Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment

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"documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2021;156:235-42" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "Revisión" "titulo" => "Anemia de las enfermedades crónicas: fisiopatología, diagnóstico y tratamiento" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "235" "paginaFinal" => "242" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2061 "Ancho" => 2167 "Tamanyo" => 391989 ] ] "descripcion" => array:1 [ "es" => "Síntesis de hepcidina. La IL-6 activa la vía de señalización JAK-STAT3 (janus kinasa-signal transducer and activator of transcription); la IL1 y la activina B (Act-B) aumentan la transcripción de HAMP a través de la señalización BMP/SMAD. El hierro plasmático, unido a la transferrina (Tf-Fe2) (holotransferrina), es un sensor de los hepatocitos para regular la transcripción de hepcidina porque activa la ruta BMP-HJV-SMAD (bone morphogenetic protein-hemojuvelina-small mothers against decapentaplegic). En las situaciones de hiposideremia, la holotransferrina se une al receptor de la transferrina1 (TfR1), no se activa la vía BMP-SMAD y no se sintetiza hepcidina, lo que facilita la llegada de hierro al plasma. Cuando la hiposideremia se ha subsanado, la holotransferrina se desplaza hacia el receptor TfR2 y forma un complejo con HFE (proteína de la hemocromatosis humana), que activa la vía BMP en presencia de sus receptores (BMPR1 y BMPR2), HJV y neoginina (NEO), promoviendo la síntesis de hepcidina. La eritroferrona (ERFE), GDF15 (growth differentiation factor) y TWSG1 (twisted gastrulation BMP signaling modulator) inhiben la síntesis de hepcidina porque bloquean la vía SMAD. Otro inhibidor de la hepcidina es la matriptasa-2 (MT-2), que bloquea la HJV impidiendo la activación del complejo BMP. La hipoxia tisular y la eritropoyetina también inhiben la síntesis de hepcidina." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ricardo de las Cuevas Allende, Lucía Díaz de Entresotos, Susana Conde Díez" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Ricardo" "apellidos" => "de las Cuevas Allende" ] 1 => array:2 [ "nombre" => "Lucía" "apellidos" => "Díaz de Entresotos" ] 2 => array:2 [ "nombre" => "Susana" "apellidos" => "Conde Díez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020621000528" "doi" => "10.1016/j.medcle.2020.07.022" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621000528?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320306539?idApp=UINPBA00004N" "url" => "/00257753/0000015600000005/v1_202102240836/S0025775320306539/v1_202102240836/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020621000498" "issn" => "23870206" "doi" => "10.1016/j.medcle.2020.04.030" "estado" => "S300" "fechaPublicacion" => "2021-03-12" "aid" => "5203" "copyright" => "Elsevier España, S.L.U." 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IL-6 activates the JAK-STAT3 (janus kinase-signal transducer and activator of transcription) signalling pathway; IL1 and activin B (Act-B) increase HAMP transcription through BMP/SMAD signalling. Plasma iron, bound to transferrin (Tf-Fe2) (holo-transferrin), is a sensor of hepatocytes to regulate hepcidin transcription because it activates the BMP-HJV-SMAD (bone morphogenetic protein-hemojuvelin-small mothers against decapentaplegic) pathway. In hyposideraemia, holo-transferrin binds to the transferrin receptor-1 (TfR1), the BMP-SMAD pathway is not activated, and the hepcidin is not synthesised, which aids the entry of iron into the plasma. When the hyposideraemia has been resolved, the holo-transferrin binds to the TfR2 receptor and forms a complex with HFE (hereditary hemochromatosis protein), which activates the BMP pathway in the presence of its receptors (BMPR1 and BMPR2), of HJV and neogenin (NEO), promoting the hepcidin synthesis. Erythroferrone (Erfe), GDF15 (growth differentiation factor) and TWSG1 (twisted gastrulation BMP signalling modulator) inhibit hepcidin synthesis by blocking the SMAD pathway. Another inhibitor of hepcidin is matriptase-2 (MT-2), which blocks HJV by preventing the activation of the BMP complex. Tissue hypoxia and erythropoietin also inhibit hepcidin synthesis." ] ] ] "textoCompleto" => "IntroductionAnaemia of chronic disease (ACD) or anaemia of inflammation occurs in the context of an inflammatory process, in which there is an activation of the immune system with the release of cytokines and elevation of hepcidin, that decreases plasma iron with suppression of erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The anaemia is mild/moderate (hemoglobin between 8 and 12 g/dL) and is usually normocytic, normochromic, and hypoproliferative.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> It is the second most prevalent anaemia after iron deficiency anaemia, and it is the most common in the elderly. Up to a third of elderly people who present anaemia have ACD.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Also, it is the most frequent anaemia among hospitalised patients or those with chronic diseases. It is estimated that up to 40% of anaemias worldwide are ACD, or combinations with other types of anaemia but where the contribution of ACD is very important.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>All the processes that include chronic inflammatory phenomena are potentially generators of an ACD, such as rheumatoid arthritis, systemic lupus erythematosus, vasculitis, sarcoidosis, inflammatory bowel disease, neoplastic diseases, chronic kidney disease (CKD), acute/chronic bacterial infections, fungal, viral and parasitic diseases, as well as chronic rejection of organ transplants, respiratory failure, heart failure, obesity and other chronic processes.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Elevated hepcidin levels in infections represent a host defense mechanism against infections because it limits the availability of iron to the microorganisms.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a>Regulation of iron metabolismHepcidin, the main regulator of iron metabolism, is synthesised in the liver and its function is to control the entry of iron into the plasma. Iron is supplied with food in the ferric form and, after being reduced to the ferrous form, it is absorbed by the duodenal enterocytes and subsequently released into the plasma.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The ferroportin is responsible for the release of iron from the enterocytes, macrophages and hepatocytes into the plasma.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Hepcidin binds to ferroportin and blocks its function, preventing the release of iron into the plasma. This causes hyposideraemia and the accumulation of iron, in the form of ferritin, in enterocytes, macrophages and hepatocytes.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> Hepcidin plays a fundamental role in all iron disorders, both in excess and in deficit. An excess of hepcidin contributes to the development of anaemia due to iron deficiency or its restricted use in the ACD, while its deficiency causes iron overload.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In chronic inflammatory diseases high hepcidin levels produce functional iron deficiency anaemia, because there is no reserve excess iron available for erythropoiesis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,5</a> Hepcidin is an acute phase reactant that responds to a wide variety of inflammatory mediators and signals, which stimulate its transcription through different signalling pathways.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Regulation of the hepcidin expressionHepcidin transcription, encoded by the HAMP gene (hepcidin antimicrobial peptide), is carried out by different activating and inhibiting signals acting in a synchronised manner<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The former include the inflammatory processes and the plasma iron level.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> In inflammatory diseases, the increase in hepcidin is mediated by cytokines produced by the activation of the immune system, especially IL-6 and IL-22, which activate the JAK-STAT3 (janus kinase-signal transducer and activator of transcription) signalling pathway.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> IL1 and activin B (Act-B) also intervene, by increasing the HAMP transcription via BMP/SMAD (bone morphogenetic protein-small mothers against decapentaplegic) signaling.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Both pathways are closely connected,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> so much so that efficient induction of hepcidin by the inflammatory pathway requires a threshold of BMP6/SMAD signaling.<a class="elsevierStyleCrossRef" href="#bib0035">7</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Hepcidin regulation by plasma iron is carried out through the BMP/SMAD pathway. The mechanism involves the secretion of BMP6 by the liver’s sinusoidal endothelial cells, which bind to the BMP type I (ALK2, ALK3, ALK6) and type II (ActRIIA, BMPRII) receptors in the hepatocytes, in order to activate the SMAD cascade signaling.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> Iron-bound transferrin (Tf-Fe2) (holo-transferrin) is a hepatocyte sensor for the control of the hepcidin transcription. In hyposideraemia, the Tf-Fe2 complex binds to the transferrin receptor-1 (TfR1), the BMP-SMAD pathway is not activated, and the hepcidin is not synthesised, which aids the entry of iron into the plasma. When the hyposideraemia has been resolved, the holo-transferrin binds to the TfR2 receptor and forms a complex with HFE (hereditary hemochromatosis protein),<a class="elsevierStyleCrossRef" href="#bib0040">8</a> which activates the BMP pathway in the presence of its receptors (BMPR1 and BMPR2), of HJV (hemojuvelin) and neogenin, promoting the SMAD1/5/8 phosphorylation, the transcription of HAMP and the hepcidin synthesis<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,8</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).The inhibitory signals of hepcidin come from the erythropoiesis and are related to different proteins, produced in the erythroblasts, which block its production when iron is needed for the synthesis of haemoglobin.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> The most important protein is erythroferrone (Erfe), but there are others such as growth differentiation factor 15 (GDF15) and twisted gastrulation BMP signaling modulator (TWSG1) which inhibit the SMAD pathway<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Matriptase-2 (MT-2), encoded by the TMPRSS6 gene, is another hepcidin inhibitor because it blocks the HJV and prevents the activation of the BMP complex.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Other inhibitory signs of hepcidin synthesis are tissue hypoxia and erythropoietin (EPO), which generate erythroblastic hyperplasia with the consequent increase in Erfe, GDF15 and TWSG1 levels.<a class="elsevierStyleCrossRefs" href="#bib0050">10,12</a>PathophysiologyThe cause of anaemia in chronic diseases is multifactorial and the origin is in the activation of the immune system by autoantigens, microbial molecules or tumour antigens, which gives rise to the release of multiple inflammatory cytokines and free radicals that favour the increase of the hepcidin.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a> The cytokines involved are IL-6, IL-1b, IL-22, lipopolysaccharides (LPS), tumor necrosis factor alpha (TNF〈), interferon gamma (INFγ) and other.