Anemia of inflammation and iron metabolism in chronic diseases

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Conde Díez, R. de las Cuevas Allende, E. Conde García" "autores" => array:3 [ 0 => array:3 [ "nombre" => "S." "apellidos" => "Conde Díez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "R." "apellidos" => "de las Cuevas Allende" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "E." "apellidos" => "Conde García" "email" => array:1 [ 0 => "condeeulogio@yahoo.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Medicina de Familia, Servicio Cántabro de Salud, Centro de Salud Camargo Costa, Maliaño, Cantabria, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medicina de Familia, Servicio Cántabro de Salud, Centro de Salud Altamira, Puente de San Miguel, Cantabria, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hematólogo jubilado [jefe del Servicio de Hematología del Hospital Marqués de Valdecilla, Santander. Catedrático de Medicina de la Universidad de Cantabria], Santander, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anemia de la inflamación y metabolismo del hierro en las enfermedades crónicas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1654 "Ancho" => 1605 "Tamanyo" => 335666 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of anemia of inflammation. A. Activation of the immune system. In inflammatory processes, immune system cells are activated by means of the TLR4 receptors that detect danger caused by various substances such as PAMP (pathogen-associated molecular patterns), DAMP (damage-associated molecular patterns), LPS (lipopolysaccharides), autoantigens or tumour antigens, resulting in an acute inflammatory response with the release of cytokines (IL-6, IL-1, IL-22, interferon-γ [IFN-γ] and tumour necrosis factor alpha [TNF-α]), both of which are responsible for hepcidin increases and which also activate macrophages thus facilitating erythrophagocytosis. On the other hand, they reduce renal EPO production and prevent haemoglobinization of the erythroblasts. B. Alteration of iron metabolism. Hepcidin blocks ferroportin (FPN) from enterocytes, macrophages, and hepatocytes, resulting in hypoferremia and iron sequestration in the macrophages in the form of ferritin. Hypoferremia plays a central role in anemia since there is a stop in erythropoiesis because no iron is being transferred to the erythroblasts via the transferrin receptor (TfR). Erythropoiesis stoppage also occurs due to a decrease in renal EPO and lower expression of the EPO receptor (EpoR), due to the cytokine action and lack of iron that prevents synthesis of a regulator called scribble (SCB). Likewise, the stop to erythropoiesis has a negative impact on the hepcidin inhibitors erythroferrone (ERFE), GDF15 (growth differentiation factor) and TWSG1. The main pathways for suppressing hepcidin in hypoxia situations are also shown; one is mediated by renal EPO and ERFE and the other by increased hepatic FGL1 (fibrinogen-like 1) that inhibits the BMP/SMAD pathway. C. Different chronic diseases that present with AI. AI is associated with a series of diseases such as infectious diseases caused by any type of pathogen, chronic kidney disease, patients hospitalised for extended periods and particularly in the ICU, patients with neoplasms, patients with chronic lung disease and heart failure and patients with autoimmune diseases. With all of these clinical situation situations there is a foundational inflammatory process with elevated hepcidin and other alterations specific to each of the described diseases. TLR4: Toll-like receptor 4; PAMP: pathogen-associated molecular patterns; DAMP: damage-associated molecular patterns; LPS: lipopolysaccharides; AI: Anemia of inflammation; Fe: Iron; EPO: Erythropoietin; FGF23: fibroblast growth factor 23." ] ] ] "textoCompleto" => "IntroductionAnemia of inflammation (AI), also known as anemia of chronic disease (ACD), is a multifactorial type of anemia that occurs in the context of an inflammatory process due to immune system activation with cytokine release and elevated hepcidin, which responsible for iron sequestration in the cells of the mononuclear phagocyte system (MPS), resulting in hypoferremia and a stop in erythropoiesis due to lack of iron.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> AI is the second most prevalent type of anemia after iron deficiency anemia, occurs in chronic diseases, and is most common in hospitalised patients and the elderly.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> AI is mild/moderate (haemoglobin between 8 and 12 g/dl), normocytic, normochromic, and hypoproliferative.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Inflammation is a biological reaction that is a part of a host’s defence mechanisms and whose purpose is to neutralise harmful, infectious agents that reach the organism, as well as to facilitate the repair of damaged tissue.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The cells that trigger inflammation form part of the innate immune system and recognise aggressions in order to release various mediators that increase vascularisation of the area, causing local swelling, while also recruiting other cells at the site of the lesion. The mediators released are proinflammatory cytokines IL6, IL1, IL-22, tumour necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), as well as others that promote various biological processes resulting in acute phase reactants.<a class="elsevierStyleCrossRefs" href="#bib0010">2–4</a>The released cytokines are involved in multiple processes, such as producing proteins like hepcidin, whose beneficial action during the acute phase is to prevent iron from reaching the microorganisms responsible for the infection; however, when an inflammatory process becomes chronic, hepcidin ultimately becomes responsible for iron metabolism alteration and anemia.<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a> Here we review the most relevant aspects of AI in chronic diseases, including the pathophysiology, diagnosis, and treatment.Iron metabolism regulationIron is an essential nutrient in all living beings and is fundamental to multiple biological processes. Adults contain around 4 g of iron, of which 2.5 g are found in haemoglobin; the body loses 1 to 2 mg every day, about the same amount that is absorbed by the duodenum.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The iron cycle starts with absorption in the duodenal enterocytes and subsequent transferrin-bound circulation to reach the bone marrow (BM), where it is taken up by erythroblasts via transferrin receptors (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In the erythroblasts, iron reaches the mitochondria where it binds to protoporphyrin to form heme and, after binding to globin, starts the erythrocyte haemoglobinization process (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Senescent erythrocytes are phagocytized by the macrophages, where the haemoglobin breaks down and part of the iron goes into plasma via ferroportin (FPN) and the rest accumulates in the form of ferritin<a class="elsevierStyleCrossRef" href="#bib0035">7</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Hepcidin synthesises in the liver depending on the body’s iron stores and inflammatory signals (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Circulating iron is always bound to transferrin, but when transferrin is saturated, the excess nontransferrin bound iron (NTBI) is toxic and can cause cell death due to ferroptosis since it produces free radicals and lipid peroxidation.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> There is no physiologic mechanism for iron elimination, and in the case of excess NTBI, it binds to albumin and chaperone proteins to prevent toxicity.<a class="elsevierStyleCrossRefs" href="#bib0010">2,8</a> NTBI promotes BMP6 expression in the liver sinusoidal endothelial cells (LSEC) to increase hepcidin production and prevent iron toxicity.<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a>Hepcidin synthesis regulationHepcidin is a small peptide with 25 amino acids that is synthesised in the liver and encoded by the HAMP gene (hepcidin antimicrobial peptide) via different activation and inhibition signals. Elevated hepcidin blocks ferroportin in the enterocytes and macrophages, preventing the export of iron to plasma, producing hypoferremia with the subsequent decrease in erythropoiesis due to insufficient iron provision, resulting in AI<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).Hepcidin synthesis activation signalsIron-activated mediationHepcidin synthesis is controlled by plasma iron by means of the BMP-HJV-SMAD pathway (bone morphogenetic protein-hemojuvelin-sons of mothers against decapentaplegic). Transferrin-bound plasma iron (Tf-Fe2) (holotransferrin) is a hepatocyte sensor that participates in controlling hepcidin transcription. If hypoferremia is present, transferrin receptor 1 (TfR1) levels rise to increase the uptake of iron coming from the Tf-Fe2 complex, and the BMP-SMAD pathway is not activated, which helps the iron to reach the plasma<a class="elsevierStyleCrossRefs" href="#bib0005">1,9</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). When the hypoferremia has resolved, NTBI increases the expression of BMP6 due to the LSEC and, simultaneously, holotransferrin is moved to the transferrin receptor 2 (TfR2) and forms a complex with HFE (human homeostatic iron regulator protein), which activates the BMP pathway in the presence of its BMPR1 and BMPR2 receptors, HJV, neogenin (NEO), and promotes phosphorylation of SMAD1/5/8, HAMP transcription, and hepcidin synthesis<a class="elsevierStyleCrossRefs" href="#bib0010">2,10</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Inflammation-mediated activationThe other pathway for hepcidin synthesis is mediated by the cytokines produced during immune system activation, particularly IL6 that activates the JAK-STAT3 signalling pathway (Janus kinase-signal transducer and activator of transcription) in the presence of activin B (Act-B)<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).Hepcidin synthesis inhibiting signalsHypoxia triggers a physiological response with increased renal production of EPO and an increase in ERFE by BM erythroblasts<a class="elsevierStyleCrossRefs" href="#bib0065">13,14</a> and, in addition, positive regulation of FGL-1<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and matriptase-2 (MT-2)<a class="elsevierStyleCrossRef" href="#bib0010">2</a> by the hepatocytes, thus blocking the BMP-HJV-SMAD pathway with hepcidin inhibition and an increase in serum iron (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Hepcidin inhibition due to FGL-1 is mediated by hypoxia, but unlike ERFE, it is not related to EPO.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> The inhibitory effect of hepcidin caused by ERFE and by FGL-1 takes place in a coordinated manner as has been shown in acute hemorrhage-induced anemia in rats; the maximum serum level of ERFE occurs in the first 24 hours of anemia while the mRNA expression of FGL-1 is delayed by up to 3 days after bleeding.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> The coordinated inhibitory activity of ERFE and FGL-1 guarantee effective negative hepcidin regulation and provision of the iron needed by the erythroid cells for hemoglobin synthesis and erythrocyte production.