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1 s2.0 S2387020617301675 Main 2
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2017;148(5):218–224
www.elsevier.es/medicinaclinica
Review
a r t i c l e i n f o a b s t r a c t
Article history: Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin
Received 22 September 2016 deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of
Accepted 26 October 2016 iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the
Available online 23 March 2017
synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals
and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level
Keywords: and also those related to chronic inflammatory diseases. The most important inhibitory signals are related
Iron metabolism
to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesized has helped design
Hepcidin
Ferroportin
new pharmacological treatments whose main target is the hepcidin. In the near future, there will be
Hepcidin agonists effective treatments aimed at correcting the defect of many of these iron metabolism disorders.
Hepcidin antagonists © 2016 Elsevier España, S.L.U. All rights reserved.
r e s u m e n
Palabras clave: La hepcidina es el principal regulador del metabolismo del hierro y el factor patogénico más importante en
Metabolismo del hierro sus trastornos. La deficiencia de hepcidina provoca sobrecarga de hierro, mientras que su exceso da lugar
Hepcidina o contribuye al desarrollo de anemias por déficit o restricción de hierro en las enfermedades crónicas.
Ferroportina
Conocemos los mecanismos implicados en la síntesis de hepcidina y, en condiciones fisiológicas, hay un
Agonistas de la hepcidina
equilibrio entre las señales activadoras e inhibidoras que regulan su síntesis. Las primeras incluyen las
Antagonistas de la hepcidina
relacionadas con la concentración plasmática de hierro y con las enfermedades inflamatorias. Las señales
inhibidoras más importantes están relacionadas con la eritropoyesis activa y con la matriptasa-2. Conocer
cómo se sintetiza la hepcidina ha servido para diseñar nuevos tratamientos farmacológicos cuya diana
principal es la hepcidina. En un futuro próximo, se dispondrá de tratamientos eficaces dirigidos a corregir
el defecto de muchos de los trastornos del metabolismo del hierro.
© 2016 Elsevier España, S.L.U. Todos los derechos reservados.
Introduction cellular immune response.1 In the adult, the total amount of iron in
the body is 3–4 g, of which 65% is in haemoglobin, 25% in deposit
Iron is an essential nutrient in the body which plays a central organs (liver, reticuloendothelial system macrophages and bone
role in cellular energy metabolism, anaerobic respiration, synthe- marrow) and the remaining 10% in myoglobin, cytochromes, per-
sis of haemoglobin and nucleotide synthesis, additionally, it is also oxidase and catalases.2 Every day, 1–2 mg/d of iron is absorbed
involved in many other processes of exudative metabolism and from the diet, which is the same amount lost daily, but it should
be noted that the organism does not have an active iron excretion
mechanism, so that control of the duodenal absorption plays a vital
role in iron homeostasis.3 Plasma iron circulates bound to trans-
夽 Please cite this article as: Conde Diez S, de las Cuevas Allende R, Conde García
ferrin and it comes from the iron which is absorbed and the iron
E. Estado actual del metabolismo del hierro: implicaciones clínicas y terapéuticas.
that comes from deposit organs, which release it into the plasma
Med Clin (Barc). 2017;148:218–224.
∗ Corresponding author. through ferroportin.1–3 Their accumulation leads to iron overload
E-mail addresses: euconde@humv.es, condee@unican.es (E. Conde García). that is toxic and can damage tissues and cause cell death by free
Hepcidin macrophages, which contain the iron coming from recycled senes-
cent red blood cells, and that released from the deposits (Fig. 2).
