Iron deficiency or anemia of inflammation?
Iron deficiency or anemia of inflammation?
Manfred Nairz 0 1 2
Igor Theurl 0 1 2
Dominik Wolf 0 1 2
Günter Weiss 0 1 2
0 Schlüsselwörter Entzündungsanämie · Anämie bei chronischer Erkrankung · Eisen · Hepcidin · Makrophage
1 D. Wolf Medical Clinic III, Department of Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB) , Bonn , Germany
2 M. Nairz ( ) · I. Theurl · G. Weiss ( ) Department of Internal Medicine VI, Infectious Diseases , Immunology, Rheumatology, Pneumology , Medical University of Innsbruck , Anichstraße 35, 6020 Innsbruck , Austria
Differential diagnosis and mechanisms of anemia of inflammation Summary Iron deficiency and immune activation are the two most frequent causes of anemia, both of which are based on disturbances of iron homeostasis. Iron deficiency anemia results from a reduction of the body's iron content due to blood loss, inadequate dietary iron intake, its malabsorption, or increased iron demand. Immune activation drives a diversion of iron fluxes from the erythropoietic bone marrow, where hemoglobinization takes place, to storage sites, particularly the mononuclear phagocytes system in liver and spleen. This results in iron-limited erythropoiesis and anemia. This review summarizes current diagnostic and pathophysiological concepts of iron deficiency anemia and anemia of inflammation, as well as combined conditions, and provides a brief outlook on novel therapeutic options.
Anemia of inflammation; Anemia of chronic disease; Iron; Hepcidin; Macrophage
Eisenmangel oder Entzündungsanämie?
Differenzialdiagnose und Mechanismen der
Zusammenfassung Eisenmangel und
Immunaktivierung sind die zwei häufigsten Ursachen der Anämie.
Iron deficiency (ID) can occur in two major forms:
absolute and functional ID. Both forms of ID can
manifest either isolated or combined, and will result in
iron-deficient erythropoiesis and, if unrecognized or
left untreated, in anemia [
Absolute ID, as defined by a decrease in the body’s
iron content, usually develops when the absorption
of dietary iron in the duodenum and proximal
jejunum (Fig. 1a) cannot compensate for an increased
iron demand or blood loss. Despite adaptive
induction of expression of the transmembrane iron
transporters divalent metal transporter (DMT)-1 and
ferroportin (FPN)-1 in enterocytes upon ID, iron
absorption can only be increased by 2- to 3-fold to
mately 5 mg per day [
]. Due to this relatively
inefficient process, iron stores, particularly
ferritin-associated iron in liver and spleen, can become depleted
during chronic bleeding episodes, repetitive blood
donations, helminth infestations, through materno-fetal
transfer, or during growth .
In very rare cases, genetic mutations of iron
homeostasis proteins such as DMT1 or TMPRSS6
(Transmembrane Protease, Serine 6), the latter encoding for
matriptase-2, can result in inadequate iron
absorption and development of anemia [
]. Similarly, lack
of the iron-carrying serum protein transferrin (TF),
due to genetic deficiency, auto-antibody production,
or proteinuria, can cause absolute ID . Inadequate
iron absorption has also been found in association
with Helicobacter pylori infection, hypergastrinemia,
celiac disease, or vitamin D deficiency [
Prolonged ID results in the inability to regenerate skin
and mucosal membranes and in iron deficiency
anemia (IDA) with its classical symptoms such as fatigue.
Details on the clinical implications of ID are reviewed
elsewhere in this special issue.
Iron deficiency or anemia of inflammation?
Functional ID has a more complex
pathophysiology and is commonly defined as a redistribution of
iron from the key sites of its utilization (erythron,
epidermis, mucosal surfaces) to storage sites,
particularly the hepatic and splenic mononuclear
phagocyte system (MPS). Moreover, in states of increased
erythropoiesis such as during therapy with
erythropoiesis-stimulating agent (ESA) or after major blood
loss, erythropoiesis may become iron-restricted so
long as the mobilization of storage iron cannot catch
up with its demand for hemoglobin (Hb) synthesis
(see the interpretation of CHr (Content of reticulocyte
hemoglobin), HYPO (Hypochromic erythrocytes), and
ZnPP (Zinc protoporphyrin) in diagnostic section).
