Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study.

0.34 MB·English

by  van Eijk, Lucas T

vanEijketal.CriticalCare2011,15:R9
http://ccforum.com/content/15/1/R9
RESEARCH Open Access
Inflammation-induced hepcidin-25 is associated
with the development of anemia in septic
patients: an observational study
Lucas T van Eijk1,2,3,4, Joyce JC Kroot2, Mirjam Tromp3,4, Johannes G van der Hoeven1,4,
Dorine W Swinkels2,4, Peter Pickkers1,4*
Abstract
Introduction: Anemia is a frequently encountered problem during inflammation. Hepcidin is an interleukin-6 (IL-6)-
induced key modulator of inflammation-associated anemia. Human sepsis is a prototypical inflammatory syndrome,
often complicated by the development of anemia. However, the association between inflammation, hepcidin
release and anemia has not been demonstrated in this group of patients. Therefore, we explored the association
between hepcidin and sepsis-associated anemia.
Methods: 92 consecutive patients were enrolled after presentation on the emergency ward of a university hospital
with sepsis, indicated by the presence of a proven or suspected infection and ≥ 2 extended systemic inflammatory
response syndrome (SIRS) criteria. Blood was drawn at day 1, 2 and 3 after admission for the measurement of IL-6
and hepcidin-25. IL-6 levels were correlated with hepcidin concentrations. Hemoglobin levels and data of blood
transfusions during 14 days after hospitalisation were retrieved and the rate of hemoglobin decrease was
correlated to hepcidin levels.
Results: 53menand39womenwithameanageof53.3±1.8yrswereincluded.Hepcidinlevelswerehighestat
admission(median[IQR]):17.9[10.1to28.4]nmol/landdecreasedtonormallevelsinmostpatientswithin3days(9.5[3.4
to17.9]nmol/l).HepcidinlevelsincreasedwiththenumberofextendedSIRScriteria(P=0.0005).HighestIL-6levels
weremeasuredatadmission(125.0[46.3to330.0]pg/ml)andlog-transformedIL-6levelssignificantlycorrelatedwith
hepcidinlevelsatadmission(r=0.28,P=0.015),day2(r=0.51,P<0.0001)andday3(r=0.46,P<0.0001).Twelve
patientsreceivedoneormorebloodtransfusionsduringthefirst2weeksofadmission,notrelatedtoactivebleeding.
Thesepatientshadborderlinesignificanthigherhepcidinlevelatadmissioncomparedtonon-transfusedpatients(26.9
[17.2to53.9]vs17.9[9.9to28.8]nmol/l,P=0.052).IL-6concentrationsdidnotdifferbetweenbothgroups.Correlation
analysesshowedsignificantassociationsbetweenhepcidinlevelsonday2and3andtherateofdecreasein
hemoglobin(Spearman’srrangingfrom-0.32,P=0.03to-0.37,P=0.016,respectively).
Conclusions: These data suggest that hepcidin-25 may be an important modulator of anemia in septic patients
with systemic inflammation.
Introduction This b-defensin-like peptide was found to be a principle
Inflammation-associated anemiarepresents an important regulator of systemic iron homeostasis. In concordance
andhighlyprevalentclinicalproblem.In2000,Krauseetal. withthisdualfunction,itsexpressionismodulatedbysys-
described a peptide that was later called ‘hepcidin’ based temicironrequirementsandinflammatorystimuli,asitis
on its hepatic expression and antimicrobial activity [1,2]. inducedbycytokinessuchasIL-6[3].Itsroleinthedevel-
opment of anemia was first suggested in 2001 [4]. Since
*Correspondence:[email protected] then it has been demonstrated that hepcidin is a central
1DepartmentofIntensiveCareMedicine,RadboudUniversityNijmegen modulatorofinflammation-associatedanemia,notonlyby
MedicalCentre,Nijmegen,GeertGrooteplein-Zuid10,P.O.Box9201,6500
controllingtheexpressionofferroportinonintestinalcells
HBNijmegen,TheNetherlands
Fulllistofauthorinformationisavailableattheendofthearticle
©2011vanEijkLTetal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
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andmacrophages[5],butalsoviaadirectinhibitoryeffect corpuscular volume (MCV), mean cell Hb (MCH), and
of hepcidin on erythropoiesis [6]. In humans, increased red cell distribution width (RDW) were analyzed. Blood
concentrationsofhepcidinweredetectedinpatientswith transfusions during hospital stay were recorded. We
chronic infections and severe inflammatory diseases [7]. hypothesized that the effect of sustained elevated levels
The association of increased concentrations of hepcidin ofhepcidincouldbefirstseenintheHblevelafteraper-
with anemia has been determined in patients suffering iod of 7 to 14 days. This was based on the assumption
fromchronicinflammation[8],chronickidneydisease[9], thaterythrocytescirculateforapproximately120days.If
andcancer[10].Inaddition,acutesystemicinflammation erythropoiesis would be abrogated by hypoferremia due
evokedbyexperimentalendotoxemiainhumansresulted to an increased hepcidin level, it would therefore take
in an increase in hepcidin release, associated with a approximately 12 days to reduce the Hb levels by 10%.