1-2 mg/d Ferroportin is responsible for the efflux of iron from enterocytes,
FPN Macrophage
Enterocyte FPN macrophages and hepatocytes into the plasma. Hepcidin binds
to ferroportin for its destruction by endocytosis into the cell’s
lysosomes resulting, on the one hand, in a hyposideremia by low-
ering the iron transferred to the plasma and, on the other hand,
to the accumulation of iron as ferritin enterocytes, macrophages
Liver FPN Plasma 20-30 RBCs
1000mg 3-4mg 2500 mg and hepatocytes.1–3 The control of iron homeostasis by hepcidin
mg/d
is a classic endocrine regulation system; in the words of Ganz,
the relationship of hepcidin with iron is similar to that of insulin
with glucose.4 Hepcidin is therefore the principal regulator of iron
and plays a key role in all its abnormalities, whether having to do
Fe losses
BM with deficiency or excess. Hepcidin deficiency causes iron over-
1-2 mg/d
load, while its excess favours iron sequestration in the liver and
Fig. 1. Body iron homeostasis. The interaction of hepcidin with ferroportin (FPN) macrophages and contributes to the development of iron deficiency
controls the main efflux of iron into plasma. anaemias or because of its misuse in anaemia of chronic disease.5
In these cases, a functional iron deficiency anaemia occurs because
iron reserves are not available for erythropoiesis.5,6 Increased
radical formation and lipid peroxidation. For this reason, the circu-
hepcidin also occurs in chronic inflammatory processes by an
lating iron is never found in free form, it is always attached to other
increase in IL6, which also represents a host defence mechanism
molecules, mainly transferrin, but when concentrations of plasma
against infection by limiting the availability of extracellular iron
iron are high and transferrin is saturated, the excess iron is bound
to microorganisms.5 Hepcidin production is negatively regulated
to other plasma molecules of low molecular weight such as citrate,
by erythropoiesis through mediators that prevent its production
acetate and albumin.2
when iron is required for haemoglobin synthesis.5 Hepcidin is an
The iron in the body follows a cycle consisting of duodenal
acute phase reactant that responds to a variety of inflammatory
absorption, distribution through the plasma bound to transferrin
mediators and signals that activate transcription through different
and transfer to cells via the transferrin receptor, located in the cyto-
signalling pathways.5
plasmic membrane, for use in different metabolic processes or for
storing it in deposit organs.1–3 When red blood cells age, they are
destroyed in macrophages, mainly in the spleen, and iron is reused
Regulation of hepcidin expression
after passing through the plasma (Fig. 1). Foods containing ferric
iron which, after being reduced to the ferrous form, it is absorbed
Hepcidin, encoded by the gene HAMP, is the hormone that reg-
by duodenal enterocytes and subsequently released into plasma
ulates iron metabolism. It is a 25-amino acid peptide produced by
through ferroportin (Fig. 2).
hepatocytes interacting with the ferroportin found in the cell mem-
brane of enterocytes, macrophages and hepatocytes.7 Regulation
Regulation of iron homeostasis. Hepcidin-ferroportin axis of hepcidin is a multifactorial process involving different stimu-
latory and inhibitory signals which, in various ways, control its
Hepcidin is the main hormone that regulates iron metabolism. final transcript.7,8 Hepcidin is regulated by plasma iron through
It is synthesized in the liver and its main mission is to con- a feedback mechanism which involves intra and extracellular iron
trol the arrival of iron in plasma from food through enterocytes, sensors coupled to one or more signal transduction pathways.
Fer
ritin
Hepcidin
FPN
FPN
Fig. 2. Dietary iron is absorbed by duodenal enterocytes. Nonheme iron occurs primarily in the ferric state (Fe 3+) in the intestine and is reduced to ferrous iron (Fe 2+) by the
action of ferrireductases, especially duodenal cytochrome b (Dcytb). Ferrous iron passes through the duodenal enterocytes of the divalent metal transporter-1 (DMT1). Once
in the enterocyte, the ferrous iron can be stored in it as ferritin or can be released into the bloodstream through ferroportin (FPN). Ferrous iron is oxidized by a ferroxidase
identified as hephaestin, which after converting into ferric iron, it binds to transferrin and thus circulates in plasma. Furthermore, senescent erythrocytes are phagocytosed
by macrophages, primarily in the spleen, but also in the liver and the bone marrow (BM). During erythropoiesis, erythroblasts acquire iron for haemoglobin synthesis from
transferrin via transferrin receptors. Excess iron is stored in the liver and in macrophages as ferritin, which is oxidized to hemosiderin. Hepcidin plays a key role in the release
of iron from the deposits depending on the requirements (e.g.: increased erythropoiesis, etc.).
