MARROW RESPONSES TO AGING AND INFLAMMATION

Anemia in Elderly Patients: An Emerging Problem for the 21

Century

Gary J. Vanasse

1,2

and Nancy Berliner

st

Associate Director for Translational Research; Division of Hematology/Department of Internal Medicine,

Brigham and Womens Hospital, Harvard Medical School, Boston, MA

Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with
nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the
etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell
displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is
hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney
to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with
increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity.
Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of
anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine
suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that
may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate
the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the
pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival
and quality of life in the aging population.

Epidemiology of Anemia in Elderly Patients

Anemiaofanydegreeisrecognizedasasignificantindependent
1,2

contributortomorbidity,mortality,andfrailtyinelderlypatients.
Althoughanemiahasoftenbeenconsideredanormalconsequence
ofaging,thepathophysiologyofsuchanagerelateddeclinein
erythrocyteproductionisobscure,andeffortstounderstandanemia
inelderlyindividualshavebecomeamajortargetofresearch
interest.Recentstudiessuggestthat,althoughanemialikelyarises
inpartfromthecumulativeeffectofagerelatedcomorbiditiesand
physicaldecline,therearestillagespecificchangesinthehemato
poieticsystemthatinfluenceredbloodcellproduction.Understand
ingofthesechangescouldhaveimportantdiagnosticandtherapeu
ticimplicationsforaddressingthiscommonproblem.Becausethe
numberofelderlyindividualsisexpectedtoreachunprecedented
st

levelsinthe21 century,anemiarepresentsanemergingglobal
healthproblemnegativelyimpactingqualityoflifeinasignificant
proportionoftheelderlypopulationandrequiringanevergreater
allocationofhealthcareresources.

IntheThirdNationalHealthandNutritionExaminationSurvey
(NHANESIII)study,theincidenceofanemiainmenandwomen
3

olderthanage65was11%and10%,respectively. Theprevalence
ofanemiaroserapidlyaftertheageof50,approachingarategreater
than20%inthoseindividualsaged85yearsorolder.Itisestimated
thatmorethan3millionAmericansaged65yearsandolderare
anemic.Oftheanemicpatients,onethirdwereidentifiedtohave
nutritionaldeficiency,onethirdwerediagnosedonthebasisofiron
studiestohaveanemiaofinflammation,andonethirdwere
3

diagnosedwithunexplainedanemia. Awideethnicdisparitywas
alsonoted,withnonHispanicblackshavingarateofanemiathat
wasthreetimesthatofnonHispanicwhites;afindingthatis
consistentwiththeresultsseeninotherstudies.

4,5

Theprevalenceof

anemiaandtherelationshipbetweenanemiasubtypesand
mortalitywereexaminedintheWomensHealthandAging
StudyI,acohortof688severelydisabled,communitydwelling
womenaged65yearsorolder.Thisanalysissimilarlyrevealed
thatonethirdofanemiaremainedunexplained,andfoundthat
theanemiaofinflammationandanemiaofchronicrenaldisease
wasassociatedwithsignificantlyincreasedmortality,with
unexplainedanemiaassociatedwithatrendtowardhigher
6

mortalitythatdidnotreachstatisticalsignificance. Morerecent
followupanalysisofanemiaandmortalityinNHANESIII
revealsthatraceandethnicityappeartobeimportant
determinantsofhemoglobinconcentration,andvariousanemia
subtypesappeartobeassociatedwithdifferentialrisksof
7

mortality. Inthewakeofthesestudies,severalimportant
questionsremaintobeanswered:

Hematology 2010

1.WhyistherateofanemiasomuchhigherinnonHispanic
blacks?Thewelldocumenteddifferencesinbloodcountsseenin
AfricanAmericanshavecausedsomeresearcherstosuggestthatthe
statednormalrangeforhemoglobin,hematocrit,andmeancorpus
cularvolume(MCV)intheAfricanAmericanpopulationshouldbe
4

modified.BeutlerandWest examinedthesenormsintheKaiser
Permanenterecordsandpresenteddataon1491AfricanAmerican
individuals,comparedwithmorethan31,000whitesubjects.They
reportthattheseparameterswerealllowerinblacksthaninage
matchedwhites,whereastheserumferritinwashigher.After
correctingfortheincidenceofthalassemiaandirondeficiency,the
differencesweresmaller,butstillstatisticallysignificant.Ofnote,
thedifferenceinmenwasquitesmall,withameancloseto14.5
g/dLinbothAfricanAmericansandwhitepatients.Itseems
unlikelytoexplainallofthedifferencesinanemiaincidenceamong
blackpatients,since,intheBeutlerstudy,aftercorrectingfor
thalassemiaandirondeficiency,thepercentagesofanemiain

