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Hepcidin, the master regulator of systemic iron homeostasis, tightly influences erythrocyte production. High hepcidin levels block intestinal iron absorption and macrophage iron recycling, causing iron restricted erythropoiesis and anemia. Low hepcidin levels favor bone marrow iron supply for hemoglobin synthesis and red blood cells production. Expanded erythropoiesis, as after hemorrhage or erythropoietin treatment, blocks hepcidin through an acute reduction of transferrin saturation and the release of the erythroblast hormone and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis, limiting iron consumption, increases transferrin saturation and stimulates hepcidin transcription. Deregulation of hepcidin synthesis is associated with anemia in three conditions: iron refractory iron deficiency anemia (IRIDA), the common anemia of acute and chronic inflammatory disorders, and the extremely rare hepcidin-producing adenomas that may develop in the liver of children with an inborn error of glucose metabolism. Inappropriately high levels of hepcidin cause iron-restricted or even iron-deficient erythropoiesis in all these conditions. Patients with IRIDA or anemia of inflammation do not respond to oral iron supplementation and show a delayed or partial response to intravenous iron. In hepcidin-producing adenomas, anemia is reverted by surgery. Other hepcidin-related anemias are the “iron loading anemias” characterized by ineffective erythropoiesis and hepcidin suppression. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and some forms of hemolytic anemias as pyruvate kinase deficiency. The paradigm is non-transfusion-dependent thalassemia where the release of erythroferrone from the expanded pool of immature erythroid cells results in hepcidin suppression and secondary iron overload that in turn worsens ineffective erythropoiesis and anemia. In thalassemia murine models, approaches that induce iron restriction ameliorate both anemia and the iron phenotype. Manipulations of hepcidin might benefit all the above-described anemias. Compounds that antagonize hepcidin or its effect may be useful in inflammation and IRIDA, while hepcidin agonists may improve ineffective erythropoiesis. Correcting ineffective erythropoiesis in animal models ameliorates not only anemia but also iron homeostasis by reducing hepcidin inhibition. Some targeted approaches are now in clinical trials: hopefully they will result in novel treatments for a variety of anemias.
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Frontiers in Physiology | www.frontiersin.org 1 October 2019 | Volume 10 | Article 1294
MINI REVIEW
published: 09 October 2019
doi: 10.3389/fphys.2019.01294
Edited by:
Anna Bogdanova,
University of Zurich, Switzerland
Reviewed by:
Kostas Pantopoulos,
McGill University, Canada
Elizabeta Nemeth,
David Geffen School of Medicine at
UCLA, United States
*Correspondence:
Clara Camaschella
camaschella.clara@hsr.it
Specialty section:
This article was submitted to
Red Blood Cell Physiology,
a section of the journal
Frontiers in Physiology
Received: 31 August 2019
Accepted: 25 September 2019
Published: 09 October 2019
Citation:
Pagani A, Nai A, Silvestri L and
Camaschella C (2019) Hepcidin and
Anemia: A Tight Relationship.
Front. Physiol. 10:1294.
doi: 10.3389/fphys.2019.01294
Hepcidin and Anemia:
A Tight Relationship
AlessiaPagani1, AntonellaNai1,2, LauraSilvestri1,2 and ClaraCamaschella1
*
1 Division of Genetics and Cell Biology, San Raffaele Scientic Institute, Milan, Italy, 2 Vita-Salute San Raffaele University, Milan, Italy
Hepcidin, the master regulator of systemic iron homeostasis, tightly inuences erythrocyte
production. High hepcidin levels block intestinal iron absorption and macrophage iron
recycling, causing iron restricted erythropoiesis and anemia. Low hepcidin levels favor
bone marrow iron supply for hemoglobin synthesis and red blood cells production.
Expanded erythropoiesis, as after hemorrhage or erythropoietin treatment, blocks hepcidin
through an acute reduction of transferrin saturation and the release of the erythroblast
hormone and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis,
limiting iron consumption, increases transferrin saturation and stimulates hepcidin
transcription. Deregulation of hepcidin synthesis is associated with anemia in three
conditions: iron refractory iron deciency anemia (IRIDA), the common anemia of acute
and chronic inammatory disorders, and the extremely rare hepcidin-producing adenomas
that may develop in the liver of children with an inborn error of glucose metabolism.
Inappropriately high levels of hepcidin cause iron-restricted or even iron-decient
erythropoiesis in all these conditions. Patients with IRIDA or anemia of inammation do
not respond to oral iron supplementation and show a delayed or partial response to
intravenous iron. In hepcidin-producing adenomas, anemia is reverted by surgery. Other
hepcidin-related anemias are the “iron loading anemias” characterized by ineffective
erythropoiesis and hepcidin suppression. This group of anemias includes thalassemia
syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and
some forms of hemolytic anemias as pyruvate kinase deciency. The paradigm is
non-transfusion-dependent thalassemia where the release of erythroferrone from the
expanded pool of immature erythroid cells results in hepcidin suppression and secondary
iron overload that in turn worsens ineffective erythropoiesis and anemia. In thalassemia
murine models, approaches that induce iron restriction ameliorate both anemia and the
iron phenotype. Manipulations of hepcidin might benet all the above-described anemias.
Compounds that antagonize hepcidin or its effect may beuseful in inammation and
IRIDA, while hepcidin agonists may improve ineffective erythropoiesis. Correcting ineffective
erythropoiesis in animal models ameliorates not only anemia but also iron homeostasis
by reducing hepcidin inhibition. Some targeted approaches are now in clinical trials:
hopefully they will result in novel treatments for a variety of anemias.