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a>Pathophysiology of anemia of inflammationThe cause of anemia in chronic disease is complex and linked to the underlying chronic disease that causes immune system activation due to the autoantigens, microbial molecules, or tumour antigens that cause the release of numerous cytokines leading to elevated hepcidin and subsequent alteration of iron metabolism, whose most notable processes are hypoferremia with erythropoiesis suppression, reduced erythropoietin, and shortened erythrocyte half-life<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Immune system activationThis represents the start of AI. The innate immune system activates against any external or internal aggression as a way to eliminate pathogens, prevent cell damage, and to facilitate resolution of the inflammatory response. Immune cells have PRR (pattern recognition receptors) of which the Toll-like (TLRs) receptors, and specifically TLR4, detect the danger and activate due to PAMP (pathogen-associated molecular patterns), DAMP (damage-associated molecular patterns), lipopolysaccharides (LPS), autoantigens, and tumour antigens, resulting in an acute inflammatory response with cytokine release and the recruitment of leukocytes and monocytes from blood vessels to heal and repair tissue damage<a class="elsevierStyleCrossRef" href="#bib0085">17</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A). While many proinflammatory cytokines are released, IL6 is responsible for the increase in hepcidin in the liver (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A). If TLR4 activation is excessive or prolonged, this causes a massive cytokine release, sometimes even causing a “cytokine storm” that can put the host’s life at risk.<a class="elsevierStyleCrossRef" href="#bib0025">5</a><elsevierMultimedia ident="fig0020"></elsevierMultimedia>Alterations of iron homeostasis, EPO reduction, and erythropoiesis suppressionIncreases in hepcidin cause ferroportin to break down in the enterocytes, macrophages, and hepatocytes, facilitating iron sequestration in MPS macrophages and hypoferremia<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B). Iron deficiency in circulating blood plays a significant role in anemia since erythropoiesis stops because iron is not reaching the erythroblasts via TfR<a class="elsevierStyleCrossRef" href="#bib0010">2</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B). Simultaneously, the stop to erythropoiesis is caused due to a reduction in EPO due to the inhibitory effect of IL-1 and TNF-α in the kidneys, mediated by the GATA-2 transcription gene,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> and also due to the reduced expression of the EPO receptor (EpoR) in the erythroblasts due to the action of the cytokines and due to the lack of iron that prevents the synthesis of an EpoR regulator called scribble (SCB)<a class="elsevierStyleCrossRef" href="#bib0090">18</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B). Erythropoiesis suppression has a negative impact on ERFE that stops hepcidin synthesis because it inhibits the SMAD pathway<a class="elsevierStyleCrossRefs" href="#bib0095">19,20</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B).Shortened erythrocyte half-lifeShortened erythrocyte half-life is another pathogenic factor in an inflammatory context and occurs due to macrophage activation by cytokines<a class="elsevierStyleCrossRef" href="#bib0005">1</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B). It is a lesser pathogenic factor in AI, but takes on greater protagonism in serious infections and in critical situations since cytokines enhance erythrophagocytosis and hemolysis.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In these situations, anemia occurs in the initial days of the process, before any decrease in erythropoiesis, meaning the anemia can be explained by the shortened half-life of the erythrocytes and because of hemodilution, which is common in these clinical situations.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Anemia of inflammation in chronic diseaseAll the processes that occur with chronic inflammatory phenomena can potentially cause AI and this occurs with acute/chronic bacterial, fungal, viral, and parasitic infections, in chronic kidney disease (CKD), hospitalised patients (particularly those in the intensive care unit [ICU]), neoplasms, chronic lung disease and chronic heart failure, autoimmune diseases, obesity, and in elderly patients.<a class="elsevierStyleCrossRefs" href="#bib0030">6,11</a> Anemia promotes adverse clinical evolution with higher risk of hospitalisation and neuromuscular and cognitive decline.<a class="elsevierStyleCrossRefs" href="#bib0010">2,5</a>Infectious diseasesElevated hepcidin in infections represents a defence mechanism in the host against said infection because it limits the iron available to microorganisms.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> The interaction between infections, iron homoeostasis, and anemia has been studied in the COVID-19 and HIV epidemics.<a class="elsevierStyleCrossRefs" href="#bib0105">21–23</a> In serious infections, such as COVID-19, there is a hyperinflammatory state that results in cytokine storm with elevated IL-6, hepcidin, serum ferritin, and hypoferremia levels<a class="elsevierStyleCrossRefs" href="#bib0010">2,6</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C). Controlling infections improves inflammation and corrects iron imbalances, but it does not always resolve anemia.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> In patients with COVID-19, the prevalence of anemia is 25%, but 70% of the patients with anemia had AI.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Chronic kidney diseaseChronic kidney disease presents with inflammatory processes and progressive kidney failure that causes patients to require dialysis and, occasionally, kidney transplant. The causes of anemia in CKD include reduced EPO production, absolute and/or functional iron deficiency and elevated hepcidin levels<a class="elsevierStyleCrossRef" href="#bib0025">5</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C). The prevalence of anemia in CKD is 21–62%.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> CKD presents with a bone-mineral homoeostasis disturbance, and both inflammation and iron deficiency promote the production of FGF23 (fibroblast growth factor 23) in the osteocytes, which regulates production and vitamin D homoeostasis and has a negative effect on erythropoiesis because it blocks erythroid differentiation of hematopoietic stem cells.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> FGF23 uses αKlotho to perform its physiological functions and its elevation in CKD has the purpose of promoting renal phosphate excretion to prevent hyperphosphatemia, however it also promotes 1,25-dihydroxyvitamin D suppression and parathyroid hormone (PTH) elevation, causing secondary hyperparathyroidism.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>Intensive care unit (ICU)Anemia is common in critical patients admitted to the ICU, particularly when they are admitted for more than one week.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In addition to the specific alterations of AI, anemia in the ICU is associated with bleeding and shortened red blood cell lifespan due to erythrophagocytosis.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> In sepsis, it is common to see reduced plasma iron levels and elevated ferritin, IL-6, and hepcidin levels, all parameters that are associated with the evolution of sepsis.<a class="elsevierStyleCrossRefs" href="#bib0030">6,27</a>CancerIn patients with neoplasms, anemia can be caused by BM infiltration, antineoplastic treatment, or disease progression, but it can also be due to malnutrition or substances produced by the neoplastic cells such as amyloid or antibodies that cause hemolytic anemia or procoagulating factors that result in thrombotic processes or disseminated intravascular coagulation and microangiopathic hemolysis.<a class="elsevierStyleCrossRefs" href="#bib0140">28,29</a> Cancers produce inflammatory processes and a tumour microenvironment in which immune system cells are activated by tumour antigens or by DAMP mediators produced by the dying cells. Cytokines are released that are responsible for elevated hepcidin and the alteration of iron metabolism that negatively affect erythropoiesis, resulting in AI<a class="elsevierStyleCrossRefs" href="#bib0030">6,30</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C).Chronic pulmonary disease and congestive heart failureRespiratory failure with hypoxia presents with elevated EPO and erythropoiesis, leading to secondary polycythemia with ERFE elevation that inhibits hepcidin synthesis and promotes an increase in plasma iron, thus facilitating expansive erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> However, in chronic obstructive pulmonary disease (COPD) and pulmonary hypertension, there tends to be a sustained inflammatory process with immune system activation, cytokine release, hepcidin elevation, alteration of iron metabolism, hypoferremia, and AI<a class="elsevierStyleCrossRefs" href="#bib0155">31,32</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C).Patients with congestive heart failure (CHF), particularly those with reduced ejection fraction, tend to present with AI and all the processes that accompany it such as inflammation, elevated cytokines and hepcidin, and alteration of iron metabolism; however, they also present with pseudo-anemia due to hemodilution via activation of the renin-angiotensin-aldosterone system that causes sodium and water retention.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> The prevalence of anemia in patients with CHF ranges from 37 to 61%.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Autoimmune diseasesIn autoimmune diseases there is an alteration in immune tolerance with the generation of autoantigens and autoreactive T cells that instruct the B lymphocytes to produce autoantibodies of different specificities that affect multiple organs and whose clinical manifestations can be mild or severe.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Inflammation is mediated by autoantigens that activate the immune system and produce cytokines, elevated hepcidin levels, hypoferremia, and AI<a class="elsevierStyleCrossRefs" href="#bib0030">6,36</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C). Immunosuppressive therapy can affect erythropoiesis and erythrocyte half-life, thus promoting anemia.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The prevalence of AI is 33–60% in patients with rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Anemia in patients with inflammatory bowel disease (IBD) can also be caused by chronic intestinal bleeding, malnutrition due to malabsorption, or intestinal resections.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The prevalence of anemia in patients with IBD ranges from 6% to 74%; AI is more common in Crohn’s disease and iron deficiency anemia is more common in ulcerative colitis.<a class="elsevierStyleCrossRefs" href="#bib0185">37,38</a>Diagnosis of anemia of inflammationAI diagnosis is mainly by exclusion. AI should be suspected in patients with mild/moderate normocytic, normochromic and hypoproliferative anemia that appears within the context of a chronic disease.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Inflammatory processes can be unpredictable as they evolve, so it is normal to observe variations in the parameters that allow us to assess iron activity. In addition, iron availability may be “absolute” or “functional”, so it is important to perform a differential diagnosis between AI and iron deficiency anemia for an appropriate diagnostic and therapeutic approach.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>With AI there is functional iron deficiency, meaning iron stores are normal or elevated because the iron is “trapped” in the MPS cells and cannot be released because hepcidin is blocking the ferroportin, resulting in “relative” hypoferremia. In addition to hypoferremia, patients with AI present low transferrin saturation (<20%), with normal or low transferrin levels, reticulocytopenia, normal or increased serum ferritin (>100 ng/mL),<a class="elsevierStyleCrossRefs" href="#bib0015">3,40</a> normocytic, normochromic red blood cells, and an increase in hepcidin levels and levels of other acute phase reactants such as C-reactive protein or IL-6.On the other hand, in true iron deficiency anemia, there is an absolute iron deficiency, with no iron in the MPS stores due to blood losses. Hypoferremia is present with microcytic and hypochromic red blood cells, low transferrin saturation, elevated transferrin, reticulocytopenia, and low serum ferritin (<30 ng/mL).<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> Hepcidin levels do not help with clinical decision-making when assessing anemia due to the technical difficulties in measuring it and because there are no universal reference ranges available, meaning they are only used in research.