271

AfricanAmericanswasstillstrikinglyhigherthaninwhites
(11.26inblacksvs3.83forwhites).Dr.Beutlerinitially
recommendedagainstadjustingthenormsfordetermining
anemia,giventhebroadimplicationsandcomplexvariablesthat
gointotheseparameters,butratherrecommendedgreater
consciousnessoftheseconsiderationsinpracticingclinical
4

judgment. Inasubsequentstudy,however,heevaluatesthe
WorldHealthOrganization(WHO)classificationofanemiaand
recommendsthatthelowerlimitofnormalforblackmenabove
andbelowtheageof60beplacedat12.9and12.9,respectively
(vs13asdefinedintheWHOstandards),andthattheequivalent
8

forwhitemenbeplacedat13.2and13.7,respectively. To
extendtheseobservations,itisimportanttodeterminewhether
themorbidityandmortalityassociatedwithmildanemiausing
eithersetofnormsisthesameintheblackpopulationasinthe
whitepopulation.Furthermore,ifonecandeterminethecause
ofunexplainedanemia,itmayprovideinsightintotheparticular
geneticvariablesthatinfluencetheincreasedincidenceof
anemiainthenonwhitepopulation.

Whatistheroleofchronicinflammationintheetiologyof
unexplainedanemia?Thereisstrongevidencethatmanymarkers
ofinflammation,includingtumornecrosisfactor(TNF)and
interleukin(IL)6,areincreasedintheelderlypopulation,regardless

requiredtodeterminewhetherchronicinflammationplaysarolein
thepathogenesisofunexplainedanemiaintheelderlypopulation.

Howmuchoftheanemiaofagingcanbeexplainedby
comorbidity?Thehighfrequencyofcomorbidconditionsin
elderlypatientsconfoundstheestablishmentoftheetiologyof
anindependenttendencyforreductioninhematocritwithage.
Althoughthereappearstobeacomponentofagerelated
anemia,eveninhealthyindividuals,theincidenceismuch
12

higherinpatientswithcomorbiddisease. Wepostulatethatthe
tendencytowardaproinflammatorystateintheelderly
populationpredisposesthemtoaccentuateddebilityintheface
ofcomorbiddisease.Wefurtherproposethatgeneticfactors
determiningthelevelofproinflammatorymarkerscontributeto
thelikelihoodofdevelopingfeaturesoffrailtyinresponseto
otherstressors.

Age-Related Expression of Inflammatory Markers,

Anemia, and Frailty

9,10

ofhealthstatus. However,studiesdetailingevidencefora
chronicproinflammatorystatecontributingtothepathogenesisof
unexplainedanemiaintheelderlypopulationhavebeenfewin
numberandlimitedbysmallsamplesizes,lackofcorrelationwith
hepcidinandEPOlevels,andrelianceonmeasurementsofperiph
eralbloodcytokinelevelsasdeterminantsofthepresenceofa
chronicinflammatorystate.Geneticvariationsdeterminingoverall
inflammatoryresponsivenessmay,infact,bebettermarkersof
11

diseasesusceptibilitythanperipheralcytokinelevels, particularly
whenexaminingtheimpactofproinflammatorystatesonthebone
marrow,aspecializedcompartmentinwhichlocalexposureto
inflammatorymediatorsislikelydistinctfromwhatisdetectableby
plasmaassays.Therefore,largerstudiescorrelatinggenotypic
variationinproinflammatorygeneswithperipheralbloodcytokine
levelsandwithestablishedbiomarkersofinflammationwillbe

Agingandthedevelopmentofagerelatedcomorbiditieshasbeen
associatedwithchronicallyincreasedlevelsofproinflammatory
cytokines,suchasTNF,IL6,IL1,macrophagemigration
9,10,13

inhibitoryfactor(MIF),andacutephaseproteins.
Itisunclear
whetherthischronicinflammatorystatereflectsprimaryagerelated
immunedysregulationorasystemicresponsetothepresenceof
comorbidconditions.Somestudieshavesuggestedthat,innormal

healthyelderlyindividuals,thecirculatinglevelsofinflammatory
cytokinesarenotelevated,whereasothershavesuggestedthatthese
markersareelevatedevenintheabsenceofcomorbiddisease.Inthe
largeInCHIANTI(InvecchiareinChianti,agingintheChiantiarea)
studyofmorethan1300individuals,levelsofIL6,IL1receptor
antagonist,IL18,Creactiveprotein,andfibrinogenwereall
elevatedinpatientsoverage65,althoughwhenadjustedfor
10