decreaseinserumiron[11].Nevertheless,theassociation Adecreaseof10%wasconsideredaclinicallyrelevantand
between the innate immune response, hepcidin release reliablydetectable difference.However,duetoapossible
and consequent decrease in hemoglobin (Hb) has not directinhibitoryeffectofhepcidinonerythropoiesis,anda
been established in patients with an acute systemic reduced erythrocyte half-life during inflammation, a
inflammation. detectable reduction of Hb from day seven onwards was
Human sepsis is a prototypical acute inflammatory anticipated.
syndrome frequently complicated by the development of
anemia. As the incidence of sepsis is high [12], determi- Laboratory measurements
nation of this putative pathway of the development of IL-6levelsweremeasuredonanImmulite2500(Siemens,
anemia is of clinical importance. Therefore, we explored Breda,TheNetherlands),basedonasolid-phase,enzyme-
the correlation between IL-6 and hepcidin, and the sub- labelled, chemiluminescent sequential immunometric
sequent rate of Hb decrease and number of blood trans- method. Serum hepcidin-25 measurements were
fusions received in septic patients. performed by a combination of weak cation exchange
chromatography and time-of-flight mass spectrometry
Materials and methods (TOF-MS), using a Microflex LT matrix-enhanced
Subjects and sampling laser desorption/ionisation TOF-MS platform (Bruker
This is an explorative observational study in which data Daltonics,Bremen,Germany).Aninternalstandard(syn-
of the subjects were retrieved from a prospectively thetic hepcidin-24; Peptide International Inc., Louisville,
aggregated database of patients with sepsis. Following KT,USA)wasusedforquantification[15,16].
Dutch law, the local Institutional Review Board of Arn-
hem-Nijmegen indicated that no formal approval was Calculations and statistical analysis
required for this study. Patients were informed, but no Log-transformed IL-6 concentrations were correlated
written consent was necessary. Ninety-two consecutive with hepcidin-25 concentrations using Pearson’s correla-
septic patients were enrolled after presentation on the tion coefficient. Hepcidin-25 was correlated with the
emergency ward and subsequent hospital admission. rate of decrease of Hb between day 1 and 14, using
Sepsis was defined by the presence of two or more Spearman’s correlation coefficient. The rate of decrease
extended criteria for systemic inflammation (body tem- of Hb was calculated per patient by linear regression
perature >38.3 or < 36°C, acutely altered mental status, using all available Hb measurements. If Hb levels were
shivering, heart rate >90 bpm, systolic blood pressure not measured at days 7 to 14, or if patients received a
<90 mmHg or mean arterial pressure < 65 mmHg, blood transfusion during their stay, they were excluded
respiratory rate >20 breaths/min, hyperglycemia in from this analysis. Hepcidin levels at admission (prior to
absence of diabetes) and a proven or suspected source any transfusion) of patients who received a blood trans-
of infection [13]. The total number of extended systemic fusion during the first 14 days of hospitalization were
inflammatory response syndrome (SIRS) scores were cal- compared with patients who did not.
culated. Patients were given usual care according to the To test whether the presence of comorbidity affected
guidelines of the Surviving Sepsis Campaign [14]. Blood the rate of Hb decrease, we divided different forms of
was drawn at day one, two and three of admission for comorbidity into eight categories (chronic kidney dis-
the measurement of IL-6 and hepcidin-25. Hb measure- ease, hematologic, malignancy, pulmonary, rheumatic/
ments were not taken as part of a protocol, but Hb autoimmune, cardiologic, urologic, and other) and per-
levels that were determined as part of standard hospital formed a step-wise multi-variate analysis in which hep-
care during the first 14 days after hospital admission cidin levels and the eight categories of comorbidity were
were retrieved and used for further analysis, Hemoblo- added to the model. If a comorbidity was found to sig-
bin levels were checked regularly, but not every day in nificantly attribute to the prediction of Hb decrease, it
every patient. Also the accompanying indices of mean was left in the model, but otherwise discarded. Data are
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expressed as mean ± standard error of the mean or Table 2Bloodculture results
median (25th to 75th percentile) depending on their dis- Organismsandculturesites Numberofpatients
tribution. Correlations were expressed as Spearman’s
Organisms
correlation coefficient, except for the correlations
Aeromonasspecies 1
between hepcidin and log-transformed IL-6 concentra-
Candidaspecies 2
tions that were expressed as Pearson’s r.