The ultimate consequence of these functional
disturbances of iron homeostasis is anemia, which is often
referred to as anemia of inflammation (AI) or anemia
of chronic disease (ACD).
Absolute and functional iron deficiency may also
coexist. Such combined conditions render the
interpretation of erythrocyte indices and parameters of
iron status challenging. While new diagnostic
parameters are not yet readily used in clinical routine, this
Leucopenia/leucocytosis in the
absence of infection
RPI > 3
Hx, physical exam,
Bleeding (w yet
conserved iron stores)
Mechanical valve replacement
Iron indices, CH r, ZnPP
Additional tests (if applicable)
RPI = Reticulocyte count *
differential is important as the therapeutic approach
varies. In addition, the random detection of AI during
routine blood sampling should prompt a search for
the underlying disease.
Iron deficiency anemia
While IDA poses a major public-health problem in
developing countries [
], it is also frequently observed
in industrialized countries: in 5–10 % of individuals,
as detailed elsewhere in this special issue. Isolated
IDA can be detected by a complete blood count, and
iron status based on the reticulocyte count or
reticulocyte production index (RPI), erythrocyte indices,
ferritin (FT), and transferrin saturation (TSAT).
Typically, IDA is an isolated hyporegenerative microcytic
hypochromic anemia, with reduced FT concentration
and TSAT as indicators of a depletion of iron stores
and serum iron, respectively [
]. The RPI can
easily be estimated by one of two established formulas
ID results in difficulties regenerating epidermis and
mucosal epithelia, while also affecting the clinical
course of associated chronic diseases. For instance,
ID has negative effects on mitochondrial respiration
and tissue oxygen consumption and, thus, on cardiac
function and the clinical course of congestive heart
failure (CHF) [
]. The importance of anemia for
CHF is underscored by a linear increase of mortality
with declining Hb levels [
]. Likewise, parenteral
iron substitution has been found to improve the
clinical course of CHF in patients with coexisting ID
Anemia of inflammation
AI can be viewed as a spectrum of acute and chronic
forms of anemia whose common pathophysiological
denominator is their occurrence as a result of immune
Acute and chronic infections, inflammatory
disorders, and malignancies are the principal disease types
underlying AI. However, AI shares features with the
renal anemia observed in patients with chronic kidney
disease (CKD), the anemia in patients with chronic
obstructive pulmonary disease (COPD), the anemia in
patients with CHF without or with cardio-renal
syndrome, and the anemia of the elderly [
23, 27, 28
The anemia of critical illness occurring after acute
events such as major surgery, severe trauma,
myocardial infarction or sepsis may be classified as a
specific acute form of AI. Moreover, some features of AI
also characterize the anemias occurring in
hematologic disorders such as multiple myeloma or
malignant lymphoma [
In addition, combined forms of IDA and AI may
be present. This scenario is typically observed in
inflammatory bowel disease (IBD) or gastrointestinal or
urogenital malignancy. Mucosal erosions and
ulcerations are associated with recurrent bleeding episodes
and lead to a substantial loss of iron, since 0.5 mg of
iron are contained within the Hb of 1 ml of blood. At
the same time, the underlying disease provides an
inflammatory stimulus for the sequestration of iron in
the MPS. Moreover, menstruation, hemodialysis, the
requirement for repetitive blood sampling, and
anticoagulant or antiplatelet drugs may contribute to iron
loss in CKD and other chronic diseases.
Multiple players in the pathophysiology of AI
The activation of immune cells by infectious agents,
auto-antigens, or neoplastic cells initiates and
maintains the development of AI by several mechanisms
which coexist and are cross-regulatory (Fig. 1b). The
excessive production of inflammatory mediators
diverts iron to the MPS, rendering it relatively
unavailable for erythroid progenitors [
]. A paradigm for
such a mediator is hepcidin anti-microbial peptide
(HAMP). HAMP is the hormonal negative-feedback
regulator of serum iron, as it limits iron-fluxes to
the circulation. Upon iron excess or inflammation,
HAMP is produced by hepatocytes and, in much
Iron deficiency or anemia of inflammation?