Keywords: anemia, iron, hepcidin, erythropoiesis, inammation
Pagani et al. Hepcidin and Anemia
Frontiers in Physiology | www.frontiersin.org 2 October 2019 | Volume 10 | Article 1294
INTRODUCTION
Anemia is one of the most common disorders worldwide and
anemia due to iron deciency is the prevalent form according
to multiple analyses (review in Camaschella, 2019). is type
of anemia results from the total body iron deciency and the
inability to supply the large amount of iron that the bone
marrow consumes to produce an adequate number of red blood
cells in order to maintain tissue oxygenation.
e iron availability is controlled by the liver peptide hormone
hepcidin. e body iron increase causes the production of
hepcidin, which is released in the circulation and acts on its
receptor ferroportin, a transmembrane iron exporter protein
highly expressed on enterocyte, macrophages, and hepatocytes.
Hepcidin reduces the iron entry to plasma from absorptive
duodenal cells and iron recycling macrophages by blocking
iron export (Aschemeyer et al., 2018) and by degrading the
iron exporter ferroportin (Nemeth etal., 2004). By regulating
plasma iron and systemic iron homeostasis, the hepcidin/
ferroportin axis strongly aects erythropoiesis, hence the possible
development of anemia.
THE IRON-ERYTHROPOIESIS
CONNECTION
e process of red blood cells production consumes approximately
80% of circulating iron for hemoglobin synthesis of maturing
erythroblasts. Most iron (20–25 mg/daily) is recycled by
macrophages, while a limited amount (1–2 mg daily) derives
from intestinal absorption. e kidney hormone erythropoietin
(EPO) controls the proliferation of erythroid progenitors,
especially of CFU-e and at a lower degree of BFU-e, and the
early phase of terminal erythropoiesis, while iron needs are
increased in the late dierentiation stages from proerythroblasts
to reticulocyte, for the synthesis of heme incorporated into
hemoglobin (Muckenthaler et al., 2017).
Hepcidin regulation requires a crosstalk between liver
endothelial sinusoidal cells (LSEC) that produce the bone
morphogenetic proteins (BMPs) to activate the BMP-SMAD
pathway and hepatocytes that produce and release hepcidin
(Babitt et al., 2006; Rausa et al., 2015). BMP6 and BMP2 are
the most important BMPs that upregulate hepcidin, while BMP6
expression is iron dependent (Andriopoulos etal., 2009; Meynard
et al., 2009) BMP2 appears less iron-responsive (Canali et al.,
2017; Koch et al., 2017).
Hepcidin levels are low in absolute iron deciency and iron
deciency anemia. In these conditions, the iron stores are
exhausted and the BMP-SMAD signaling is switched o at
multiple levels. First, BMP6 expression is suppressed; next, the
activity of TMPRSS6, a protease that cleaves the BMP co-receptor
hemojuvelin (Silvestri etal., 2008), is strongly increased (Lakhal
etal., 2011); and third, histone deacetylase3 (HDAC3) suppresses
the hepcidin locus (Pasricha et al., 2017). In conditions of
iron deciency, the reduction of hepcidin production is an
adaptation mechanism that facilitates dietary and pharmacological
iron absorption (Camaschella and Pagani, 2018).
When anemia is severe, the coexisting hypoxia stimulates
erythropoiesis through increased kidney synthesis and release
of EPO. is leads to suppression of hepcidin transcription by
erythroferrone (ERFE), an EPO target gene produced by
erythroblasts (Kautz etal., 2014), by molecules (e.g., PDGF-BB)
released by other tissues (Sonnweber etal., 2014), and likely by
soluble components of transferrin receptors (TFR), sTFR1 (Beguin,
2003), and sTFR2 (Pagani et al., 2015). e nal aim is to
supply enough iron for the needs of an expanded erythropoiesis.
ANEMIAS WITH ABNORMAL
HEPCIDIN LEVELS
Anemias may be classied on the basis of hepcidin levels as
anemias with high and low hepcidin. It is intuitive that persistently
high hepcidin levels, by blocking iron absorption, cause iron
deciency anemia because of decreased iron supply to erythropoiesis.
Conversely, ineective erythropoiesis characterizes the so-called
iron-loading anemias that have low hepcidin levels and iron
overload. ese two groups of anemias are the outcome of opposite
pathophysiology mechanisms (Figure 1). In the rst group, anemia
is due to the inhibitory eect exerted by hepcidin on iron
absorption and recycling that leads to systemic iron deciency;
in the second group, anemia is due to hepcidin suppression by
an expanded abnormal erythropoiesis (Camaschella and Nai, 2016).
Anemia Associated With High
Hepcidin Levels
is group includes two inherited rare disorders (iron refractory
iron deciency anemia and hepcidin-producing adenomas in
an inborn error of glucose metabolism) and an acquired common
condition: anemia of inammation (Table 1 ).
Iron Refractory Iron Deciency Anemia
Iron refractory iron deciency anemia (IRIDA) is a rare recessive
disorder characterized by hypochromic microcytic anemia, low
transferrin saturation, and inappropriately normal/high hepcidin
levels. It is caused by mutations of TMPRSS6 (Finberg et al.,
2008), a gene that encodes the type II serine protease, matriptase-2
(Du et al., 2008). Mutations of TMPRSS6 are spread along the
gene and may aect dierent domains especially the catalytic
domain (De Falco et al., 2014). is transmembrane protease,
highly expressed in the liver, inhibits hepcidin transcription by
cleaving the cell surface BMP co-receptor hemojuvelin, thus
attenuating the BMP signaling and hepcidin synthesis (Silvestri
et al., 2008). TMPRSS6 function is essential in iron deciency
to allow the compensatory mechanism of increased iron absorption.