cardiovascularriskfactorsandmorbidity,theelevationwassmall.
Otherstudies,particularlyfromtheinfectiousdiseasesliterature,
havenotedthelimitationsofthebloodcompartmentinassessing
periodic,butpathogenicallyrelevant,increasesinproinflammatory
14

cytokines. Takentogether,thereexistssomedebateastowhether
assayingcytokinelevelsintheperipheralbloodisanaccurate
methodforestimatingchronicinflammatorystates.Thisislikelyto
beespeciallytrueinexaminingtheimpactofproinflammatory
statesonthebonemarrow,whichisaspecializedcompartmentthat
mayhavelocalexposuretoinflammatorymediatorsthatisdistinct
fromwhatisdetectablebyplasmaassays.Furthermore,cytokine
levelsmaybevariableandsubjecttotransientperturbationsinthe
settingofacutestressesandcomorbidities.Therefore,studies
linkingcytokinepromoterpolymorphismstothedevelopmentof
variousinflammatorydiseasessuggestthatgeneticvariationsthat
determineoverallinflammatoryresponsivenessmaybebetter
markersofdiseasesusceptibilitythanperipheralcytokinelevels.
Consequently,theassessmentoffunctionalpolymorphismsin
candidategenesoffersaworthwhileinvestigativeapproachto
assessingclinicaloutcomes.

ofinflammatorydisorders.Itactsonmacrophagestoinduce
releaseofmanyproinflammatorymediators,suchasIL6,and
servesastheupstreamregulatorofTNF.Furthermore,both
MIFandTNFhavebeenshowntoimpairerythroidcolony
formation,andMIFhasbeenimplicatedinthepathogenesisof
15

anemiaassociatedwithmalaria. TheTNF,IL6,MIF,andIL
1geneshavefunctionalpolymorphismsthataffectthelevelof
cytokineexpression.

11,16

TNFpolymorphismshavebeenlinked
17

tosusceptibilitytoseveremalarialanemia andlepromatous
18

leprosy, andmaypredicttheresponsetoantiTNFtreatmentin
19

rheumatoidarthritis. HighactivityMIFalleleshavebeen
20

associatedwithinflammatoryarthritis, inflammatorybowel
21

22

disease, andsarcoidosis. IL6polymorphismsappearto

influencethephenotypicexpressionofawidevarietyofboth
benignandmalignantdisorders.

23

Anemiaandinflammationarestronglyassociatedwith,andmay
contributeto,thedevelopmentoffrailty,apoorlydefined
syndromeoftheelderlypopulationassociatedwithweightloss,
24

impairedmobility,generalizedweakness,andpoorbalance. Some
studieshavesuggestedthatelevatedproinflammatorymarkersare
24

associatedwithdevelopmentoffrailty. Furthermore,anemiais
associatedwithanincreaseinnearlyallmarkersoffrailtyinelderly
populations,suggestingthattheremaybealinkbetweenthe
25

pathogenesisofthetwosyndromes. Forexample,IL6elevation
25

Chronicallyincreasedlevelsofproinflammatorycytokines
suchasIL6,TNF,IL1,andMIFhavebeenassociated
withthedevelopmentofanumberofagerelatedcomorbidities.
MIFisacytokinewithbroadimmuneactivatingpropertiesthat
issecretedbymacrophagesandTcells,andincreasedinahost

272

hasbeenassociatedwithfrailty, andIL6isalsothemaininducer
ofhepcidinsecretion,thusprovidingapotentialcommonpathway
forthedevelopmentofanemiainthatsetting.Therefore,genetic
variationinthelevelofcytokineexpressionmayhaveanimpacton
thefrequencywithwhicholderindividualsdevelopcertainsubtypes
ofanemiaandothermanifestationsoffrailty.

American Society of Hematology

Anemia of Inflammation

OurunderstandingofAIhasbeentransformedbythediscovery
26

Anemiaofinflammation(AI)hashistoricallybeentermedthe
anemiaofchronicdiseaseandismostcommonlyseenin
associationwithinfection,rheumatologicdisorders,malignancy,
andotherchronicillnesses.Onabiochemicallevel,itis
classicallycharacterizedbylowserumironandlowironbinding
capacityinthesettingofanelevatedserumferritin.Although
theetiologyofclassicalAIhasbeenattributedtodecreasedred
cellsurvival,disorderedironlimitederythropoiesis,and
progressiveEPOresistanceoferythroidprogenitors,the
relativeroleandinterplayofthesethreemechanismsinthe
developmentofanemiaremainunknown,asarethepotential
commonpathwaysthatmaylinkthem.

