Anemia of Chronic Disorders: New Diagnostic Tools and

New Treatment Strategies

Guenter Weiss

Anemia in the setting of chronic inflammatory disorders is a very frequent clinical condition, which is,
however, often neglected or not properly treated given the problems often caused by the diseases
underlying the development of anemia. Mechanistically, anemia is mainly caused by inflammation-driven
retention of iron in macrophages making the metal unavailable for heme synthesis in the course of
erythropoiesis, and further by impaired biological activity of the red blood cell hormone erythropoietin
and the reduced proliferative capacity of erythroid progenitor cells. Anemia can be aggravated by chronic
blood loss, as found in subjects with gastrointestinal cancers, inflammatory or infectious bowel disease, or
iatrogenic blood loss in the setting of dialysis, all resulting in true iron deficiency. The identification of
such patients is a clinical necessity because these individuals need contrasting therapies in comparison to
subjects suffering from only classical anemia of chronic disorders. The diagnosis is challenging because no
state of the art laboratory test is currently available that can clearly separate patients with inflammatory
anemia from those with additional true iron deficiency. However, based on our expanding knowledge on
the pathophysiology of inflammatory anemia, new diagnostic markers, including the iron-regulatory
hormone hepcidin, and hematologic parameters emerge. Apart from traditional anemia treatments such as
blood transfusions, recombinant erythropoietin, and iron, including new high-molecular-weight
formulations, new therapeutics are currently under preclinical and clinical evaluation. These novel
compounds aim at correcting anemia by multiple pathways, including antagonizing the inflammation-
and hepcidin-driven retention of iron in the monocyte–macrophage system and thereby promoting the
supply of iron for erythropoiesis or by stimulating the endogenous formation of erythopoietin via
stabilization of hypoxia-regulated factors.
Semin Hematol 52:313–320. C 2015 Elsevier Inc. All rights reserved.

EPIDEMIOLOGY present with the typical features of ACD, although a specific

underlying inflammatory disease remains often unidentified.3–5
Anemia of chronic disorders (ACD) also termed as anemia
Although anemia negatively impacts on quality of life or
of chronic disease or anemia of (chronic) inflammation is
cardiovascular performance, it is often neglected as a clinical
considered to be the second most frequent anemia in the
problem and therefore not properly diagnosed and treated.3
world and is primarily found in subjects suffering from
The development of ACD is considered as an evolu-
disorders that evolve from the activation of the immune
tionary efficient defense strategy against infections.6 As most
system.1 These diseases include mainly infections, cancer and
microbes are highly dependent on a sufficient supply of iron
chronic inflammatory auto-immune disorders but also extend
to achieve full pathogenicity and to maintain reproduction,
to patients with chronic kidney disease specifically if they
the reduction of circulating iron levels limits pathogen
undergo regular dialysis or subjects with congestive heart
growth and may also positively affect innate immune effector
failure or individuals after transplantation.1,2 In addition,
pathways, a strategy for which the term “nutritional immun-
many subjects suffering from the anemia of the elderly
ity” has been coined.6,7 Anemia and iron limitation may also
negatively affect the growth of proliferating malignant cells,
Department of Internal Medicine VI, Infectious Diseases, Immunol- whereas in the setting of non-infectious chronic inflamma-
ogy, Rheumatology, Pneumology, Medical University of Innsbruck, tory diseases, anemia can be considered as a collateral damage
Innsbruck, Austria.
Financial disclosure/conflicts of interest: G.W. received lecturing fees
of an uncontrolled immune activation.2,8
from Pharmacosmos and Vifor over the past 5 years.
Address correspondence to Günter Weiss, MD, Department of Internal
Medicine VI, Medical University of Innsbruck, Anichstr. 35, A-6020 PATHOPHYSIOLOGY
Innsbruck, Austria.. E-mail: [email protected]
0037-1963/$ - see front matter
Although the reasons for ACD are multifactorial, three
& 2015 Elsevier Inc. All rights reserved. immunity-driven pathophysiological pathways are central
http://dx.doi.org/10.1053/j.seminhematol.2015.07.004 for its development.

