have previously shown that hepatic reticuloendothelial system (RES) iron deposition is associated with an advanced degree of nonalcoholic steatohepatitis (NASH) in humans. In this study, we aimed to determine differentially expressed genes related to iron overload, inflammation and oxidative stress pathways, with the goal of identifying factors associated with NASH progression. Seventy five patients with NAFLD were evaluated for their biochemical parameters and their liver tissue analyzed for NASH histological characteristics. Gene expression analysis of pathways related to iron homeostasis, inflammation and oxidative stress was performed using real-time PCR. Gene expression was compared between subjects based on disease status and presence of hepatic iron staining. We observed increased gene expression of hepcidin (HAMP) (2.3 fold, p = 0.027), transmembrane serine proteinase 6 (TMPRSS6) (8.4 fold, p = 0.003), signal transducer and activator of transcription 3 (STAT3) (5.5 fold, p = 0.004), proinflammatory cytokines; IL-1β (2.7 fold, p = 0.046) and TNF-α (3.8 fold, p = 0.001) in patients with NASH. TMPRSS6, a negative regulator of HAMP, is overexpressed in patients with NASH and HIF1α (hypoxia inducible factor-1) is downregulated. NAFLD patients with hepatic iron deposition exhibited higher hepcidin expression (3.1 fold, p = 0.04) but lower expression of cytokines. In conclusion, we observed elevated hepatic HAMP expression in patients with NASH and in NAFLD patients who had hepatic iron deposition, while proinflammatory cytokines displayed elevated expression only in patients with NASH, suggesting a regulatory role for hepcidin in NAFL to NASH transition and in mitigating inflammatory responses.

Hepcidin: an important iron metabolism regulator in chronic kidney disease / Hepcidina: um importante regulador do metabolismo de ferro na doença renal crônica

Abstract Anemia is a common complication and its impact on morbimortality in patients with chronic kidney disease (CKD) is well known. The discovery of hepcidin and its functions has contributed to a better understanding of iron metabolism disorders in CKD anemia. Hepcidin is a peptide mainly produced by hepatocytes and, through a connection with ferroportin, it regulates iron absorption in the duodenum and its release of stock cells. High hepcidin concentrations described in patients with CKD, especially in more advanced stages are attributed to decreased renal excretion and increased production. The elevation of hepcidin has been associated with infection, inflammation, atherosclerosis, insulin resistance and oxidative stress. Some strategies were tested to reduce the effects of hepcidin in patients with CKD, however more studies are necessary to assess the impact of its modulation in the management of anemia in this population.

Resumo Anemia é uma complicação frequente e seu impacto na morbimortalidade é bem conhecido em pacientes com doença renal crônica (DRC). A descoberta da hepcidina e de suas funções contribuíram para melhor compreensão dos distúrbios do metabolismo de ferro na anemia da DRC. Hepcidina é um peptídeo produzido principalmente pelos hepatócitos, e através de sua ligação com a ferroportina, regula a absorção de ferro no duodeno e sua liberação das células de estoque. Altas concentrações de hepcidina descritas em pacientes com DRC, principalmente em estádios mais avançados, são atribuídas à diminuição da excreção renal e ao aumento de sua produção. Elevação de hepcidina tem sido associada à ocorrência de infecção, inflamação, aterosclerose, resistência à insulina e estresse oxidativo. Algumas estratégias foram testadas para diminuir os efeitos da hepcidina em pacientes com DRC, entretanto, serão necessários mais estudos para avaliar o impacto de sua modulação no manejo da anemia nessa população.