oftheantimicrobialpeptidehepcidin. Hepcidinisapeptide
synthesizedbytheliverthatisakeyregulatorofiron
metabolism.Ithasbeendemonstratedtoinhibitintestinal
absorptionofironandtoblockreleaseofironfrom
macrophages.Overexpressionofhepcidinintransgenicmice
resultsinperinatalmortalityfromirondeficiencyunlessthe
27

micearesalvagedwithintravenousiron, whereasmicein
whichthehepcidingeneisablateddevelopsevereiron
28

overload PatientswithAI,asdiagnosedbyelevatedferritin
andlowironandironbindingcapacity,havebeendemonstrated
tohaveelevatedlevelsofhepcidin.Furthermore,patientswith
transfusionalironoverloadhavebeenshowntoexpress
elevatedhepcidinlevels.TheNHANESIIIstudyprecededthe
identificationofhepcidinasanimportantfactorinthe
developmentofanemia,andthereforeitspotentialroleinthe
etiologyofunexplainedanemiawasnotassessed.

Regulationofhepcidinsynthesisiscomplexandincludesa
numberofinflammatorymediatedcellularpathways.Hepcidin
isanacutephasereactantpotentlyinducedbyIL6,and
hepcidinisimplicatedinmediatingironlimitederythropoiesis
26,29

inpatientswithacuteandchronicinflammatorystates.
A
recentanalysisofasubgroupofparticipantsintheInCHIANTI
studyexaminedtheassociationbetweenurinaryhepcidinlevels,
proinflammatorymarkers,andanemia,andfoundthatalthough
IL6andCreactiveproteinwereassociatedwithanemiaand
lowironstatus,theywerenotassociatedwithhigherurinary
hepcidin,leadingtheauthorsofthestudytopostulatethat
increasedhepcidinsynthesisoccursonlyinsituationsofovert
30

inflammation. Aswithalldiseaseassociationstudies,these
findingswillneedtobeconfirmedinlargercohortsofpatients
andwillalsobenefitfromfurtheranalysisusinganassayof
serumhepcidin.However,theobservationsdosupportour
hypothesisthatanemiamaybemediatedthroughhepcidin
independentproinflammatorypathways,suchasTNF.

menandwomenolderthanage60years(n5100)andfoundthat
vitaminDdeficiencywasassociatedwithanemiaindependentof
age,sex,race/ethnicity,withtheoddsforanemiabeingincreased
approximately60%inthepresenceofvitaminDdeficiency(odds
ratio[OR]1.6;95%CI[1.37;1.95];P.05).Usingphase2data,we
nextexaminedtheprevalenceofvitaminDdeficiencyinanemia
subtypesinmenandwomenolderthanage60years(n2657)and
foundthat,amongthosewithanemia,vitaminDdeficiencywas
mostprevalentamongthosewithAI.TheriskofAIwassignifi
cantlyincreasedinvitaminDdeficientversusnondeficientpartici
pants(OR1.85;95%CI[1.64;2.07];P.05).Thesearethefirst
populationbasedstudiesdemonstratinganassociationbetween
vitaminDdeficiencyandanemia,particularlyAI,inanolderadult
cohort(T.PerlsteinandG.Vanasse,manuscriptsubmitted,2010)
andprovidecompellingevidencethatvitaminDdeficiencymaybe
apreviouslyunrecognizedcontributortothedevelopmentofanemia
inrelativelyhealthyolderindividualsandisparticularlyprevalent
amongthosewithAI.ThepotentialefficacyofvitaminDin
amelioratinginflammatoryanemiainelderlypatientsandthe
physiologicmechanismsbywhichvitaminDmayabrogateanemia
remaintobestudied.

Leptinanadipokineassociatedwithinflammation,bodyfat
mass,andenergymetabolismhasalsobeenrecentlyshownto
inducehepcidinviaJAK2/STAT3signaling,potentiallylinking
31

obesitytoinflammationandironhomeostasis. Multiple
polymorphicalleleswithintheleptingeneinfluenceleptin

Unexplained Anemia in the Elderly Population

32

expression, andlowleptinlevelshavebeenassociatedwith
impairedEPOresponsivenessoferythroidprogenitorsandthe
33

syndromeoffrailtyintheelderlypopulation. Hepcidinisalso
downregulatedbyhypoxia,andrecentstudiesrevealthatAI
patientswhorespondtohighdoseEPOtherapyhave
34

concomitantdecreasesinhepcidin. However,itremainstobe
determinedwhetherhypoxiainduciblefactor1,thebodys
primaryhypoxiasensor,directlysuppresseshepcidinsynthesis.