<a class="elsevierStyleCrossRefs" href="#bib0005">1,13</a> The consequences of these disorders are changes in iron homeostasis, especially hyposideraemia, erythropoiesis suppression, shortened erythroid survival, and decreased EPO production<a class="elsevierStyleCrossRefs" href="#bib0005">1,4</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Alteration of iron homeostasisHepcidin increase causes ferroportin degradation resulting, on the one hand, in hyposideraemia due to a decrease in iron transferred to plasma, and on the other, in the accumulation of iron in the form of ferritin in enterocytes, macrophages and hepatocytes<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Hyposideraemia is one of the most important factors in ACD, as functional iron deficiency anaemia occurs because iron, although it is abundant in the storage organs, is not available for effective erythropoiesis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Erythropoiesis suppressionThe second pathogenic factor in ACD is erythropoiesis suppression, directly related to EPO. In most patients with ACD, the EPO levels are lower than expected for the degree of anaemia they usually present. This may be the result of two causes; on the one hand, hyposideraemia gives rise to an iron deficiency in the erythroblasts, which reduces the EPO receptor gene (EPOR) expression via a blunted expression of an EpoR control regulator known as scribble (SCB)<a class="elsevierStyleCrossRefs" href="#bib0015">3,14</a> and, also, due to the inhibitory effect of the cytokines (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). On the other hand, lower levels of EPO may be related to an inhibitory effect of IL-1 and TNF-α at the renal level, by the mediated GATA-2 transcription gene, since EPO-mediated signalling is reduced and is inversely linked to the circulating levels of cytokines<a class="elsevierStyleCrossRefs" href="#bib0015">3,13</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Hypoxia and the reduced availability of EPO in ACD negatively impact the hepcidin blockers, such as Erfe, GDF15 and TWSG1, which under physiological conditions slow down the hepcidin synthesis because they inhibit the SMAD pathway<a class="elsevierStyleCrossRefs" href="#bib0045">9,13,15</a> (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 3</a>).Erythrophagocytosis and a shortened erythrocyte half-lifeReduction in the erythrocyte half-life due to erythrophagocytosis is another common pathogenic factor in the inflammatory setting.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> This phenomenon is produced by activation of macrophages by cytokines<a class="elsevierStyleCrossRef" href="#bib0015">3</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Shortened red blood cell survival is a minor pathogenic factor in ACD, but it plays a greater role in severe infections and in critical situations accompanied by a massive release of cytokines that promote erythrophagocytosis and hemolysis.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> In these situations, anaemia occurs in the first days of the event, before there is a decrease in erythropoiesis, so that anaemia is explained by the shortened erythrocyte half-life and by hemodilution, which is common in these clinical situations.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>DiagnosisIn addition to the specific symptoms of the underlying disease and the associated systemic inflammatory process, patients, who are elderly, in general, present an increase in acute phase reactants, such as a sedimentation rate, C-reactive protein and others. These, together with anaemia, give rise to a whole procession of clinical data, more or less intense, depending on the hemoglobin levels. Some critical patients with acute inflammatory processes may present a clinical symptoms similar to that of «cytokine release syndrome», with massive rise in cytokines, especially IL-6. Symptoms of anaemia are the consequence of hypoxia, but effective iron deficiency displays additional symptoms because it also impairs mitochondrial function, cellular metabolism, enzyme activities, and neurotransmitter synthesis.<a class="elsevierStyleCrossRefs" href="#bib0005">1,16</a> Patients with ACD have a «functional iron deficiency» and the anaemia they present is characteristically mild to moderate normocytic/normochromic.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>The diagnosis of inflammatory anaemia is mainly one of exclusion. It is best diagnosed by documenting an anaemia of low production in the context of an inflammatory disease. Patients with ACD often present hyposideraemia, low transferrin saturation, reticulocytopenia, and important findings are increased hepcidin and serum ferritin levels, which translate into elevated iron stores in the MPS macrophages.<a class="elsevierStyleCrossRefs" href="#bib0015">3,16</a> The differential diagnosis should be made with the true iron deficiency anaemia, in which there is an absolute deficit of iron, with lab results that show microcytic and hypochromic anaemia with hyposidaeremia, increased transferrin, and reticulocytopenia, but with low levels of ferritin and hepcidin, which would rule out ACD.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> In addition, the soluble transferrin receptor is elevated in iron deficiency anaemia and normal in ACD. Sometimes, the ACD can coexist with a true iron deficiency, in which case the location of blood loss should be investigated. However, in these cases the ferritin is not usually elevated, it can be normal or a little low<a class="elsevierStyleCrossRef" href="#bib0080">16</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). An evaluation of «inadequately low» ferritin, in the context of an iron-deficient ACD, can be difficult to define in clinical practice, but considering this aspect is important because, in these cases, intravenous iron treatment can be effective.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>TreatmentThe ACD treatment objective should be to cure the underlying disease, and if this is not possible, to achieve the best possible control of the symptoms. Anaemia is usually a consequence of the disease and it often contributes to greater clinical manifestations depending on its severity, so correcting the anaemia would improve the patient’s quality of life.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In general, the anaemia is moderate which means that blood transfusions are unnecessary. However, if the anaemia is severe, they will need to be used as an emergency treatment.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Intravenous iron treatment may be justified as a temporary measure, in some cases of ACD, but in the long run it can be harmful as it causes the patient to have an excess of iron.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> EPO may be beneficial in some patients, as an alternative to chronic red blood cell transfusion, but it is not approved for ACD and its use is based on the fact that it sometimes improves anaemia, and the similarity that exists between ACD and CKD anaemia, as it is approved for the latter.<a class="elsevierStyleCrossRefs" href="#bib0015">3,17</a>As hyposideraemia is the cause of anaemia, the therapeutic goal should be to increase plasma iron levels.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> New treatment strategies for its increase focus on reversing the overexpression of hepcidin, in order to favour the mobilisation of iron sequestered in MPS cells.<a class="elsevierStyleCrossRefs" href="#bib0090">18–20</a> The strategies being investigated are aimed at enhancing erythropoiesis and increasing endogenous erythropoietin levels on the one hand, and at preventing the action of hepcidin, either by blocking its synthesis, neutralizing circulating hepcidin or preventing the action of hepcidin on ferroportin on the other<a class="elsevierStyleCrossRefs" href="#bib0005">1,3,18–20</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Much research is being conducted involving the various agents that could modify the hepcidin-ferroportin axis or the various regulators involved.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> Most of these agents are effective in animal models and several are undergoing human testing. In ACD, the target is IL6 because its neutralisation reduces the hepcidin levels and corrects the anaemia, as has been shown in the treatment of inflammatory diseases and in Castleman’s disease,<a class="elsevierStyleCrossRefs" href="#bib0105">21,22</a> but these agents must be well tolerated as well as being effective.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Erythropoiesis potentiationThe increase in erythropoiesis leads to erythropoiesis hyperplasia and an elevation of erythropherrone that blocks the SMAD pathway and slows down the synthesis of hepcidin. Therefore, any agent that improves erythropoiesis could be effective in the control of ACD. High doses of EPO may be able to overcome the resistance to EPO observed in these diseases, by partial suppression of hepcidin.<a class="elsevierStyleCrossRefs" href="#bib0015">3,17</a> It is known that the kidneys of CKD patients retain the ability to produce erythropoietin and that in hypoxic situations the prolyl hydroxylase enzyme activity decreases, physiologically leading to an increase in the transcriptional activity of the hypoxia inducible factor (HIF), which induces the endogenous EPO expression, corrects functional iron deficiency, and activates erythropoiesis.<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> Pharmacological prolyl hydroxylase inhibitors (PHI) mimic the natural hypoxic response, thereby increasing HIF. There are several PHI agents that, by increasing endogenous EPO, improve erythropoiesis and reduce hepcidin levels in patients with anaemia and chronic inflammatory processes. Effective agents already in phase II/III trials are: vadadustat (AKB-6548), molidustat (BAY85-3934), daprodustat (GSK1278863) and roxadustat (FG-4592).<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a> In two phase III studies in patients with CKD and anaemia, an oral PHI (roxadustat) was compared with erythropoietin-α; in one of the studies, the patients were not on hemodialysis and in the other they were already on dialysis.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> The results were that the increase in hemoglobin in the roxadustat group was greater than that of the placebo in those not on dialysis<a class="elsevierStyleCrossRef" href="#bib0130">26</a> and it was not inferior to erythropoietin-α in hemodialysis patients.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Therefore, stabilisation of HIF through inhibition of the prolyl-hydroxylase enzymes family is a novel approach and may be an effective therapeutic target in the treatment of CKD anaemia, since the increase in EPO is physiological thereby avoiding higher doses of conventional EPO and the resulting cardiovascular side effects.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> However, prolyl hydroxylase inhibitors correct the CKD anaemia through multiple biological pathways, such as increasing erythropoietin levels, stimulating erythropoiesis, decreasing erythropherrone-mediated hepcidin levels, and the correcting hyposideraemia, and due to their angiogenic action they are not exempt from side effects. So monitoring the consequences of their long-term use will be essential.<a class="elsevierStyleCrossRefs" href="#bib0120">24,28</a>Hepcidin antagonistsHepcidin is the main cause of anaemia in chronic diseases because it generates hyposideraemia and retains iron in the MPS cells, so its pharmacological inhibition would facilitate iron mobilisation, favouring erythropoiesis and the correction of anaemia.