Hematology, October/December 2004 Vol. 9 (5/6), pp.

357362

Hepcidin and Cytokines in Anaemia*

ROBERT T. MEANS, Jr.a,b,
a
Medical Service (111), VA Medical CenterRoom A 429, 1101 Veterans DriveLexington KY40502,USA; bThe Hematology/Oncology Division,
University of Kentucky College of Medicine/ Markey Cancer CenterLexington KYUSA

(Received 11 September 2004; In final form 19 September 2004)

Hepcidin is a cytokine-induced antibacterial protein

which is produced in the liver, circulates in the blood,
and is excreted in the urine. It is a major regulator of iron
balance in the intestinal mucosa, and appears to have a
significant role in the pathogenesis of haemochromatosis
and related disorders. Hepcidin appears to be a major
contributor to the hypoferraemia associated with inflammation. Serum ferritin concentration is strongly correlated with hepcidin protein levels in either urine or
serum, and certain patients with hepatic adenomas
exhibit a microcytic, hypoferraemic hepcidin-dependent
anaemia. For these reasons, it has been proposed that
hepcidin is a primary factor in the pathogenesis of the
anaemia of chronic disease (ACD), a cytokine-mediated
anaemia commonly encountered in clinical practice and
characterized by hypoferraemia with adequate reticuloendothelial iron stores. However, the pathogenetic basis
of ACD is not entirely due to changes in iron metabolism,
but also involves abnormalities in red cell survival and
the erythropoietic response to anaemia. In this review,
the evidence for involvement of hepcidin as a major
mediator of ACD is evaluated. Hepcidin appears to be a
major factor in the systemic iron abnormalities seen in
ACD; whether it contributes to the other aspects of the
pathogenesis of the syndrome requires further
investigation.
Keywords: Anaemia of chronic disease; Cytokines; Ferritin;
Hepcidin; Inflammation; Iron

INTRODUCTION
Acquired anaemia is generally a sign of disease and
of the degree of disease activity rather than a disease
itself. For this reason, it is no surprise that anaemia is
an independent predictor of morbidity and mortality
[1]. The classic example of anaemia reflecting disease

activity is the common clinical syndrome called

the anaemia of chronic disease (ACD). Overall, only
blood loss with consequent iron deficiency is more
frequent as an etiology of anaemia [2]; in the subset
of hospitalized patients on Internal Medicine wards,
it is likely that ACD is the most prevalent anaemia
syndrome. The ACD, usually defined as a hypoproliferative anaemia accompanied by a low serum
iron concentration despite adequate reticuloendothelial iron stores, has been associated traditionally
with chronic infectious, inflammatory, and neoplastic diseases; but progress in understanding its
pathogenesis has led to the recognition of a broader
range of associations [3,4]. Syndromes differing from
ACD only in rapidity of onset are observed in
critically ill patients in intensive care units [5], in the
post-surgical setting [6], and following severe
trauma [7].

CYTOKINES IN ANAEMIA
There are three major processes are involved in the
pathogenesis of ACD. A modest (, 10%) shortening
of red cell survival creates a demand for a slight
increase in red cell production by the bone marrow
to which the marrow cannot respond adequately due
to impaired erythropoiesis and impaired mobilization of reticuloendothelial system iron stores [8].
The impairment of erythropoiesis, in turn, results
from two processes: blunting of the expected
increment erythropoietin (EPO) production in
response to anaemia [9,10], and a decreased response
of the erythroid progenitors to EPO [11 13].
For nearly 50 years, it has been recognized that

*Presented in part as a State of the Art lecture at the Southern Societies Clinical Research Meeting, New Orleans LA USA, February 13,
2004

Tel.: 1-859-281-4919. Fax: 1-859-281-4939. E-mail: robert.means2@med.va.gov

ISSN 1024-5332 print/ISSN 1607-8454 online q 2004 Taylor & Francis Ltd
DOI: 10.1080/10245330400018540