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>The diagnostic problem arises when patients with AI also have absolute iron deficiency, something that occurs on some occasions and, in these cases, ferritin tends to not be elevated, but rather normal or low.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> If the differential diagnosis is not clear after evaluating iron tests, measuring the soluble transferrin receptor (sTFR) and sTFR-ferritin index allows for differentiation as these are elevated in iron deficiency anemia and normal in AI. What’s more, reticulocyte hemoglobin content (Ret-Hb) is low in iron deficiency.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> In these cases, we must investigate the site of bleeding since “inappropriately low” ferritin assessment in the context of AI with iron deficiency is not easy to define in clinical practise, but it is important to bear in mind because treatment with intravenous iron tends to be effective.<a class="elsevierStyleCrossRef" href="#bib0200">40</a>Treatment of anemia of inflammationThe treatment goal is to improve the clinical condition of the patient, but not necessarily to normalise hemoglobin levels since higher morbidity-mortality has been observed in patients with terminal CKD when hemoglobin levels were normalised; therefore the recommendation is to not exceed hemoglobin levels of 11–12 g/dL.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Symptoms are related to the underlying disease, so the therapeutic goal should be focused on curing or improving the underlying condition,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> though anemia correction would improve patient quality of life.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Since anemia is moderate, red blood cell transfusions are not typically needed and should only be considered as an emergency treatment when anemia is severe (Hb, <8 g/L) and there is no time to wait for a response from other therapies.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Treatment with oral or intravenous iron supplements should only be considered in patients with concomitant iron deficiency (ferritin <30 ng/mL, transferrin saturation <20% and elevated soluble transferrin receptor); in these cases, intravenous iron is preferable since it tends to be more effective and faster.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> However, if there is no evidence of associated iron deficiency, iron therapy is not indicated because the patient has excess iron stores.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Erythropoiesis stimulating agents (ESA), like EPO, must be administered to patients with symptomatic anemia who do not respond to treatment of their underlying disease or in the case of true associated iron deficiency that does not respond to treatment with iron supplements.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> For ESAs to stimulate red blood cell production, there needs to be sufficient serum iron concentration. Therefore, hepcidin-mediated iron restriction can contribute to the hyporesponsiveness of ESAs that is commonly observed in CKD, and which has led to the use of high doses of EPO administered jointly with intravenous iron.<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a>Emerging treatmentsThe therapeutic goal of AI is to increase plasma iron levels by promoting mobilisation of the iron sequestered in the MPS cells, thereby preventing hypoferremia and facilitating the transport of iron to the erythroid progenitors, thus promoting erythropoiesis.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> The therapeutic target is hepcidin and various targeted strategies have been used, on the one hand correcting hypoxia with prolyl hydroxylase inhibitors<a class="elsevierStyleCrossRef" href="#bib0210">42</a> and on the other modifying the hepcidin-ferroportin axis.<a class="elsevierStyleCrossRefs" href="#bib0215">43,44</a>Prolyl hydroxylase inhibitorsIn situations of hypoxia, the activity of the prolyl hydroxylase (PHI) enzyme decreases, resulting in an increase in the hypoxia-inducible factor (HIF) that induces the production of endogenous EPO.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> Pharmacological PHI inhibitors stimulate renal EPO production that activates erythropoiesis, increasing ERFE and reducing hepcidin levels, thus promoting iron mobilisation, overcoming even the hyporesponsiveness that is sometimes observed with ESAs.<a class="elsevierStyleCrossRefs" href="#bib0225">45,46</a> There are many oral medications used in patients with CKD and anemia (roxadustat, daprodustat, vadadustat, molidustat, enarodustat and others). Roxadustat has been evaluated in 16 phase III studies and in all of them has been shown to increase EPO levels, reduce hepcidin levels, and increase serum iron, erythropoiesis, and hemoglobin levels, however it can cause hypertension and thrombosis so the recommendation is to replace it with molidustat in patients at risk for either of those two conditions.<a class="elsevierStyleCrossRefs" href="#bib0230">46,47</a> Treatment with HIF-PHI must be administered jointly with intravenous iron if transferrin saturation indices are low.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>Hepcidin-ferroportin axisThe current therapeutic approaches aim to neutralise the role of hepcidin to facilitate the mobilisation of iron trapped in the macrophages and correct hypoferremia. Multiple agents have been researched that are effective in animal and human models.<a class="elsevierStyleCrossRefs" href="#bib0215">43,44</a> The main therapeutic strategies aimed at preventing the action of hepcidin involve blocking its synthesis, neutralising circulating hepcidin or blocking the hepcidin-ferroportin axis.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Hepcidin synthesis inhibitorsThere are two ways to prevent hepcidin synthesis, one related to plasma iron levels via the BMP6-HJV-SMAD pathway while the other is related to the inflammatory processes via the IL6-JAK-ATAT3 pathway.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>Inhibition via the plasma iron pathwayHepcidin synthesis is prevented by blocking the BMP-HJV-SMAD pathway; the most important target is HJV, against which various monoclonal antibodies (ABT-207, h5F9-AM8 y h5F9-23) have been designed that prevent SMAD phosphorylation.<a class="elsevierStyleCrossRefs" href="#bib0250">50,51</a> Another option for inhibiting the BMP pathway is recombinant erythroferrone that suppresses hepcidin by inhibiting liver signalling of BMP/SMAD.<a class="elsevierStyleCrossRefs" href="#bib0260">52,53</a> The inhibitory activity of hepcidin attributed to FGL1 represents another therapeutic approach that should be explored.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Inhibition via the inflammatory pathwayThis pathway inhibits hepcidin with anti-IL6 antibodies (siltuximab) and anti-IL6 receptor antibodies (tociluzumab), which are already approved for the treatment of rheumatoid arthritis and Castleman disease.<a class="elsevierStyleCrossRefs" href="#bib0270">54–56</a> Similar results have been obtained in patients with rheumatoid arthritis treated with TNFα antibodies (golimumab, adalimumab, infliximab) via indirect suppression of IL6.<a class="elsevierStyleCrossRef" href="#bib0285">57</a> These treatments produce immunosuppression and increase infection risk, which limit their use outside of pre-approved treatment indications.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Neutralisation of circulating hepcidinThese are substances that neutralise hepcidin by promoting the mobilisation of iron trapped in MPS cells, thereby correcting hypoferremia and facilitating erythropoiesis. The most commonly used are humanized monoclonal antibodies (12B9m and LY2787106),<a class="elsevierStyleCrossRefs" href="#bib0290">58,59</a> anticalins, designed proteins that bind to hepcidin and inhibit its activity (PRS-080)<a class="elsevierStyleCrossRef" href="#bib0300">60</a> and aptamers of L-ARN, called Spiegelmer, that are three-dimensional structured L-oligoribonucleotides against the mirror-image of the target (NOX-H94).<a class="elsevierStyleCrossRefs" href="#bib0305">61,62</a>Blocking the hepcidin-ferroportin axisBlocking the binding of hepcidin to ferroportin facilitates the release of iron trapped in the cells and corrects anemia. This has been achieved with a monoclonal antibody (LY2928057)<a class="elsevierStyleCrossRef" href="#bib0315">63</a> and with fursultiamine, a derivative of thiamine that blocks the C326 thiol residue that is the binding point between hepcidin and ferroportin.<a class="elsevierStyleCrossRef" href="#bib0320">64</a>ConclusionsAnemia of inflammation is common in patients with chronic disease, in the elderly, and in hospitalised patients, and can negatively impact their quality of life. Since anemia tends to be mild/moderate and occur with other, often more important diseases, anemia diagnosis and treatment typically garners little attention. However, in this paper we have provided some clear guidelines for proper diagnosis and therapeutic approach that will improve patient quality of life. Knowledge of iron metabolism and the role of hepcidin in hypoferremia and in stopping erythropoiesis is the foundation for new therapeutic options whose aim is to release the iron sequestered in MPS cells and increase circulating iron to facilitate effective erythropoiesis and increased hemoglobin levels. Preclinical research has shown that this is possible and there are many clinical trials that have provided us with initial agents that are effective at addressing anemia treatment in these patients.FundingWe did not receive any type of funding.Conflicts of interestThe authors declare that they have no conflicts of interest." 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"secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Iron-activated mediation" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Inflammation-mediated activation" ] ] ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Hepcidin synthesis inhibiting signals" ] ] ] ] ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "Pathophysiology of anemia of inflammation" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Immune system activation" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Alterations of iron homeostasis, EPO reduction, and erythropoiesis suppression" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Shortened erythrocyte half-life" ] ] ] 8 => array:3 [ "identificador" => "sec0060" "titulo" => "Anemia of inflammation in chronic disease" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Infectious diseases" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Chronic kidney disease" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Intensive care unit (ICU)" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Cancer" ] 4 => array:2 [ "identificador" => "sec0085" "titulo" => "Chronic pulmonary disease and congestive heart failure" ] 5 => array:2 [ "identificador" => "sec0090" "titulo" => "Autoimmune diseases" ] ] ] 9 => array:2 [ "identificador" => "sec0095" "titulo" => "Diagnosis of anemia of inflammation" ] 10 => array:3 [ "identificador" => "sec0100" "titulo" => "Treatment of anemia of inflammation" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0105" "titulo" => "Emerging treatments" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0110" "titulo" => "Prolyl hydroxylase inhibitors" ] 1 => array:3 [ "identificador" => "sec0115" "titulo" => "Hepcidin-ferroportin axis" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0120" "titulo" => "Hepcidin synthesis inhibitors" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0125" "titulo" => "Inhibition via the plasma iron pathway" ] 1 => array:2 [ "identificador" => "sec0130" "titulo" => "Inhibition via the inflammatory pathway" ] ] ] 1 => array:2 [ "identificador" => "sec0135" "titulo" => "Neutralisation of circulating hepcidin" ] 2 => array:2 [ "identificador" => "sec0140" "titulo" => "Blocking the hepcidin-ferroportin axis" ] ] ] ] ] ] ] 11 => array:2 [ "identificador" => "sec0145" "titulo" => "Conclusions" ] 12 => array:2 [ "identificador" => "sec0150" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0155" "titulo" => "Conflicts of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-06-17" "fechaAceptado" => "2024-06-25" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1904867" "palabras" => array:5 [ 0 => "Iron metabolism" 1 => "Hepcidin" 2 => "Anemia" 3 => "Inflammation" 4 => "Chronic diseases" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1904869" "palabras" => array:50 [ 0 => "AI" 1 => "Act-B" 2 => "ACD" 3 => "ESA" 4 => "mRNA" 5 => "BMPR1 and BMPR2" 6 => "BMP-HJV-SMAD" 7 => "COVID-19" 8 => "DAMP" 9 => "EPO" 10 => "COPD" 11 => "CKD" 12 => "ERFE" 13 => "FGF23" 14 => "FGL1" 15 => "HIF" 16 => "FPN" 17 => "GATA" 18 => "HAMP" 19 => "HFE" 20 => "HIF-PHI" 21 => "CHF" 22 => "IL1" 23 => "INF" 24 => "JAK-STAT3" 25 => "LPS" 26 => "LSEC" 27 => "MT-2" 28 => "NEO" 29 => "NTBI" 30 => "PAMP" 31 => "PHI" 32 => "PRR" 33 => "PTH" 34 => "EpoR" 35 => "Ret-Hb" 36 => "TfR" 37 => "SCB" 38 => "MPS" 39 => "sTfR" 40 => "TIBC" 41 => "Tf" 42 => "Tf-Fe2" 43 => "TfR1" 44 => "TfR2" 45 => "TMPRSS2" 46 => "TNF" 47 => "TLRs" 48 => "ICU" 49 => "HIV" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1904868" "palabras" => array:5 [ 0 => "Metabolismo hierro" 1 => "Hepcidina" 2 => "Anemia" 3 => "Inflamación" 4 => "Enfermedades crónicas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Anemia of Inflammation begins with the activation of the immune system and the subsequent release of cytokines that lead to an elevation of hepcidin, responsible for hypoferremia, and a suppression of erythropoiesis due to lack of iron. The anemia is usually mild/moderate, normocytic/normochromic and is the most prevalent, after iron deficiency anemia, and is the most common in patients with chronic diseases, in the elderly and in hospitalized patients. Anemia can influence the patient’s quality of life and have a negative impact on survival. Treatment should be aimed at improving the underlying disease and correcting the anemia. Intravenous iron, erythropoietin and prolyl hydroxylase inhibitors are the current basis of treatment, but future therapy is directed against hepcidin, which is ultimately responsible for anemia." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La Anemia de la Inflamación comienza con la activación del sistema inmune y la posterior liberación de citocinas que dan lugar a una elevación de la hepcidina, responsable de la hiposideremia y de la supresión de la eritropoyesis por falta de hierro. La anemia suele ser leve/moderada, normocítica/normocrómica, es la más prevalente después de la anemia ferropénica y es la más frecuente en los pacientes con enfermedades crónicas, en los ancianos y en los pacientes hospitalizados. La anemia puede influir en la calidad de vida del paciente y tener un impacto negativo en la supervivencia. El tratamiento debe dirigirse a mejorar la enfermedad de base y a corregir la anemia. El hierro endovenoso, la eritropoyetina y los inhibidores de la prolil hidroxilasa son la base actual del tratamiento, pero el futuro terapéutico va dirigido contra la hepcidina que es la responsable final de la anemia." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1393 "Ancho" => 1509 "Tamanyo" => 292542 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Iron metabolism. Enterocyte: Iron in the diet is absorbed by the duodenal enterocytes, presents in the ferric state (Fe 3+), and is reduced to ferrous iron (Fe 2+) due to the action of the DCYTB (duodenal cytochrome B reductase) ferrireductase. Ferrous iron moves through the enterocytes via mediation of the DMT1 transporter (divalent metal transporter 1). In the enterocyte, ferrous iron can be stored in the form of ferritin by iron chaperone PCBP1/2 (poly(rC)-binding protein 1/2), or it is released through the action of NCOA4 (nuclear receptor coactivator 4) to export it to blood circulation by means of ferroportin (FPN). Ferrous iron is oxidised by ferroxidase hephaestin, transformed into ferric iron that binds to transferrin (Tf) and is then transported by circulating blood (CB). Bone Marrow (BM): In BM, erythroblasts capture the iron transported by TF through the transferrin receptors (TfR) and by means of endocytosis they enter side the erythroblasts where the iron is transported to the mitochondria (MC) by mitoferrin-1 (Mfrn1) and is incorporated into protoporphyrin IX (PP-IX) for the formation of the heme that binds to globin and starts the hemoglobinization process that results in erythrocytes that are released into CB for oxygen transport. Macrophage: Senescent erythrocytes are phagocytized by liver and spleen macrophages that break down hemoglobin to release the heme that is processed by HMOX1 (heme oxygenase 1), therefore releasing the iron that is exported through the FPN. The leftover iron is stored as ferritin in the spleen, liver, and BM macrophages. Liver: Hepcidin expression in the liver is induced by the body’s iron stores and inflammatory signalling from the BMP/SMAD and IL6/JAK/STAT3 pathways, respectively, and plays an essential role in releasing iron from its stores via FPM, according to need." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1204 "Ancho" => 1350 "Tamanyo" => 188645 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Hepcidin synthesis. Ferric activation. The main axis that controls hepcidin synthesis is the BMP-HJV-SMAD pathway (bone morphogenetic protein-hemojuvelin-sons of mothers against decapentaplegic). Transferrin-bound plasma iron (Tf-Fe2) (holotransferrin) is a hepatocyte sensor for regulating hepcidin transcription because it activates the BMP-HJV-SMAD pathway. In situations of hypoferremia, holotransferrin binds to the transferrin receptor 1 (TfR1), does not activate the BMP-SMAD pathway, and does not synthesize hypoferremia, which helps iron reach the plasma. When iron deficiency is resolved, the excess nontransferrin bound iron (NTBI) is absorbed by liver sinusoidal endothelial cells (LSEC) and increases BMP6 expression; simultaneously, holotransferrin is moved to the transferrin receptor 2 (TfR2) and forms a complex with HFE (human homeostatic iron regulator protein) that activates BMP2,5,6, pathway in the presence of its receptors (BMPR1 and BMPR2), HJV, and neogenin (NEO) and promotes phosphorylation of SMAD1/5/8, HAMP transcription, and hepcidin synthesis. Activation due to inflammation. The other hepcidin synthesis route is inflammation via various cytokines, particularly IL6 and activin B (Act-B), that activate the JAK-STAT3 pathway (Janus kinase-signal transducer and activator of transcription) and BMP. Inhibition due to hypoxia. In hypoxia conditions, there are three hepcidin inhibition pathways. One is through renal EPO that causes expansive erythropoiesis with an increase in erythroblasts that produce erythroferrone (ERFE), GDF15 (growth differentiation factor), and TWSG1 (twisted gastrulation BMP signalling modulator) and inhibit hepcidin synthesis because they block the SMAD pathway and thereby facilitate an increase in serum iron. Another is an increase in FGL1 (fibrinogen-like 1) in the liver that blocks BMP6 and suppresses hepcidin; the third is mediated by matriptase-2 (MT-2), encoded by gene TMPRSS6 in the liver, which produces proteolysis of HJV preventing the activation of the BMP2,5,6 complex and hepcidin synthesis." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1257 "Ancho" => 800 "Tamanyo" => 111354 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiological mechanisms that contribute to hypoferremia and anemia of inflammation (AI). IL: Interleukin; TNF: Tumour necrosis factor; INF: Interferon; MPS: mononuclear phagocyte system; EPO: erythropoietin." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1654 "Ancho" => 1605 "Tamanyo" => 335666 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of anemia of inflammation. A. Activation of the immune system. In inflammatory processes, immune system cells are activated by means of the TLR4 receptors that detect danger caused by various substances such as PAMP (pathogen-associated molecular patterns), DAMP (damage-associated molecular patterns), LPS (lipopolysaccharides), autoantigens or tumour antigens, resulting in an acute inflammatory response with the release of cytokines (IL-6, IL-1, IL-22, interferon-γ [IFN-γ] and tumour necrosis factor alpha [TNF-α]), both of which are responsible for hepcidin increases and which also activate macrophages thus facilitating erythrophagocytosis. On the other hand, they reduce renal EPO production and prevent haemoglobinization of the erythroblasts. B. Alteration of iron metabolism. Hepcidin blocks ferroportin (FPN) from enterocytes, macrophages, and hepatocytes, resulting in hypoferremia and iron sequestration in the macrophages in the form of ferritin. Hypoferremia plays a central role in anemia since there is a stop in erythropoiesis because no iron is being transferred to the erythroblasts via the transferrin receptor (TfR). Erythropoiesis stoppage also occurs due to a decrease in renal EPO and lower expression of the EPO receptor (EpoR), due to the cytokine action and lack of iron that prevents synthesis of a regulator called scribble (SCB). Likewise, the stop to erythropoiesis has a negative impact on the hepcidin inhibitors erythroferrone (ERFE), GDF15 (growth differentiation factor) and TWSG1. The main pathways for suppressing hepcidin in hypoxia situations are also shown; one is mediated by renal EPO and ERFE and the other by increased hepatic FGL1 (fibrinogen-like 1) that inhibits the BMP/SMAD pathway. C. Different chronic diseases that present with AI. AI is associated with a series of diseases such as infectious diseases caused by any type of pathogen, chronic kidney disease, patients hospitalised for extended periods and particularly in the ICU, patients with neoplasms, patients with chronic lung disease and heart failure and patients with autoimmune diseases. With all of these clinical situation situations there is a foundational inflammatory process with elevated hepcidin and other alterations specific to each of the described diseases. TLR4: Toll-like receptor 4; PAMP: pathogen-associated molecular patterns; DAMP: damage-associated molecular patterns; LPS: lipopolysaccharides; AI: Anemia of inflammation; Fe: Iron; EPO: Erythropoietin; FGF23: fibroblast growth factor 23." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:64 [ 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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Anemia of inflammation and iron metabolism in chronic diseases

Anemia de la inflamación y metabolismo del hierro en las enfermedades crónicas

S. Conde Díeza, R. de las Cuevas Allendeb, E. Conde Garcíac,

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condeeulogio@yahoo.com

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a Medicina de Familia, Servicio Cántabro de Salud, Centro de Salud Camargo Costa, Maliaño, Cantabria, Spain

b Medicina de Familia, Servicio Cántabro de Salud, Centro de Salud Altamira, Puente de San Miguel, Cantabria, Spain