smaller quantities, by immune cells and other cell
types. HAMP’s specific receptor is FPN1, whose only
known function is to act as an export protein for
ionic iron. Binding of HAMP to FPN1 tags the latter
for internalization from the cell membrane and for
lysosomal degradation [
Activation of pattern recognition receptors such as
Toll-like receptor (TLR)-4, as well as pro- and
antiinflammatory cytokines regulate HAMP expression,
while similar pathways control transcriptional
expression of iron transporters transferrin receptor (TFR)-1,
DMT1, and FPN1, as well as the iron storage protein
For instance, lipopolysaccharide as a component of
the Gram-negative cell wall enhances HAMP
production while stimulating DMT1 expression in myeloid
cells, thereby favoring iron sequestration [
parallel, interleukin (IL)-10 increases TFR1 and FT
transcription, which may aggravate AI in patients with IBD
Increased HAMP levels are also well documented
in infections, rheumatoid disorders, and IBD.
Furthermore, in almost all patient cohorts, HAMP
concentration positively correlates with disease activity linking
the extent of inflammation to the severity of iron
sequestration in the MPS [
The liver is a key organ initiating and maintaining AI
]. Hepatocytes are the key source of HAMP, while
Kupffer cells (KC) are a major site of
inflammationdriven iron storage. Interestingly, KC dampen HAMP
production in homeostatic conditions but may be
required for inflammation-driven HAMP secretion
]. IL-6 is essential for the up-regulation of
HAMP upon inflammation and IL-6 blockade for the
treatment of rheumatoid arthritis lowers both
disease activity and circulating HAMP levels [
TF is a major product of hepatocytes and one of
a limited number of negative acute phase reactants.
IL-6 and other pro-inflammatory cytokines result in
a downregulation of TF expression in the liver, thus
reducing the serum’s capacity to transport iron [
This mechanism may additionally contribute to iron
sequestration in the MPS. Since TF-bound iron and
TFR1 form the key mechanism of iron uptake for
erythroid progenitors, a central role for the development
of AI is implicit. TFR1 is also expressed by neoplastic
cells in solid tumors and hematologic malignancies,
including chronic lymphocytic leukemia, suggesting
that inflammation associated with malignant diseases
may also limit iron availability for cancer cells [
]. However, potential functional consequences for
tumor-associated monocytes/macrophages (TAM)
are not sufficiently addressed. In addition, several
pathogens are able to acquire TF-bound iron [
Therefore, the reduction of serum TF appears to be
one of the mechanisms of microbial iron withdrawal
Serum iron (TF-bound iron), the amount of stored
iron (FT-stored iron), and the iron demand for
erythropoiesis are key variables that are integrated by
hepatocytes to adapt HAMP production to current
metabolic needs. Serum iron levels are sensed
by a machinery involving TFR1, TFR2, and the
hemochromatosis-associated HFE protein [
However, in being the primary iron source for
erythropoiesis, TF also indirectly regulates HAMP expression
via erythroid progenitor-derived mediators,
suggesting that the pathways of HAMP regulation are
An increase in the erythropoietic activity as
observed after blood loss or erythropoietin (EPO)
administration suppresses HAMP production [
]. Part of
this effect may be mediated via erythroferrone (ERFE),
a lack of which delays the recovery from AI in a mouse
]. Growth-differentiation factor (GDF)-15,
whose levels are increased in thalassemia and AI with
or without ID, also inhibits HAMP expression [
Hypoxia has a similar effect on HAMP that is mediated
via platelet-derived growth factor isoform BB
(PDGFBB), which may enable the required increase of Hb
levels at high altitude .
Iron accumulation in the liver induces bone
morphogenetic protein (BMP)-6, which is essential to
maintain body iron homeostasis. BMP6 binds to
a heterodimeric receptor complexed with
hemojuvelin (HJV) and matriptase-2 (the gene product of
TMPRSS6), and stimulates HAMP expression [
]. Notably, BMP6 is primarily produced by
nonparenchymal liver cells and may act in a paracrine
manner on adjacent hepatocytes .