358

R.T. MEANS

the severity of ACD is correlated with the activity of

the associated disease [9,14]. This observation
prompted a search for a common pathophysiologic
mechanism which could apply to disorders of
infectious, immunologic, or neoplastic origin, and
led investigators to consider mediators of the
immune and inflammatory response, such as tumor
necrosis factor (TNF), interleukin 1 (IL1) and
interferons (IFN) as factors potentially involved in
the development of ACD. Concentrations of these
cytokines have been reported to be increased in
patients with disorders associated with ACD
(reviewed in Refs. [15 17]), and they can be
implicated in all of the pathophysiologic processes
implicated in ACD [4,17].
Cytokines and Iron Metabolism
As previously noted, the diagnostic feature of ACD
is hypoferraemia in the setting of normal or
increased iron stores [8]. The presence of reticuloendothelial iron stores is generally indicated by a
serum ferritin in the mid-normal range or higher,
although it can also be demonstrated by bone
marrow examination. Serum total iron binding
capacity (TIBC) and/or transferrin concentration
typically is normal or decreased in ACD; however,
in a multicenter study involving hospitalized
anaemic patients undergoing marrow examination,
95% patients of iron deficient patients had normal
or decreased TIBC [18]. The impaired iron
mobilization implied by these findings in ACD
has been attributed to inflammatory cytokines. A
correlation between the immune activation marker
neopterin and increasing ferritin levels in patients
with malignancies has been reported, suggesting a
role for immune activation in the altered iron
metabolism of ACD [19]. Other investigators have
reported that rodents injected with recombinant
TNF develop a hypoferraemic anaemia associated
with impaired reticuloendothelial iron release and
incorporation into erythrocytes [20,21]. The IL1
(a cytokine implicated in ACD) increases translation of ferritin mRNA, and it has been proposed
that this additional ferritin could act as a trap for
iron that might otherwise be available for erythropoiesis [22]. Nitric oxide (NO) has similar effects on
ferritin translation and also interferes with translation of transferrin receptor mRNA [23 28]. In
addition, inflammatory effects on cellular iron
uptake may also directly inhibit erythroid progenitor differentiation and proliferation. The acutephase reacting protein a1antitrypsin appears to
inhibit erythropoiesis by impairing transferrin
binding to its receptor and subsequent internalization of the receptortransferrin complex by
erythroid cells [29]. These mechanisms are
summarized in Table I.

TABLE I Proposed mechanisms of cytokine involvement in iron

metabolism in ACD
Proposed mechanism

Cytokines implicated

Upregulation of ferritin message

Nitric oxide induction (IRP/IRE)
Downregulation of erythroid TfR receptor
number/function
Hepcidin induction

IL-1, IFN - g
TNF, IL-1
Unknown
IL-6, IL-1 via IL-6

IRPIron regulatory protein; IREIron response element; TfRtransferrin

receptor. Other abbreviations as in text.

Hepcidin and Iron Metabolism

Hepcidin, also called liver-expressed antimicrobial
peptide - 1 (LEAP-1), was independently isolated by
two groups from plasma and urine, respectively
[30,31]. Consistent with its role as a primordial
mediator of innate immunity, the structure of
hepcidin is highly conserved among mammalian
species [32]. Induced iron overload leads to hepcidin
mRNA overexpression in hepatocytes, as does
exposure to lipopolysaccharide [33]. This presumably reflects a regulatory response defending against
adverse effects of iron overload, since knockout mice
lacking hepcidin exhibit severe parenchymal iron
deposition [34]. In terms of its role in physiologic
iron balance, hepcidin appears to enhance iron
uptake and retention by reticuloendothelial cells in
the duodenal crypts, while decreasing dietary iron
absorption [35].
Abnormalities of hepcidin production and regulation have been reported in patients with disorders
of iron storage or metabolism. Two families with
severe haemochromatosis mutations in the hepcidin
gene have been reported [36]. More generally,
transferrin saturation by iron is inversely correlated
with hepcidin gene expression in patients with
hereditary haemochromatosis hepcidin expression
rises as transferrin saturation falls [37]. Patients with
compensated haemochromatosis have urinary hepcidin excretion in the normal range, while patients
with iron overload had elevated urinary hepcidin
[38]. Human volunteers given oral iron supplementation and mice switched from and iron-deficient to
an iron-replete diet show a rapid and transient
increase in urinary hepcidin excretion [39]. In
addition, studies evaluating either urinary hepcidin
excretion or serum hepcidin concentration in a
variety of clinical circumstances show a strong
correlation with serum ferritin concentration [38,40].
Hepcidin and Cytokines
The effects of inflammation (and presumably,
cytokine activation) on hepatocyte hepcidin mRNA
expression has been investigated in in vivo and
in vitro systems. Nicolas and colleagues used
the turpentine abscess technique to induce