AgrowingbodyofevidencelinkslowvitaminDlevelswithpoor
outcomesassociatedwithcardiovasculardiseaseandvariouscancer
diagnoses.AsvitaminDsupplementationamongthepopulationis
becomingmoreandmorecommonplaceingeneralclinicalpractice,
ourgroupexaminedthecorrelationoflowvitaminDlevelswith
anemiainphases1and2ofNHANESIII(19881994).Anemia
wasdefinedasahemoglobin13g/dLand12g/dLformenand
women,respectively.Anemiasubtypes(nutritional,AI,unex
plainedanemia,chronicrenaldisease)weredefinedusingphase2
3

dataasdescribed. Inkeepingwithgenerallyacceptedguidelines,
weclassifiedvitaminDdeficiencyasvitaminD3levelsof20ng/dL.
Statisticalcomparisonswereperformedusinglogisticregression
modelsthatadjustedforthecharacteristicsusedforsampling(age,
sex,race/ethnicity).Inphases1and2ofNHANESIII,we
examinedtheassociationbetweenanemiaandvitaminDlevelsin

Hematology 2010

273

Thepathophysiologyofunexplainedanemiainelderlypatientsis
poorlyunderstood,anditremainsprimarilyadiagnosisofexclu
sion.Althoughmyelodysplasiaandotheruncommoncausesof
anemiamaypotentiallyexplainaportionofthosewithunexplained
anemia,theircombinedcontributionisfelttoberelativelylow.The
impactofvitamindeficiency,beyondiron,vitaminB12,andfolate
deficiencies,orthepotentialimpactofsubclinicalrenaldiseaseon
thedevelopmentofunexplainedanemiaremainspoorlystudied.We
postulatethatoverexpressionofproinflammatorycytokinesisan
importantdeterminantofunexplainedanemiainelderlypatients,
andthattheyinduceanemiabysuppressionoferythroidcolony
formation(MIF/TNF/IL1)ontheonehandandimpairmentof
ironutilization(IL6/hepcidin)ontheother.Wesuggestthatthe
classicanemiaofinflammationisatoneendofthespectrumofthe
twoinflammatorypathways,butthatpatientsmayalsodevelop
clinicallyapparentanemiainaproinflammatorystatewithout
havingtheclassicironabnormalitiesdescribedfortheanemiaof
inflammation.InouranalysisoftheassociationofvitaminD
deficiencywithanemiainolderindividualsinNHANESIII,wedid
notfindacorrelationbetweenlowvitaminDlevelsandunexplained
35

anemia.Ferruccietal useddatacollectedfromarepresentative
sampleofelderlyindividualsenrolledintheInCHIANTIstudyto
examinetheassociationbetweenproinflammatorymediatorsand
elderlysubjectswithunexplainedanemia.Inthisstudy,42of124
anemicindividualsmetthecriteriaforunexplainedanemia.The

unexplainedanemiacohortwasfoundtohavelowserumEPO
levels,lowlevelsofproinflammatorymarkers,andlow
lymphocytecounts,thusleadingtheauthorstoconcludethatthe
bluntedEPOresponseassociatedwithunexplainedanemiawas
35

notassociatedwithincreasedlevelsofinflammation. The
mainlimitationsofthisareitssmallsamplesizeandbyitssole
relianceonmeasurementsofserumlevelsofproinflammatory
mediators(IL6,TNF,andCreactiveprotein)usedtodefine
thepresenceofachronicinflammatorystate.

proinflammatorystateonanagingpopulation.Anemiaisthe
mostcommonhematologicmorbidityofHIVinfection,andis
associatedwithdecreasedsurvival,increasedprogressionof
disease,anddecreasedqualityoflife.AstheHIVpopulation
ages,itisatriskforanemiarelatedtoHIV,aswellasthe
anemiaofaging.TheetiologyofanemiainthesettingofHIV
infectionismultifactorialandincludesopportunisticinfections,
decreasedEPOlevels,effectsonthekineticsofhematopoietic
celldifferentiation,nutritionaldeficiency,andassociated
malignancyandmedications.