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a> The hepcidin antagonists under study are aimed at blocking its synthesis, at neutralising circulating hepcidin and, also, at preventing the action of hepcidin on the ferroportin.<a class="elsevierStyleCrossRefs" href="#bib0090">18–20</a> The interest in these studies is very great, as evidenced by the fact that in October 2019, in ClinicalTrials.gov, there were 221 registered clinical trials on hepcidin, 67 of which were investigating hepcidin in chronic diseases or cancer.Inhibition of hepcidin productionThere are two main pathways that control hepcidin synthesis. One is related to the plasma iron level, through the BMP6-HJV-SMAD pathway, and the other is related to inflammatory processes through the IL6-JAK-STAT3 pathway. The latter has more prominence in the ACD<a class="elsevierStyleCrossRef" href="#bib0020">4</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The in vitro studies have revealed the existence of a cross connection between the two pathways, since treatments that block the BMP pathway also inhibit the expression of hepcidin through the IL-6-STAT3 inflammatory signalling pathway and, also, efficient induction of hepcidin by the inflammatory pathway requires a threshold of BMP6/SMAD signaling.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Suppression of the inflammatory pathwayHepcidin is activated by IL-6 through the IL-6 receptor (IL-6R) and JAK2-STAT3 signalling. So, blocking IL6 with siltuximab,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> the IL6 receptor with tocilizumab<a class="elsevierStyleCrossRef" href="#bib0145">29</a> and JAK1/2 with momelotinib<a class="elsevierStyleCrossRefs" href="#bib0150">30,31</a> prevent STAT3 phosphorylation, decrease hepcidin levels, normalise sideremia and improve anaemia in monkeys with arthritis, in patients with Castleman’s disease and in patients with neoplasms<a class="elsevierStyleCrossRefs" href="#bib0110">22,29,32,33</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Similarly, in patients with rheumatoid arthritis, tocilizumab reduced hepcidin and improved anaemia.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> The same results were obtained in patients with rheumatoid arthritis treated with anti-TNF antibodiesα (golimumab or infliximab), possibly as an indirect result of concomitant suppression of IL-6<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The main drawback of anti-cytokine therapies is that they generate immunosuppression and an increased risk of infections.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Similar effects have been achieved in cell models and in mice with chemical inhibitors of the IL-6/STAT3 signalling pathway, such as AG490<a class="elsevierStyleCrossRef" href="#bib0185">37</a> and PpYLKTK, which prevent STAT3 phosphorylation.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Both compounds decrease IL6-dependent hepcidin expression in humans.<a class="elsevierStyleCrossRefs" href="#bib0185">37,38</a> However, the development of these agents as hepcidin inhibitors is hampered either because of a lack of specificity, as happens with all STAT3 inhibitors, or because of poor pharmacokinetics<a class="elsevierStyleCrossRefs" href="#bib0150">30,37,38</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Other hepcidin inhibitors that improve anaemia of chronic diseases, include vitamin D, testosterone, 17-estradiol, and statins which prevent SMAD phosphorylation<a class="elsevierStyleCrossRefs" href="#bib0195">39–42</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). In addition, several orally active indazole inhibitors, DS28120313 and DS79182026, have been shown to antagonise the induction of hepcidin in mice injected with IL-6<a class="elsevierStyleCrossRefs" href="#bib0215">43,44</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Hepcidin also inhibits SPRC (S-propargyl-cysteine), an analogue of S-allyl-cysteine, which increases endogenous production of H2S and hydrogen sulfide and blocks the IL-6/JAK2/STAT3 pathway, reducing levels of hepcidin and improving the saturation of tranferrin in vivo, in models of acute and chronic inflammatory anaemia.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> Also, some plant extracts, such as curcumin, inhibit STAT3 signalling, and consequently, hepcidin levels decrease in humans. This supports the idea that turmeric could be useful in the treatment of anaemia in inflammatory processes<a class="elsevierStyleCrossRef" href="#bib0230">46</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Another medicinal plant Caulis spatholobi or jixueteng, has a powerful inhibitory effect on the HAMP expression through the suppression of SMAD 1/5/8 phosphorylation<a class="elsevierStyleCrossRef" href="#bib0235">47</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Inhibitors of the BMP6/HJV pathwayThe BMP-HJV-SMAD pathway is the other pathway that controls hepcidin synthesis, so its inhibition would decrease HAMP expression and plasma hepcidin levels.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> HJV has been targeted by several monoclonal antibodies (mAb) (ABT-207, h5F9-AM8 and h5F9-23), which prevent the binding of BMP with its receptors and block the SMAD pathway, suppress hepcidin and correct anaemia in rats with chronic inflammatory processes<a class="elsevierStyleCrossRefs" href="#bib0240">48,49</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Another mAb that blocks the binding of BMP6 with its receptor is LY3113593. It has been tested in CKD patients, achieving a reduction in hepcidin levels, an increase in hemoglobin and a reduction in ferritin, compared to placebo.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Likewise, LDN-193189, a dorsomorphine derivative and an inhibitor of BMPR1 in rats and human hepatoma cells has been shown to prevent hepcidin synthesis.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> The same effect is achieved with a fusion protein that binds soluble HJV (sHJV) and the Fc fragment of the immunoglobulins (sHJV-Fc), which blocks the binding of BMP with BMPR and prevents the SMAD phosphorylation.<a class="elsevierStyleCrossRefs" href="#bib0090">18,52</a> Another way to inhibit the BMP pathway is with antisense oligonucleitides. They block hepcidin synthesis regulator genes and RNA interference and are tools for mRNA (siRNA) silencing of the genes that encode hepcidin, TfR2, and HJV<a class="elsevierStyleCrossRefs" href="#bib0255">51,53</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Its administration in a mouse model of chronic inflammatory anaemia decreased hepcidin concentrations and corrected anaemia.<a class="elsevierStyleCrossRefs" href="#bib0035">7,53</a> These agents are effective, but they are not without side effects and are therefore subject to further research.Heparin binds with high affinity to BMP6 and blocks hepcidin synthesis.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> In mice and cell lines, it inhibits the phosphorylation of SMAD1/5/8 proteins, caused by the BMPs, and thus decreases the hepcidin expression and increases serum iron. This behaviour is similar to that which occurs in patients treated with heparin to prevent deep vein thrombosis.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> Its anticoagulant activity limits therapeutic use as a hepcidin inhibitor, but modified heparin analogues have been designed that lack anticoagulant activity, but retain the suppressive property of hepcidin<a class="elsevierStyleCrossRef" href="#bib0270">54</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Recently, erythroferrone has been shown to be a potent competitive inhibitor of BMP6.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Therefore, its use to treat anaemia of inflammatory processes that occur with increased hepcidin has been put forward. Any agent that mimics the activity of Erfe would be effective in reducing hepcidin levels, promoting increased serum iron and erythropoiesis.<a class="elsevierStyleCrossRefs" href="#bib0045">9,28</a>Neutralisation of circulating hepcidinDirect inhibitors of hepcidin such as mAbs, anticalins and L-RNA aptamers (called spiegelmers, German for «mirror»), are effective because they increase the circulating iron, promote erythropoiesis and correct anaemia; these effects are potentiated with EPO in mouse models and in monkeys with ACD.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> A human anti-hepcidin antibody, 12B9m, has been tested in transgenic mice with inflammatory anaemia caused by Brucella abortus and in monkeys. Neutralisation of hepcidin by mAb increased erythropoiesis and haemoglobin levels<a class="elsevierStyleCrossRef" href="#bib0275">55</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Another antihepcidin humanised mAb, LY2787106, improves anaemia in cancer patients by favouring iron mobilisation from the deposits.<a class="elsevierStyleCrossRef" href="#bib0280">56</a>Anticalins are therapeutic proteins that bind to ligands developed from lipocalins and they can recognise and bind tightly to a wide range of medically relevant targets.<a class="elsevierStyleCrossRef" href="#bib0285">57</a> In a phase I study and in healthy volunteers, the pegylated anticalin PRS-080 neutralised hepcidin and increased serum iron,<a class="elsevierStyleCrossRef" href="#bib0290">58</a> which is why a phase II study has been initiated in anaemic patients with CKD<a class="elsevierStyleCrossRef" href="#bib0285">57</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Aptamers (spiegelmers) are designed L-oligoribonucleotides, with a three-dimensional mirror-image form of the target, to which they bind with high affinity. They are stable in the circulation and immunologically passive because their structure contains L-ribose, instead of D-ribose, which gives them a high resistance to nuclease degradation.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Lexaptepid (NOX-H94) is an antihepcidin aptamer that inhibits human hepcidin and increases plasma iron and transferrin saturation in human volunteers injected with LPS and in patients with neoplasms<a class="elsevierStyleCrossRef" href="#bib0295">59</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Blocking the hepcidin-ferroportin interactionHepcidin to ferroportin binding occurs in an extracellular region of the ferroportin that contains Cys326 - the sulfhydryl residue, surrounded by hydrophobic residues.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> Some treatments are aimed at blocking this interaction to prevent the action of hepcidin on ferroportin and facilitate the release of iron into the circulation. An example of these agents is fursultiamine, a thiamine derivative approved by the FDA (Food and Drug Administration), which blocks the C326 thiol residue of ferroportin, preventing the hepcidin action and aiding the increase in serum iron<a class="elsevierStyleCrossRef" href="#bib0300">60</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Another humanised mAb that blocks the binding of hepcidin to ferroportin is LY2928057; in CKD-patients it increases plasma iron, promotes erythropoiesis, corrects anaemia and reduces ferritin levels, compared with placebo.