c Hematólogo jubilado [jefe del Servicio de Hematología del Hospital Marqués de Valdecilla, Santander. Catedrático de Medicina de la Universidad de Cantabria], Santander, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anemia of inflammation &#40;AI&#41;&#44; also known as anemia of chronic disease &#40;ACD&#41;&#44; is a multifactorial type of anemia that occurs in the context of an inflammatory process due to immune system activation with cytokine release and elevated hepcidin&#44; which responsible for iron sequestration in the cells of the mononuclear phagocyte system &#40;MPS&#41;&#44; resulting in hypoferremia and a stop in erythropoiesis due to lack of iron&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> AI is the second most prevalent type of anemia after iron deficiency anemia&#44; occurs in chronic diseases&#44; and is most common in hospitalised patients and the elderly&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> AI is mild&#47;moderate &#40;haemoglobin between 8 and 12&#160;g&#47;dl&#41;&#44; normocytic&#44; normochromic&#44; and hypoproliferative&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Inflammation is a biological reaction that is a part of a host&#8217;s defence mechanisms and whose purpose is to neutralise harmful&#44; infectious agents that reach the organism&#44; as well as to facilitate the repair of damaged tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The cells that trigger inflammation form part of the innate immune system and recognise aggressions in order to release various mediators that increase vascularisation of the area&#44; causing local swelling&#44; while also recruiting other cells at the site of the lesion&#46; The mediators released are proinflammatory cytokines IL6&#44; IL1&#44; IL-22&#44; tumour necrosis factor alpha &#40;TNF-&#945;&#41;&#44; and interferon gamma &#40;IFN-&#947;&#41;&#44; as well as others that promote various biological processes resulting in acute phase reactants&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The released cytokines are involved in multiple processes&#44; such as producing proteins like hepcidin&#44; whose beneficial action during the acute phase is to prevent iron from reaching the microorganisms responsible for the infection&#59; however&#44; when an inflammatory process becomes chronic&#44; hepcidin ultimately becomes responsible for iron metabolism alteration and anemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> Here we review the most relevant aspects of AI in chronic diseases&#44; including the pathophysiology&#44; diagnosis&#44; and treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Iron metabolism regulation</span><p id="par0020" class="elsevierStylePara elsevierViewall">Iron is an essential nutrient in all living beings and is fundamental to multiple biological processes&#46; Adults contain around 4&#160;g of iron&#44; of which 2&#46;5&#160;g are found in haemoglobin&#59; the body loses 1 to 2&#160;mg every day&#44; about the same amount that is absorbed by the duodenum&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The iron cycle starts with absorption in the duodenal enterocytes and subsequent transferrin-bound circulation to reach the bone marrow &#40;BM&#41;&#44; where it is taken up by erythroblasts via transferrin receptors &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In the erythroblasts&#44; iron reaches the mitochondria where it binds to protoporphyrin to form heme and&#44; after binding to globin&#44; starts the erythrocyte haemoglobinization process &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Senescent erythrocytes are phagocytized by the macrophages&#44; where the haemoglobin breaks down and part of the iron goes into plasma via ferroportin &#40;FPN&#41; and the rest accumulates in the form of ferritin<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Hepcidin synthesises in the liver depending on the body&#8217;s iron stores and inflammatory signals &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Circulating iron is always bound to transferrin&#44; but when transferrin is saturated&#44; the excess nontransferrin bound iron &#40;NTBI&#41; is toxic and can cause cell death due to ferroptosis since it produces free radicals and lipid peroxidation&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> There is no physiologic mechanism for iron elimination&#44; and in the case of excess NTBI&#44; it binds to albumin and chaperone proteins to prevent toxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8</span></a> NTBI promotes BMP6 expression in the liver sinusoidal endothelial cells &#40;LSEC&#41; to increase hepcidin production and prevent iron toxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Hepcidin synthesis regulation</span><p id="par0030" class="elsevierStylePara elsevierViewall">Hepcidin is a small peptide with 25 amino acids that is synthesised in the liver and encoded by the HAMP gene &#40;hepcidin antimicrobial peptide&#41; via different activation and inhibition signals&#46; Elevated hepcidin blocks ferroportin in the enterocytes and macrophages&#44; preventing the export of iron to plasma&#44; producing hypoferremia with the subsequent decrease in erythropoiesis due to insufficient iron provision&#44; resulting in AI<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Hepcidin synthesis activation signals</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Iron-activated mediation</span><p id="par0035" class="elsevierStylePara elsevierViewall">Hepcidin synthesis is controlled by plasma iron by means of the BMP-HJV-SMAD pathway &#40;bone morphogenetic protein-hemojuvelin-sons of mothers against decapentaplegic&#41;&#46; Transferrin-bound plasma iron &#40;Tf-Fe2&#41; &#40;holotransferrin&#41; is a hepatocyte sensor that participates in controlling hepcidin transcription&#46; If hypoferremia is present&#44; transferrin receptor 1 &#40;TfR1&#41; levels rise to increase the uptake of iron coming from the Tf-Fe2 complex&#44; and the BMP-SMAD pathway is not activated&#44; which helps the iron to reach the plasma<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; When the hypoferremia has resolved&#44; NTBI increases the expression of BMP6 due to the LSEC and&#44; simultaneously&#44; holotransferrin is moved to the transferrin receptor 2 &#40;TfR2&#41; and forms a complex with HFE &#40;human homeostatic iron regulator protein&#41;&#44; which activates the BMP pathway in the presence of its BMPR1 and BMPR2 receptors&#44; HJV&#44; neogenin &#40;NEO&#41;&#44; and promotes phosphorylation of SMAD1&#47;5&#47;8&#44; HAMP transcription&#44; and hepcidin synthesis<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Inflammation-mediated activation</span><p id="par0040" class="elsevierStylePara elsevierViewall">The other pathway for hepcidin synthesis is mediated by the cytokines produced during immune system activation&#44; particularly IL6 that activates the JAK-STAT3 signalling pathway &#40;Janus kinase-signal transducer and activator of transcription&#41; in the presence of activin B &#40;Act-B&#41;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Hepcidin synthesis inhibiting signals</span><p id="par0045" class="elsevierStylePara elsevierViewall">Hypoxia triggers a physiological response with increased renal production of EPO and an increase in ERFE by BM erythroblasts<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> and&#44; in addition&#44; positive regulation of FGL-1<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and matriptase-2 &#40;MT-2&#41;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> by the hepatocytes&#44; thus blocking the BMP-HJV-SMAD pathway with hepcidin inhibition and an increase in serum iron &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Hepcidin inhibition due to FGL-1 is mediated by hypoxia&#44; but unlike ERFE&#44; it is not related to EPO&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The inhibitory effect of hepcidin caused by ERFE and by FGL-1 takes place in a coordinated manner as has been shown in acute hemorrhage-induced anemia in rats&#59; the maximum serum level of ERFE occurs in the first 24&#160;hours of anemia while the mRNA expression of FGL-1 is delayed by up to 3 days after bleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The coordinated inhibitory activity of ERFE and FGL-1 guarantee effective negative hepcidin regulation and provision of the iron needed by the erythroid cells for hemoglobin synthesis and erythrocyte production&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a></p></span></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pathophysiology of anemia of inflammation</span><p id="par0050" class="elsevierStylePara elsevierViewall">The cause of anemia in chronic disease is complex and linked to the underlying chronic disease that causes immune system activation due to the autoantigens&#44; microbial molecules&#44; or tumour antigens that cause the release of numerous cytokines leading to elevated hepcidin and subsequent alteration of iron metabolism&#44; whose most notable processes are hypoferremia with erythropoiesis suppression&#44; reduced erythropoietin&#44; and shortened erythrocyte half-life<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Immune system activation</span><p id="par0055" class="elsevierStylePara elsevierViewall">This represents the start of AI&#46; The innate immune system activates against any external or internal aggression as a way to eliminate pathogens&#44; prevent cell damage&#44; and to facilitate resolution of the inflammatory response&#46; Immune cells have PRR &#40;pattern recognition receptors&#41; of which the Toll-like &#40;TLRs&#41; receptors&#44; and specifically TLR4&#44; detect the danger and activate due to PAMP &#40;pathogen-associated molecular patterns&#41;&#44; DAMP &#40;damage-associated molecular patterns&#41;&#44; lipopolysaccharides &#40;LPS&#41;&#44; autoantigens&#44; and tumour antigens&#44; resulting in an acute inflammatory response with cytokine release and the recruitment of leukocytes and monocytes from blood vessels to heal and repair tissue damage<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#46; While many proinflammatory cytokines are released&#44; IL6 is responsible for the increase in hepcidin in the liver &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#46; If TLR4 activation is excessive or prolonged&#44; this causes a massive cytokine release&#44; sometimes even causing a &#8220;cytokine storm&#8221; that can put the host&#8217;s life at risk&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Alterations of iron homeostasis&#44; EPO reduction&#44; and erythropoiesis suppression</span><p id="par0060" class="elsevierStylePara elsevierViewall">Increases in hepcidin cause ferroportin to break down in the enterocytes&#44; macrophages&#44; and hepatocytes&#44; facilitating iron sequestration in MPS macrophages and hypoferremia<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46; Iron deficiency in circulating blood plays a significant role in anemia since erythropoiesis stops because iron is not reaching the erythroblasts via TfR<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46; Simultaneously&#44; the stop to erythropoiesis is caused due to a reduction in EPO due to the inhibitory effect of IL-1 and TNF-&#945; in the kidneys&#44; mediated by the GATA-2 transcription gene&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and also due to the reduced expression of the EPO receptor &#40;EpoR&#41; in the erythroblasts due to the action of the cytokines and due to the lack of iron that prevents the synthesis of an EpoR regulator called <span class="elsevierStyleItalic">scribble</span> &#40;SCB&#41;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46; Erythropoiesis suppression has a negative impact on ERFE that stops hepcidin synthesis because it inhibits the SMAD pathway<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Shortened erythrocyte half-life</span><p id="par0065" class="elsevierStylePara elsevierViewall">Shortened erythrocyte half-life is another pathogenic factor in an inflammatory context and occurs due to macrophage activation by cytokines<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46; It is a lesser pathogenic factor in AI&#44; but takes on greater protagonism in serious infections and in critical situations since cytokines enhance erythrophagocytosis and hemolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In these situations&#44; anemia occurs in the initial days of the process&#44; before any decrease in erythropoiesis&#44; meaning the anemia can be explained by the shortened half-life of the erythrocytes and because of 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="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Anemia of inflammation in chronic disease</span><p id="par0070" class="elsevierStylePara elsevierViewall">All the processes that occur with chronic inflammatory phenomena can potentially cause AI and this occurs with acute&#47;chronic bacterial&#44; fungal&#44; viral&#44; and parasitic infections&#44; in chronic kidney disease &#40;CKD&#41;&#44; hospitalised patients &#40;particularly those in the intensive care unit &#91;ICU&#93;&#41;&#44; neoplasms&#44; chronic lung disease and chronic heart failure&#44; autoimmune diseases&#44; obesity&#44; and