HEPCIDIN AND CYTOKINES IN ANAEMIA

an inflammatory state in mice [41]. A single

turpentine injection in normal mice produced a sixfold increase in hepcidin mRNA, as well as a marked
decrease in serum iron concentration. When hepcidin-deficient mice were injected with turpentine,
however, the anticipated drop in iron concentration
did not occur [41]. In a patient with acute
epididymitis studied by Nemeth et al., urinary
hepcidin excretion was markedly elevated early in
the course of the infection (when the inflammatory
reaction and cytokine activation was presumably
greatest) and declined as the clinical syndrome
resolved [38].
In in vitro studies of hepatocytes, IL-6 and
lipolysaccharide induced hepcidin mRNA within
8 h of exposure, while IL-1 and TNF had no similar
effects. This induction pattern indicated that hepcidin
is a type II acute-phase protein. Prolonged exposure
to IL-1 did induce hepcidin message, but the
investigators speculated that this was mediated by
IL-1-induced IL-6 [38]. In a subsequent study, the
same group confirmed that IL-6 is required for
hepcidin induction by inflammation, but not for the
transient hepcidin induction associated with iron
supplementation. TNF was shown to down regulate
hepcidin message expression, and IL-1 had no effect
[39]. When concentrations of hepcidin and of cytokine
mediators of ACD (IL-1, IL-6, TNF, gIFN)) in serum
samples submitted for ferritin analysis from 33
anaemic patients who could be characterized as
having either ACD (12 patients), iron deficiency
(12 patients), or anaemias of other etiologies
(9 patients) were determined, a different pattern of
cytokine/hepcidin association was observed. Serum
hepcidin, IL-1 and gIFN concentrations correlated
with serum ferritin. Serum IL-1 concentration
significantly correlated with serum hepcidin in both
the overall population and in the ACD subset; gIFN
showed a significant correlation with hepcidin in the
ACD subset only. These correlations lost significance
when controlled for serum ferritin [42]. However,
these results may require reinterpretation in light of
the reported counter-regulation of hepcidin
expression by TNF [39]: many of the patients reported
had significantly elevated serum TNF concentrations.

HEPCIDIN AND ANAEMIA SYNDROMES

In a mouse model, increased demand for red cell
production, was either due to acute anaemia from
induced haemolysis or from phlebotomy, or due to
hypoxia. It was also associated with a decrease in
hepatic hepcidin gene expression [41]. A similar
result was observed in mice treated with recombinant EPO [43].
With regard to human studies, a cohort of patients
with type 1a glycogen storage disease, large hepatic

359

adenomas, and microcytic anaemia associated with

hypoferraemia and refractory to iron therapy, has
been reported by Weinstein et al. [44]. This anaemia
appeared to be dependent upon the presence of the
adenomas, since their removal was associated with a
return to a normal haemglobin concentration.
Evaluation of hepcidin mRNA expression in liver
tissue from these patients showed a marked increase
in the adenomas but not in the adjacent normal
tissue. Inflammatory cytokines associated with ACD
were expressed in normal liver tissues at the same
level as in the adenomas [44].
Determinations of hepcidin protein (as opposed to
gene expression) have been reported by Nemeth and
co-workers [38,39], and by Dallalio and colleagues
[40]. In the initial report by Nemeth et al., urinary
hepcidin (normalized to creatinine) was evaluated in
patients with iron overload, compensated haemochromatosis, iron deficiency anaemia, and anaemia
of inflammation, which was defined as anaemia
with an elevated serum ferritin concentration in an
appropriate clinical setting. Urinary hepcidin
excretion was significantly greater in the anemia of
inflammation subset than it was in normal controls
or iron deficient patients [38]. Urinary hepcidin
excretion exhibited a strong correlation with serum
ferritin concentration, and, in a patient with
epididymitis and sepsis, decreased from an initially
elevated level as the clinical syndrome improved.
Dallalio and colleagues, using a commercially
available antihepcidin antibody, performed Western
blot assays for hepcidin on stored serum specimens
from anaemic patients undergoing diagnostic bone
marrow examination, and on stored serum specimens submitted for ferritin determination [40]. No
significant correlations were observed between
serum hepcidin concentrations and any laboratory
parameters reflecting iron status other than ferritin,
or with the degree of anaemia. When the specimens
from subjects who had undergone bone marrow
examination were classified into categories of
anaemia syndromes (ACD, defined as hypoferraemia in the presence of marrow iron stores;
iron deficiency; or anaemia as of other etiologies), the
syndromes could not be separated on the basis of
hepcidin concentration (Fig. 1) [40,42]. Although the
mean hepcidin concentration of ACD patients was
greater than the mean of the other subsets, the
individual patient values overlapped so extensively
that the differences were not significant.
Both of these studies shared a significant conclusion in common: serum ferritin concentration was
strongly correlated with hepcidin, whether
measured in serum or urine. The principal difference
between the findings of the two studies is that serum
hepcidin concentration did not appear to distinguish
iron deficiency from ACD, while urinary hepcidin
clearly separated the anaemia of inflammation

360

R.T. MEANS

production. A strong correlation with serum ferritin

concentration characterizes all the studies described
in this review, and Tilg et al. have reported data
suggesting that hyperferritinaemia itself may contribute to anaemia [47]. Although this is a possibility, it
would not explain the anaemia reported in those
patients with hepcidin-expressing hepatic adenomas, in whom serum ferritin concentrations were
normal or only modestly elevated [44].