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>ConclusionsThe anaemia of chronic inflammatory processes is common in everyday clinical practice. However, despite the fact that it deteriorates the quality of life of the patient and can negatively affect survival, it is often neglected and not fully assessed by doctors because it is associated with other, usually serious, diseases upon which all therapeutic objectives are focused. In recent years, we have learned about the complex regulation of the iron metabolism, which has allowed us to explore new therapeutic options to correct anaemia. The ultimate goal is to control hepcidin levels, which are ultimately responsible for anaemia, in order to release the iron trapped in the MPS cells, facilitate erythropoiesis, and raise haemoglobin levels. Many therapeutic strategies have emerged thanks to furthering the pathophysiological knowledge on anaemia, derived from and validated in preclinical/clinical studies and in randomised clinical trials. We now have the first effective agents available to control anaemia associated with chronic inflammatory processes.Contribution of the authorsRCA, LDE and SCD have equally contributed to the bibliographic review, the writing of the paper and the discussion of its content.Ethical responsibilitiesIt is a review paper in which there are no patients or animals.FundingThis work has not received any type of funding.Conflict of interestThe authors declare that they have no conflict of interest.ThanksWe are grateful to Eulogio Conde García, retired haematologist and professor of haematology, for the critical review of the paper, as well as his contributions and suggestions." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres1479762" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1347693" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1479761" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1347694" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Regulation of iron metabolism" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Regulation of the hepcidin expression" ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Pathophysiology" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Alteration of iron homeostasis" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Erythropoiesis suppression" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Erythrophagocytosis and a shortened erythrocyte half-life" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Diagnosis" ] 8 => array:3 [ "identificador" => "sec0045" "titulo" => "Treatment" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Erythropoiesis potentiation" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Hepcidin antagonists" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Inhibition of hepcidin production" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Suppression of the inflammatory pathway" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Inhibitors of the BMP6/HJV pathway" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Neutralisation of circulating hepcidin" ] 6 => array:2 [ "identificador" => "sec0080" "titulo" => "Blocking the hepcidin-ferroportin interaction" ] ] ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Contribution of the authors" ] 11 => array:2 [ "identificador" => "sec0095" "titulo" => "Ethical responsibilities" ] 12 => array:2 [ "identificador" => "sec0100" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 14 => array:2 [ "identificador" => "sec0110" "titulo" => "Thanks" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-05-14" "fechaAceptado" => "2020-07-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1347693" "palabras" => array:5 [ 0 => "Iron metabolism" 1 => "Interleukin-6" 2 => "Hepcidin" 3 => "Ferroportin" 4 => "Hepcidin antagonists" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1347694" "palabras" => array:5 [ 0 => "Metabolismo hierro" 1 => "Interleucina-6" 2 => "Hepcidina" 3 => "Ferroportina" 4 => "Antagonistas hepcidina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Anaemia of chronic disease (ACD) is generated by the activation of the immune system by autoantigens, microbial molecules or tumour antigens resulting in the release of cytokines that cause an elevation of serum hepcidin, hypoferraemia, suppression of erythropoiesis, decrease in erythropoietin (EPO) and shortening of the half-life of red blood cells. Anaemia is usually normocytic and normochromic, which is the most prevalent after iron deficiency anaemia, and it is the most frequent in the elderly and in hospitalized patients. If the anaemia is severe, the patient’s quality of life deteriorates, and it can have a negative impact on survival. Treatment is aimed at controlling the underlying disease and correcting anaemia. Sometimes intravenous iron and EPO have been used, but the therapeutic future is directed against hepcidin, which is the final target of anaemia." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La anemia de las enfermedades crónicas (AEC) se genera por la activación del sistema inmune por autoantígenos, moléculas microbianas o antígenos tumorales, que dan lugar a la liberación de citocinas que originan una elevación de la hepcidina sérica, hiposideremia, supresión de la eritropoyesis, disminución de la eritropoyetina (EPO) y acortamiento de la vida media de los hematíes. La anemia suele ser normocítica/normocrómica, es la más prevalente, después de la anemia ferropénica, y es la más frecuente en los ancianos y en los pacientes hospitalizados. Si la anemia es grave, la calidad de vida del paciente se deteriora y puede tener un impacto negativo en la supervivencia. El objetivo del tratamiento va dirigido a controlar la enfermedad de base y a corregir la anemia. En ocasiones se ha utilizado hierro endovenoso y EPO, pero el futuro terapéutico va dirigido contra la hepcidina, que es la diana responsable final de la anemia." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: de las Cuevas Allende R, Díaz de Entresotos L, Conde Díez S. Anemia de las enfermedades crónicas: fisiopatología, diagnóstico y tratamiento. Med Clin (Barc). 2021;156:235–242." ] 1 => array:3 [ "etiqueta" => "◊" "nota" => "Both authors have contributed equally as first authors." "identificador" => "fn0005" ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2086 "Ancho" => 2216 "Tamanyo" => 316839 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Synthesis of hepcidin. IL-6 activates the JAK-STAT3 (janus kinase-signal transducer and activator of transcription) signalling pathway; IL1 and activin B (Act-B) increase HAMP transcription through BMP/SMAD signalling. Plasma iron, bound to transferrin (Tf-Fe2) (holo-transferrin), is a sensor of hepatocytes to regulate hepcidin transcription because it activates the BMP-HJV-SMAD (bone morphogenetic protein-hemojuvelin-small mothers against decapentaplegic) pathway. In hyposideraemia, holo-transferrin binds to the transferrin receptor-1 (TfR1), the BMP-SMAD pathway is not activated, and the hepcidin is not synthesised, which aids the entry of iron into the plasma. When the hyposideraemia has been resolved, the holo-transferrin binds to the TfR2 receptor and forms a complex with HFE (hereditary hemochromatosis protein), which activates the BMP pathway in the presence of its receptors (BMPR1 and BMPR2), of HJV and neogenin (NEO), promoting the hepcidin synthesis. Erythroferrone (Erfe), GDF15 (growth differentiation factor) and TWSG1 (twisted gastrulation BMP signalling modulator) inhibit hepcidin synthesis by blocking the SMAD pathway. Another inhibitor of hepcidin is matriptase-2 (MT-2), which blocks HJV by preventing the activation of the BMP complex. Tissue hypoxia and erythropoietin also inhibit hepcidin synthesis." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1841 "Ancho" => 1667 "Tamanyo" => 158308 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of ACD. ACD: Anaemia of chronic diseases or inflammatory anaemia; IL: Interleukin; EPO: Erythropoietin; Fe: Serum iron; MPS: Mononuclear phagocyte system." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1979 "Ancho" => 2167 "Tamanyo" => 351992 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Physiopathological mechanisms of anaemia in chronic diseases. In inflammatory processes, the cytokines (IL-6, IL-1, IL-22, lipopolysaccharides [LPS], interferon-γ [IFN-γ], and tumour necrosis factor alpha [TNFα]) increase, and are responsible for the increase in hepcidin. The hepcidin blocks the ferroportin (FPN) of the enterocytes, macrophages, and hepatocytes, leading to hyposideraemia, and the accumulation of iron in macrophages, in the form of ferritin. The cytokines activate the macrophages, facilitating erythrophagocytosis and also decrease the renal EPO production and prevent hemoglobinisation of erythroblasts. Hyposideraemia plays a central role in the suppression of erythropoiesis because there is no transfer of iron to the erythroblasts through the transferrin receptor (R-Tf). Erythropoiesis is also inhibited by the decrease in renal EPO and the reduced expression of the EPO receptor (EPOR), due to the action of cytokines and the lack of iron that prevents the synthesis of a regulator called scribble (SCB). In turn, the suppression of erythropoiesis has a negative impact on the hepcidin blockers, ERFE, GDF15 and TWSG1." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1527 "Ancho" => 1667 "Tamanyo" => 160291 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for normocytic anaemias in chronic diseases. ACD: Anaemia of chronic disease." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inhibitor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Action and target \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">References \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inhibition of hepcidin synthesis</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL6/STAT3 pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-IL6 (siltuximab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL6 sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0105">[21]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-IL6r (tocilizumab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL6 receptor sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0110">[22,34]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Momelotinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">JAK 1/2 inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0145">[29,30]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">mAb TNF-〈 (infliximab, golimumab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Indirect effect of IL-6 suppression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0175">[35,36]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DS28120313, DS79182026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL6-induced low hepcidin in mice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0215">[43,44]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S-Propargyl-Cystene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocks IL6/JAK2/STAT3 pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0225">[45]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AG490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">STAT3 phosphorylation inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0185">[37,38]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PpYLKTK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prevents STAT3 dimerisation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0190">[38]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMPs/BMPR/HJV pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-HJV mAb (ABT-207, h5F9-AM8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMPs/SMAD path inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0240">[48,49]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LY3113593 mAb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocks the binding of BMP6 to its receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0250">[50]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HJVs-Fc (FMX-8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMPs/SMAD path inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0090">[18,52]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LDN-193189 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMPR1 phosphorylation inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0255">[51]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-MBP6 mAb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMP6 sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0035">[7,18]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">siHep, siHJV, siTfR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Degradation of the mRNA of hepcidin, HJV or TfR2 inhibitors of the BMPs/SMAD pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0090">[18,52,53]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Modified heparin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0270">[54]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antihepcidin agents</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antihepcidin mAb (12B9m) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0095">[19,55]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antihepcidin mAb (LY2787106) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0280">[56]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spiegelmer NOX-H94 (lexaptepid) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0295">[59]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pegylated anticalin (PRS-080) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepcidin protein sequestration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0285">[57,58]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepcidin-ferroportin interaction</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antiferroportin mAb (LY2928057) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interferes with hepcidin-ferroportin (FPN) binding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0250">[50]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fursultiamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cys326-HS sequestration (FPN-hepcidin binding) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0300">[60]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other inhibitors</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1,25-dihydroxyvitamin D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suppresses SMAD 1/5/8 phosphorylation. Vitamin D receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0195">[39]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Testosterone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suppresses SMAD 1/5/8 phosphorylation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0200">[40]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17-estradiol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suppresses SMAD 1/5/8 phosphorylation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0205">[41]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Statins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decreased hepcidin - anti-inflammatory action \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0210">[42]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Curcumin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocks STAT3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0230">[46]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chinese medicinal plant: Caulis spatholobi (jixueteng) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suppresses SMAD 1/5/8 phosphorylation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0235">[47]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2546365.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Hepcidin inhibitors and their corresponding targets." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anemia of inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T. 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Anaemia of chronic diseases: Pathophysiology, diagnosis and treatment

Anemia de las enfermedades crónicas: fisiopatología, diagnóstico y tratamiento

Ricardo de las Cuevas Allendea,◊, Lucía Díaz de Entresotosb, Susana Conde Díezc,

,◊

a Servicio Cántabro de Salud, Centro de Salud El Alisal, Santander, Cantabria, Spain

b Servicio Cántabro de Salud, Santander, Cantabria, Spain

c Servicio Cántabro de Salud, Centro de Salud Altamira, Cantabria, Spain

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respiratory failure&#44; heart failure&#44; obesity and other chronic processes&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Elevated hepcidin levels in infections represent a host defense mechanism against infections because it limits the availability of iron to the microorganisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Regulation of iron metabolism</span><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hepcidin</span>&#44; the main regulator of iron metabolism&#44; is synthesised in the liver and its function is to control the entry of iron into the plasma&#46; Iron is supplied with food in the ferric form and&#44; after being reduced to the ferrous form&#44; it is absorbed by the duodenal enterocytes and subsequently released into the plasma&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The <span class="elsevierStyleItalic">ferroportin</span> is responsible for the release of iron from the enterocytes&#44; 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which stimulate its transcription through different signalling pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Regulation of the hepcidin expression</span><p id="par0020" class="elsevierStylePara elsevierViewall">Hepcidin transcription&#44; encoded by the HAMP gene <span class="elsevierStyleItalic">&#40;hepcidin antimicrobial peptide</span>&#41;&#44; is carried out by different activating and inhibiting signals acting in a synchronised manner<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The former include the inflammatory processes and the plasma iron level&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In inflammatory diseases&#44; the increase in hepcidin is mediated by cytokines produced by the activation of the immune system&#44; especially IL-6 and IL-22&#44; which activate the JAK-STAT3 <span class="elsevierStyleItalic">&#40;janus kinase-signal transducer and activator of transcription&#41;</span> signalling pathway&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> IL1 and activin B &#40;Act-B&#41; also intervene&#44; by increasing the HAMP transcription via BMP&#47;SMAD &#40;<span class="elsevierStyleItalic">bone morphogenetic protein-small mothers against decapentaplegic</span>&#41; signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Both pathways are closely connected&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> so much so that efficient induction of hepcidin by the inflammatory pathway requires a threshold of BMP6&#47;SMAD signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Hepcidin regulation by plasma iron is carried out through the BMP&#47;SMAD pathway&#46; The mechanism involves the secretion of BMP6 by the liver&#8217;s sinusoidal endothelial cells&#44; which bind to the BMP type I &#40;ALK2&#44; ALK3&#44; ALK6&#41; and type II &#40;ActRIIA&#44; BMPRII&#41; receptors in the hepatocytes&#44; in order to activate the SMAD cascade signaling&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Iron-bound transferrin &#40;Tf-Fe2&#41; &#40;holo-transferrin&#41; is a hepatocyte sensor for the control of the hepcidin transcription&#46; In hyposideraemia&#44; the Tf-Fe2 complex binds to the transferrin receptor-1 &#40;TfR1&#41;&#44; the BMP-SMAD pathway is not activated&#44; and the hepcidin is not synthesised&#44; which aids the entry of iron into the plasma&#46; When the hyposideraemia has been resolved&#44; the holo-transferrin binds to the TfR2 receptor and forms a complex with HFE &#40;hereditary hemochromatosis protein&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> which activates the BMP pathway in the presence of its receptors &#40;BMPR1 and BMPR2&#41;&#44; of HJV &#40;hemojuvelin&#41; and neogenin&#44; promoting the SMAD1&#47;5&#47;8 phosphorylation&#44; the transcription of HAMP and the hepcidin synthesis<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;8</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The inhibitory signals of hepcidin come from the erythropoiesis and are related to different proteins&#44; produced in the erythroblasts&#44; which block its production when iron is needed for the synthesis of haemoglobin&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> The most important protein is erythroferrone &#40;Erfe&#41;&#44; but there are others such as <span class="elsevierStyleItalic">growth differentiation factor 15</span> &#40;GDF15&#41; and <span class="elsevierStyleItalic">twisted gastrulation BMP</span> signaling <span class="elsevierStyleItalic">modulator</span> &#40;TWSG1&#41; which inhibit the SMAD pathway<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Matriptase-2 &#40;MT-2&#41;&#44; encoded by the <span class="elsevierStyleItalic">TMPRSS6</span> gene&#44; is another hepcidin inhibitor because it blocks the HJV and prevents the activation of the BMP complex&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Other inhibitory signs of hepcidin synthesis are tissue hypoxia and erythropoietin &#40;EPO&#41;&#44; which generate erythroblastic hyperplasia with the consequent increase in Erfe&#44; GDF15 and TWSG1 levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;12</span></a></p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pathophysiology</span><p id="par0035" class="elsevierStylePara elsevierViewall">The cause of anaemia in chronic diseases is multifactorial and the origin is in the activation of the immune system by autoantigens&#44; microbial molecules or tumour antigens&#44; which gives rise to the release of multiple inflammatory cytokines and free radicals that favour the increase of the hepcidin&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a> The cytokines involved are IL-6&#44; IL-1b&#44; IL-22&#44; lipopolysaccharides &#40;LPS&#41;&#44; tumor necrosis factor alpha &#40;TNF&#9001;&#41;&#44; interferon gamma &#40;INF&#947;&#41; and other&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;13</span></a> The consequences of these disorders are changes in iron homeostasis&#44; especially hyposideraemia&#44; erythropoiesis suppression&#44; shortened erythroid survival&#44; and decreased EPO production<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Alteration of iron homeostasis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Hepcidin increase causes ferroportin degradation resulting&#44; on the one hand&#44; in hyposideraemia due to a decrease in iron transferred to plasma&#44; and on the other&#44; in the accumulation of iron in the form of ferritin in enterocytes&#44; macrophages and hepatocytes<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Hyposideraemia is one of the most important factors in ACD&#44; as functional iron deficiency anaemia occurs because iron&#44; although it is abundant in the storage organs&#44; is not available for effective erythropoiesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Erythropoiesis suppression</span><p id="par0045" class="elsevierStylePara elsevierViewall">The second pathogenic factor in ACD is erythropoiesis suppression&#44; directly related to EPO&#46; In most patients with ACD&#44; the EPO levels are lower than expected for the degree of anaemia they usually present&#46; This may be the result of two causes&#59; on the one hand&#44; hyposideraemia gives rise to an iron deficiency in the