Seminars in Hematology, Vol 52, No 4, October 2015, pp 313–320 313

314 G. Weiss

First, inflammatory mediators significantly impact on Because anemia results in hypoxia and impairment of
iron homeostasis, which results in iron limitation for organ functions a number of counterbalancing pathways
erythropoiesis and subsequent development of anemia. are induced to correct anemia or to overcome iron
The inducers of these alterations of iron traffic are acute- retention in ACD. Anemia results in hypoxia, which
phase proteins and cytokines. The mainly liver-derived induces the formation of erythropoietin in the kidney
peptide hepcidin, which can be induced by iron loading following activation and stabilization of hypoxia-inducible
but also upon stimulation with inflammatory cytokines factors (HIFs). The underlying mechanisms is hypoxia
such as interleukin (IL)-1 or IL-6, is the central iron- mediated inhibition of prolyl hydroxylases (PDH), which
regulatory hormone.9,10 Hepcidin controls cellular iron under normoxic conditions mediate rapid degradation of
homeostasis upon binding to the only known cellular iron HIFs.17 HIFs do not only stimulate erythropoietin pro-
export protein, ferroportin, causing ferroportin internal- duction but also increase duodenal iron absorption by
ization, degradation, and blockade of cellular iron egress. inducing ferroportin expression, but HIF stabilization also
This results in reduced uptake of dietary iron from enter- negatively affects hepcidin formation, which is mediated
ocytes but also in impaired iron recycling by macrophages, via HIF-inducible erythropoietin production.21 One
which deliver approximately 95% of the daily needs of iron underlying mechanism for this latter observation has been
for erythropoiesis to the circulation originating from elucidated recently upon description of erythroferron, a
degraded senescent erythrocytes taken up by macrophages bone marrow-derived erythropoiesis-inducible peptide that
via a process called erythrophagocytosis.9,11 Iron homeo- blocks hepcidin expression in the liver.22 In addition,
stasis in the course of inflammation is further affected by hypoxia stimulates the expression of platelet derived
cytokine or lipopolysaccharide inducible mechanisms. growth factor-BB, which also inhibits hepcidin transcrip-
Cytokines such as IL-1, IL-6, IL-10, and tumor necrosis tion thereby increasing iron availability for erythropoie-
factor (TNF) stimulate the uptake of iron into macro- sis.23 However, the role of these factors for the
phages by different pathways, including stimulation of pathogenesis of ACD and their therapeutic potential
erythrophagocytosis, and then promote iron storage and awaits further elucidation.
incorporation into ferritin.1,12,13 In parallel, iron export via
ferroportin is blocked transcriptionally and post-transla-
DIAGNOSIS
tionally, either by interferon-gamma (IFNγ) and LPS
mediated blockade of ferroportin transcription,13,14 as well ACD is diagnosed upon the presence of subnormal
as by degradation of ferroportin on the cell surface by hemoglobin levels, increased concentration of markers of
circulating and macrophage-derived hepcidin, which acts in inflammation such as C-reactive protein or IL-6 and
an autocrine fashion.15 All of these events lead to a blunted characteristic alterations of iron homeostasis (Table 1).
dietary iron absorption and iron retention in macrophages, The latter are low circulating iron levels and a reduced
which is reflected by low circulating iron (hypoferremia) saturation of transferrin with the metal (TfS) along with
and normal or increased ferritin levels.9,11,16 normal or increased serum concentrations of the iron
Second, inflammation negatively affects the formation storage protein ferritin.1,24 The latter feature distinguishes
and biological activity of the major red bllod cell hormone ACD from iron deficiency anemia (IDA) where ferritin
erythropoietin. This is on the one hand due to reduced levels are below 30 ng/mL. Moreover, although reticulo-
formation of the hormone caused by inhibitory cytokines cyte counts are reduced with both forms of anemia, ACD
such as TNF and IL-1, and on the other hand linked to is normochromic and normocytic, whereas IDA is char-
reduced erythropoietin receptor expression on erythroid acterized as hypochromic and microcytic anemia. Impor-
progenitors and limited availability of iron.8,17 tantly, concomitant factors contributing to anemia such as
Third, cytokines and most specifically type I and II vitamin deficiencies or hemolysis should be ruled out. A
interferons,18 as well as inflammation-inducible radicals, diagnostic challenge is the differentiation of patients with
inhibit the proliferation and differentiation of erythroid classical ACD from subjects with ACD plus true iron
progenitor cells by multiple mechanisms, which are deficiency (ACD/IDA) because these patients need con-
reviewed in detail elsewhere.8,19 The reduced availability trasting therapies. The development of true iron deficiency
of iron and blunted activity of erythropoietin further in patients with ACD is mostly a consequence of blood
contribute to dyserythropoiesis. loss. That can be due to either gastrointestinal bleeding in
Additionally, ACD can be aggravated by concomitant subjects with inflammatory bowel disease, gastrointestinal
deficiencies in cobalamine, folic acid, or vitamin D, the cancer, or infested gastrointestintal helminths or referred
latter has been found to negatively affect hepcidin expres- to urogenital bleeding or severe menstruation. An impair-
sion thereby increasing circulating iron levels and ameli- ment of intestinal iron absorption as a consequence of low
orating anemia.20 Moreover, renal insufficiency, calorie intake, Helicobacter pylori infection, celiac disease,
hemolysis, bone marrow infiltration by parasites and or inflammation-driven mucosal blockade may further
tumor cells, and the side effects of medications and thus contribute to the development of ACD/IDA. Although
far poorly characterized polymorphisms in iron genes can ferritin is mostly a superb indicator of iron stores in the
contribute to the severity of anemia.8 absence of inflammation, its diagnostic potential is hampered
Anemia of chronic disorders 315