39

EPO and Anemia in the Elderly Population

EPOisthemajorcytokineinfluencingredbloodcell
developmentandisinducedinthesettingofanemiathroughan
oxygensensingmechanism.ImpairedEPOresponsivenessof
thehematopoieticstemcellhasbeenimplicatedinthe
36

pathophysiologyofanemiainelderlypatietns. TheBaltimore
LongitudinalStudyonAgingdemonstratedthatEPOlevelsrose
withageinhealthy,nonanemicindividuals,andthattheslopeof
therisewasgreaterforindividualswithoutdiabetesor
37

hypertension. Thosewithanemiaalsohadalowerslopeof
rise,suggestingthatanemiareflectedafailureofanormal
compensatoryriseinEPOlevelswithage.LowEPOlevelshave
beenpreferentiallyassociatedwithunexplainedanemiainthe
35

elderlypopulation, butthemechanismforthisinadequate
EPOresponseremainstobedetermined,andthefindingsofthis
studyneedtobeconfirmedinlargercohortsofelderlypatients.
Takentogether,thisinappropriatelyreducedEPOresponse
suggestsprogressiveEPOresistanceofthehematopoieticstem
cellinthefaceofaging.Whetherthisreflectsinflammatory
cytokinemediatedimpairmentofnormalEPOdependent
cellularpathwaysorothercomplex,agerelatedcomorbidities
anddecreasesinrenalfunctionthatblunttheEPOresponseto
anemiaoracombinationofthetworemainstobe
determined.Insomepatients,thisisprimarilymanifestedas
EPOinsufficiency;inothers,thereissufficienthepcidin
expressiontoinducetheclassicfeaturesofAI.Supportingthis
hypothesisistheobservationthattheconcomitantadministra
tionofEPOandintravenousironhasshownsomesuccessin
amelioratingcertainsubgroupsofpatientswithinflammation
38

associatedanemia. Analternativeandasyetuntested
hypothesisisthatredbloodcelllifespanmaybeshorterinolder
individuals,resultinginacompensatoryriseinEPOlevelsin
responsetoincreasedredbloodcellturnover.

Anemia and Human Immunodeficiency Virus

Disease

Asthepopulationofthoseinfectedwiththehuman
immunodeficiencyvirus(HIV)continuestoage,itprovidesus
withanopportunitytostudytheimpactofachronic

TobetterstudyanemiainanagingHIVpopulation,ourgroupis
currentlyinvolvedinanalyzinganemiawithinTheVeteransAging
CohortStudy(VACS),anobservationalstudyof3213veterans
with,and3161demographicallysimilarveteranswithout,HIV
infection.Morethan75%ofVACSsubjectsareblackorLatino,
andthemedianageis54years.TheVACScohortisdesignedfor
the

studyofanagingpopulation.WithintheHIVpopulation,
patientsolderthanage50areconsideredolder,and,aswe
havehypothesized,theyarelikelytoshowthetrendsseenin

Acknowledgment

olderpatientsearlierthantheirHIV counterparts.Also,anage
stratifiedpopulationlikeVACSshouldallowustostudy
whethertheeffectsofagingonthedevelopmentofanemia
reflectaspectrumofchangesthatdevelopoverthepatients
lifetime.Wehaveperformedapreliminarystudyofanemiaand
survivalinrelationtoMCVin6870HIVinfectedmenwithin
theVeteransAdministration(VA)systemusingdatafromthe
centralizedVArecords.AnemiawasdefinedbytheWHO
standardasahemoglobin13g/dL,andcharacterizedbyMCV
asmicrocytic(80fL),normocytic(8198fL),ormacrocytic
(98fL).Anemiawaspresentin35%ofHIVmen,withthe
followingdistribution:microcytic,11%;normocytic,74%;and
macrocytic,15%.InamultivariateCoxproportionalhazards
modelofsurvival,adjustedforage,hepatitisC,logviralload,
CD4count,HAART(HighlyActiveAntiretroviralTherapy)
therapy,diabetes,andliverdisease,thehazardratiowas1.5for
microcyticanemia,1.6fornormocyticanemia,and2.5for
macrocyticanemia,withmacrocyticanemiabeingan
independentpredictorofdecreasedsurvival(P.05)(G.V.and
N.B.,manuscriptinpreparation).Furtherstudiesexaminingthe
roleofinflammationinthedevelopmentofanemiasubtypesin
VACSarepresentlyunderway.

ThisworkwassupportedbyNationalInstitutesofHealthgrant
RO1AG29154(N.B.).

Disclosures

Conflictofinterestdisclosure:Theauthorsdeclareno
competingfinancialinterests.

Offlabeldruguse:Nonedisclosed.