erythroblasts&#44; which reduces the EPO receptor gene &#40;EPOR&#41; expression via a blunted expression of an EpoR control regulator known as <span class="elsevierStyleItalic">scribble</span> &#40;SCB&#41;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;14</span></a> and&#44; also&#44; due to the inhibitory effect of the cytokines &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; On the other hand&#44; lower levels of EPO may be related to an inhibitory effect of IL-1 and TNF-&#945; at the renal level&#44; by the mediated GATA-2 transcription gene&#44; since EPO-mediated signalling is reduced and is inversely linked to the circulating levels of cytokines<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;13</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Hypoxia and the reduced availability of EPO in ACD negatively impact the hepcidin blockers&#44; such as Erfe&#44; GDF15 and TWSG1&#44; which under physiological conditions slow down the hepcidin synthesis because they inhibit the SMAD pathway<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;13&#44;15</span></a> &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1 and 3</a>&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Erythrophagocytosis and a shortened erythrocyte half-life</span><p id="par0050" class="elsevierStylePara elsevierViewall">Reduction in the erythrocyte half-life due to erythrophagocytosis is another common pathogenic factor in the inflammatory setting&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This phenomenon is produced by activation of macrophages by cytokines<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Shortened red blood cell survival is a minor pathogenic factor in ACD&#44; but it plays a greater role in severe infections and in critical situations accompanied by a massive release of cytokines that promote erythrophagocytosis and hemolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In these situations&#44; anaemia occurs in the first days of the event&#44; before there is a decrease in erythropoiesis&#44; so that anaemia is explained by the shortened erythrocyte half-life and by hemodilution&#44; which is common in these clinical situations&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diagnosis</span><p id="par0055" class="elsevierStylePara elsevierViewall">In addition to the specific symptoms of the underlying disease and the associated systemic inflammatory process&#44; patients&#44; who are elderly&#44; in general&#44; present an increase in acute phase reactants&#44; such as a sedimentation rate&#44; C-reactive protein and others&#46; These&#44; together with anaemia&#44; give rise to a whole procession of clinical data&#44; more or less intense&#44; depending on the hemoglobin levels&#46; Some critical patients with acute inflammatory processes may present a clinical symptoms similar to that of &#171;cytokine release syndrome&#187;&#44; with massive rise in cytokines&#44; especially IL-6&#46; Symptoms of anaemia are the consequence of hypoxia&#44; but effective iron deficiency displays additional symptoms because it also impairs mitochondrial function&#44; cellular metabolism&#44; enzyme activities&#44; and neurotransmitter synthesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;16</span></a> Patients with ACD have a &#171;functional iron deficiency&#187; and the anaemia they present is characteristically mild to moderate normocytic&#47;normochromic&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The diagnosis of inflammatory anaemia is mainly one of exclusion&#46; It is best diagnosed by documenting an anaemia of low production in the context of an inflammatory disease&#46; Patients with ACD often present hyposideraemia&#44; low transferrin saturation&#44; reticulocytopenia&#44; and important findings are increased hepcidin and serum ferritin levels&#44; which translate into elevated iron stores in the MPS macrophages&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;16</span></a> The differential diagnosis should be made with the true iron deficiency anaemia&#44; in which there is an absolute deficit of iron&#44; with lab results that show microcytic and hypochromic anaemia with hyposidaeremia&#44; increased transferrin&#44; and reticulocytopenia&#44; but with low levels of ferritin and hepcidin&#44; which would rule out ACD&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In addition&#44; the soluble transferrin receptor is elevated in iron deficiency anaemia and normal in ACD&#46; Sometimes&#44; the ACD can coexist with a true iron deficiency&#44; in which case the location of blood loss should be investigated&#46; However&#44; in these cases the ferritin is not usually elevated&#44; it can be normal or a little low<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; An evaluation of &#171;inadequately low&#187; ferritin&#44; in the context of an iron-deficient ACD&#44; can be difficult to define in clinical practice&#44; but considering this aspect is important because&#44; in these cases&#44; intravenous iron treatment can be effective&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment</span><p id="par0065" class="elsevierStylePara elsevierViewall">The ACD treatment objective should be to cure the underlying disease&#44; and if this is not possible&#44; to achieve the best possible control of the symptoms&#46; Anaemia is usually a consequence of the disease and it often contributes to greater clinical manifestations depending on its severity&#44; so correcting the anaemia would improve the patient&#8217;s quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In general&#44; the anaemia is moderate which means that blood transfusions are unnecessary&#46; However&#44; if the anaemia is severe&#44; they will need to be used as an emergency treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Intravenous iron treatment may be justified as a temporary measure&#44; in some cases of ACD&#44; but in the long run it can be harmful as it causes the patient to have an excess of iron&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> EPO may be beneficial in some patients&#44; as an alternative to chronic red blood cell transfusion&#44; but it is not approved for ACD and its use is based on the fact that it sometimes improves anaemia&#44; and the similarity that exists between ACD and CKD anaemia&#44; as it is approved for the latter&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;17</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">As hyposideraemia is the cause of anaemia&#44; the therapeutic goal should be to increase plasma iron levels&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> New treatment strategies for its increase focus on reversing the overexpression of hepcidin&#44; in order to favour the mobilisation of iron sequestered in MPS cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;20</span></a> The strategies being investigated are aimed at enhancing erythropoiesis and increasing endogenous erythropoietin levels on the one hand&#44; and at preventing the action of hepcidin&#44; either by blocking its synthesis&#44; neutralizing circulating hepcidin or preventing the action of hepcidin on ferroportin on the other<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;18&#8211;20</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Much research is being conducted involving the various agents that could modify the hepcidin-ferroportin axis or the various regulators involved&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Most of these agents are effective in animal models and several are undergoing human testing&#46; In ACD&#44; the target is IL6 because its neutralisation reduces the hepcidin levels and corrects the anaemia&#44; as has been shown in the treatment of inflammatory diseases and in Castleman&#8217;s disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> but these agents must be well tolerated as well as being effective&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Erythropoiesis potentiation</span><p id="par0075" class="elsevierStylePara elsevierViewall">The increase in erythropoiesis leads to erythropoiesis hyperplasia and an elevation of erythropherrone that blocks the SMAD pathway and slows down the synthesis of hepcidin&#46; Therefore&#44; any agent that improves erythropoiesis could be effective in the control of ACD&#46; High doses of EPO may be able to overcome the resistance to EPO observed in these diseases&#44; by partial suppression of hepcidin&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;17</span></a> It is known that the kidneys of CKD patients retain the ability to produce erythropoietin and that in hypoxic situations the prolyl hydroxylase enzyme activity decreases&#44; physiologically leading to an increase in the transcriptional activity of the hypoxia inducible factor &#40;HIF&#41;&#44; which induces the endogenous EPO expression&#44; corrects functional iron deficiency&#44; and activates erythropoiesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> Pharmacological prolyl hydroxylase inhibitors &#40;PHI&#41; mimic the natural hypoxic response&#44; thereby increasing HIF&#46; There are several PHI agents that&#44; by increasing endogenous EPO&#44; improve erythropoiesis and reduce hepcidin levels in patients with anaemia and chronic inflammatory processes&#46; Effective agents already in phase II&#47;III trials are&#58; vadadustat &#40;AKB-6548&#41;&#44; molidustat &#40;BAY85-3934&#41;&#44; daprodustat &#40;GSK1278863&#41; and roxadustat &#40;FG-4592&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> In two phase III studies in patients with CKD and anaemia&#44; an oral PHI &#40;roxadustat&#41; was compared with erythropoietin-&#945;&#59; in one of the studies&#44; the patients were not on hemodialysis and in the other they were already on dialysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> The results were that the increase in hemoglobin in the roxadustat group was greater than that of the placebo in those not on dialysis<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> and it was not inferior to erythropoietin-&#945; in hemodialysis patients&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Therefore&#44; stabilisation of HIF through inhibition of the prolyl-hydroxylase enzymes family is a novel approach and may be an effective therapeutic target in the treatment of CKD anaemia&#44; since the increase in EPO is physiological thereby avoiding higher doses of conventional EPO and the resulting cardiovascular side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> However&#44; prolyl hydroxylase inhibitors correct the CKD anaemia through multiple biological pathways&#44; such as increasing erythropoietin levels&#44; stimulating erythropoiesis&#44; decreasing erythropherrone-mediated hepcidin levels&#44; and the correcting hyposideraemia&#44; and due to their angiogenic action they are not exempt from side effects&#46; So monitoring the consequences of their long-term use will be essential&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;28</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Hepcidin antagonists</span><p id="par0080" class="elsevierStylePara elsevierViewall">Hepcidin is the main cause of anaemia in chronic diseases because it generates hyposideraemia and retains iron in the MPS cells&#44; so its pharmacological inhibition would facilitate iron mobilisation&#44; favouring erythropoiesis and the correction of anaemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a> The hepcidin antagonists under study are aimed at blocking its synthesis&#44; at neutralising circulating hepcidin and&#44; also&#44; at preventing the action of hepcidin on the