In the context of inflammation, IL-6 and IL-22
stimulate HAMP expression via specific receptors signaling
through signal transducer and activator of
transcription (STAT)-3, while alpha-1 antitrypsin may do so
via HJV and matriptase-2 [
inflammation also feeds into the BMP6 signaling pathway,
adding further complexity; not only to the regulation
of iron homeostasis, but also to the pathophysiology
of AI and the clinical interpretation of iron indices
In their reproductive years, women have an
increased iron demand. Estradiol, whose levels increase
after menstrual bleeding during the first half of the
menstrual cycle (follicular phase) until ovulation,
inhibits HAMP transcription in hepatocytes, which may
allow for higher intestinal iron absorption to
compensate for the average 20–80 ml of monthly menstrual
blood loss [
]. In contrast, progesterone, which
rises after ovulation and dominates the second half
of the cycle (luteal phase) until menstrual bleeding,
rather stimulates HAMP expression . Given the
resulting fluctuations of HAMP and iron indices, the last
five days of the menstrual cycle have been proposed
for blood sampling to allow for a more representative
evaluation of iron status in women [
Recently, the concept has emerged that drugs may
have undesired side effects on iron homeostasis,
since the mTOR inhibitor rapamycin may increase
HAMP levels after heart transplantation, thus
inducing a functional ID and anemia [
The spleen contributes to the pathogenesis of AI as
site of iron retention in macrophages. Furthermore,
splenomegaly may result in hypersplenism and a
reduced half-life of red blood cells (RBC) as a
consequence of the increased RBC elimination by red pulp
macrophages (RPM). Similarly, evidence from mouse
models suggests that increased erythrophagocytosis
contributes to the rapid Hb drop in acute and
subacute forms of AI [
]. Under conditions of
excessive inflammation as seen in sepsis patients,
reactive oxygen intermediates may further accelerate RBC
damage and their removal by complement-dependent
While hepatic HAMP formation is increased during
inflammation, EPO production in the kidney is
subject to inhibition by inflammatory mediators such as
tumor necrosis factor (TNF) and IL-1 [
CKD with a glomerular filtration rate (GFR) < 40 ml/
min/m2 results in insufficient or deregulated
production of EPO and of 1, 25-dihydroxy-cholecalciferole,
both of which are negative regulators of HAMP [
]. Theoretically, for the assessment of whether the
renal EPO response is adequate in AI, the EPO
concentration as measured should be corrected for the
actual Hb level (comparable to RPI for the correction
of reticulocyte counts). However, no consensus
exists on a correction formula for EPO for subjects with
normal renal function or for CKD patients [
Independently, glomerulopathy may result in
proteinuria and the loss of the 80-kD serum protein TF,
which is the major shuttle between compartments of
iron absorption (intestine)/iron recycling (MPS) and
the erythron. While isolated antibodies to TF may
lead to IDA, such auto-antibodies have not yet been
reported in systemic autoimmune diseases. However,
it is known that a functionally distinct type of
antiTF antibodies in monoclonal gammopathies may
result in hyperferritinemia and increase of hepatic iron
A resistance of the erythron to EPO is another
mechanism underlying AI, since it reduces the erythropoietic
drive even in the setting of normal or adequately
increased serum EPO concentrations. Part of this may
be attributed to downregulation of the EPO receptor
on erythroid cells by interferon (IFN)-γ [
Furthermore, a range of inflammatory mediators including
TNF, IL-1, IFN-γ, and reactive intermediates inhibits
the proliferation and differentiation of erythroid
progenitors or induces their apoptosis [
pathways ultimately culminate in an insufficient
renal EPO response and hematopoietic EPO resistance
further aggravating anemia in AI .