Citrobacterspecies 1
Paired observations over time were tested with
Corynebacteriumjeikeium 1
Wilcoxon matched-pairs test and unpaired observations
Coxiellaspecies 4
with a Mann-Whitney test.
Enterobacterspecies 1
Enterococcusspecies 5
Results
Escherichiacoli 10
Demographic data
Haemophilusinfluenzae 1
Demographic data of the subjects are displayed in Table
Klebsiellaspecies 2
1. Two patients died during hospitalization. Blood cul-
Morganellaspecies 1
ture results are presented in Table 2. Twenty percent of
Pseudomonasspecies 3
the patients had a positive blood culture. This relatively
Salmonellaspecies 1
low percentage is probably due to the fact that in most
Staphylococcusspecies 2
Streptococcusspecies 3
Viralinfection(positiveserologicaltest) 6
Nopathogencultured 50
Table 1Demographic data ofthe subjects
Sites
Number(%)
Blood 18
Total 92(100)
Urine 18
Male/female 53/39(58/42)
Other 4
Age(years) 53.3±1.8
Multipleorganisms 2
ICUadmissions 3(3)
Multiplesites 2
Deaths 2(2)
Medianhospitallengthofstay(days) 6(4-11)
NumberofSIRScriteriapresent 2.5±0.9 cases the general practitioner had already initiated anti-
Numberofpatientstransfused 12(13) microbial therapy before admission to the hospital.
Siteofinfection
Lung 28(30) IL-6 and hepcidin
Abdomen 12(13) IL-6washighestatadmission(125.0(46.3to330.0)pg/ml),
Urinarytract 24(26) anddecreasedondaytwo(37.2(16.8to112.8)pg/ml)and
Skin/softtissue 4(4) daythree(19.5(7.4to55.7)pg/ml).Asimilarpatternwas
Bone/joint 3(3) observed for hepcidin levels, being highest at admission
Blood 2(2) (17.9 (10.1 to 28.4) nmol/l) and declining to 9.5 (3.4 to
Cerebral 1(1) 17.9) nmol/l on day three, which is still increased
Other 3(3) comparedwithcontrolvalues.Log-transformedIL-6levels
Unknown 9(10) correlatedsignificantlywithhepcidinlevelsonadmission,
Noinfectiousfocus 6(7) day two and day three, (Pearson’s r = 0.28, P = 0.015;
Comorbidity r = 0.512, P< 0.0001; r = 0.458, P< 0.0001, respectively;
None 36(39) Figure1a).Also,thenumberofextendedSIRScriteriapre-
Chronickidneydisease 13(14) sentcorrelatedwithhepcidinlevels(Figure1b).
Hematologicdisease 7(8)
Malignancy 8(9) Hepcidin and hemoglobin
Lungdisease 6(7) Hbwas12.0(11.2to13.4)g/dlatadmissionanddecreased
Rheumatic/autoimmunedisease 2(2) toanaverageof11.3(10.3to12.8)g/dlatday7to14(P=
Cardialdisease 1(1) 0.004)inpatientswhodidnotreceiveabloodtransfusion.
Urologicaldisease 5(5) DuringhospitalizationtheHblevelsdecreasedatleast0.8
Other 14(15) g/dlin69(86%)of80patientswhodidnotreceiveablood
Dataareexpressedasabsolutenumbersandpercentagesoftotal,mean± transfusion. There was no correlation between hepcidin
standarderrorofthemeanormedian(25thto75thpercentile).Multivariate levels and Hb levels at admission (r = 0.21, P = 0.07).