IRIDA is present since birth and usually diagnosed in
childhood. Compared with classic iron deciency, iron parameters
are atypical and raise the suspicion of the disease. e percent
saturation of transferrin is strongly reduced (less than 10%)
as in other forms of iron deciency; however, at variance with
iron deciency, levels of serum ferritin are normal/increased
(Camaschella, 2013; De Falco et al., 2013). is reects an
increased ferritin accumulation in macrophages, due to the
high hepcidin levels that induce store iron sequestration.
Pagani et al. Hepcidin and Anemia
Frontiers in Physiology | www.frontiersin.org 3 October 2019 | Volume 10 | Article 1294
None of the tests proposed for IRIDA diagnosis covers 100%
of the cases. e genetic test identies that TMPRSS6 mutations,
that in some cases (non-sense, frame-shi, and splicing
mutations), are clearly causal. In other cases, as for previously
unreported missense mutations, functional studies are needed
to demonstrate causality (Silvestri et al., 2013). However, these
tests are scarcely available. Serum hepcidin levels are usually
increased/normal, independently of iron deciency, and consistent
with high/normal ferritin. It is important to exclude inammation
by concomitantly dosing C-reactive protein.
Some patients with a phenotype of refractory iron deciency
have been reported to have a single TMPRSS6 mutated allele;
here, the debate is whether they should be considered IRIDA
or not. A spectrum of conditions can be envisaged ranging
from classic severe IRIDA due to homozygous or compound
heterozygous TMPRSS6 mutations to increased susceptibility to
iron deciency conferred by single mutations/polymorphic changes.
One approach proposed to predict classic IRIDA is hepcidin
normalization on other iron parameters, as ratios transferrin
saturation (Tsat)/log hepcidin or Tsat/log Ferritin (Donker etal.,
2016). According to other authors, most patients with a severe
IRIDA phenotype have biallelic TMPRSS6 mutations and, when
unidentied, the second allele may begenetically occult (Heeney
et al., 2018). In general terms, subjects with a single allele have
a milder phenotype than those with two mutations and respond
better to iron treatment (Donker et al., 2016). Interestingly,
several TMPRSS6 SNPs have been shown to provide susceptibility
to iron deciency in some populations (An et al., 2012) and
in blood donors (Sorensen et al., 2019).
A digenic inheritance has been reported in a 5-year-old
female originally found to have an atypical IRIDA genotype
with one TMPRSS6 (I212T) causal and one (R271Q) silent
mutation (De Falco et al., 2014). She was later diagnosed
Fibrodysplasia ossicans progressiva (FOP), a rare dominant
AB
FIGURE 1 | Schematic representation of mechanisms of anemias with high (left panel) and low hepcidin (right panel). Panel (A). Molecular pathogenesis of anemia
associated with high hepcidin levels. LSEC, liver sinusoidal endothelial cells producing bone morphogenetic proteins (BMPs); BMPRs, BMP receptors; IL6,
interleukin 6; HC, hepatocytes; HAMP, hepcidin gene. Fe, iron; FPN, ferroportin; 1, IRIDA; 2, Anemia of inammation; 3, hepcidin producing adenoma. Panel (B).
Molecular pathogenesis of hepcidin variation in anemias due to ineffective erythropoiesis. ERFE, erythroferrone sequestering BMPs. Other mechanisms inhibiting
hepcidin in this type of anemia, as decrease of transferrin saturation and hypoxia, are not shown. See text for details.
Pagani et al. Hepcidin and Anemia
Frontiers in Physiology | www.frontiersin.org 4 October 2019 | Volume 10 | Article 1294
disorder with ectopic bone formation in so tissues due to
mutated BMP type I receptor gene ACVR1, encoding ALK2
(Shore et al., 2006). e pathological allele ALK2R258S is
constitutively active since the mutation aects the glycine-
serine-rich domain of the gene and renders the BMP/SMAD
pathway overactive being unable to bind its specic inhibitor
FKBP12 (Pagani et al., 2017).
is rare case is especially illustrative. First, since the ALK2
glycine-serine-rich domain interacts with FKBP12 and the
mutation destabilizes the binding, it has revealed a previously
unsuspected role for FKBP12 as a modulator of liver ALK2
and hepcidin (Colucci etal., 2017). Second, it has led to identify
a link between activation of bone and liver BMP type Ireceptors.
ird, the case strengthens the relevance of intact TMPRSS6in
controlling the hepatic BMP/SMAD signaling, since no IRIDA
was identied among other FOP patients with the same ACVR1
mutation and presumably normal TMPRSS6 (Pagani et al.,
2017). Finally, this case is consistent with the concept that
TMPRSS6 haploinsuciency cannot cause classic IRIDA.
e optimal treatment of IRIDA is undened. Oral iron is
ineective, since it is not absorbed. e addition of vitamin
C allows sporadic response. Intravenous iron induces a partial
response usually at a slower rate in comparison with patients
with acquired iron deciency. EPO is ineective in classic
cases (De Falco et al., 2013; Heeney and Finberg, 2014).
Anemia of Hepcidin-Producing Adenomas
is is an extremely rare condition in adult patients aected
by glycogen storage disease 1a, a recessive disorder due to
deciency of glucose-6 phosphatase, which catalyzes a reaction
involved in both glycogenolysis and gluconeogenesis. A common
dangerous disease symptom is hypoglycemia. e current
treatment leads to prolonged survival of aected children up
to adult age with the occurrence of several complications, such
as anemia and liver adenomas. Anemia is microcytic and
hypochromic, iron decient, and refractory to oral iron treatment.
Anemia reverted aer surgical adenoma resection. Adenoma
tissue was found positive for hepcidin mRNA, while normal
surrounding tissue showed hepcidin suppression, as expected
because of the ectopic uncontrolled hepcidin production
(Weinstein et al., 2002). e hematological features of patients
resemble those of IRIDA as they share high hepcidin levels
as a common mechanism of anemia.