in elderly patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;11</span></a> Anemia promotes adverse clinical evolution with higher risk of hospitalisation and neuromuscular and cognitive decline&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a></p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Infectious diseases</span><p id="par0075" class="elsevierStylePara elsevierViewall">Elevated hepcidin in infections represents a defence mechanism in the host against said infection because it limits the iron available to microorganisms&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The interaction between infections&#44; iron homoeostasis&#44; and anemia has been studied in the COVID-19 and HIV epidemics&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;23</span></a> In serious infections&#44; such as COVID-19&#44; there is a hyperinflammatory state that results in cytokine storm with elevated IL-6&#44; hepcidin&#44; serum ferritin&#44; and hypoferremia levels<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;6</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46; Controlling infections improves inflammation and corrects iron imbalances&#44; but it does not always resolve anemia&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In patients with COVID-19&#44; the prevalence of anemia is 25&#37;&#44; but 70&#37; of the patients with anemia had AI&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Chronic kidney disease</span><p id="par0080" class="elsevierStylePara elsevierViewall">Chronic kidney disease presents with inflammatory processes and progressive kidney failure that causes patients to require dialysis and&#44; occasionally&#44; kidney transplant&#46; The causes of anemia in CKD include reduced EPO production&#44; absolute and&#47;or functional iron deficiency and elevated hepcidin levels<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46; The prevalence of anemia in CKD is 21&#8211;62&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> CKD presents with a bone-mineral homoeostasis disturbance&#44; and both inflammation and iron deficiency promote the production of FGF23 &#40;fibroblast growth factor <span class="elsevierStyleItalic">23</span>&#41; in the osteocytes&#44; which regulates production and vitamin D homoeostasis and has a negative effect on erythropoiesis because it blocks erythroid differentiation of hematopoietic stem cells&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> FGF23 uses &#945;Klotho to perform its physiological functions and its elevation in CKD has the purpose of promoting renal phosphate excretion to prevent hyperphosphatemia&#44; however it also promotes 1&#44;25-dihydroxyvitamin D suppression and parathyroid hormone &#40;PTH&#41; elevation&#44; causing secondary hyperparathyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Intensive care unit &#40;ICU&#41;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Anemia is common in critical patients admitted to the ICU&#44; particularly when they are admitted for more than one week&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In addition to the specific alterations of AI&#44; anemia in the ICU is associated with bleeding and shortened red blood cell lifespan due to erythrophagocytosis&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In sepsis&#44; it is common to see reduced plasma iron levels and elevated ferritin&#44; IL-6&#44; and hepcidin levels&#44; all parameters that are associated with the evolution of sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;27</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Cancer</span><p id="par0090" class="elsevierStylePara elsevierViewall">In patients with neoplasms&#44; anemia can be caused by BM infiltration&#44; antineoplastic treatment&#44; or disease progression&#44; but it can also be due to malnutrition or substances produced by the neoplastic cells such as amyloid or antibodies that cause hemolytic anemia or procoagulating factors that result in thrombotic processes or disseminated intravascular coagulation and microangiopathic hemolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> Cancers produce inflammatory processes and a tumour microenvironment in which immune system cells are activated by tumour antigens or by DAMP mediators produced by the dying cells&#46; Cytokines are released that are responsible for elevated hepcidin and the alteration of iron metabolism that negatively affect erythropoiesis&#44; resulting in AI<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;30</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Chronic pulmonary disease and congestive heart failure</span><p id="par0095" class="elsevierStylePara elsevierViewall">Respiratory failure with hypoxia presents with elevated EPO and erythropoiesis&#44; leading to secondary polycythemia with ERFE elevation that inhibits hepcidin synthesis and promotes an increase in plasma iron&#44; thus facilitating expansive erythropoiesis&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However&#44; in chronic obstructive pulmonary disease &#40;COPD&#41; and pulmonary hypertension&#44; there tends to be a sustained inflammatory process with immune system activation&#44; cytokine release&#44; hepcidin elevation&#44; alteration of iron metabolism&#44; hypoferremia&#44; and AI<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;32</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Patients with congestive heart failure &#40;CHF&#41;&#44; particularly those with reduced ejection fraction&#44; tend to present with AI and all the processes that accompany it such as inflammation&#44; elevated cytokines and hepcidin&#44; and alteration of iron metabolism&#59; however&#44; they also present with pseudo-anemia due to hemodilution via activation of the renin-angiotensin-aldosterone system that causes sodium and water retention&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> The prevalence of anemia in patients with CHF ranges from 37 to 61&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Autoimmune diseases</span><p id="par0105" class="elsevierStylePara elsevierViewall">In autoimmune diseases there is an alteration in immune tolerance with the generation of autoantigens and autoreactive T cells that instruct the B lymphocytes to produce autoantibodies of different specificities that affect multiple organs and whose clinical manifestations can be mild or severe&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Inflammation is mediated by autoantigens that activate the immune system and produce cytokines&#44; elevated hepcidin levels&#44; hypoferremia&#44; and AI<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;36</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46; Immunosuppressive therapy can affect erythropoiesis and erythrocyte half-life&#44; thus promoting anemia&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The prevalence of AI is 33&#8211;60&#37; in patients with rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Anemia in patients with inflammatory bowel disease &#40;IBD&#41; can also be caused by chronic intestinal bleeding&#44; malnutrition due to malabsorption&#44; or intestinal resections&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The prevalence of anemia in patients with IBD ranges from 6&#37; to 74&#37;&#59; AI is more common in Crohn&#8217;s disease and iron deficiency anemia is more common in ulcerative colitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a></p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Diagnosis of anemia of inflammation</span><p id="par0110" class="elsevierStylePara elsevierViewall">AI diagnosis is mainly by exclusion&#46; AI should be suspected in patients with mild&#47;moderate normocytic&#44; normochromic and hypoproliferative anemia that appears within the context of a chronic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Inflammatory processes can be unpredictable as they evolve&#44; so it is normal to observe variations in the parameters that allow us to assess iron activity&#46; In addition&#44; iron availability may be &#8220;absolute&#8221; or &#8220;functional&#8221;&#44; so it is important to perform a differential diagnosis between AI and iron deficiency anemia for an appropriate diagnostic and therapeutic approach&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">With AI there is functional iron deficiency&#44; meaning iron stores are normal or elevated because the iron is &#8220;trapped&#8221; in the MPS cells and cannot be released because hepcidin is blocking the ferroportin&#44; resulting in &#8220;relative&#8221; hypoferremia&#46; In addition to hypoferremia&#44; patients with AI present low transferrin saturation &#40;&#60;20&#37;&#41;&#44; with normal or low transferrin levels&#44; reticulocytopenia&#44; normal or increased serum ferritin &#40;&#62;100&#160;ng&#47;mL&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;40</span></a> normocytic&#44; normochromic red blood cells&#44; and an increase in hepcidin levels and levels of other acute phase reactants such as C-reactive protein or IL-6&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">On the other hand&#44; in true iron deficiency anemia&#44; there is an absolute iron deficiency&#44; with no iron in the MPS stores due to blood losses&#46; Hypoferremia is present with microcytic and hypochromic red blood cells&#44; low transferrin saturation&#44; elevated transferrin&#44; reticulocytopenia&#44; and low serum ferritin &#40;&#60;30&#160;ng&#47;mL&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Hepcidin levels do not help with clinical decision-making when assessing anemia due to the technical difficulties in measuring it and because there are no universal reference ranges available&#44; meaning they are only used in research&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The diagnostic problem arises when patients with AI also have absolute iron deficiency&#44; something that occurs on some occasions and&#44; in these cases&#44; ferritin tends to not be elevated&#44; but rather normal or low&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> If the differential diagnosis is not clear after evaluating iron tests&#44; measuring the soluble transferrin receptor &#40;sTFR&#41; and sTFR-ferritin index allows for differentiation as these are elevated in iron deficiency anemia and normal in AI&#46; What&#8217;s more&#44; reticulocyte hemoglobin content &#40;Ret-Hb&#41; is low in iron deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> In these cases&#44; we must investigate the site of bleeding since &#8220;inappropriately low&#8221; ferritin assessment in the context of AI with iron deficiency is not easy to define in clinical practise&#44; but it is important to bear in mind because treatment with intravenous iron tends to be effective&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Treatment of anemia of inflammation</span><p id="par0130" class="elsevierStylePara elsevierViewall">The treatment goal is to improve the clinical condition of the patient&#44; but not necessarily to normalise hemoglobin levels since higher morbidity-mortality has been observed in patients with terminal CKD when hemoglobin levels were normalised&#59; therefore the recommendation is to not exceed hemoglobin levels of 11&#8211;12&#160;g&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Symptoms are related to the underlying disease&#44; so the therapeutic goal should be focused on curing or improving the underlying condition&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> though anemia correction would improve patient quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Since anemia is moderate&#44; red blood cell transfusions are not typically needed and should only be considered as an emergency treatment when anemia is severe &#40;Hb&#44; &#60;8&#160;g&#47;L&#41; and there is no time to wait for a response from other therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Treatment with oral or intravenous iron supplements should only be considered in patients with concomitant iron deficiency &#40;ferritin &#60;30&#160;ng&#47;mL&#44; transferrin saturation &#60;20&#37; and elevated soluble transferrin receptor&#41;&#59; in