Regulación del metabolismo del hierro: dos sistemas, un mismo objetivo / Iron metabolism regulation: two systems, one goal

La existencia humana está indisolublemente unida al hierro, que es parte de una amplia variedad de enzimas claves como catalasas, aconitasas, ribonucleótido reductasa, peroxidasas y citocromos, que explotan la flexibilidad de su química redox para ejecutar un elevado número de reacciones esenciales para la vida. El cuerpo humano ha evolucionado para conservar el hierro en diferentes formas, incluido su reciclaje después de la ruptura de los eritrocitos y la retención en ausencia de un mecanismo de excreción. El metabolismo del hierro está balanceado por dos sistemas regulatorios: uno sistémico basado en la hormona hepcidina y la proteína exportadora ferroportina, y el otro que controla el metabolismo celular través de las proteínas reguladoras de hierro (IRP) que se unen a los elementos de respuesta al hierro (IRE) de los ARNm regulados. Estos sistemas funcionan de modo coordinado lo que evita, tanto la deficiencia como el exceso del mineral(AU)

Human existence is indissolubly linked to iron, which is part of a wide variety of key enzymes such as catalase, aconitases, ribonucleotide reductase, peroxidases and cytochromes, exploiting the flexibility of its redox chemistry to run a large number of reactions essential for life. Human body has evolved to keep iron in different forms, including recycling after rupture of erythrocytes and the retention without excretion mechanism. Iron metabolism is balanced by two regulatory systems: one based on systemic hormone hepcidin protein export and ferroportin, and the other, which controls cell metabolism through the iron regulatory protein (IRP) binding to the mRNAs regulated iron regulatory elements (IRE). These systems work in a coordinated manner avoiding both deficiency and excess(AU)

Molecular cloning and antibacterial activity of hepcidin from Chinese rare minnow (Gobiocypris rarus)

Background Hepcidins, a kind of cysteine-rich antimicrobial peptides, play important roles in host immunological processes and iron regulation, which have been identified from several fish species. The rare minnow (Gobiocypris rarus), an endemic cyprinid fish in China, has been used extensively as model animal in laboratory. However, little is known about its hepcidin. Here, we report the cloning and characterization of a hepcidin gene from the liver of Chinese rare minnow. Results The full-length cDNA of rare minnow hepcidin is 662 bp, which contains an ORF of 273 bp encoding a prepropeptide of 90 amino acid residues. The predicted prepropeptide contains three domains: a signal peptide of 24 amino acids, a prodomain of 41 amino acids, and a mature peptide of 25 amino acids. Sequence alignment showed eight conserved cysteine residues in the mature peptide, which formed four disulfide bonds in spatial structure. The deduced structure of mature peptide showed a high degree of homology to the human hepcidin. Phylogenetic analysis showed that it had a close relationship with zebrafish hepcidin, and clustered in a clade with these from Cyprinidae. Synthetic peptide of rare minnow hepcidin could inhibit the growth of Gram positive bacterium Staphylococcus aureus and Gram negative bacteria Escherichia coli and Aeromonas hydrophila. Conclusion These results suggested that rare minnow hepcidin had typical structure of hepcidins and antibacterial activity. It could participate in innate immune response as an antibacterial agent and be used as antibiotic substance.

Prevalência de anemia ferropriva em obesos em preparo para cirurgia bariátrica / Iron deficiency anemia prevalence in obese in preparation for bariatric surgery

INTRODUÇÃO: Atualmente é crescente o número de realizações de cirurgias bariátricas, tendo sido comprovada como a ferramenta mais eficaz no controle e tratamento da obesidade mórbida. Dentre as complicações nutricionais após a cirurgia, podemos citar a deficiência de ferro e anemia ferropriva que podem ocorrer, especialmente, em cirurgias com disabsorção como o bypass em Y-de-Roux. Alguns pacientes obesos já apresentam essa deficiência mesmo antes de serem submetidos à restrição e disabsorção e devem ser tratados para que o quadro não seja agravado. OBJETIVO: Realizar uma revisão sistemática da literatura científica sobre a prevalência de anemia ferropriva em pacientes obesos candidatos ao bypass gástrico em Y-de-Roux. MÉTODOS: Foi realizado um levantamento bibliográfico de artigos científicos, no período de 2000 a 2015 publicados nas bases de dados em conformidade aos descritores em Ciências da Saúde. RESULTADOS: Foram selecionados 62 artigos, nas línguas inglesa, espanhola e portuguesa. Após serem aplicados os critérios de exclusão, restaram 34 artigos que foram utilizados para elaboração da revisão. Dos 34 (54,8%) artigos utilizados, 12 eram artigos originais, 22 de revisão de literatura. CONSIDERAÇÕES: Poucos estudos foram encontrados relatando a deficiência de ferro em indivíduos com obesidade em situação pré- -operatória. Mais pesquisas são necessárias para determinar os fatores que regulam o estado de ferro em populações obesas, como contribuição para identificação de tal deficiência antes do procedimento cirúrgico para, então, reduzir ou minimizar intercorrências no período pós-operatório