Table 1. Diagnostic Parameters for the Evaluation of Patients With Anemia Of Chronic Disorders
(ACD) and Those With Associated True Iron Deficiency (ACD/IDA)
Meaning/
Parameter Threshold Values* Interpretation Comment
Iron Low In ACD and ACD/IDA Serum iron levels underlie
diurnal variation
Ferritin o30 ng/mL Indicative for true iron Iron limitation for
deficiency in general erythropoiesis can exist
4100-200 ng/mL Adequate iron stores even with high ferritin
in the setting of levels under inflammatory
inflammation conditions. Diagnostic
window between ferritin
levels of 30–200 ng/mL
Transferrin Normal to reduced ACD Concentration may be
Normal to high ACD with IDA affected by nutritional
status
Transferrin saturation Low (o16%–20%) With ACD and ACD/ Diurnal variation based on
IDA changes in serum iron
levels
Soluble transferrin High levels indicate Expression is also
receptor (sTfR) iron needs for negatively affected by
erythropoiesis. inflammation. Accuracy
of diagnostic separation
between ACD versus
ACD/IDA unclear.
sTfR/log ferritin 42 Indicative for IDAþ Better differentiation
ACD between ACD and ACD/
o1 ACD without true iron IDA than sTfR alone,
deficiency however, some overlap
Mean corpuscular Levels below the lower Overlap, MCV and MCH
volume (MCV) limit normal can be may be normal in
Mean cellular found in subjects ACDþIDA
hemoglobin content with ACDþIDA as
(MCH) compared to ACD
alone
Hepcidin High levels in ACD Hepcidin levels are more
Normal or reduced stringently controlled by
concentrations in the needs for iron for
ACD/IDA erythropoiesis than by
inflammation
Reticulocyte Reduced in ACD/IDA Indicator for ongoing
hemoglobin content as compared to ACD; erythropoiesis and iron
availability for
reticulocytes ; prospective
evaluation not available
Hypochromic red 45%–6% Higher percentage in Indicator for iron
blood cells true iron deficiency; availability for
erythropoiesis; sensitivity
for IDA in comparison to
other methods unclear;
C-reactive protein, Increased in ACD and Higher concentrations of
IL-6 ACD/IDA inflammation markers are
associated with more
severe anemia
316 G. Weiss

Table 1. (continued )

Meaning/
Parameter Threshold Values* Interpretation Comment
Vitamin D3 Insufficiently explored Low levels may be
in ACD causatively linked to iron
deficiency
Folic acid, vitamin B12 Typically reduced in Part of initial evaluation of
makrocytic, anemic patients with
hyperchromic chronic inflammatory
anemia; diseases
combinations with
ACD can exist;
*Based on country and laboratory-specific normal values .
Adapted from Weiss G, Schett G. Nat Rev Rheumatol 2013;9:205-15.