Correspondence

NancyBerliner,MD,Chief,DivisionofHematology,Brigham
andWomensHospital,andProfessorofMedicine,Harvard
rd

Conclusions

Anemiaisasignificantprobleminelderlypatients.Althoughmany
anemicelderlypatientscanbediagnosedwithnutritionaldefi
ciency,anemiaofchronicinflammationorcomorbiddiseasesthat
explaintheirdecreasedhematocrit,theetiologyofanemiaina
significantfractionremainsobscure.Theimpactofinflammatory
mediators,EPOinsensitivity,orotherfactorsthatmayactonthe
hematopoieticstemcelltodecreaseerythropoiesisareunderactive
studyandshouldservetoelucidatethepathophysiologyofthis
importantcauseofmorbidityandmortalityinelderlyindividuals.A
betterunderstandingofthepathophysiologyofanemiaintheelderly
populationshouldprovidecriticalentrypointsforinterventionsthat
willimprovesurvivalandqualityoflifeintheagingpopulation.

274

MedicalSchool,75FrancisStreet,MidCampus,3 Floor,
Boston,MA02115;Phone:(617)7325840;Fax:(617)264
5215;Email:nberliner@partners.org

References

WoodmanR,FerrucciL,GuralnikJ.Anemiainolderadults.
CurrOpinHematol.2005;12:123128.

KikuchiM,InagakiT,ShinagawaN.Fiveyearsurvivalofolder
peoplewithanemia:variationwithhemoglobinconcentration.
JAmGeriatrSoc.2001;49:12261228.

American Society of Hematology

GuralnikJM,EisenstaedtRS,FerrucciL,KleinHG,Woodman
RC.Prevalenceofanemiainpersons65yearsandolderinthe
UnitedStates:evidenceforahighrateofunexplainedanemia.
Blood.2004;104:22632268.

BeutlerE,WestC.HematologicdifferencesbetweenAfrican
Americansandwhites:therolesofirondeficiencyandalpha

thalassemiaonhemoglobinlevelsandmeancorpuscularvol
ume.Blood.2005;106:740745.

JohnsonSpearMA,YipR.Hemoglobindifferencebetween
blackandwhitewomenwithcomparableironstatus:justifica
tionforracespecificanemiacriteria.AmJClinNutr.1994;60:
117121.

ImaharaSD,OKeefeGE.Geneticdeterminantsoftheinflam
matoryresponse.CurrOpinCritCare.2004;10:318324.
SembaRD,RicksMO,FerrucciL,etal.Typesofanemiaand
mortalityamongolderdisabledwomenlivinginthecommu
nity:theWomensHealthandAgingStudyI.AgingClinExp
Res.2007;19:259264.

PatelKV,LongoDL,ErshlerWB,etal.Haemoglobinconcen
trationandtheriskofdeathinolderadults:differencesby
race/ethnicityintheNHANESIIIfollowup.BrJHaematol.
2009;145:514523.

BeutlerE,WaalenJ.Thedefinitionofanemia:whatisthelower
limitofnormalofthebloodhemoglobinconcentration?Blood.
2006;107:17471750.

BruunsgaardH,PedersenBK.Agerelatedinflammatorycyto
kinesanddisease.ImmunolAllergyClinNorthAm.2003;23:15
39.

McGuireW,KnightJC,HillAV,AllsoppCE,GreenwoodBM,
KwiatkowskiD.Severemalarialanemiaandcerebralmalaria
areassociatedwithdifferenttumornecrosisfactorpromoter
alleles.JInfectDis.1999;179:287290.

RoyS,McGuireW,MascieTaylorCG,etal.Tumornecrosis
factorpromoterpolymorphismandsusceptibilitytoleproma
tousleprosy.JInfectDis.1997;176:530532.

PadyukovL,LampaJ,HeimburgerM,etal.Geneticmarkers
fortheefficacyoftumournecrosisfactorblockingtherapyin
rheumatoidarthritis.AnnRheumDis.2003;62:526529.

BaughJA,ChitnisS,DonnellySC,etal.Afunctionalpromoter
polymorphisminthemacrophagemigrationinhibitoryfactor
(MIF)geneassociatedwithdiseaseseverityinrheumatoid
arthritis.GenesImmun.2002;3:170176.

FerrucciL,CorsiA,LauretaniF,etal.Theoriginsofage
relatedproinflammatorystate.Blood.2005;105:22942299.
NoharaH,OkayamaN,InoueN,etal.Associationofthe173
G/Cpolymorphismofthemacrophagemigrationinhibitory
KnightJC.Regulatorypolymorphismsunderlyingcomplex
diseasetraits.JMolMed.2005;83:97109.

ArtzAS,FergussonD,DrinkaPJ,etal.Mechanismsof
unexplainedanemiainthenursinghome.JAmGeriatrSoc.
2004;52:423427.