Numerous infectious agents (e. g., parvovirus B19
and human herpes virus-6) and neoplastic cells may
infiltrate the bone marrow, which eventually disturbs
erythropoiesis by several mechanisms, including
direct damage to erythroid cells and putative negative
effects on the microenvironment and the stem cell
niche. In addition, there may be direct toxic
effects of drugs including chemotherapeutics and of
radiation therapy on hematopoietic stem/progenitor
cells. Cytopenia, including anemia, is a concern of
methotrexate treatment for rheumatoid arthritis [
However, immunological deregulation induced by
biologics such as anti-TNF therapy may also induce
aplastic anemia [
While in its classical form AI constitutes a
hyporegenerative anemia, hemolysis may contribute
to the development of AI or aggravate its degree in
several settings. For instance, several bacteria
including Staphylococcus aureus produce hemolysins [
These destroy RBC, liberating heme for its uptake into
bacteria by specific receptors. Different mechanisms
of heme iron acquisition are exploited by
intraerythrocytic infectious agents such as Plasmodium [
In addition, malaria induces HAMP, suggesting that
iron sequestration is a major contributing factor to
malarial anemia [
]. Elevated HAMP levels
have also been reported in patients with HIV
(Human immunodeficiency virus) infection, in which
they are associated with anemia and independently
predict mortality . While auto-antibodies against
RBC can be induced by acute Epstein–Barr virus
and Mycoplasma pneumoniae infections resulting in
cold agglutinin disease, auto-immune hemolysis may
also occur in the setting of chronic infections or as
a side effect of medication [
]. In addition, the life
span of circulating RBC may be negatively affected
by inflammatory mediators such as TNF and by
mechanical stress [
]. Therefore, hemolysis may also
contribute to AI in conditions such as CHF associated
with mechanical valve replacement or endocarditis,
or when microangiopathy is present. However, due
to fluid retention, the degree of anemia tends to be
overestimated in CHF patients.
Similar to the concurrent presence of absolute ID in
the setting of AI, deficiencies in other nutrients
essential to erythropoiesis, such as folate and vitamin
B12, may be contributory. For instance, celiac disease
Iron deficiency or anemia of inflammation?
may cause profound malassimilation of various
nutrients or poor food intake may aggravate the anemia
of the elderly. Particularly in elderly patients,
anemia due to clonal hematopoietic diseases, including
myelodysplastic syndromes (MDS), has to be
considered as well.
Current and promising diagnostic tools
Complete blood count, reticulocyte production
index, and red blood cell indices
Both IDA and AI typically manifest as isolated anemia.
As detailed elsewhere in this special issue, both
absolute ID and inflammation can also result in
thrombocytosis due to the effects of altered thrombopoietin,
EPO, and IL-6 levels on megakaryopoiesis [
In addition, the disorders underlying AI or the
immune-modulatory therapy required for their control
can affect circulating leukocyte numbers [
differential blood count can be recommended for
unclear cases of anemia where monoclonality may be
suspected as an underlying disease (Fig. 2). Serum
protein electrophoresis and bone marrow aspiration
or trephine biopsy may reveal additional diagnostic
clues. The reticulocyte count allows for the
differentiation of hyporegenerative anemias (disorders of
erythroid proliferation and maturation) vs. regenerative
anemias (hemolysis or hemorrhage). However, to
account for the increased proportion of reticulocytes in
anemia and the increased presence of prematurely
released reticulocytes in the circulation, the RPI should
be calculated (Fig. 2).
Erythrocyte staining indices do not define the cause
of anemia, but they may be helpful during the
diagnostic workup. IDA is a microcytic hypochromic
anemia, while AI may be microcytic hypochromic or
normocytic normochromic in appearance. High normal
to elevated MCV and MCH may be due to a complex
metabolic disorder (e. g., in alcoholism), severe
nutrient deficiency (e. g., in celiac disease), or an
alternative diagnosis such as MDS.
In addition, clinical signs along with the
measurement of TSH (Thyroid stimulating hormone) and
PTH (Parathyroid hormone) will help to rule out
endocrine disorders (specifically hyperthyroidism,
hypothyroidism, panhypopituitarism, and
hyperparathyroidism) as the cause of a hyporegenerative,
normocytic normochromic anemia.