Anemia of Inammation
Anemia of inammation (AI), previously known as anemia
of chronic diseases, is a moderate normochromic-normocytic
anemia that develops in conditions of systemic inammation
and immune activation. It occurs in several common disorders,
including chronic infections, autoimmune diseases, advanced
cancer, chronic kidney disease, congestive heart failure, chronic
obstructive pulmonary disease, anemia of the elderly (at least
partly), and gra versus host disease. AI is one of the most
common anemias worldwide and the most frequent anemia
in hospitalized patients. Acute inammation contributes to the
severity of anemia in intensive care units. Molecular mechanisms
underlying AI are multiple and complex. Overproduction of
cytokines such as IL1-β, TNF-α, and IL-6 by macrophages
and INF-γ by lymphocytes blunts EPO production, impairs
the erythropoiesis response, increases hepcidin levels, and may
activate erythrophagocytosis, especially in the acute forms (Wei ss
and Goodnough, 2005; Ganz, 2019).
Hepcidin is activated by IL-6 through IL-6 receptor (IL-6R)
and JAK2-STAT3 signaling. Full hepcidin activation requires
an active BMP-SMAD pathway because inactivation of BMP
signaling decreases hepcidin in animal models of inammation
(eurl et al., 2011). e deregulation of systemic iron
homeostasis causes macrophage iron sequestration and reduced
absorption and recycling that leads to low saturation of transferrin
and iron restriction of erythropoiesis and other tissues.
Traditional treatment of AI is based on reversibility/control
of the underlying disease, whenever possible. If the disease is
untreatable and anemia is mild, a careful evaluation of risks-
benets is needed to avoid side eects of any treatment.
Pathophysiology-based treatments are limited to erythropoietin-
like compounds and iron. e use of erythropoiesis stimulating
agents (ESA) suppresses hepcidin by inducing erythropoiesis
expansion. is approach is widely used in patients with chronic
kidney disease, low-risk myelodysplastic syndromes, and cancer
undergoing chemotherapy. However, a careful clinical control
is necessary because high doses have cardiovascular side eects.
e administration of intravenous iron may relieve iron
restriction, caused by ESA-dependent expansion of erythropoiesis.
Oral iron is usually ineective since the high hepcidin levels
counteract its intestinal absorption. Inhibitors of prolyl
hydroxylase (hypoxia inducible factor, HIF stabilizers) are
experimental in chronic kidney disease, to the aim of increasing
endogenous EPO. Chronic treatment with red blood cells
transfusions is not recommended because of transient eect
and adverse reactions; it is limited to severe refractory anemia
(Camaschella, 2019; Weiss et al., 2019).
TABLE 1 | Anemias classied according to hepcidin levels.
High-hepcidin anemias
Hereditary OMIM n. Prevalence
Iron refractory iron deciency anemia (IRIDA) #206200 Rare
Hepcidin-producing adenomas* #232200 Rare
Acquired
Anemia of acute inammation Common**
Anemia of chronic inammation
(anemia of chronic disease)
Common
Low-hepcidin anemias
Hereditary – iron loading anemias OMIM n.
β-thalassemia #613985 Common***
Congenital dyserythropoietic anemia #224100 Rare
Sideroblastic anemias #300751 Rare
Acquired
Low risk MDS with ringed sideroblasts Rare
OMIM, online Mendelian Inheritance In Man; MDS, myelodysplastic
syndromes.*Described in glycogen-storage-disease 1a.
**In hospitalized patients and in intensive care units.
***In people of Mediterranean or southern-east Asian origin.
Pagani et al. Hepcidin and Anemia
Frontiers in Physiology | www.frontiersin.org 5 October 2019 | Volume 10 | Article 1294
Anemias Associated With
Low Hepcidin Levels
Ineective erythropoiesis and low or inappropriately normal
hepcidin levels, with consequent iron overload, are typical
features of the “iron-loading anemias. e prototype is
β-thalassemia, a genetic recessive disease due to β-globin gene
mutations that cause anemia and excess α-globin chain production.
e latter precipitates as hemichromes in the bone marrow,
damaging maturing erythroid precursors and leading to ineective
erythropoiesis. is occurs in non-transfusion-dependent
thalassemia or thalassemia intermedia, whose erythropoiesis is
characterized by the prevalence of immature cells that release
erythroferrone to inhibit liver hepcidin expression. Hepcidin
levels are usually greater in transfusion-dependent thalassemia,
where endogenous ineective erythropoiesis is at least partially
suppressed by transfusions (Camaschella and Nai, 2016).
Hepcidin suppression is mediated by the increased cytokine
erythroferrone (ERFE), a member of the TNF-α family encoded
by ERFE gene, synthesized by erythroblasts upon EPO stimulation
(Kautz et al., 2014). ERFE is released into the circulation and
sequesters BMPs, especially BMP6 (Arezes etal., 2018), attenuating
the hepcidin signaling in response to iron. In addition, an
epigenetic suppression occurs at the hepcidin locus by histone
deacetylase HDAC3 (Pasricha etal., 2017). When anemia causes
hypoxia, other mediators such as PDGF-BB (Sonnweber et al.,
2014), which is released by dierent cell types, suppress hepcidin.
Hepcidin levels are decreased by a special mechanism in
low-risk myelodysplasia with ringed sideroblasts, a clonal disorder
due to mutations of the spliceosome gene SF3B1. Iron accumulates
in mitochondria, leading to ineective erythropoiesis and systemic
iron overload. An abnormally spliced, elongated ERFE protein
is more powerful than wild type ERFE in suppressing hepcidin
(Bondu et al., 2019) and causing transfusion-independent
iron loading.