under inflammatory conditions because cytokines can different stimuli in opposing ways, the diagnostic usefulness
induce ferritin expression independent of iron availability. of this parameter has been extensively studied.31–33 While
Thus, the diagnostic utility of ferritin as a reflection of most analyses used thus far were based on mass-spectrometry
body iron stores in inflammatory diseases causing ACD is and matrix-assisted laser desorption/ionization (MALDI-
significantly impaired. Efforts have been undertaken to TOF) techniques, the introduction of commercially available
find better diagnostic tests, which allow an estimation of enzyme-linked immunosorbent assay (ELISA) tests offer a
iron stores and iron availability in the setting of inflam- broader clinical use of hepcidin determination in either
mation driven anemia. The circulating concentrations of serum or urine.34–36 Hepcidin levels have been determined
soluble transferrin receptor (sTfR) are increased with iron in several patient groups with ACD with/without concom-
limited erythropoiesis, but due to inhibitory effects of itant true iron deficiency. While in ACD hepcidin levels are
cytokines such as IFNγ on its expression, the diagnostic higher as compared to healthy controls, they are low or are
potential of this test is limited.8 This resulted in the even undetectable in IDA. In subjects with ACD/IDA,
introduction of the sTfR/log ferritin ratio, which better hepcidin levels appear to be significantly lower than in
discriminated between ACD and ACD/IDA, although subjects with ACD alone, which is due to the fact that the
there are still a significant number of patients in a inhibitory effect of iron deficiency dominates over the
“diagnostic grey zone” who could not be correctly classi- inflammation-driven stimulation of hepcidin expression.16,37
fied.25 A popular diagnostic approach was thus to study However, as with many other tests there is still overlap of
hemoglobinization of erythroid progenitors as a marker for hepcidin levels between subjects with ACD and ACD/IDA
iron availability/needs for erythropoiesis. These tests such as and a much better discriminative potential is necessary to
the determination of the percentage of hypochromic red guide clinical decisions.16,30 Nonetheless, hepcidin determi-
blood cells or the hemoglobin content of reticulocytes need nation may be a reliable diagnostic tool to predict the
specific technical equipment.26,27 Although they may response of anemia treatment. High circulating levels of
indicate the availability of iron for erythropoiesis, their hepcidin were associated with reduced erythrocyte iron
clinical utility has not been evaluated on the basis of a gold incorporation in anemic children38 and an impaired response
standard for erythropoiesis such as bone marrow aspira- of inflammatory anemia to treatment with recombinant
tion.26,28,29 It is also reliable to use classical hematologic erythropoietin.39 However, there is still an urgent need to
indices such as mean corpuscular hemoglobin (MCH) or develop more sensitive and specific tests or algorithms for the
red blood cell hemoglobin content or low hemoglobin detection of treatable iron deficiency in the setting of
density, as well as mean cellular volume (MCV), which are inflammation.
lower in patients with ACDþIDA as compared to ACD
alone, although with significant overlap.16,29,30 In order to
TREATMENT
increase the diagnostic sensitivity and specificity for the
identification of true iron deficiency in the setting of The rational for the correction of anemia is to
inflammatory anemia diagnostic blots, which combine ameliorate the negative effects of anemia and iron defi-
several parameters, such as the “Thomas blot”, have been ciency on tissue oxygenation and cellular respiration40,41
introduced; however, their clinical practicability needs to be in order to increase cardiovascular41 and mental perform-
confirmed in a prospective fashion.27 ance along with a gain in quality of life.42 Anemia
Based on the central role of hepcidin in the pathophysi- improves or even disappears upon treatment and cure of
ology of ACD and given that its expression is regulated by the disease underlying ACD.1 However, this goal can
Anemia of chronic disorders 317