220 S. Conde Diez et al. / Med Clin (Barc). 2017;148(5):218–224
tion Iron activation Inflammation in the presence of neoginin, promoting SMAD1/5/8 phosphoryla-
nhibi
sis i act tion, HAMP transcription and finally hepcidin synthesis12,13 (Fig. 3).
poie Tf - Fe2 iva
ro ti Another important mediator in hepcidin synthesis is the inflamma-
Eryth
on
Tf - Fe2
Tf - Fe2 BMP6 tion through IL6 and other cytokines (IL1, IL22) and activin B (Act-B)
which activate the JAK-STAT3 and BMP signalling pathway7,9
B
MT - 2
Act -
TfR2 B
e TfR1 B IL6
HFE
ErF M HJV
M
P
R
P (Fig. 3).
NEO R
1
2
Inhibitory signals
SMAD
1/5/8 The main hepcidin inhibitory signal comes from erythropoiesis
and is related to different proteins such as erythroferrone, growth
differentiation factor 15 (GDF15) and twisted gastrulation BMP
EPO P SMAD
JAK - STAT3 signalling modulator (TWSG1) that inhibits the SMAD pathway7
Hypoxia 1/5/8
(Fig. 3). Matriptase-2 also has an inhibiting effect on hepcidin,
encoded by the TMPRSS6 gene, as it blocks HJV and prevents BMP
complex activation.10 Other inhibitory signals of hepcidin synthe-
sis are tissue hypoxia and erythropoiesis stimulating factors such
as erythropoietin (EPO).1,2
SMAD4
STAT3 Hepcidin Disorders associated with hepcidin abnormalities
HAMP
Hemochromatosis is the most common cause of genetic iron hepcidin, without distinguishing between the complete hepcidin
overload. There are many mutations that lead to the clinical syn- (hepcidin-25) and the smaller isoforms (hepcidin-20, -22, -23 and
drome previously mentioned, but the most common is inherited as -24), besides, its concentrations are usually higher in CKD due to
an autosomal recessive trait, affecting the HFE gene, which encodes a dysfunction in hepcidin clearance.24 Urinary hepcidin measure-
the HFE protein (Type 1 Hemochromatosis). The most common sub- ment correlates with plasma hepcidin, but urinary detection may
type affects homozygous patients with Cys282Tyr mutation (type be distorted by the high concentration of small isoforms and in
1A). Heterozygous patients may have mixed Cys282Tyr/His63Asp CKD.24
mutations (type 1B). There are also cases that have mutations in
genotypes other than HFE, for example, Ser65Cys (Type 1C).13,18,19
Hepcidin as a therapeutic target
More penetrating and severe forms of hereditary hemochromato-
sis are rare and are caused by mutations in genes HJV (type 2A),
Hepcidin is the main target of diseases related to iron
hepcidin (type 2B), or TfR2 (type 3).9,18 Mutations in the gene that
metabolism disorders and, therefore, new hepcidin agonists or
controls TfR2 prevent this from binding to HFE and consequently,
antagonist drug therapies are being researched.10,11 The interest of
the BMP-HJV-SMAD complex is not activated and hepcidin is not
these studies is huge, as evidenced by the fact that in July 2016 there
synthesized.18 Another rare form of hemochromatosis is due to
were 120 registered clinical trials of hepcidin in ClinicalTrials.gov.