TARGETED THERAPIES FOR HEPCIDIN-
RELATED ANEMIAS
e identication of molecular mechanisms responsible of the
previously discussed anemias has stimulated research in developing
targeted therapies to replace current symptomatic treatment
(Sebastiani etal., 2016; Crielaard etal., 2017). Approaches dier
according to the type of anemia and the aim of decreasing or
increasing hepcidin levels or their eects (Tab l e 2).
Experimental Therapies to Decrease
Hepcidin Levels/Increase Ferroportin
Function
Except for hepcidin producing tumors, which have to besurgically
removed, compounds that antagonize hepcidin or its eects
may be useful in all anemias characterized by high hepcidin
levels. eir main application would bein chronic inammatory
diseases in order to reverse hypoferremia and anemia.
Several experimental therapies aimed at manipulating the hepcidin
pathway and its function have been investigated in preclinical
studies. Hepcidin antagonists are inhibitors of hepcidin synthesis/
regulators (Ganz, 2019), hepcidin binders that block its function,
and compounds that interfere with hepcidin-ferroportin interaction
(Tab l e 2). Some compounds are in clinical trials especially in
chronic kidney disease (Sheetz etal., 2019). In IRIDA, manipulation
of the hepcidin pathway has been proposed in preclinical studies
with the use of anti-HJV MoAb (Kovac et al., 2016).
Experimental Therapies to Increase Hepcidin
Levels/Decrease Ferroportin Function
Increasing hepcidin levels may not only reduce iron overload
but also partially control ineective erythropoiesis in iron
loading anemias. β-thalassemia is the most studied among these
conditions (Casu et al., 2018; Gupta et al., 2018). Proposed
drugs are hepcidin analogs (some in clinical trials), hepcidin
modulators, especially TMPRSS6 inhibitors, or compounds that
interfere with hepcidin-ferroportin interaction decreasing iron
export (Tabl e 2).
While compounds that increase hepcidin reduce ineective
erythropoiesis due to the vicious cycle between ineective
erythropoiesis and iron loading (Camaschella and Nai, 2016),
drugs that favor erythroid precursor maturation, as the activin
receptor IIB ligand trap, luspatercept, not only improve anemia
but also ameliorate iron homeostasis by reducing hepcidin
inhibition (Piga et al., 2019).
Some targeted approaches now in clinical trials will hopefully
result in novel treatments for a variety of anemias.
TABLE 2 | Experimental therapies targeting the hepcidin-ferroportin axis.
Mechanism Compounds
Compounds that decrease hepcidin or increase ferroportin function
Class I Reduction of the signaling
pathway stimulating hepcidin
Anti IL6-R, anti IL-6
Anti-BMP6 MoAb*
BMPR inhibitors
Anti-HJV MoAb
Non anticoagulant heparins
Class II Hepcidin binders Anti-HAMP MoAb
Oligonucelotides aptamers
Class III Interfering with hepcidin-FPN
interaction
Anti-FPN MoAb, GDP
Compounds that increase hepcidin or decrease ferroportin function
Class I Hepcidin mimics Hepcidin analogues*
Minihepcidin
Class II Activating hepcidin BMPs (preclinical studies)
Blocking the hepcidin inhibitor Anti-TMPRSS6 (siRNA, ASO*)
Blocking the hepcidin
receptor
FPN Inhibitors*
Class III Others Human transferrin infusions
Protoporphyrin IX (inhibition of HO)
Bone marrow TFR2 inactivation
BMPR, BMP receptor; HAMP, hepcidin gene; HJV, hemojuvelin; MoAb, monoclonal
antibody; FPN, ferroportin; siRNA, small interfering RNA; ASO, antisense oligonucleotides;
GDP, guanosine 5 diphosphate; HO, heme oxygenase; TFR2, transferrin receptor 2.
Compounds indicated by * are in clinical trials.
Pagani et al. Hepcidin and Anemia
Frontiers in Physiology | www.frontiersin.org 6 October 2019 | Volume 10 | Article 1294
CONCLUSION
e spectacular advances in understanding the regulation
of iron metabolism and hepcidin allowed a better
understanding of erythropoiesis control, since together with
erythropoietin iron is a fundamental factor for erythroid
cells maturation. Conditions that lead to anemia can
be associated with high and low hepcidin levels. In both
instances, contrasting hepcidin deregulation may ameliorate/
correct anemia in preclinical models, oering new tools that
are already or will besoon clinically explored for the treatment
of specic anemias.
AUTHOR CONTRIBUTIONS
AP draed the paper. CC developed the nal version. AN
and LS contributed to writing and to critical review the
manuscript. All the authors approved the nal version.
FUNDING
is paper was supported in part by an EHA Advanced Research
Grant in 2018 to AP. Cariplo Foundation Young Investigator
Grant n° 2017-0916 to AN.
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Conict of Interest: CC is a consultant of Vifor Pharma, Celgene, and Novartis.
e remaining authors declare that the research was conducted in the absence
of any commercial or nancial relationships that could beconstrued as a potential
conict of interest.
Copyright © 2019 Pagani, Nai, Silvestri and Camaschella. is is an open-access
article distributed under the terms of the Creative Commons Attribution License (CC
BY). e use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice. No
use, distribution or reproduction is permitted which does not comply with these terms.
... Hepcidin is a key regulator of the entry of iron into the circulation in mammals (Pandey et al., 2018). Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemia, and its excess is associated with anemia of inflammation, chronic disease and iron deficiency anemia (IDA) (Pagani et al., 2019). Liver is the main source of Hepc (Nemeth and Ganz, 2021). ...
... Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell (Pagani et al., 2019). Ferroportin is the only known iron exporter, it is present on the basolateral surface of duodenal enterocytes; that export absorbed iron into blood, as well as on macrophages and other storage cells, which export stored iron into the circulation (Sukhbaatar and Weichhart, 2018). ...
... During conditions in which the Hepc level is abnormally high, such as inflammation; serum iron falls due to iron trapping within macrophages and liver cells and decreased gut iron absorption (Madeddu et al., 2018). This typically leads to anemia due to an inadequate amount of serum iron being available for developing red blood cells (Pagani et al., 2019). ...
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Abstract Endometrial carcinoma (EC) is a common malignancy in female reproductive system, and its incidence is increasing. Surgery and postoperative radiotherapy are routinely used methods for treating this condition, but there is still a lack of effective treatment for recurrent or progressive EC. Thus, there is an urgent need to identify additional biological markers for the prognostic prediction of EC. Fifty seven patients with EC and 55 healthy women (with age up to 35 year) were involved in this study during their attendance at the Medicine City Hospital of Baghdad and Al-Yarmok hospital. The study was conducted from October 2020 to October 2021, written informal consent was obtained from all patients and the study was approved by ethical committees: Ref.: CSEC/0122/0061, January 20, 2022 of department of Biology, College of Science, University of Baghdad. Blood samples were collected from each participants via vein puncture for assessment the follwing interleukins: interleukin-27 (IL-27), interleukin-31 (IL31), interleukin -33 (IL-33), interleukin- 35 (IL-35), interleukin-36 (IL-36) and interleukin-38 (IL38). Some proteins also assesment in this study, include: Transforming growth factor-beta (TGF�β), Hepcidin (Hepc), Phosphatase and Tensin Homolog (PTEN), C-reactive protein (CRP) and Tumor marker Human epididymis protein 4 (HE4). As well as, the fresh blood was collected for deoxyribonucleic acid (DNA) extraction. PCR products: was performed for sequencing by the genetic analyzer, for forward and reverse primers, in macrogen company; (South Korea) to detect the polymorphism in of rs2735343 SNP of PTEN gene in EC patients. The results in present study showed a highly significant (P≤0.01) increase in IL-27, IL-31, IL-33, IL-35, IL-36 and IL-38 concentration in women with EC compared with healthy controls. Also, statistical analyses of this study showed that there was a highly significant (P≤0.01) increase II of TGF- β, HE4 hepc hormone level and CRP in women with EC compared with healthy controls. While, PTEN protein concentration was show highly significant (P≤0.01) decrease in EC patients compared with healthy control. DNA isolated from: patients and controls was amplification of PTEN by using new set of primers to amplify 450 bp from rs2735343 SNP for being use in sequencing. The genotypes frequency of C allele is in higher in EC rs2735343 (0.54) than healthy (0.17), while G allele was lowest percentage, in patients (0.46) than in healthy women (0.83). The SNP rs2735343 genotypes frequency in patients describe as follow: GG (18.18%), GC (56.36%) and CC (25.45%). While, in healthy group, the genotypes frequency was: GG (70.18%), GC (26.32%) and CC (3.50%). The SNP rs2735343 genotypes frequency showed a highly significant different (P≤0.01) in Wild type (GG) in control grop when compered with patients of EC. And highly, significant (P≤0.01) increase in mutant genotype (CC) in EC patient when compered with healthy control. The result show significant (P≤0.05) increase in heterozygous (GC) genotype in EC patient compered with healthy women. It can be concluded that the increase the level of some interleukins like: IL-27, 31, 33, 35, 36 and 38 could be used in the early diagnosis for EC and in accurate prognostic diagnosis. Also, TGF- β and HE-4 proteins could be used in the early diagnosis for EC. Addition of hepcidin and CRP estimation to TGF- β and HE-4 proteins results in accurate prognostic diagnosis. Polymorphesm of rs2735343 SNP in PTEN gene also can help in predignosis of EC.
... Enhanced erythroid hematopoiesis excessively suppresses hepcidin production. Thalassemia patients who are not dependent on blood transfusions can also develop iron overload and low serum hepcidin levels have been reported in patients with thalassemia [23]. Ineffective hematopoiesis in thalassemia promotes erythroblast formation in the bone marrow and promotes the secretion of GDF-15 or erythroferrone from erythroblast progenitor cells [22,24]. ...
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Background Neonatal hemochromatosis causes acute liver failure during the neonatal period, mostly due to gestational alloimmune liver disease (GALD). Thalassemia causes hemolytic anemia and ineffective erythropoiesis due to mutations in the globin gene. Although neonatal hemochromatosis and thalassemia have completely different causes, the coexistence of these diseases can synergistically exacerbate iron overload. We report that a newborn with εγδβ-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation. Case presentation A 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδβ-thalassemia by genetic testing, and required frequent red blood cell transfusions. At 2 months after birth, exacerbation of jaundice, grayish-white stool, and high serum ferritin levels were observed, and liver biopsy showed iron deposition in hepatocytes and Kupffer cells. Magnetic resonance imaging scans showed findings suggestive of iron deposits in the liver, spleen, pancreas, and bone marrow. The total amount of red blood cell transfusions administered did not meet the criteria for post-transfusion iron overload. Administration of an iron-chelating agent was initiated, but iron overload rapidly progressed to liver failure without improvement in jaundice and liver damage. He underwent living-donor liver transplantation from his mother, after which iron overload disappeared, and no recurrence of iron overload was observed. Immunohistochemical staining for C5b-9 in the liver was positive. Serum hepcidin levels were low and serum growth differentiation factor-15 levels were high prior to living-donor liver transplantation. Conclusions We reported that an infant with εγδβ-thalassemia developed NH due to GALD, and that coexistence of ineffective erythropoiesis in addition to erythrocyte transfusions may have exacerbated iron overload. Low serum hepcidin levels, in this case, might have been caused by decreased hepcidin production arising from fetal liver damage due to neonatal hemochromatosis and increased hepcidin-inhibiting hematopoietic mediators due to the ineffective hematopoiesis observed in thalassemia.