ferroportin&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;20</span></a> The interest in these studies is very great&#44; as evidenced by the fact that in October 2019&#44; in ClinicalTrials&#46;gov&#44; there were 221 registered clinical trials on hepcidin&#44; 67 of which were investigating hepcidin in chronic diseases or cancer&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inhibition of hepcidin production</span><p id="par0085" class="elsevierStylePara elsevierViewall">There are two main pathways that control hepcidin synthesis&#46; One is related to the plasma iron level&#44; through the BMP6-HJV-SMAD pathway&#44; and the other is related to inflammatory processes through the IL6-JAK-STAT3 pathway&#46; The latter has more prominence in the ACD<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The in vitro studies have revealed the existence of a cross connection between the two pathways&#44; since treatments that block the BMP pathway also inhibit the expression of hepcidin through the IL-6-STAT3 inflammatory signalling pathway and&#44; also&#44; efficient induction of hepcidin by the inflammatory pathway requires a threshold of BMP6&#47;SMAD signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Suppression of the inflammatory pathway</span><p id="par0090" class="elsevierStylePara elsevierViewall">Hepcidin is activated by IL-6 through the IL-6 receptor &#40;IL-6R&#41; and JAK2-STAT3 signalling&#46; So&#44; blocking IL6 with siltuximab&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> the IL6 receptor with tocilizumab<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and JAK1&#47;2 with momelotinib<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a> prevent STAT3 phosphorylation&#44; decrease hepcidin levels&#44; normalise sideremia and improve anaemia in monkeys with arthritis&#44; in patients with Castleman&#8217;s disease and in patients with neoplasms<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;29&#44;32&#44;33</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Similarly&#44; in patients with rheumatoid arthritis&#44; tocilizumab reduced hepcidin and improved anaemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> The same results were obtained in patients with rheumatoid arthritis treated with anti-TNF antibodies&#945; &#40;golimumab or infliximab&#41;&#44; possibly as an indirect result of concomitant suppression of IL-6<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The main drawback of anti-cytokine therapies is that they generate immunosuppression and an increased risk of infections&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Similar effects have been achieved in cell models and in mice with chemical inhibitors of the IL-6&#47;STAT3 signalling pathway&#44; such as AG490<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and PpYLKTK&#44; which prevent STAT3 phosphorylation&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Both compounds decrease IL6-dependent hepcidin expression in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> However&#44; the development of these agents as hepcidin inhibitors is hampered either because of a lack of specificity&#44; as happens with all STAT3 inhibitors&#44; or because of poor pharmacokinetics<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;37&#44;38</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Other hepcidin inhibitors that improve anaemia of chronic diseases&#44; include vitamin D&#44; testosterone&#44; 17-estradiol&#44; and statins which prevent SMAD phosphorylation<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#8211;42</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In addition&#44; several orally active indazole inhibitors&#44; DS28120313 and DS79182026&#44; have been shown to antagonise the induction of hepcidin in mice injected with IL-6<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Hepcidin also inhibits SPRC &#40;S-propargyl-cysteine&#41;&#44; an analogue of S-allyl-cysteine&#44; which increases endogenous production of H2S and hydrogen sulfide and blocks the IL-6&#47;JAK2&#47;STAT3 pathway&#44; reducing levels of hepcidin and improving the saturation of tranferrin in vivo&#44; in models of acute and chronic inflammatory anaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Also&#44; some plant extracts&#44; such as curcumin&#44; inhibit STAT3 signalling&#44; and consequently&#44; hepcidin levels decrease in humans&#46; This supports the idea that turmeric could be useful in the treatment of anaemia in inflammatory processes<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Another medicinal plant <span class="elsevierStyleItalic">Caulis spatholobi</span> or <span class="elsevierStyleItalic">jixueteng</span>&#44; has a powerful inhibitory effect on the HAMP expression through the suppression of SMAD 1&#47;5&#47;8 phosphorylation<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Inhibitors of the BMP6&#47;HJV pathway</span><p id="par0105" class="elsevierStylePara elsevierViewall">The BMP-HJV-SMAD pathway is the other pathway that controls hepcidin synthesis&#44; so its inhibition would decrease HAMP expression and plasma hepcidin levels&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> HJV has been targeted by several monoclonal antibodies &#40;mAb&#41; &#40;ABT-207&#44; h5F9-AM8 and h5F9-23&#41;&#44; which prevent the binding of BMP with its receptors and block the SMAD pathway&#44; suppress hepcidin and correct anaemia in rats with chronic inflammatory processes<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Another mAb that blocks the binding of BMP6 with its receptor is LY3113593&#46; It has been tested in CKD patients&#44; achieving a reduction in hepcidin levels&#44; an increase in hemoglobin and a reduction in ferritin&#44; compared to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Likewise&#44; LDN-193189&#44; a dorsomorphine derivative and an inhibitor of BMPR1 in rats and human hepatoma cells has been shown to prevent hepcidin synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> The same effect is achieved with a fusion protein that binds soluble HJV &#40;sHJV&#41; and the Fc fragment of the immunoglobulins &#40;sHJV-Fc&#41;&#44; which blocks the binding of BMP with BMPR and prevents the SMAD phosphorylation&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;52</span></a> Another way to inhibit the BMP pathway is with antisense oligonucleitides&#46; They block hepcidin synthesis regulator genes and RNA interference and are tools for mRNA &#40;siRNA&#41; silencing of the genes that encode hepcidin&#44; TfR2&#44; and HJV<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;53</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Its administration in a mouse model of chronic inflammatory anaemia decreased hepcidin concentrations and corrected anaemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;53</span></a> These agents are effective&#44; but they are not without side effects and are therefore subject to further research&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Heparin binds with high affinity to BMP6 and blocks hepcidin synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In mice and cell lines&#44; it inhibits the phosphorylation of SMAD1&#47;5&#47;8 proteins&#44; caused by the BMPs&#44; and thus decreases the hepcidin expression and increases serum iron&#46; This behaviour is similar to that which occurs in patients treated with heparin to prevent deep vein thrombosis&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Its anticoagulant activity limits therapeutic use as a hepcidin inhibitor&#44; but modified heparin analogues have been designed that lack anticoagulant activity&#44; but retain the suppressive property of hepcidin<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Recently&#44; erythroferrone has been shown to be a potent competitive inhibitor of BMP6&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Therefore&#44; its use to treat anaemia of inflammatory processes that occur with increased hepcidin has been put forward&#46; Any agent that mimics the activity of Erfe would be effective in reducing hepcidin levels&#44; promoting increased serum iron and erythropoiesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;28</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Neutralisation of circulating hepcidin</span><p id="par0120" class="elsevierStylePara elsevierViewall">Direct inhibitors of hepcidin such as mAbs&#44; anticalins and L-RNA aptamers &#40;called <span class="elsevierStyleItalic">spiegelmers</span>&#44; German for &#171;mirror&#187;&#41;&#44; are effective because they increase the circulating iron&#44; promote erythropoiesis and correct anaemia&#59; these effects are potentiated with EPO in mouse models and in monkeys with ACD&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> A human anti-hepcidin antibody&#44; 12B9m&#44; has been tested in transgenic mice with inflammatory anaemia caused by <span class="elsevierStyleItalic">Brucella abortus</span> and in monkeys&#46; Neutralisation of hepcidin by mAb increased erythropoiesis and haemoglobin levels<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Another antihepcidin humanised mAb&#44; LY2787106&#44; improves anaemia in cancer patients by favouring iron mobilisation from the deposits&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Anticalins are therapeutic proteins that bind to ligands developed from lipocalins and they can recognise and bind tightly to a wide range of medically relevant targets&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> In a phase I study and in healthy volunteers&#44; the pegylated anticalin PRS-080 neutralised hepcidin and increased serum iron&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> which is why a phase II study has been initiated in anaemic patients with CKD<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Aptamers &#40;<span class="elsevierStyleItalic">spiegelmers</span>&#41; are designed L-oligoribonucleotides&#44; with a three-dimensional mirror-image form of the target&#44; to which they bind with high affinity&#46; They are stable in the circulation and immunologically passive because their structure contains L-ribose&#44; instead of D-ribose&#44; which gives them a high resistance to nuclease degradation&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Lexaptepid &#40;NOX-H94&#41; is an antihepcidin aptamer that inhibits human hepcidin and increases plasma iron and transferrin saturation in human volunteers injected with LPS and in patients with neoplasms<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Blocking the hepcidin-ferroportin interaction</span><p id="par0135" class="elsevierStylePara elsevierViewall">Hepcidin to ferroportin binding occurs in an extracellular region of the ferroportin that contains Cys326 - the sulfhydryl residue&#44; surrounded by hydrophobic residues&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Some treatments are aimed at blocking this interaction to prevent the action of hepcidin on ferroportin and facilitate the release of iron into the circulation&#46; An example of these agents is fursultiamine&#44; a thiamine derivative approved by the FDA &#40;<span class="elsevierStyleItalic">Food and Drug Administration</span>&#41;&#44; which blocks the C326 thiol residue of ferroportin&#44; preventing the hepcidin action and aiding the increase in serum iron<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Another humanised mAb that blocks the binding of hepcidin to ferroportin is LY2928057&#59; in CKD-patients it increases plasma iron&#44; promotes erythropoiesis&#44; corrects anaemia and reduces ferritin levels&#44; compared