INTRODUCTION: The number of bariatric surgeries is currently increasing and this treatment is been the most effective tool in the control and treatment of morbid obesity. Iron deficiency and iron anemia are common nutritional complications after surgery, especially in malabsorptive surgeries such as bypass Roux-en-Y. Some obese patients have this nutritional deficiency before restriction and malabsorption and it should be treaten not to get worse. OBJECTIVE: To perform a review of scientific literature on the prevalence of iron deficiency and anemia in obese patients candidates to gastric bypass Roux-en-Y. METHODS: A literature review of periodics was conducted in the period from 2000 to 2015 published in the databases according to the descriptors in Health Sciences. RESULTS: From a total of 62 articles in English, Spanish and Portuguese, 34 articles (54.8%) attended all the inclusion criteria. Twelve studies were original and 22 , were review articles. CONSIDERATIONS: Few studies were found reporting iron deficiency in patients with preoperative situation in obesity. More research is needed to determine the factors that regulate the iron status in obese populations, as a contribution to identifying such deficiency before surgery to then reduce or minimize complications in the postoperative period.

Sox2 function as a negative regulator to control HAMP expression

BACKGROUND: Hepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores. Abnormal levels of HAMP expression alter plasma iron parameters and lead to iron metabolism disorders. Therefore,itis animportant goal to understand the mechanisms controlling HAMP gene expression. RESULTS: Overexpression of Sox2 decrease basal expression of HAMP or induced by IL-6 or BMP-2, whereas, knockdown of Sox2 can increase HAMP expression, furthermore, two potential Sox2-binding sites were identified within the human HAMP promoter. Indeed, luciferase experiments demonstrated that deletion of any Sox2-binding site impaired the negative regulation of Sox2 on HAMP promoter transcriptional activity in basal conditions. ChIP experiments showed that Sox2 could directly bind to these sites. Finally, we verified the role of Sox2 to negatively regulate HAMP expression in human primary hepatocytes. CONCLUSION: We found that Sox2 as a novel factor to bind with HAMP promoter to negatively regulate HAMP expression, which may be further implicated as a therapeutic option for the amelioration of HAMP-overexpression-related diseases, including iron deficiency anemia.

Integración de la hepcidina a las respuestas y adaptaciones a la hipoxia en el deporte / Integration of hepcidin in responses and adaptation to hypoxia in sport

Entre las distintas estrategias empleadas con objeto de mejorar el rendimiento deportivo se ha empleado tradicionalmente las concentraciones de entrenamiento en altura. En la actualidad dicha práctica se ha hecho más común, al posibilitarse la realización de exposiciones a estímulos de hipoxia intermitente, gracias a la utilización de distintas tecnologías como las cámaras hipobáricas. Algunos estudios han intentado comprobar el efecto de distintos protocolos de exposición a ambientes hipóxicos sobre el rendimiento deportivo y sobre las variables relacionadas con el sistema sanguíneo. Sin embargo, con frecuencia, no se tiene en cuenta que, como respuesta a la hipoxia, el cuerpo reacciona con una serie de respuestas y adaptaciones a nivel multisistémico. Además, el descubrimiento de la hepcidina ha hecho comprender mejor el conocimiento existente acerca del metabolismo del hierro. Dado que condiciones de hipoxia podrían alterar la síntesis de hepcidina, el objetivo del presente estudio de revisión bibliográfica ha sido doble: I) comprobar las distintas respuestas y adaptaciones a nivel multisistémico a condiciones de hipoxia; II) integrar la hepcidina como posible variable que interviene en las respuestas que tienen lugar en relación al metabolismo del hierro.