analysisdemonstratedthatcomorbiditieswerenotindependentlyassociated
withhemoglobindecrease.SIRS,systemicinflammatoryresponsesyndrome. Hepcidinlevelsondayoneofadmissiondidnotcorrelate
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80
60 (a) (b)
p=0.0005
L) R=0.51 L)6600
// //
ol 40 P<0.0001 ol
m m
n n
( (40
n(cid:3) n(cid:3)
di di
cipc 2200 R=0.46 ipc20
e e
H P<0.0001 H
0 0
00 11 22 33 44 55 66 77 11 22 33 44 55
Ln(cid:3)IL(cid:882)6(cid:3)(pg/mL) Nr.(cid:3)extended(cid:3)SIRS(cid:3)criteria(cid:3)present
) 2.0 (c) 80 (d)
k p=0.052
e
e
w L)
L/ 1.0 ol/ 60
d R=(cid:882)0.32,(cid:3)p=0.03 m
/
g n
( (
e(cid:3)e 00.00 n(cid:3)n 4400
as di
e ci
r p
c
e(cid:882)1.0 e20
d R=(cid:882)0.37,(cid:3)p=0.016 H
b(cid:3)
HH
(cid:882)2.0 0
0 10 20 30 40 50 60 0 1 2 3 4
Hepcidin(cid:3)(nmol/L) Number(cid:3)of(cid:3)packed(cid:3)red(cid:3)cells(cid:3)transfused
Figure1AssociationbetweenIL-6,hepcidinandhemoglobindecrease.(a)Humoralrelationbetweeninflammationandhepcidinlevels:
Pearson’scorrelationbetweenthenaturallogarithm(Ln)ofIL-6andhepcidin-25onday2(blackdiamonds,uninterruptedline),andday3(greydots,
dashedline.Thecorrelationonday1(r=0.28,P=0.015),wasomittedforreasonsofclarity.Themedianreferencelevelofserumhepcidin-25is4.2
nM,range0.5to13.9nM[15].(b)Clinicalrelationbetweeninflammationandhepcidinlevels:hepcidin-25levelsaccordingtothenumberofextended
systemicinflammatoryresponsesyndrome(SIRS)criteriaatpresentationattheemergencyward[13].DifferencesweretestedwithKruskal-Wallis.
(c)Spearman’scorrelationbetweenrateofhemoglobin(Hb)decreaseandhepcidin-25concentrationonday2(blackdots,uninterruptedline)and
day3(opentriangles,dashedline).TherateofdecreasewasonlycalculatedinpatientsthatdidnotreceiveabloodtransfusionandofwhomHbwas
measuredatleastoncebetweenday7and14ofhospitaladmission(n=44).(d)Relationbetweenhepcidin-25levelsatadmissionandthenumberof
bloodtransfusionsreceivedduring14daysoffollowup.Boxesrepresentmedianandinterquartilerange,whiskersrepresent5thand95thpercentile.
Differencebetweentransfusedandnon-transfusedpatientswastestedwithaMannWhitneytest.
withtherateofdecreaseinHb(r=-0.13,P=0.39).Hep- day7to14(P=0.011).RDWincreasedfrom13.9(13.1to
cidin on day two and day three significantly correlated 15.4) to an average of 15.9 (14.2 to 17.0)% (P = 0.002).
withtherateofdecreaseofHb(r=-0.32,P=0.03andr= MCH remained unchanged during 14 days of follow up
-0.37,P=0.016;Figure1c). (from1.84 (1.75to 1.90)fmoltoan averageof1.82 (1.76
Twelvepatientsreceivedoneormorebloodtransfusions to 1.90) fmol at day 7 to 14 (P = 0.39)). None of the
duringthefirsttwoweeksofadmission,notrelatedtoactive changes in red cell indices correlated with the hepcidin
bleeding.Thesepatientshadborderlinesignificanthigher levelsondaysonetothree.
hepcidinlevelatadmission (precedinganybloodtransfu-
sion)comparedwithnon-transfusedpatients(26.9(17.2to Discussion
53.9)vs17.9(9.9to28.8)nmol/l,P=0.052;Figure1d). In the present study, three novel findings emerged. This
MCVslightlyincreasedduringhospitaladmissionfrom is the first study to show that: hepcidin-25 is increased
86.0(84.0to90.0)toanaverageof88.5(85.7to92.6)flat during human sepsis; in septic patients the degree of
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inflammation, indicated by IL-6 levels and number of abrograte erythroid colony formation in situations
SIRS criteria present, is associated with the elevated where erythropoietin concentrations are reduced, as is
concentrations of hepcidin; and persistently increased the case during sepsis [6]. Furthermore, inflammation
levels of hepcidin-25 at day two and day three after leads to sequestration of iron in cells resulting in a
admission are associated with a decrease in Hb during blocked transport of iron to the bone marrow. Consider-
hospitalization. Naturally, in patients who received a ing the fact that the lifespan of erythrocytes of approxi-
transfusion, the effect of hepcidin on Hb could not be mately 120 days might be shortened due to
determined and these patients were excluded from this inflammation and the fact that hepcidin suppresses ery-
part of the analysis. In a separate analysis, we showed thropoiesis itself, we hypothesized that if hepcidin is
that transfused patients showed a trend towards higher upregulated by inflammation and thereby suppresses
hepcidin levels than those who were not. These findings serum iron levels, a measurable effect on Hb level was
combined suggest that the observed association between expected from seven days onwards after the diagnosis of
elevated hepcidin and a decrease in Hb is likely to be an sepsis. Furthermore, we anticipated a swift decrease in
underestimation. inflammation in treated septic patients. For these rea-
This study does not necessarily indicate a causal rela- sons we determined IL-6 and hepcidin levels for three
tion between elevated hepcidin and Hb decrease in sep- days and the rate of Hb decrease within 7 to 14 days.