mutations in the ferroportin gene (type 4). These mutations, C326S
and SLC11A3, lead to a hepcidin-resistant ferroportin, so that the
iron is exported to the circulation, even in the presence of ele- Hepcidin agonists
vated levels of hepcidin.18,20 Phlebotomy is the treatment of choice
in iron overload and it is estimated that 1 mg of iron is lost with Increase levels of circulating hepcidin may be beneficial in
each millilitre of red cells removed and, therefore, the mobilization patients with processes that occur with iron overload, such as
of excess iron accumulated in the tissues is promoted to restore hemochromatosis and thalassemia. This could be achieved with
erythropoiesis.2 drugs that have a hepcidin-like activity or stimulating its endoge-
ˇ-Thalassemia is another disease that occurs with anaemia, nous production, but the design of a hepcidin similar to that of
iron overload and low levels of hepcidin. Iron overload is the oneself does not seem to be the solution, because its half-life is
leading cause of morbidity and mortality in these patients, very short and because of the costs involved in its production.10
both in non-transfusion-dependent thalassemia as well as in
the dependent one. Defective -globin chain production during Minihepcidins
erythropoiesis results in the precipitation of ␣-chains produced They have a hepcidin-like action with a better bioavailability
in excess and many erythroid precursors may die early, which and a longer circulating half-life. Their action is exerted by bind-
results in an ineffective erythropoiesis.21,22 To minimize anaemia, ing to ferroportin and blocking the efflux of iron from enterocytes,
a series of compensatory mechanisms are activated, such as an macrophages and hepatocytes, leading to decreased plasma iron
increase in erythropoietin which causes a erythroblastic hyperpla- levels.11,25–27 Its efficacy has been demonstrated in knockout HAMP
sia, extramedullary haematopoiesis, splenomegaly and increased −/− mice, a model of severe hemochromatosis with lack of hep-
intestinal absorption of iron which, in the absence of transfusion, cidin, in which a plasma iron reduction and tissue iron overload
is the cause of iron overload.23 The decrease in hepcidin levels normalization is achieved.27 In thalassaemic mice, treatment with
is the result of increased suppressor factors, erythroferrone and minihepcidins decreases iron overload and improves all haemato-
GDF15 during the development of erythroblasts.8 Transfusions par- logical parameters.25–27 This is the result of iron restriction, leading
tially correct anaemia and hepcidin suppression, but provide very to a decrease in aggregate formation and intracellular inclusion
high amounts of iron with the RBCs transfused. Iron overload in bodies and prevents oxidative stress in erythrocytes, damage in
-thalassemia is treated with iron chelators. DNA, organelle and cell membrane, with improved erythropoiesis
and anaemia correction.2,20
Table 1
Hepcidin inhibitors and their corresponding targets.
BMPs/BMPR/HJV complex
• Anti-HJV MAb (ABT-207, h5F9-AM8) Inhibitor of BMPs/SMAD pathway 33,34
IL6/SATAT3 pathway
• Anti-IL6 (xiltuximab) IL6 sequestration 42
Antihepcidin agents
• Antihepcidin MAb (12B9m) Hepcidin protein sequestration 48
Hepcidin-ferroportin interaction
• Antiferroportin MAb (LY2928057) Hepcidin-ferroportin binding interference 51
Other inhibitors
• TNF-␣ MAb (infliximab, golimumab) Indirect effect of IL6 suppression 53,54
• Chinese medicinal plant extract: Caulis spatholobi (Jixueteng) SMAD 1/5/8 phosphorylation suppressed 58
MAb: monoclonal antibody; MRNA: messenger ribonucleic acid; BMP: bone morphogenetic protein; BMPR: bone morphogenetic protein receptor; FPN: ferroportin; HJV:
hemojuvelin; sHJV-Fc: fusion protein between the soluble HJV and the Fc fragment of immunoglobulins; IL: interleukin; SMAD: sons of mothers against decapentaplegic;
STAT3: signal transducer and activator of transcription 3; TfR2: transferrin receptor 2; TNF: tumour necrosis factor.
siHep, siHJV, siTfR2: oligonucleotides silencing mRNA expression in genes encoding hepcidin, HJV or TfR2.
interfere in hepcidin-ferroportin binding and enhance their sup- modified heparin analogues have been designed to minimize its
pressive mechanisms10,11,16,31,32 (Table 1). anticoagulant effect, maintaining their inhibitory effect on hepcidin
expression to treat anaemia of inflammatory processes.40,41
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ment compensates for the molecular defect and ameliorates hemochromatosis fully human anti-hepcidin antibody modulates iron metabolism in both mice
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