Ferritin and transferrin saturation
In IDA, serum FT and TFS may enable an accurate
interpretation of body iron status. A reduction in serum
FT below 30 ng/ml shows ID with high diagnostic
accuracy because a strong correlation exists between
serum FT and the body’s total iron storage. It is
generally assumed that for each 1 ng/ml of serum FT,
10 mg of iron are stored in tissues and organs. Serum
FT appears to be iron-poor and mainly derived from
Serum FT levels in the setting of inflammation are
more difficult to interpret as a range of stimuli
result in altered production of FT. Therefore, the
clinical presentation, along with markers of
inflammation such as C-reactive protein or IL-6, needs to be
taken into account. The appearance of
hyperferritinemia >200 ng/ml in the context of a decreased TSAT is
suggestive of immune-driven iron sequestration. This
may be indicative of inflammation, cancer, infection,
or liver disease. Extraordinarily high FT levels have
been documented in patients with adult-onset Still’s
disease or hemophagocytic syndrome [
In an attempt to transport the available iron as
efficiently as possible, serum TF is increased in ID,
resulting in a TSAT < 16 %. Similar levels are observed in
AI because TF is a negative acute-phase reactant (see
Hyperferritinemia in the context of an increased
TSAT of >45 % should prompt evaluation for primary
or secondary iron overload. In the context of
microcytic anemia and Mediterranean or Asian descent,
thalassemia is a valid differential diagnosis. In the
absence of anemia, HFE-associated hemochromatosis or
dysmetabolic iron overload are possible explanations
for pathologically increased FT and TSAT.
Soluble transferrin receptor and ferritin index
TFR1 is the key receptor for iron acquisition by
erythroid cells. Its soluble form (sTFR) can be measured
in the serum and it reflects ID and erythropoietic
activity. sTFR is increased in ID, hemolytic anemias,
thalassemia, and some hematologic malignancies, while
its levels tend to be normal in AI [
]. Therefore, an
increased sTFR in the setting of AI suggests the
presence of additional absolute ID. However, the use of
sTFR is limited by the lack of its standardization and
the fact that age, ethnicity, and inflammation
influence its normal range [
The ferritin index (FTI) may also be helpful in the
differential diagnosis of AI and combined IDA/AI.
However, the lack of standardized tests for sTFR
prevents its broad recommendation. The FTI is
calculated from the sTFR divided by the logarithm of serum
FT (Fig. 2). In patients with chronic diseases and AI,
an increased FTI suggests the concurrent presence of
absolute ID requiring correction. However, the cutoff
value is largely dependent on the specific diagnostic
test used [
]. Therefore, at the current stage
of research we are unfortunately not able to provide
a universally applicable algorithm for the
differentiation between isolated AI and anemia with combined
functional and absolute ID.
Content of reticulocyte hemoglobin, percent of
hypochromic erythrocytes, and zinc protpoporphyrin
Content of reticulocyte hemoglobin (CHr), percent of
hypochromic erythrocytes (%HYPO), and zinc
protoporphyrin (ZnPP) allow for the prediction of iron
availability for erythropoiesis, but have little to no role in
the differentiation between IDA and AI.
The content of Hb in reticulocytes correlates with
the availability of iron for erythropoiesis. A CHr
< 26 pg suggests iron-limited erythropoiesis, as
observed in both IDA and AI. In response to iron
substitution, it is one of the first parameters to respond
with an increase. A lack of this predicted response
raises the concern of an alternative diagnosis, unless
CKD is present and EPO deficiency awaits correction.
HYPO is defined as the relative number of
hypochromic RBC with a Hb content <28 pg. A HYPO >10 %
indicates iron-deficient erythropoiesis due to IDA or
As erythropoiesis becomes iron-deficient, the
erythroid enzyme ferrochelatase incorporates zinc
instead of iron into protoporphyrin-IX. Since ZnPP and
heme are analogues, an increase in the ratio of ZnPP/
heme indicates ID for erythropoiesis and is observed
in IDA, AI, MDS, and sideroblastic anemias,
including the form secondary to lead intoxication .
This highlights the lack of specificity of this set of
parameters for the differential diagnosis of anemias.