often not achieved, specifically in patients with cancer and results from furin-mediated cleavage of Hjv.55 Impor-
auto-immune diseases, but also in subjects with end-stage tantly, recombinant sHjv coupled to Fc fragments has
renal disease. been proven efficient to block hepcidin expression, to
In principle, there exist three traditional treatments for reverse inflammation-induced iron retention in macro-
anemia: red blood cell transfusions, oral and intravenous phages, and to correct inflammatory anemia in rats.56
iron administration, and injection of recombinant Metabolic effects were also observed for antibodies
erythropoiesis-stimulating agents (ESAs) along with com- directed against BMP6, a key mediator of hepcidin
binations thereof. The indications as well as the benefits expression.57,58 Anti-BMP6 reduced hepcidin expression
and hazards of these specific treatments have been and increased serum iron levels in mice.58 This goes along
extensively reviewed.8,42–46 with data showing that inhibitors of the BMP-inducible
Apart from that, new treatment strategies are under SMAD 1/5/9 signaling cascade such as dorsomorphin
preclinical and clinical evaluation, which have emerged suppress hepcidin expression.59 Subsequently, the dors-
from our expanding knowledge on the mechanisms under- momorphin derivative LDN-193189, which had less off-
lying ACD and the factors that regulate erythropoiesis. target effects, was able to correct anemia in rat models of
anemia of inflammation and renal anemia, respectively, by
blocking hepcidin expression and increasing iron mobi-
Hepcidin-Lowering Agents lization for erythropoiesis.56,60
Because increased hepcidin levels have been shown to Heparins, clinically used as anticoagulants, have been
be centrally involved in the retention of iron in macro- found to interfere with BMP/SMAD signaling. Glycol-
phages and mainly responsible for an impaired dietary iron split non-anticoagulant heparins effectively downregulated
absorption in the setting of inflammation thus resulting in hepcidin expression in different mouse models including
an iron-restricted erythropoiesis, the obvious rational was an inflammatory one.61 There is a growing number of
to block hepcidin formation or activity to combat these molecules in preclinical evaluation that can affect hepcidin
effects.47 signaling and/or expression, which have been recently
The first published approach was the use of an anti- summarized in an excellent review.62
hepcidin antibody in a mouse model of anemia employing
heat inactivated Brucella.48 However, this first antibody
could only prevent the development of anemia when given Erythropoiesis and Hypoxia-Driven Effects
in combination with darbopoietin. A subsequent study of Increased erythropoietic demands or ESAs can mobilize
the same group demonstrated that an anti-human hepcidin the iron needed for erythropoiesis.63 Part of this may be
antibody per se was able to increase iron levels and to referred to the erythropoietin-inducible protein erythrofer-
stimulate erythropoiesis in humanized hepcidin knock in ron, which inhibits hepcidin formation and increases iron
mice, but also affected iron homeostasis similarly in mobilization in a mouse model of anemia of inflamma-
cynomolgus monkeys.49 In a comparable fashion small, tion.64 Because knock out of erythroferron results in partly
highly specific hepcidin binding peptides, so-called anti- reduced recovery from anemia, it is conceivable that addi-
calins, are currently studied for their therapeutic potential tional erythropoetin or anemia-inducible mediators exist
to combat the biological activity of hepcidin in vivo.50 that counterbalance the iron-retaining activity of hepcidin.
Circulating hepcidin can be bound and neutralized by Iron homeostasis and hepcidin expression are further
NOX-H94, a mirror-image L- enatiomeric oligoribonucleo- corroborated by hypoxia-mediated pathways, including
tide, called Spiegelmer. Application of NOX-H94 prevented activation of hypoxia-inducible factors that directly and
the inflammation induced reduction of serum iron levels in indirectly increase iron absorption and reduce hepcidin
cynomolgus monkeys and was recently studied in health expression.21,65 New promising drugs for the treatment of
volunteers injected with lipopolysaccharides (LPS). In this anemia of inflammation may emerge from the development
latter study, NOX-H94 delayed the drop in iron levels of prolyl hydroxylase domain-2 (PDH2) inhibitors. These
following LPS injection by several hours, thereby providing drugs can stabilize HIF-1 and -2, thereby stimulating
proof-of principle that hepcidin neutralization impacts on endogenous erythropoietin production, increasing iron
iron homeostasis in men51; whether this is sufficient to absorption, and blocking at the same time hepcidin
correct or prevent anemia needs to be determined. formation and thus promoting erythropoiesis.21,66,67
Hemojuvelin (Hjv), also known as repulsive guidance Hypoxia-inducible hormones such as platelet-derived
molecule C (RGMc) or HFE2, is a membrane-bound growth factor BB can further block hepcidin expression
glycoprotein that promotes hepcidin induction by ameli- directly in vitro and in vivo by interfering with an
orating signaling via bone morphogenetic proteins endoplasmatic reticulum stress-inducible signaling pathway
(BMPs).52 Accordingly, anti-RGMc antibodies have involving CREB-H.23,68 Erythropoietin may improve iron
recently been shown to block hepcidin induction and to availability for erythropoiesis by inhibiting the formation of
increase circulating and tissue iron concentrations in hepcidin-inducing cytokines such as IL-1 or IL-6 via a
female rats.53 Of interest, Hjv-inducible BMP signaling nuclear factor-κB (NF-κB)–dependent pathway.69 IL-6–
can be inhibited by soluble hemojuvelin (sHjv),54 which lowering therapies employing the specific antibody
318 G. Weiss