these cases&#44; intravenous iron is preferable since it tends to be more effective and faster&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; if there is no evidence of associated iron deficiency&#44; iron therapy is not indicated because the patient has excess iron stores&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Erythropoiesis stimulating agents &#40;ESA&#41;&#44; like EPO&#44; must be administered to patients with symptomatic anemia who do not respond to treatment of their underlying disease or in the case of true associated iron deficiency that does not respond to treatment with iron supplements&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> For ESAs to stimulate red blood cell production&#44; there needs to be sufficient serum iron concentration&#46; Therefore&#44; hepcidin-mediated iron restriction can contribute to the hyporesponsiveness of ESAs that is commonly observed in CKD&#44; and which has led to the use of high doses of EPO administered jointly with intravenous iron&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a></p><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Emerging treatments</span><p id="par0150" class="elsevierStylePara elsevierViewall">The therapeutic goal of AI is to increase plasma iron levels by promoting mobilisation of the iron sequestered in the MPS cells&#44; thereby preventing hypoferremia and facilitating the transport of iron to the erythroid progenitors&#44; thus promoting erythropoiesis&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> The therapeutic target is hepcidin and various targeted strategies have been used&#44; on the one hand correcting hypoxia with prolyl hydroxylase inhibitors<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> and on the other modifying the hepcidin-ferroportin axis&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44</span></a></p><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Prolyl hydroxylase inhibitors</span><p id="par0155" class="elsevierStylePara elsevierViewall">In situations of hypoxia&#44; the activity of the prolyl hydroxylase &#40;PHI&#41; enzyme decreases&#44; resulting in an increase in the hypoxia-inducible factor &#40;HIF&#41; that induces the production of endogenous EPO&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Pharmacological PHI inhibitors stimulate renal EPO production that activates erythropoiesis&#44; increasing ERFE and reducing hepcidin levels&#44; thus promoting iron mobilisation&#44; overcoming even the hyporesponsiveness that is sometimes observed with ESAs&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46</span></a> There are many oral medications used in patients with CKD and anemia &#40;roxadustat&#44; daprodustat&#44; vadadustat&#44; molidustat&#44; enarodustat and others&#41;&#46; Roxadustat has been evaluated in 16 phase III studies and in all of them has been shown to increase EPO levels&#44; reduce hepcidin levels&#44; and increase serum iron&#44; erythropoiesis&#44; and hemoglobin levels&#44; however it can cause hypertension and thrombosis so the recommendation is to replace it with molidustat in patients at risk for either of those two conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a> Treatment with HIF-PHI must be administered jointly with intravenous iron if transferrin saturation indices are low&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Hepcidin-ferroportin axis</span><p id="par0160" class="elsevierStylePara elsevierViewall">The current therapeutic approaches aim to neutralise the role of hepcidin to facilitate the mobilisation of iron trapped in the macrophages and correct hypoferremia&#46; Multiple agents have been researched that are effective in animal and human models&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44</span></a> The main therapeutic strategies aimed at preventing the action of hepcidin involve blocking its synthesis&#44; neutralising circulating hepcidin or blocking the hepcidin-ferroportin axis&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Hepcidin synthesis inhibitors</span><p id="par0165" class="elsevierStylePara elsevierViewall">There are two ways to prevent hepcidin synthesis&#44; one related to plasma iron levels via the BMP6-HJV-SMAD pathway while the other is related to the inflammatory processes via the IL6-JAK-ATAT3 pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Inhibition via the plasma iron pathway</span><p id="par0170" class="elsevierStylePara elsevierViewall">Hepcidin synthesis is prevented by blocking the BMP-HJV-SMAD pathway&#59; the most important target is HJV&#44; against which various monoclonal antibodies &#40;ABT-207&#44; h5F9-AM8 y h5F9-23&#41; have been designed that prevent SMAD phosphorylation&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a> Another option for inhibiting the BMP pathway is recombinant erythroferrone that suppresses hepcidin by inhibiting liver signalling of BMP&#47;SMAD&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#44;53</span></a> The inhibitory activity of hepcidin attributed to FGL1 represents another therapeutic approach that should be explored&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Inhibition via the inflammatory pathway</span><p id="par0175" class="elsevierStylePara elsevierViewall">This pathway inhibits hepcidin with anti-IL6 antibodies &#40;siltuximab&#41; and anti-IL6 receptor antibodies &#40;tociluzumab&#41;&#44; which are already approved for the treatment of rheumatoid arthritis and Castleman disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#8211;56</span></a> Similar results have been obtained in patients with rheumatoid arthritis treated with TNF&#945; antibodies &#40;golimumab&#44; adalimumab&#44; infliximab&#41; via indirect suppression of IL6&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> These treatments produce immunosuppression and increase infection risk&#44; which limit their use outside of pre-approved treatment indications&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Neutralisation of circulating hepcidin</span><p id="par0180" class="elsevierStylePara elsevierViewall">These are substances that neutralise hepcidin by promoting the mobilisation of iron trapped in MPS cells&#44; thereby correcting hypoferremia and facilitating erythropoiesis&#46; The most commonly used are humanized monoclonal antibodies &#40;12B9m and LY2787106&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a> anticalins&#44; designed proteins that bind to hepcidin and inhibit its activity &#40;PRS-080&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> and aptamers of L-ARN&#44; called <span class="elsevierStyleItalic">Spiegelmer</span>&#44; that are three-dimensional structured L-oligoribonucleotides against the mirror-image of the target &#40;NOX-H94&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Blocking the hepcidin-ferroportin axis</span><p id="par0185" class="elsevierStylePara elsevierViewall">Blocking the binding of hepcidin to ferroportin facilitates the release of iron trapped in the cells and corrects anemia&#46; This has been achieved with a monoclonal antibody &#40;LY2928057&#41;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> and with fursultiamine&#44; a derivative of thiamine that blocks the C326 thiol residue that is the binding point between hepcidin and ferroportin&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a></p></span></span></span></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conclusions</span><p id="par0190" class="elsevierStylePara elsevierViewall">Anemia of inflammation is common in patients with chronic disease&#44; in the elderly&#44; and in hospitalised patients&#44; and can negatively impact their quality of life&#46; Since anemia tends to be mild&#47;moderate and occur with other&#44; often more important diseases&#44; anemia diagnosis and treatment typically garners little attention&#46; However&#44; in this paper we have provided some clear guidelines for proper diagnosis and therapeutic approach that will improve patient quality of life&#46; Knowledge of iron metabolism and the role of hepcidin in hypoferremia and in stopping erythropoiesis is the foundation for new therapeutic options whose aim is to release the iron sequestered in MPS cells and increase circulating iron to facilitate effective erythropoiesis and increased hemoglobin levels&#46; Preclinical research has shown that this is possible and there are many clinical trials that have provided us with initial agents that are effective at addressing anemia treatment in these patients&#46;</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Funding</span><p id="par0195" class="elsevierStylePara elsevierViewall">We did not receive any type of funding&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Conflicts of interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Abbreviations"
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          "titulo" => "Resumen"
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        5 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        6 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Iron metabolism regulation"
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            0 => array:3 [
              "identificador" => "sec0015"
              "titulo" => "Hepcidin synthesis regulation"
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                  "identificador" => "sec0020"
                  "titulo" => "Hepcidin synthesis activation signals"
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                      "titulo" => "Iron-activated mediation"
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                      "titulo" => "Inflammation-mediated activation"
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                  "titulo" => "Hepcidin synthesis inhibiting signals"
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          "titulo" => "Pathophysiology of anemia of inflammation"
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              "identificador" => "sec0045"
              "titulo" => "Immune system activation"
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              "titulo" => "Alterations of iron homeostasis&#44; EPO reduction&#44; and erythropoiesis suppression"
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              "identificador" => "sec0055"
              "titulo" => "Shortened erythrocyte half-life"
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          "titulo" => "Anemia of inflammation in chronic disease"
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              "identificador" => "sec0075"
              "titulo" => "Intensive care unit &#40;ICU&#41;"
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            3 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Cancer"
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            4 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Chronic pulmonary disease and congestive heart failure"
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            5 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Autoimmune diseases"
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          "identificador" => "sec0095"
          "titulo" => "Diagnosis of anemia of inflammation"
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          "titulo" => "Treatment of anemia of inflammation"
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              "titulo" => "Emerging treatments"
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                  "titulo" => "Prolyl hydroxylase inhibitors"
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                  "titulo" => "Hepcidin-ferroportin axis"
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                      "titulo" => "Hepcidin synthesis inhibitors"
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                          "titulo" => "Inhibition via the inflammatory pathway"
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                      "titulo" => "Neutralisation of circulating hepcidin"
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                      "titulo" => "Blocking the hepcidin-ferroportin axis"