Hepcidin and its regulators
Hepcidin (HAMP) may be helpful in the differential
diagnosis of anemias, as well as in the assessment
of therapeutic options. For instance, HAMP is
suppressed in IDA, in the normal range in IDA/AI, and
elevated in AI [
]. High HAMP at the time of
initiation of therapy with ESA may predict poor
treatment response in AI . In addition, high HAMP
predicts poor response to oral iron in IDA patients
. In CKD patients, the predictive power of HAMP
for the indication for iron therapy is limited [
]. Attempts have been undertaken to harmonize
the different diagnostic methods for hepcidin
determination to allow the broad clinical use of this method
. GDF15 is normal in IDA and elevated in AI and
In the future, information technology may provide
us with software based on complex algorithms for
a more accurate assessment of iron status and, just as
importantly, guide therapy for the most appropriate
treatment. For instance, we may witness that mobile
applications based on a combined panel of HAMP,
EPO, ERFE, GDF15, BMP6, and other parameters,
such as high sensitive CRP and IL-6, enter clinical
Since the AI is a direct consequence of an active
immune-driven disease, its first-line therapy is treatment
of the underlying condition. However, the subsequent
therapeutic approach to AI remains a matter of
debate and ongoing clinical trials. Iron
supplementation, ESA, and transfusion of packed RBC are the
current specific treatment options for AI.
It is generally assumed, similar to the hypoferremia
of the acute phase response, that AI is the
pathophysiological consequence of the body’s attempt to
reduce the availability of iron for infectious agents.
Therefore, there is the concern that iron
supplementation may stimulate pathogen proliferation or result
in a flare of an underlying inflammatory disorder or
54, 124, 125
]. Similarly, ESA and RBC
transfusions may have adverse immune-modulatory
effects [126–129]. The target therapeutic Hb levels
have not yet been defined in prospective trials;
however, data from studies in patients with anemia and
CKD or cancer suggest a slightly anemic target range
between 11–12 g/dl to be safe [130, 131].
Isolated IDA can often be prevented by iron
fortification/supplementation and, once it has manifested, is
preferentially treated by oral iron salts. For instance,
approximately 100 mg of elemental iron contained in
300–350-mg ferrous sulfate preparations can be
prescribed as a daily dose. These iron salts are absorbed
by the sequential action of DMT1 and FPN1 and
associated oxidoreductases, but have a low
bioavailability. However, products using heme rather than ionic
iron have entered the market. These are absorbed
by alternative pathways that are incompletely
characterized, since the proposed solute carrier SLC46A1
absorbs folate more efficiently than heme [132, 133].
A recent study in non-anemic young women with ID
has shown that a single morning dose of 40–80 mg
ferrous sulfate resulted in adequate iron absorption yet
elicited a transient rise in serum HAMP levels, which
argues against twice-daily dosage. Whether or not
alternate day supplementation provides a benefit awaits
investigation in prospective trials .
Parenteral iron supplementation is an alternative to
consider, especially when a rapid correction is needed,
or gastrointestinal (GI) malassimilation or active
inflammatory disease dampens dietary iron absorption
in AI [135, 136]. Also, in patients with intolerance to
oral iron supplements, parenteral iron is the therapy
of choice. Currently, six different forms of parenteral
iron are available for clinical use, i. e., ferric
carboxymaltose, ferumoxytol, iron dextran, iron gluconate,
iron isomaltoside, and iron sucrose. These represent
macromolecules in which iron is complexed to
saccharides. The complexes are endocytotically taken up
by the MPS and ionic iron is distributed into the
cirIron deficiency or anemia of inflammation?
culation via FPN1 by macrophages [
have been raised regarding the risk of severe
anaphylactic reactions when using intravenous iron
preparations. However, these are infrequent and specific
precautions are recommended in at-risk patients, to
minimize the occurrence of such adverse events [
In addition, parenteral iron supplements harbor an
intrinsic risk of inducing hypophosphatemia. Therefore,
serum phosphate may be measured when
erythropoietic and iron indices are determined to evaluate the
response to treatment [
Despite the fact that the MPS has a lower threshold
to respond to increased HAMP than have duodenal
enterocytes, parenteral iron remains effective when
intestinal iron absorption is hampered by immune
]. Since parenteral iron stimulates HAMP
secretion, as documented in hemodialysis patients,
frequent administration of low doses may be
]. Prospective trials are required to optimize
treatment regiments to ensure adequate efficiency of
parenteral supplementation in different clinical
In the context of AI, parameters which predict
the subsequent response to EPO therapy are being
evaluated in prospective studies. In CKD patients,
iron therapy is specifically recommended to replenish
stores prior to initiation of ESA therapy. TSAT < 20 %
and FT < 100 ng/ml have been proposed as cutoffs
for absolute ID in non-dialysis CKD patients [
Further details are reviewed elsewhere .