KrabbeKS,PedersenM,BruunsgaardH.Inflammatorymedia
torsintheelderly.ExpGerontol.2004;39:687699.

McDevittMA,XieJ,GordeukV,BucalaR.Theanemiaof
malariainfection:roleofinflammatorycytokines.CurrHema
tolRep.2004;3:97106.

MartineyJA,SherryB,MetzCN,etal.Macrophagemigration
inhibitoryfactorreleasebymacrophagesafteringestionof
Plasmodiumchabaudiinfectederythrocytes:possibleroleinthe
pathogenesisofmalarialanemia.InfectImmun.2000;68:2259
2267.

factorgenewithulcerativecolitis.JGastroenterol.
2004;39:242246.

AmoliMM,DonRP,ThomsonW,etal.Macrophagemigration
inhibitoryfactorgenepolymorphismisassociatedwithsarcoid
osisinbiopsyprovenerythemanodosum.JRheumatol.
2002;29:16711673.

HohausS,GiacheliaM,DiFeboA,etal.Polymorphismin
cytokinegenesasprognosticmarkersinHodgkinslymphoma.
AnnOncol.2007;18:13761381.

RoubenoffR.Catabolismofaging:isitaninflammatory
process?CurrOpinClinNutrMetabCare.2003;6:295299.

LengS,ChavesP,KoenigK,WalstonJ.Seruminterleukin6
andhemoglobinasphysiologicalcorrelatesinthegeriatric
syndromeoffrailty:apilotstudy.JAmGeriatrSoc.2002;50:
12681271.

AndrewsNC.Anemiaofinflammation:thecytokinehepcidin
link.JClinInvest.2004;113:12511253.

NicolasG,BennounM,PorteuA,etal.Severeirondeficiency
anemiaintransgenicmiceexpressingliverhepcidin.ProcNatl
AcadSciUSA.2002;99:45964601.

NicolasG,BennounM,DevauxI,etal.Lackofhepcidingene
expressionandseveretissueironoverloadinupstreamstimula
toryfactor2(USF2)knockoutmice.ProcNatlAcadSciUSA.
2001;98:87808785.

GanzT.Hepcidin,akeyregulatorofironmetabolismandmediator
ofanemiaofinflammation.Blood.2003;102:783788.

FerrucciL,SembaRD,GuralnikJM,etal.Proinflammatory
state,hepcidinandanemiainolderpersons.Blood.2010;115:
38103826.

ChungB,MatakP,McKieAT,SharpP.Leptinincreasesthe
expressionoftheironregulatoryhormonehepcidininHuH7
humanhepatomacells.JNutrition.2007;137:23662370.

HoffstedtJ,ErikssonP,MottaguiTabarS,ArnerP.Apolymor
phismintheleptinpromoterregion(2548G/A)influencesgene
expressionandadiposetissuesecretionofleptin.HormMetab
Res.2002;34:355359.

HubbardRE,SineadOMahonyM,WoodhouseKW.Erythro
poietinandanemiainagingandfrailty.JAmGeriatrSoc.
2008;56:21642165.

WeissG,TheurlI,EderS,etal.Serumhepcidinconcentration
inchronichaemodialysispatients:associationsandeffectsof
dialysis,ironanderythropoietintherapy.EurJClinInvest.
2009;39:883890.

FerrucciL,GuralnikJM,BandinelliS,etal.Unexplained
anaemiainolderpersonsischaracterisedbylowerythropoietin
andlowlevelsofproinflammatorymarkers.BrJHaematol.
2007;136:849855.

KarioK,MatsuoT,NakaoK.Serumerythropoietinlevelsinthe
elderly.Gerontology.1991;37:345348.

ErshlerWB,ShengS,McKelveyJ,etal.Serumerythropoietin
andaging:alongitudinalanalysis.JAmGeriatrSoc.2005;53:
13601365.

KoutroubakisIE,KarmirisK,MakreasS,XidakisC,Niniraki
M,KouroumalisEA.Effectivenessofdarbepoetinalfain
combinationwithintravenousironsucroseinpatientswith
inflammatoryboweldiseaseandrefractoryanaemia:apilot
study.EurJGastroenterolHepatol.2006;18:421425.

SullivanPS,HansonDL,ChuSY,JonesJL,WardJW.
Epidemiologyofanemiainhumanimmunodeficiencyvirus
(HIV)infectedpersons:resultsfromthemultistateadultand
adolescentspectrumofHIVdiseasesurveillanceproject.Blood.
1998;91:301308.

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