Among the various strategies used to improve athletic performance has traditionally been used concentrations altitude training. Today this practice has become more common, making it possible exposures to intermittent hypoxia stimuli, through the use of various technologies such as hypobaric chambers. Some studies have attempted to test the effect of different protocols of exposure to hypoxic environments on athletic performance and related variables on the blood system. However, often is not taken into account that, in response to hypoxia, the body has a number of responses and adaptations to multisystem level. Furthermore, the discovery of hepcidin has done to change the existing knowledge of iron metabolism. Since hypoxic conditions could alter the synthesis of hepcidin, the objective of this literature review study was twofold: i) to test the different responses and adaptations to multisystem level hypoxic conditions; ii) integrate hepcidin as a possible intervening variable in responses that occur in relation to iron metabolism.

Metabolismo do ferro na cardiomiopatia chagásica crônica: [Carta ao Editor] / Iron metabolism in chronic Chagas cardiomyopathy: [Letter to Editor]

É notória uma intensa resposta inflamatória em indivíduos infectados com adoença de Chagas (Trypanosoma cruzi), enfermidade crônica degenerativa na qual estão envolvidos eventos inflamatórios que atingem um dos principais órgãos-alvo, o coração, com demonstrados efeitos colaterais cardiometabólicos.1 De fato, segundo relatos de Pinto2 e confirmado em estudos, a deficiência de ferro potencializa o processo infeccioso, levando a acentuada piora no prognóstico dos pacientescom essa enfermidade.3 Análise feita em pacientes com insuficiência cardíaca revela alterações no metabolismo do ferro, sendo este fato intrínseco ao mecanismo patofisiológico da insuficiência cardíaca.4 O complexo questionamento paradoxal de um estudo de revisão Pinto2, chama a atenção e leva a hipóteses levantadas em outros estudos, em que a infecção pelo T. Cruzi ativa uma cascata imunológica. Nesse contexto, há um hormônio chamado hepcidina, que é estimulado por célulasespecíficas do sistema imunológico, tendo, portanto, participação nos mecanismos reguladores do metabolismo do ferro5. Diante disso, o paralelo entre o metabolismo do ferro descrito durante a resposta inflamatória perpassa pelo eixo hepcidina-IL-6 (citocina pró-inflamatória).

Inflamação induzida por Adjuvante de Freund: achados clínicos e efeitos sobre a expressão do RNAm da hepcidina em equinos / Freund's adjuvant-induced inflammation: clinical findings and its effect on hepcidin mRNA expression in horses

Hypoferremia observed during systemic inflammatory disorders is regulated by hepcidin. Hepcidin up-regulation is particularly important during acute inflammation, as it restricts the availability of iron, which is necessary for pathogenic microorganism growth before adaptive immunity occurs. The aim of this study was to evaluate the clinical findings and hepatic hepcidin mRNA expression in horses using a Freund's complete adjuvant (FCA) model of inflammation. The expression of hepcidin mRNA in the liver was determined in healthy horses following two intramuscular injections of FCA at 0 h and 12 h. Plasma iron and fibrinogen concentrations were measured at multiple time points between 0 h and 240 h post-FCA injection (PI). Hepcidin mRNA expression was determined by RT-qPCR using liver biopsy samples performed at 0 h (control), 6 h and 18 h PI. The mean plasma fibrinogen level was significantly different from the control values only between 120 and 216 h PI. The mean plasma iron level was significantly lower than the control between 16 and 72 h PI, reaching the lowest levels at 30 h PI (33 % of the initial value), and returned to the reference value from 96 h PI to the end of the experiment. Hepcidin mRNA expression increased at 6 h PI and remained high at 18 h PI. The iron plasma concentration was an earlier indicator of inflammatory processes in horses when compared with fibrinogen and might be useful for the early detection of inflammation in the horse. FCA administration caused the rapid onset of hypoferremia, and this effect was likely the result of up-regulated hepatic hepcidin gene expression. This study emphasizes the importance of hepcidin and iron metabolism during inflammation in horses.