Currently, the arm of therapy with ESA remains
limited to EPO analogues, as the synthetic EPO receptor
agonist peginesatide has been taken off the market
because of rare anaphylactic reactions [
Many subjects with AI who are under causative
treatment for their underlying condition do not have
an adequate Hb response to iron therapy. EPO
resistance of the erythron or renal EPO deficiency may
be present, such that ESA should be considered as
add-on therapy for anemia. Specific studies have
been conducted in patients with AI in the setting
of rheumatoid arthritis or HIV infection, in which
EPO levels <500 U/L predicted a response to ESA
]. Standard starting doses of
EPO are 100–150 U/kg, administered subcutaneously
three times a week, although higher doses may be
required for individual patients. As Hb levels
increase during efficient EPO therapy, iron parameters
should be monitored and iron supplemented in order
to maintain a TSAT ≥20 % and a FT ≥100 ng/ml for
a sufficient Hb response. In dialysis patients, higher
FT target levels have been suggested . In MDS,
ESA are in wide clinical use despite of the fact that
official approval of this approach is still pending [
The specific regimes and pitfalls in ESA therapy are
reviewed elsewhere [
130, 131, 148, 149
The HAMP–FPN1 axis as target
Given its important role for iron-sequestration in
AI, HAMP and its receptor FPN1 are attractive
targets for therapeutic interventions. Different
pharmaceutical preparations including antibodies,
antichalins, Spiegelmers, thiamine derivatives, and
heparin derivatives can bind and neutralize HAMP [
]. Moreover, direct blockage of HAMP expression
via sHJV or BMP signaling inhibitors have shown
efficiency in blocking HAMP function and ameliorating
anemia . Some of these treatments are already
being evaluated in clinical trials [
an FPN1 stabilizing antibody is currently also under
Since the HIF–EPO axis forms an alternative
targetable pathway, prolyl hydroxylase inhibitors have
entered clinical trials. This class of drugs can be
orally administered and protects HIF from
degradation, which increases EPO levels and erythropoietic
iron availability [
The precise differential diagnosis between IDA, AI,
and a combination of both forms is of clinical
importance because of differing treatment strategies.
Currently, the lack of data from prospective clinical
trials prevents definitive recommendations on
diagnostic algorithms and prognostic indices. These
problems are aggravated by the lack of standardization in
otherwise promising tests, such as measurement of
sTFR. However, within the next few years,
standardized tests for novel parameters such as HAMP or ERFE
will become available for more accurate differential
diagnosis, stratification of treatment indications, and
prediction of therapeutic response. Furthermore, the
HAMP–FPN1 axis continues to receive a lot of
attention as a therapeutic target. Blocking HAMP
expression or processing, neutralization of circulating HAMP,
and blockage of its interaction with FPN1 are under
active investigation for the treatment of AI.
Moreover, different forms of AI may have to be
taken into account. Dependent on the underlying
conditions and dominant pathophysiological
pathways, a more personalized approach to optimal
management of distinct forms of anemias will be required.
Funding information This work was supported by grants
from the Austrian Research Fund (FWF; project TRP-188
to G.W.; projects P28302-B30 and P24749-B13 to I.T.), the
“Theodor Körner Fonds” (to M.N.), the intramural funding
program of the Medical University Innsbruck for young
scientists MUI-START (project 2012032003 to M.N.), and by the
“Verein zur Förderung von Forschung und Weiterbildung in
Infektiologie und Immunologie an der Medizinischen
Open access funding provided by University of Innsbruck
and Medical University of Innsbruck.
Conflict of interest M. Nairz, I. Theurl, D. Wolf, and G. Weiss
declare that they have no competing interests.
Open Access This article is distributed under the terms of
the Creative Commons Attribution 4.0 International License
permits unrestricted use, distribution, and reproduction in any
medium, provided you give appropriate credit to the
original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made.
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