... Hepcidin has also been related to severe cases of anemia 61 . ...
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Iron is essential to human survival. The biological role and trafficking of this trace essential inorganic element which is also a potential toxin is constantly being researched and unfolded. Vital for oxygen transport, DNA synthesis, electron transport, neurotransmitter biosynthesis and present in numerous other heme and non-heme enzymes the physiological roles are immense. Understanding the molecules and pathways that regulate this essential element at systemic and cellular levels are of importance in improving therapeutic strategies for iron related disorders. This review highlights the progress in understanding the metabolism and trafficking of iron along with the pathophysiology of iron related disorders.
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Introduction Obesity is linked to a variety of unfavourable outcomes, including anaemia, which is a serious global public health problem. The prevalence of obesity along with anaemia suggests a relationship between obesity and anaemia. Recent studies have demonstrated strong associations between anaemia and obesity, chronic diseases, ageing, hepato-renal impairment, chronic infection, autoimmune diseases, and widespread malignancy. Thus, the intersection point of obesity and anaemia is an important area of attention. Area Covered This paper reviews the pathophysiology of obesity and anaemia. Then, It deliberates the relationship between obesity and different types of anaemia and other clinical forms associated with anaemia. Expert Opinion Obesity, especially obesity-related to excessive visceral fat distribution, is accompanied by several disturbances at the endothelial, hormonal, and inflammatory levels. These disturbances induce activation of several mechanisms that contribute to the anaemic state. Over-weight patients with chronic anaemias are required to maintain the related vitamins and minerals at optimum levels and appropriate BMI. In addition, a regular clinical follow-up is essential to be scheduled to reduce the risk of complications associated with anaemia in obese patients.
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Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. Patients with MDS with SF3B1 mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript in patients with MDS with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1 -mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with SF3B1 -mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1 -mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.
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Anemia of inflammation (AI), also known as anemia of chronic disease (ACD), is regarded as the most frequent anemia in hospitalized and chronically ill patients. It is prevalent in patients with diseases that cause prolonged immune activation, including infection, autoimmune diseases, and cancer. More recently, the list has grown to include chronic kidney disease, congestive heart failure, chronic pulmonary diseases, and obesity. Inflammationinducible cytokines and the master regulator of iron homeostasis, hepcidin, block intestinal iron absorption and cause iron retention in reticuloendothelial cells, resulting in iron-restricted erythropoiesis. In addition, shortened erythrocyte half-life, suppressed erythropoietin response to anemia, and inhibition of erythroid cell differentiation by inflammatory mediators further contribute to AI in a disease-specific pattern. Although the diagnosis of AI is a diagnosis of exclusion and is supported by characteristic alterations in iron homeostasis, hypoferremia, and hyperferritinemia, the diagnosis of AI patients with coexisting iron deficiency is more difficult. In addition to treatment of the disease underlying AI, the combination of iron therapy and erythropoiesis-stimulating agents can improve anemia in many patients. In the future, emerging therapeutics that antagonize hepcidin function and redistribute endogenous iron for erythropoiesis may offer additional options. However, based on experience with anemia treatment in chronic kidney disease, critical illness, and cancer, finding the appropriate indications for the specific treatment of AI will require improved understanding and a balanced consideration of the contribution of anemia to each patient's morbidity and the impact of anemia treatment on the patient's prognosis in a variety of disease settings.
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Juvenile hemochromatosis is a severe iron overload disorder resulting from mutations in the hemojuvelin (HJV) gene. To understand its pathogenesis, we developed Hjv−/− mice. Similar to human patients, Hjv−/− animals accumulate excess iron in the liver, pancreas and heart early in life. Tissue macrophages are iron-depleted. Hjv−/− mice express very low levels of hepcidin mRNA and, likely as a consequence, have elevated expression of the iron transporter ferroportin in enterocytes and macrophages. These results suggested that Hjv plays a role in regulating hepcidin expression. Two known Hjv homologs, Rgma and Rgmb, have previously been shown to act as bone morphogenetic protein (BMP) co-receptors. We hypothesized that Hjv regulates hepcidin expression through a BMP signal transduction pathway. We found that Hjv binds radiolabeled BMP, supporting the contention that it is a BMP co-receptor. Transfection of HepG2 cells with Hjv cDNA activated a BMP-responsive reporter construct and augmented its response to exogenous BMP. Both an anti-BMP neutralizing antibody and the natural BMP antagonist Noggin blocked this response, as did co-expressed dominant negative BMP receptor proteins. When cells were transfected with a construct carrying an Hjv mutation known to cause human disease, BMP reporter activation was significantly reduced in the presence and absence of exogenous BMP. Treatment with BMP stimulated hepcidin production in hepatoma cells and activated a reporter construct containing a fragment of the hepcidin promoter. To extend these results, we studied tissues from Hjv−/− mice. BMP signals are transduced through phosphorylation of Smad proteins. We found that Smads 1, 5 and 8 were hypophosphorylated in Hjv−/− liver, consistent with impaired BMP signaling. BMP treatment of wild type and Hjv−/− primary hepatocytes induced hepcidin expression, but induction was blunted in cells from Hjv−/− animals. Taken together, these data suggest that the normal hepatic function of Hjv is to serve as a BMP co-receptor, modulating a signal transduction pathway that culminates in hepcidin expression. [Note - Jodie L. Babitt is the first author of this abstract, but it will be presented by Franklin W. Huang, the second author]
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Anemia of inflammation is a highly prevalent syndrome associated with systemic inflammation. In its most common form, anemia of inflammation is readily diagnosed as a normocytic, normochromic anemia associated with low transferrin saturation but a high serum ferritin level. With currently available treatment approaches, therapeutic measures directed at the underlying disease are most likely to result in improved outcomes that are meaningful to patients. An increased understanding of the pathogenesis of anemia of inflammation has stimulated the ongoing development of targeted therapies that may offer additional treatment options in the future.