SUMMARY
FIGURE 1 Serum hepcidin concentrations in anaemic patients
undergoing bone marrow examination. Results by diagnosis:
ACD, iron deficiency anaemia, or anaemia of other etiology.
Results shown as mean with 95% confidence interval. IDAiron
deficiency anemia. Data from Ref. [40].

from iron deficiency. However, this difference may

be more apparent that real. The definition of ACD
employed by Dallalio et al. was hypoferraemia in the
presence of adequate iron stores (which did not
necessarily require an elevated serum ferritin [40]),
while the definition of anaemia of inflammation used
by Nemeth et al. required hyperferritinaemia [38].
Further, the definition of iron deficiency anaemia
used in the serum hepcidin study was based on the
absence of stainable iron in the bone marrow
aspirate, while the urinary hepcidin study appears
have required a low serum ferritin concentration.
A subsequent report by Dallalio et al. suggested that,
if a similar definition to that employed in the Nemeth
report was used, serum hepcidin was significantly
greater in ACD patients that in iron deficient
patients [42].
Some of the discrepancy between the findings of
these two studies may reflect characteristics of the
assays themselves. Hepcidin is a low molecular
weight molecule, and may be rapidly cleared from
the circulation: it is possible that urinary hepcidin
content, particularly normalized to a marker of
glomerular filtration like creatinine, might be a more
accurate measure of its production. The estimated
molecular weight of the circulating hepcidin peptide
is approximately 2700 kDa, while the antibody used
in the serum hepcidin assay identifies a complex
with molecular weight approximately 9000 kDa. A
similar-sized complex was identified by Kulaksiz
and colleagues, using a self-produced antibody
raised against human hepcidin [45]. The complex
detected may reflect hepcidin aggregates [46]. It is
also possible that there is both a carrier-bound and
free form of hepcidin, with the latter correlating
better with different disease states, and being
reflected more accurately in the fraction excreted in
urine.
Alternatively, the association of hepcidin with
anemia may reflect co-regulation with ferritin

Over the years, the diagnostic role of iron parameters

in ACD has led many investigators to consider that
these features reflect the dominant pathophysiologic
process involved in this syndrome. The specific iron
regulatory functions of the acute phase protein
hepcidin, as well as the anaemia syndromes observed
in patients and transgenic animals with abnormalities
of hepcidin gene expression, have led many to
consider that hepcidin is long-sought answer to the
mysteries of ACD [48,49]. Certainly the patients
reported by Weinstein et al. indicate that hepcidin or
hepcidin-induced iron abnormalities can produce
anemia [44]. However, it is not entirely clear that
what was observed with those patients was actually
ACD, as that syndrome is usually encountered. While
the degree of anaemia and hypoferraemia observed in
most patients was compatible with ACD, the degree of
microcytosis was greater, and the ferritin values
reported were lower, than is typical.
Low serum iron concentrations are commonly
observed in inflammatory or cytokine activation
states [21]. The studies discussed in this review
strongly support the contention that these effects are
mediated through hepcidin in many cases, particularly those involving IL-6 activation. The association
between hepcidin and the increased ferritin concentration commonly observed in ACD patients is
solidly established also [38,40]. However, abnormalities of iron mobilization and utilization comprise
only one of the factors involved in the pathogenesis
of ACD, as discussed earlier. It may well be that
hepcidin only contributes to this particular aspect of
the syndrome. Some authors have addressed this
point by employing a ferritin-based definition of
ACD, e.g. anemia of inflammation, in which a
central role for hepcidin is more apparent [38,39,49].
Other major components of the pathogenesis of ACD
are shortened red cell survival, blunted erythropoietin response to anemia, and relative resistance of
erythroid progenitors to erythropoietin [4]. As yet,
no role has been proposed for hepcidin in these
mechanisms. Progress in understanding the contribution of hepcidin to disordered iron regulation
and other processes involved in the development
of ACD offers opportunities to better understand

HEPCIDIN AND CYTOKINES IN ANAEMIA

the pathogenesis and management of this common

and clinically important disorder.

Acknowledgements
Supported by funds from the Medical Research
Service, U.S. Department of Veterans Affairs and by
grant HL-69418 from the U.S. National Institutes of
Health.

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