with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">The anaemia of chronic inflammatory processes is common in everyday clinical practice&#46; However&#44; despite the fact that it deteriorates the quality of life of the patient and can negatively affect survival&#44; it is often neglected and not fully assessed by doctors because it is associated with other&#44; usually serious&#44; diseases upon which all therapeutic objectives are focused&#46; In recent years&#44; we have learned about the complex regulation of the iron metabolism&#44; which has allowed us to explore new therapeutic options to correct anaemia&#46; The ultimate goal is to control hepcidin levels&#44; which are ultimately responsible for anaemia&#44; in order to release the iron trapped in the MPS cells&#44; facilitate erythropoiesis&#44; and raise haemoglobin levels&#46; Many therapeutic strategies have emerged thanks to furthering the pathophysiological knowledge on anaemia&#44; derived from and validated in preclinical&#47;clinical studies and in randomised clinical trials&#46; We now have the first effective agents available to control anaemia associated with chronic inflammatory processes&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Contribution of the authors</span><p id="par0145" class="elsevierStylePara elsevierViewall">RCA&#44; LDE and SCD have equally contributed to the bibliographic review&#44; the writing of the paper and the discussion of its content&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Ethical responsibilities</span><p id="par0150" class="elsevierStylePara elsevierViewall">It is a review paper in which there are no patients or animals&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">This work has not received any type of funding&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Thanks</span><p id="par0165" class="elsevierStylePara elsevierViewall">We are grateful to Eulogio Conde Garc&#237;a&#44; retired haematologist and professor of haematology&#44; for the critical review of the paper&#44; as well as his contributions and suggestions&#46;</p></span></span>"
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          "titulo" => "Regulation of iron metabolism"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Anaemia of chronic disease &#40;ACD&#41; is generated by the activation of the immune system by autoantigens&#44; microbial molecules or tumour antigens resulting in the release of cytokines that cause an elevation of serum hepcidin&#44; hypoferraemia&#44; suppression of erythropoiesis&#44; decrease in erythropoietin &#40;EPO&#41; and shortening of the half-life of red blood cells&#46; Anaemia is usually normocytic and normochromic&#44; which is the most prevalent after iron deficiency anaemia&#44; and it is the most frequent in the elderly and in hospitalized patients&#46; If the anaemia is severe&#44; the patient&#8217;s quality of life deteriorates&#44; and it can have a negative impact on survival&#46; Treatment is aimed at controlling the underlying disease and correcting anaemia&#46; Sometimes intravenous iron and EPO have been used&#44; but the therapeutic future is directed against hepcidin&#44; which is the final target of anaemia&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La anemia de las enfermedades cr&#243;nicas &#40;AEC&#41; se genera por la activaci&#243;n del sistema inmune por autoant&#237;genos&#44; mol&#233;culas microbianas o ant&#237;genos tumorales&#44; que dan lugar a la liberaci&#243;n de citocinas que originan una elevaci&#243;n de la hepcidina s&#233;rica&#44; hiposideremia&#44; supresi&#243;n de la eritropoyesis&#44; disminuci&#243;n de la eritropoyetina &#40;EPO&#41; y acortamiento de la vida media de los hemat&#237;es&#46; La anemia suele ser normoc&#237;tica&#47;normocr&#243;mica&#44; es la m&#225;s prevalente&#44; despu&#233;s de la anemia ferrop&#233;nica&#44; y es la m&#225;s frecuente en los ancianos y en los pacientes hospitalizados&#46; Si la anemia es grave&#44; la calidad de vida del paciente se deteriora y puede tener un impacto negativo en la supervivencia&#46; El objetivo del tratamiento va dirigido a controlar la enfermedad de base y a corregir la anemia&#46; En ocasiones se ha utilizado hierro endovenoso y EPO&#44; pero el futuro terap&#233;utico va dirigido contra la hepcidina&#44; que es la diana responsable final de la anemia&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Synthesis of hepcidin&#46; IL-6 activates the JAK-STAT3 <span class="elsevierStyleItalic">&#40;janus kinase-signal transducer and activator of transcription&#41;</span> signalling pathway&#59; IL1 and activin B &#40;Act-B&#41; increase HAMP transcription through BMP&#47;SMAD signalling&#46; Plasma iron&#44; bound to transferrin &#40;Tf-Fe2&#41; &#40;holo-transferrin&#41;&#44; is a sensor of hepatocytes to regulate hepcidin transcription because it activates the BMP-HJV-SMAD <span class="elsevierStyleItalic">&#40;bone morphogenetic protein-hemojuvelin-small mothers against decapentaplegic</span>&#41; pathway&#46; In hyposideraemia&#44; holo-transferrin binds to the transferrin receptor-1 &#40;TfR1&#41;&#44; the BMP-SMAD pathway is not activated&#44; and the hepcidin is not synthesised&#44; which aids the entry of iron into the plasma&#46; When the hyposideraemia has been resolved&#44; the holo-transferrin binds to the TfR2 receptor and forms a complex with HFE &#40;hereditary hemochromatosis protein&#41;&#44; which activates the BMP pathway in the presence of its receptors &#40;BMPR1 and BMPR2&#41;&#44; of HJV and neogenin &#40;NEO&#41;&#44; promoting the hepcidin synthesis&#46; Erythroferrone &#40;Erfe&#41;&#44; GDF15 &#40;<span class="elsevierStyleItalic">growth differentiation factor&#41;</span> and TWSG1 &#40;<span class="elsevierStyleItalic">twisted gastrulation BMP signalling modulator</span>&#41; inhibit hepcidin synthesis by blocking the SMAD pathway&#46; Another inhibitor of hepcidin is matriptase-2 &#40;MT-2&#41;&#44; which blocks HJV by preventing the activation of the BMP complex&#46; Tissue hypoxia and erythropoietin also inhibit hepcidin synthesis&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Physiopathological mechanisms of anaemia in chronic diseases&#46; In inflammatory processes&#44; the cytokines &#40;IL-6&#44; IL-1&#44; IL-22&#44; lipopolysaccharides &#91;LPS&#93;&#44; interferon-&#947; &#91;IFN-&#947;&#93;&#44; and tumour necrosis factor alpha &#91;TNF&#945;&#93;&#41; increase&#44; and are responsible for the increase in hepcidin&#46; The hepcidin blocks the ferroportin &#40;FPN&#41; of the enterocytes&#44; macrophages&#44; and hepatocytes&#44; leading to hyposideraemia&#44; and the accumulation of iron in macrophages&#44; in the form of ferritin&#46; The cytokines activate the macrophages&#44; facilitating erythrophagocytosis and also decrease the renal EPO production and prevent hemoglobinisation of erythroblasts&#46; Hyposideraemia plays a central role in the suppression of erythropoiesis because there is no transfer of iron to the erythroblasts through the transferrin receptor &#40;R-Tf&#41;&#46; Erythropoiesis is also inhibited by the decrease in renal EPO and the reduced expression of the EPO receptor &#40;EPOR&#41;&#44; due to the action of cytokines and the lack of iron that prevents the synthesis of a regulator called <span class="elsevierStyleItalic">scribble</span> &#40;SCB&#41;&#46; In turn&#44; the suppression of erythropoiesis has a negative impact on the hepcidin blockers&#44; ERFE&#44; GDF15 and TWSG1&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Action and target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">References&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibition of hepcidin synthesis</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic"><span class="elsevierStyleHsp" style=""></span>IL6&#47;STAT3 pathway</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-IL6 &#40;siltuximab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL6 sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0105">&#91;21&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-IL6r &#40;tocilizumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL6 receptor sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0110">&#91;22&#44;34&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Momelotinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JAK 1&#47;2 inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0145">&#91;29&#44;30&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>mAb TNF-&#9001; &#40;infliximab&#44; golimumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Indirect effect of IL-6 suppression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0175">&#91;35&#44;36&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>DS28120313&#44; DS79182026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL6-induced low hepcidin in mice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0215">&#91;43&#44;44&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>S-Propargyl-Cystene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blocks IL6&#47;JAK2&#47;STAT3 pathway&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0225">&#91;45&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AG490&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">STAT3 phosphorylation inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0185">&#91;37&#44;38&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PpYLKTK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prevents STAT3 dimerisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0190">&#91;38&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">BMPs&#47;BMPR&#47;HJV pathway</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-HJV mAb &#40;ABT-207&#44; h5F9-AM8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMPs&#47;SMAD path inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0240">&#91;48&#44;49&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LY3113593 mAb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blocks the binding of BMP6 to its receptor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0250">&#91;50&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HJVs-Fc &#40;FMX-8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMPs&#47;SMAD path inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0090">&#91;18&#44;52&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LDN-193189&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMPR1 phosphorylation inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0255">&#91;51&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Anti-MBP6 mAb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMP6 sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0035">&#91;7&#44;18&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>siHep&#44; siHJV&#44; siTfR2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Degradation of the mRNA of hepcidin&#44; HJV or TfR2 inhibitors of the BMPs&#47;SMAD pathway&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0090">&#91;18&#44;52&#44;53&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Modified heparin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0270">&#91;54&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antihepcidin agents</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Antihepcidin mAb &#40;12B9m&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepcidin protein sequestration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0095">&#91;19&#44;55&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Chinese medicinal plant&#58;</span> Caulis spatholobi &#40;jixueteng&#41;&nbsp;\t\t\t\t\t\t\n
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