tic patients. However, the causal relation of the We were not able to demonstrate a relation of Hb
induction of hepcidin by IL-6 and the development of decrease with a change in MCV, MCH, or RDW. This
anemia by sustaining elevated hepcidin levels has been does not invalidate the hypothesis that increased hepci-
shown by others in separate experiments [3,5,6,17]. This din attributes to the development of anemia in these
study is the first to address the combined measurement patients. It was previously shown that erythrocyte pro-
of hepcidin, IL-6 and Hb levels in patients and shows genitor cells carry iron transporter ferroportin1B on
that hepcidin probably plays a role in sepsis-associated their cell membrane [21]. During inflammation systemi-
anemia. One may argue that the correlation between cally elevated hepcidin down-regulates ferroportin on
inflammation, hepcidin and anemia is an epiphenome- these cells, thereby preventing a loss of intracellular iron
non, because more severely affected patients release and the microcytic anemia that is seen in iron-deficiency
higher levels of inflammatory parameters and also anemia. Therefore, inflammation-associated anemia is
receive more fluids during their volume resuscitation, not typically microcytic [22]. Moreover, the observed
resulting in the more pronounced decrease in Hb. This effect of hepcidin on the development on anemia may
appears not to be the case, because hepcidin concentra- have been mediated by a direct inhibitory effect on ery-
tions at admission did not predict the decrease in Hb, in thropoiesis, rather than by blocking iron transport to
contrast to more prolonged elevations in hepcidin dur- the bone marrow by sequestration.
ing the first three days. Moreover, the decrease in Hb Interestingly, hepcidin at day one did not predict the
was determined over 14 days, a period in which the rate of Hb decrease. Probably persistently elevated hep-
effects of volume resuscitation should have diminished. cidin levels are necessary to exert a relevant effect on
Nevertheless, it is important that in addition to the phy- Hb concentrations. The association we found may be an
siological role of hepcidin, several other factors that lead underestimation, because the patients in this study were
to anemia during infection have been described, such as already anemic at the time of presentation to the emer-
iatrogenic blood loss, inhibition of erythropoietin pro- gency ward and likewise it is possible that before pre-
duction [18], blunted erythropoietic response [18,19], sentation hepcidin levels were even more pronounced.
and a decreased lifespan of erythrocytes, mediated by Nevertheless, although statistically significant, the
increased adherence to the vascular wall and phagocyto- observed association between hepcidin and Hb levels is
sis by macrophages [20]. In addition, in these patients modest, indicating that other previously mentioned fac-
the presence of different comorbidities and the severity tors that influence Hb are likely to play a role.
of the disease could have influenced the development of
anemia. However, we were not able to express these Conclusions
variables in size and number, and therefore could not Anemia during acute systemic inflammation evoked by
include these parameters as a continuous variable into a sepsis is a frequently encountered clinical problem. Up
multivariate regression analysis. This may explain the to now, human data concerning the effect of hepcidin
relatively low correlation coefficients we found between release on the development of anemia during sepsis
hepcidin and Hb decrease. were absent. Our study demonstrates that inflammation
There are two known ways that hepcidin can result in in septic patients is associated with increased hepcidin-
inflammation-associated anemia. First, hepcidin can 25 concentrations. Moreover, the elevated hepcidin
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designandcoordinationandhelpedtodraftthemanuscript.
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20. KempeDS,AkelA,LangPA,HermleT,BiswasR,MuresanuJ,FriedrichB,
Competinginterests
DreischerP,WolzC,SchumacherU,PeschelA,GötzF,DöringG,WiederT,
Theauthorsdeclarethattheyhavenocompetinginterests.
GulbinsE,LangF:Suicidalerythrocytedeathinsepsis.JMolMed2007,
85:273-281.
Received:10January2010 Revised:28July2010
21. ZhangDL,HughesRM,Ollivierre-WilsonH,GhoshMC,RouaultTA:A
Accepted:10January2011 Published:10January2011
ferroportintranscriptthatlacksaniron-responsiveelementenables
duodenalanderythroidprecursorcellstoevadetranslationalrepression.
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