Frontiers in Physiology | www.frontiersin.org 1 October 2019 | Volume 10 | Article 1294
published: 09 October 2019
University of Zurich, Switzerland
McGill University, Canada
David Geffen School of Medicine at
UCLA, United States
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
Pagani A, Nai A, Silvestri L and
Camaschella C (2019) Hepcidin and
Anemia: A Tight Relationship.
Front. Physiol. 10:1294.
Hepcidin and Anemia:
A Tight Relationship
AlessiaPagani1, AntonellaNai1,2, LauraSilvestri1,2 and ClaraCamaschella1
1 Division of Genetics and Cell Biology, San Raffaele Scientic Institute, Milan, Italy, 2 Vita-Salute San Raffaele University, Milan, Italy
Hepcidin, the master regulator of systemic iron homeostasis, tightly inuences 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 deciency anemia (IRIDA), the common anemia of acute
and chronic inammatory 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-decient
erythropoiesis in all these conditions. Patients with IRIDA or anemia of inammation 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 deciency. 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 benet all the above-described anemias.
Compounds that antagonize hepcidin or its effect may beuseful in inammation 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, inammation
Pagani et al. Hepcidin and Anemia
Frontiers in Physiology | www.frontiersin.org 2 October 2019 | Volume 10 | Article 1294
Anemia is one of the most common disorders worldwide and
anemia due to iron deciency is the prevalent form according
to multiple analyses (review in Camaschella, 2019). is type
of anemia results from the total body iron deciency 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 etal., 2004). By regulating
plasma iron and systemic iron homeostasis, the hepcidin/
ferroportin axis strongly aects erythropoiesis, hence the possible
development of anemia.
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 dierentiation 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 etal., 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 deciency and iron
deciency 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 etal., 2008), is strongly increased (Lakhal
etal., 2011); and third, histone deacetylase3 (HDAC3) suppresses
the hepcidin locus (Pasricha et al., 2017). In conditions of
iron deciency, 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 etal., 2014), by molecules (e.g., PDGF-BB)
released by other tissues (Sonnweber etal., 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
Anemias may be classied 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
deciency anemia because of decreased iron supply to erythropoiesis.
Conversely, ineective 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 eect exerted by hepcidin on iron
absorption and recycling that leads to systemic iron deciency;
in the second group, anemia is due to hepcidin suppression by
an expanded abnormal erythropoiesis (Camaschella and Nai, 2016).
Anemia Associated With High
is group includes two inherited rare disorders (iron refractory
iron deciency anemia and hepcidin-producing adenomas in
an inborn error of glucose metabolism) and an acquired common
condition: anemia of inammation (Table 1 ).
Iron Refractory Iron Deciency Anemia
Iron refractory iron deciency 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 aect dierent 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 deciency
to allow the compensatory mechanism of increased iron absorption.
IRIDA is present since birth and usually diagnosed in
childhood. Compared with classic iron deciency, 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 deciency; however, at variance with
iron deciency, levels of serum ferritin are normal/increased
(Camaschella, 2013; De Falco et al., 2013). is reects 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 identies 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 deciency, and consistent
with high/normal ferritin. It is important to exclude inammation
by concomitantly dosing C-reactive protein.
Some patients with a phenotype of refractory iron deciency
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 deciency 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 etal.,
2016). According to other authors, most patients with a severe
IRIDA phenotype have biallelic TMPRSS6 mutations and, when
unidentied, the second allele may begenetically 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 deciency 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 ossicans progressiva (FOP), a rare dominant
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 inammation; 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 aects the glycine-
serine-rich domain of the gene and renders the BMP/SMAD
pathway overactive being unable to bind its specic 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 etal., 2017). Second, it has led to identify
a link between activation of bone and liver BMP type Ireceptors.
ird, the case strengthens the relevance of intact TMPRSS6in
controlling the hepatic BMP/SMAD signaling, since no IRIDA
was identied 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 haploinsuciency cannot cause classic IRIDA.
e optimal treatment of IRIDA is undened. Oral iron is
ineective, 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 deciency. EPO is ineective 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 aected
by glycogen storage disease 1a, a recessive disorder due to
deciency 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 aected children up
to adult age with the occurrence of several complications, such
as anemia and liver adenomas. Anemia is microcytic and
hypochromic, iron decient, and refractory to oral iron treatment.
Anemia reverted aer 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 Inammation
Anemia of inammation (AI), previously known as anemia
of chronic diseases, is a moderate normochromic-normocytic
anemia that develops in conditions of systemic inammation
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 inammation 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 inammation
(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-
benets is needed to avoid side eects 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 eects.
e administration of intravenous iron may relieve iron
restriction, caused by ESA-dependent expansion of erythropoiesis.
Oral iron is usually ineective 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 eect
and adverse reactions; it is limited to severe refractory anemia
(Camaschella, 2019; Weiss et al., 2019).
TABLE 1 | Anemias classied according to hepcidin levels.
Hereditary OMIM n. Prevalence
Iron refractory iron deciency anemia (IRIDA) #206200 Rare
Hepcidin-producing adenomas* #232200 Rare
Anemia of acute inammation Common**
Anemia of chronic inammation
(anemia of chronic disease)
Hereditary – iron loading anemias OMIM n.
β-thalassemia #613985 Common***
Congenital dyserythropoietic anemia #224100 Rare
Sideroblastic anemias #300751 Rare
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
Ineective 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 ineective
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 ineective 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 etal., 2018), attenuating
the hepcidin signaling in response to iron. In addition, an
epigenetic suppression occurs at the hepcidin locus by histone
deacetylase HDAC3 (Pasricha etal., 2017). When anemia causes
hypoxia, other mediators such as PDGF-BB (Sonnweber et al.,
2014), which is released by dierent 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 ineective 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
TARGETED THERAPIES FOR HEPCIDIN-
e identication of molecular mechanisms responsible of the
previously discussed anemias has stimulated research in developing
targeted therapies to replace current symptomatic treatment
(Sebastiani etal., 2016; Crielaard etal., 2017). Approaches dier
according to the type of anemia and the aim of decreasing or
increasing hepcidin levels or their eects (Tab l e 2).
Experimental Therapies to Decrease
Hepcidin Levels/Increase Ferroportin
Except for hepcidin producing tumors, which have to besurgically
removed, compounds that antagonize hepcidin or its eects
may be useful in all anemias characterized by high hepcidin
levels. eir main application would bein chronic inammatory
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 etal., 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 ineective 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 ineective
erythropoiesis due to the vicious cycle between ineective
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.
Compounds that decrease hepcidin or increase ferroportin function
Class I Reduction of the signaling
pathway stimulating hepcidin
Anti IL6-R, anti IL-6
Non anticoagulant heparins
Class II Hepcidin binders Anti-HAMP MoAb
Class III Interfering with hepcidin-FPN
Anti-FPN MoAb, GDP
Compounds that increase hepcidin or decrease ferroportin function
Class I Hepcidin mimics Hepcidin analogues*
Class II Activating hepcidin BMPs (preclinical studies)
Blocking the hepcidin inhibitor Anti-TMPRSS6 (siRNA, ASO*)
Blocking the hepcidin
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
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, oering new tools that
are already or will besoon clinically explored for the treatment
of specic anemias.
AP draed 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.
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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Conict 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 beconstrued as a potential
conict of interest.
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