tocilizumab have been shown to ameliorate inflammatory 4. Matzner Y, Levy S, Grossowicz N, Izak G, Hershko C.
anemia by reducing circulating IL-6 and subsequently Prevalence and causes of anemia in elderly hospitalized
hepcidin levels.70 patients. Gerontology. 1979;25:113-9.
5. Ferrucci L, Semba RD, Guralnik JM, et al. Proinflammatory
Apart from that, a number of promising approaches
state, hepcidin, and anemia in older persons. Blood. 2010;
discussed elsewhere such as the use of vitamin D, sexual 115:3810-6.
hormones, drugs interfering with trans cellular iron fluxes 6. Weinberg ED. Iron availability and infection. Biochim
including stimulators of ferroportin-mediated iron export, Biophys Acta. 2009;1790:600-5.
as well as combinations of such new drugs, along with 7. Nairz M, Haschka D, Demetz E, Weiss G. Iron at the
already existing treatment strategies, including ESAs or interface of immunity and infection. Frontiers Pharmacol.
iron, are already under investigation for their potential to 2014;5:152.
successfully combat anemia of inflammation.43,60,62,63,71 8. Weiss G, Schett G. Anaemia in inflammatory rheumatic
Some of these treatment strategies discussed herein are diseases. Nat Rev Rheumatol. 2013;9:205-15.
already under clinical evaluation in phase I to III trials. It 9. Ganz T, Nemeth E. Hepcidin and disorders of iron
will be of utmost interest to see which ones are able to metabolism. Annu Rev Med. 2011;62:347-60.
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evaluation of the clinical benefit of such drugs must go 11. Hentze MW, Muckenthaler MU, Galy B, Camaschella C.
beyond anemia correction but needs also to evaluate their Two to tango: regulation of Mammalian iron metabolism.
impact on the course of the disease underlying anemia and Cell. 2010;142:24-38.
the general well-being and morbidity of patients. 12. Fahmy M, Young SP. Modulation of iron metabolism in
monocyte cell line U937 by inflammatory cytokines:
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13. Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-
ACD is a frequent clinical condition in patients with mediated regulation of iron transport in human monocytic
inflammatory diseases, but often neglected by treating cells. Blood. 2003;101:4148-54.
physicians as an entity that negatively impacts on the 14. Guida C, Altamura S, Klein FA, et al. A novel inflammatory
patients’ morbidity; it is therefore often insufficiently pathway mediating rapid hepcidin-independent hypoferre-
addressed. A specific challenge is to estimate the needs mia. Blood. 2015;125:2265-75.
of iron in such patients as no gold standard diagnostic tests 15. Theurl I, Theurl M, Seifert M, et al. Autocrine formation of
are currently available. Along this line we are still lacking hepcidin induces iron retention in human monocytes.
Blood. 2008;111:2392-9.
information on how to best treat patients with ACD, what
16. Theurl I, Aigner E, Theurl M, et al. Regulation of iron
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our expanding knowledge on the pathophysiology of 17. Jelkmann W. Regulation of erythropoietin production.
ACD, new treatments are emerging that mainly interact J Physiol. 2011;589:1251-8.
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20. Perlstein TS, Pande R, Berliner N, Vanasse GJ. Prevalence
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depending on the disease underlying chronic inflammatory tion. Blood. 2011;117:2800-6.
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