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    "fechaRecibido" => "2024-06-17"
    "fechaAceptado" => "2024-06-25"
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            1 => "Hepcidin"
            2 => "Anemia"
            3 => "Inflammation"
            4 => "Chronic diseases"
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        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1904869"
          "palabras" => array:50 [
            0 => "AI"
            1 => "Act-B"
            2 => "ACD"
            3 => "ESA"
            4 => "mRNA"
            5 => "BMPR1 and BMPR2"
            6 => "BMP-HJV-SMAD"
            7 => "COVID-19"
            8 => "DAMP"
            9 => "EPO"
            10 => "COPD"
            11 => "CKD"
            12 => "ERFE"
            13 => "FGF23"
            14 => "FGL1"
            15 => "HIF"
            16 => "FPN"
            17 => "GATA"
            18 => "HAMP"
            19 => "HFE"
            20 => "HIF-PHI"
            21 => "CHF"
            22 => "IL1"
            23 => "INF"
            24 => "JAK-STAT3"
            25 => "LPS"
            26 => "LSEC"
            27 => "MT-2"
            28 => "NEO"
            29 => "NTBI"
            30 => "PAMP"
            31 => "PHI"
            32 => "PRR"
            33 => "PTH"
            34 => "EpoR"
            35 => "Ret-Hb"
            36 => "TfR"
            37 => "SCB"
            38 => "MPS"
            39 => "sTfR"
            40 => "TIBC"
            41 => "Tf"
            42 => "Tf-Fe2"
            43 => "TfR1"
            44 => "TfR2"
            45 => "TMPRSS2"
            46 => "TNF"
            47 => "TLRs"
            48 => "ICU"
            49 => "HIV"
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          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1904868"
          "palabras" => array:5 [
            0 => "Metabolismo hierro"
            1 => "Hepcidina"
            2 => "Anemia"
            3 => "Inflamaci&#243;n"
            4 => "Enfermedades cr&#243;nicas"
          ]
        ]
      ]
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Anemia of Inflammation begins with the activation of the immune system and the subsequent release of cytokines that lead to an elevation of hepcidin&#44; responsible for hypoferremia&#44; and a suppression of erythropoiesis due to lack of iron&#46; The anemia is usually mild&#47;moderate&#44; normocytic&#47;normochromic and is the most prevalent&#44; after iron deficiency anemia&#44; and is the most common in patients with chronic diseases&#44; in the elderly and in hospitalized patients&#46; Anemia can influence the patient&#8217;s quality of life and have a negative impact on survival&#46; Treatment should be aimed at improving the underlying disease and correcting the anemia&#46; Intravenous iron&#44; erythropoietin and prolyl hydroxylase inhibitors are the current basis of treatment&#44; but future therapy is directed against hepcidin&#44; which is ultimately responsible for anemia&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">La Anemia de la Inflamaci&#243;n comienza con la activaci&#243;n del sistema inmune y la posterior liberaci&#243;n de citocinas que dan lugar a una elevaci&#243;n de la hepcidina&#44; responsable de la hiposideremia y de la supresi&#243;n de la eritropoyesis por falta de hierro&#46; La anemia suele ser leve&#47;moderada&#44; normoc&#237;tica&#47;normocr&#243;mica&#44; es la m&#225;s prevalente despu&#233;s de la anemia ferrop&#233;nica y es la m&#225;s frecuente en los pacientes con enfermedades cr&#243;nicas&#44; en los ancianos y en los pacientes hospitalizados&#46; La anemia puede influir en la calidad de vida del paciente y tener un impacto negativo en la supervivencia&#46; El tratamiento debe dirigirse a mejorar la enfermedad de base y a corregir la anemia&#46; El hierro endovenoso&#44; la eritropoyetina y los inhibidores de la prolil hidroxilasa son la base actual del tratamiento&#44; pero el futuro terap&#233;utico va dirigido contra la hepcidina que es la responsable final de la anemia&#46;</p></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Iron metabolism&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Enterocyte&#58;</span> Iron in the diet is absorbed by the duodenal enterocytes&#44; presents in the ferric state &#40;Fe 3&#43;&#41;&#44; and is reduced to ferrous iron &#40;Fe 2&#43;&#41; due to the action of the DCYTB &#40;duodenal cytochrome B reductase&#41; ferrireductase&#46; Ferrous iron moves through the enterocytes via mediation of the DMT1 transporter &#40;divalent metal transporter 1&#41;&#46; In the enterocyte&#44; ferrous iron can be stored in the form of ferritin by iron chaperone PCBP1&#47;2 &#40;poly&#40;rC&#41;-binding protein 1&#47;2&#41;&#44; or it is released through the action of NCOA4 &#40;nuclear receptor coactivator 4&#41; to export it to blood circulation by means of ferroportin &#40;FPN&#41;&#46; Ferrous iron is oxidised by ferroxidase hephaestin&#44; transformed into ferric iron that binds to transferrin &#40;Tf&#41; and is then transported by circulating blood &#40;CB&#41;&#46; <span class="elsevierStyleBold">Bone Marrow &#40;BM&#41;&#58;</span> In BM&#44; erythroblasts capture the iron transported by TF through the transferrin receptors &#40;TfR&#41; and by means of endocytosis they enter side the erythroblasts where the iron is transported to the mitochondria &#40;MC&#41; by mitoferrin-1 &#40;Mfrn1&#41; and is incorporated into protoporphyrin IX &#40;PP-IX&#41; for the formation of the heme that binds to globin and starts the hemoglobinization process that results in erythrocytes that are released into CB for oxygen transport&#46; <span class="elsevierStyleBold">Macrophage&#58;</span> Senescent erythrocytes are phagocytized by liver and spleen macrophages that break down hemoglobin to release the heme that is processed by HMOX1 &#40;heme oxygenase 1&#41;&#44; therefore releasing the iron that is exported through the FPN&#46; The leftover iron is stored as ferritin in the spleen&#44; liver&#44; and BM macrophages&#46; <span class="elsevierStyleBold">Liver&#58;</span> Hepcidin expression in the liver is induced by the body&#8217;s iron stores and inflammatory signalling from the BMP&#47;SMAD and IL6&#47;JAK&#47;STAT3 pathways&#44; respectively&#44; and plays an essential role in releasing iron from its stores via FPM&#44; according to need&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Hepcidin synthesis&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">Ferric activation</span></span>&#46; The main axis that controls hepcidin synthesis is the BMP-HJV-SMAD pathway &#40;bone morphogenetic protein-hemojuvelin-sons of mothers against decapentaplegic&#41;&#46; Transferrin-bound plasma iron &#40;Tf-Fe2&#41; &#40;holotransferrin&#41; is a hepatocyte sensor for regulating hepcidin transcription because it activates the BMP-HJV-SMAD pathway&#46; In situations of hypoferremia&#44; holotransferrin binds to the transferrin receptor 1 &#40;TfR1&#41;&#44; does not activate the BMP-SMAD pathway&#44; and does not synthesize hypoferremia&#44; which helps iron reach the plasma&#46; When iron deficiency is resolved&#44; the excess nontransferrin bound iron &#40;NTBI&#41; is absorbed by liver sinusoidal endothelial cells &#40;LSEC&#41; and increases BMP6 expression&#59; simultaneously&#44; holotransferrin is moved to the transferrin receptor 2 &#40;TfR2&#41; and forms a complex with HFE &#40;human homeostatic iron regulator protein&#41; that activates BMP2&#44;5&#44;6&#44; pathway in the presence of its receptors &#40;BMPR1 and BMPR2&#41;&#44; HJV&#44; and neogenin &#40;NEO&#41; and promotes phosphorylation of SMAD1&#47;5&#47;8&#44; HAMP transcription&#44; and hepcidin synthesis&#46; <span class="elsevierStyleBold"><span class="elsevierStyleItalic">Activation due to inflammation&#46;</span></span> The other hepcidin synthesis route is inflammation via various cytokines&#44; particularly IL6 and activin B &#40;Act-B&#41;&#44; that activate the JAK-STAT3 pathway &#40;Janus kinase-signal transducer and activator of transcription&#41; and BMP&#46; <span class="elsevierStyleBold"><span class="elsevierStyleItalic">Inhibition due to hypoxia&#46;</span></span> In hypoxia conditions&#44; there are three hepcidin inhibition pathways&#46; One is through renal EPO that causes expansive erythropoiesis with an increase in erythroblasts that produce erythroferrone &#40;ERFE&#41;&#44; GDF15 &#40;growth differentiation factor&#41;&#44; and TWSG1 &#40;twisted gastrulation BMP signalling modulator&#41; and inhibit hepcidin synthesis because they block the SMAD pathway and thereby facilitate an increase in serum iron&#46; Another is an increase in FGL1 &#40;fibrinogen-like 1&#41; in the liver that blocks BMP6 and suppresses hepcidin&#59; the third is mediated by matriptase-2 &#40;MT-2&#41;&#44; encoded by gene TMPRSS6 in the liver&#44; which produces proteolysis of HJV preventing the activation of the BMP2&#44;5&#44;6 complex and hepcidin synthesis&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of anemia of inflammation&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A&#46; Activation of the immune system&#46;</span> In inflammatory processes&#44; immune system cells are activated by means of the TLR4 receptors that detect danger caused by various substances such as PAMP &#40;pathogen-associated molecular patterns&#41;&#44; DAMP &#40;damage-associated molecular patterns&#41;&#44; LPS &#40;lipopolysaccharides&#41;&#44; autoantigens or tumour antigens&#44; resulting in an acute inflammatory response with the release of cytokines &#40;IL-6&#44; IL-1&#44; IL-22&#44; interferon-&#947; &#91;IFN-&#947;&#93; and tumour necrosis factor alpha &#91;TNF-&#945;&#93;&#41;&#44; both of which are responsible for hepcidin increases and which also activate macrophages thus facilitating erythrophagocytosis&#46; On the other hand&#44; they reduce renal EPO production and prevent haemoglobinization of the erythroblasts&#46; <span class="elsevierStyleBold">B&#46; Alteration of iron metabolism</span>&#46; Hepcidin blocks ferroportin &#40;FPN&#41; from enterocytes&#44; macrophages&#44; and hepatocytes&#44; resulting in hypoferremia and iron sequestration in the macrophages in the form of ferritin&#46; Hypoferremia plays a central role in anemia since there is a stop in erythropoiesis because no iron is being transferred to the erythroblasts via the transferrin receptor &#40;TfR&#41;&#46; Erythropoiesis stoppage also occurs due to a decrease in renal EPO and lower expression of the EPO receptor &#40;EpoR&#41;&#44; due to the cytokine action and lack of iron that prevents synthesis of a regulator called scribble &#40;SCB&#41;&#46; Likewise&#44; the stop to erythropoiesis has a negative impact on the hepcidin inhibitors erythroferrone &#40;ERFE&#41;&#44; GDF15 &#40;growth differentiation factor&#41; and TWSG1&#46; The main pathways for suppressing hepcidin in hypoxia situations are also shown&#59; one is mediated by renal EPO and ERFE and the other by increased hepatic FGL1 &#40;fibrinogen-like 1&#41; that inhibits the BMP&#47;SMAD pathway&#46; <span class="elsevierStyleBold">C&#46; Different chronic diseases that present with AI&#46;</span> AI is associated with a series of diseases such as infectious diseases caused by any type of pathogen&#44; chronic kidney disease&#44; patients hospitalised for extended periods and particularly in the ICU&#44; patients with neoplasms&#44; patients with chronic lung disease and heart failure and patients with autoimmune diseases&#46; With all of these clinical situation situations there is a foundational inflammatory process with elevated hepcidin and other alterations specific to each of the described diseases&#46;</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">TLR4&#58; Toll-like receptor 4&#59; PAMP&#58; pathogen-associated molecular patterns&#59; DAMP&#58; damage-associated molecular patterns&#59; LPS&#58; lipopolysaccharides&#59; AI&#58; Anemia of inflammation&#59; Fe&#58; Iron&#59; EPO&#58; Erythropoietin&#59; FGF23&#58; fibroblast growth factor 23&#46;</p>"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2024.09.002

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