A hipoferremia observada durante os processos inflamatórios sistêmicos é mediada pela hepcidina. O aumento da expressão da hepcidina é particularmente importante durante a inflamação aguda, por restringir a disponibilidade de ferro necessária para o crescimento de microrganismos patogênicos antes que a imunidade adaptativa ocorra. O objetivo deste estudo foi avaliar os achados clínicos e a expressão hepática do RNA mensageiro (RNAm) da hepcidina em cavalos após a indução da inflamação com Adjuvante completo de Freund (FCA). A expressão hepática do RNAm da hepcidina foi determinada em cavalos sadios após duas administrações intramusculares de FCA às 0 h (M0) e 12 h (M12). As concentrações plasmáticas de ferro e fibrinogênio foram mensuradas em múltiplos momentos entre 0 h e 240 h (M240) após a primeira administração de FCA (PI). A expressão do RNAm da hepcidina foi determinada por RT-qPCR usando amostras de biopsias hepáticas colhidas as 0 h (controle), 6 h (M6) e 18 h (M18) PI. A concentração plasmática média de fibrinogênio foi estatisticamente diferente do M0 entre 120 h e 216 h PI. A concentração plasmática média de ferro foi significantemente menor que o controle entre 16 h e 72 h PI, alcançou o nível mais baixo às 30 h PI (33% do valor inicial) e retornou aos valores de referência entre 96 h PI e até o final do experimento. A expressão do RNAm da hepcidina aumentou no M6 e permaneceu alta no M18. A concentração plasmática de ferro foi um indicador precoce da inflamação quando comparada com o fibrinogênio e pode ser útil na detecção precoce da inflamação em cavalos. A administração do FCA causou um rápido início da hipoferremia, e isto foi resultante do aumento da expressão hepática da hepcidina. Estes resultados enfatizam a importância da hepcidina e do metabolismo do ferro durante a inflamação em cavalos.

Anemia de las enfermedades crónicas asociada a obesidad: papel de la hepcidina como mediador central / Hepcidin as a central mediator of anemia of chronic diseases associated with obesity

Recent evidence suggests that obesity-related inflammation may play a central role in hepcidin regulation. Hepcidin is a key regulator ofiron homeostasis and has now been suggested as a central mediator ofiron metabolism disorders involved in the pathogenesis of anemia of chronic disease. In this review, we focus on subclinical inflammation in obesity and its effect on hepcidin levels, as the most plausible explanation for the relationship between anemia of chronic disease and obesity.

Hiperpigmentación cutánea y homeostasis del hierro: rol de la hepcidina / Cutaneous hyperpigmentation and homeostasis of iron: role of the hepcidin

La hiperpigmentación cutánea por melanina en zonas expuestas al sol puede estar asociada a un desequilibrio en la homeostasis del hierro. La hepcidina es un péptido responsable de la regulación negativa de la absorción del hierro en el intestino delgado y de su liberación por los macrófagos. Posee capacidad antimicrobiana. Es sintetizada en el hígado, secretada al torrente circulatorio y excretada por la orina. La sobreexpresión causa anemia y su déficit, sobrecarga de hierro (acumulación en diferentes órganos y hemocromatosis hereditaria). Los antagonistas de la hepcidina podrían utilizarse en el tratamiento de la anemia resistente a eritropoyetina, asociada a procesos crónicos. Por su parte, los agonistas o sustancias que estimulen la producción de hepcidina, podrían constituir un tratamiento en enfermedades con sobrecarga de hierro (siderosis) y por consiguiente, corregir la hiperpigmentación asociada.

The cutaneous hyperpigmentation by melanin in zones of the skin exposed to the sun can be associated to an imbalance in the homeostasis of the iron. The hepcidin is a peptide responsible for the negative regulation of the absorption of the iron in the small intestine and of its liberation by the macrophages. It has, in addition, antimicrobial capacity. It is synthesized in the liver, secreted to the circulatory torrent and excreted by the urine. Its overexpression causes anemia and its deficit iron overload (accumulation in different organs and hereditary hemochromatosis), The antagonists of the hepcidin, could be used in the treatment of anemia resistant to erythropoyetin associated to chronic processes. On the other hand, the agonists or substances that stimulate the hepcidin production, could constitute a treatment in diseases with overload of iron (siderosis) and therefore, to correct the associate.hyperpigmentation.