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Aims: Erythropoiesis-stimulating agents used to treat anaemia in patients with chronic kidney disease (CKD) have been associated with cardiovascular adverse events. Hepcidin production, controlled by bone morphogenic protein 6 (BMP6), regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anaemia in CKD patients. To investigate alternative therapies to erythropoiesis-stimulating agents for CKD patients, monoclonal antibodies, LY3113593 and LY2928057, targeting BMP6 and ferroportin respectively, were tested in CKD patients. Methods: Preclinical in vitro/vivo data and clinical data in healthy subjects and CKD patients were used to illustrate the translation of pharmacological properties of LY3113593 and LY2928057, highlighting the novelty of targeting these nodes within the hepcidin-ferroportin pathway. Results: LY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower haemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (mean [90% confidence interval]) 1.98 [1.46-2.68] and 1.36 [1.22-1.51] fold-relative to baseline following LY2928057 600 mg and LY311593 150 mg respectively in CKD patients. LY3113593 specifically blocked BMP6 binding to its receptor and produced increases in iron and transferrin saturation and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in haemoglobin and reduction in ferritin (compared to placebo). Conclusion: LY3113593 and LY2928057 pharmacological effects (serum iron and ferritin) were translated from preclinical-to-clinical development. Such interventions may lead to new CKD anaemia treatments.
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β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
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BACKGROUND Blood donors have an increased risk of low hemoglobin (Hb) levels due to iron deficiency. Therefore, knowledge of genetic variants associated with low Hb could facilitate individualized donation intervals. We have previously reported three specific single‐nucleotide polymorphisms that were associated with ferritin levels in blood donors. In this study, we investigated the effect of these single‐nucleotide polymorphisms on Hb levels in 15,567 Danish blood donors. STUDY DESIGN AND METHODS We studied 15,567 participants in the Danish Blood Donor Study. The examined genes and single‐nucleotide polymorphisms were 1) TMPRSS6, involved in regulation of hepcidin: rs855791; 2) HFE, associated with hemochromatosis: rs1800562 and rs1799945; 3) BTBD9, associated with restless leg syndrome: rs9357271; and 4) TF, encoding transferrin: rs2280673 and rs1830084. Associations with Hb levels and risk of Hb deferral were assessed in multivariable linear and logistic regression models. RESULTS The HFE,rs1800562 G‐allele and the HFE rs1799945 C‐allele were associated with lower Hb levels in men and women, and with an increased risk of Hb below 7.8 mmol/L (12.5 g/dL) in women. Only the rs1799945 C‐allele increased the risk of Hb below 8.4 mmol/L (13.5 g/dL) in men. In TMPRSS6, the rs855791 T‐allele was associated with lower Hb levels in both men and women, and with an increased risk of low Hb among women. CONCLUSION With this study we demonstrate that HFE and TMPRSS6 are associated with Hb levels and risk of Hb below the limit of deferral. Thus, genetic testing may be useful in a future assay for personalized donation intervals.
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Iron deficiency anemia affects >1.2 billions individuals worldwide, and iron deficiency in the absence of anemia is even more frequent. Total-body (absolute) iron deficiency is caused by physiologically increased iron requirements in children, adolescents, young and pregnant women, by reduced iron intake, or by pathological defective absorption or chronic blood loss. Adaptation to iron deficiency at the tissue level is controlled by iron regulatory proteins to increase iron uptake and retention; at the systemic level, suppression of the iron hormone hepcidin increases iron release to plasma by absorptive enterocytes and recycling macrophages. The diagnosis of absolute iron deficiency is easy unless the condition is masked by inflammatory conditions. All cases of iron deficiency should be assessed for treatment and underlying cause. Special attention is needed in areas endemic for malaria and other infections to avoid worsening of infection by iron treatment. Ongoing efforts aim at optimizing iron salts–based therapy by protocols of administration based on the physiology of hepcidin control and reducing the common adverse effects of oral iron. IV iron, especially last-generation compounds administered at high doses in single infusions, is becoming an effective alternative in an increasing number of conditions because of a more rapid and persistent hematological response and acceptable safety profile. Risks/benefits of the different treatments should be weighed in a personalized therapeutic approach to iron deficiency.
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Key Points ERFE suppresses BMP/SMAD signaling in vitro and in vivo. ERFE inhibits hepcidin induction by BMP5, BMP6, and BMP7.
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Recent years have witnessed impressive advances in our understanding of iron metabolism. A number of studies of iron disorders and of their animal models have provided landmark insights into the mechanisms of iron trafficking, distribution and homeostatic regulation, the latter essential to prevent both iron deficiency and iron excess. Our perception of iron metabolism has been completely changed by an improved definition of cellular and systemic iron homeostasis, of the molecular pathogenesis of iron disorders, the fine tuning of the iron hormone hepcidin by activators and inhibitors and the dissection of the components of the hepcidin regulatory pathway. Important for haematology, the crosstalk of erythropoiesis, the most important iron consumer, and the hepcidin pathway has been at least partially clarified. Novel potential biomarkers are available and novel therapeutic targets for iron‐related disorders have been tested in murine models. These preclinical studies provided proofs of principle and are laying the ground for clinical trials. Understanding iron control in tissues other than erythropoiesis remains a challenge for the future.