w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Original
article
Ability
of
serum
ferritin
to
diagnose
iron
deficiency
anemia
in
an
elderly
cohort
Mansour
Babaei,
Sajedeh
Shafiei,
Ali
Bijani,
Behzad
Heidari
∗,
Seyed
Reza
Hosseyni,
Mohsen
Vakili
Sadeghi
BabolUniversityofMedicalSciences,Babol,Iran
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received2October2016
Accepted9February2017
Availableonline7March2017
Keywords:
Anemia Diagnosis Elderly Ferritin
Irondeficiency
a
b
s
t
r
a
c
t
Background:Diagnosisandtreatmentofirondeficiencyanemiainoldersubjectsimproves
theirqualityoflife.Serumferritinasamarkerofironstoresisanacutephaseprotein.
Inoldersubjectswhousuallyhavemanyconcomitantchronicmedicalconditions,serum
ferritinmayincreaseinresponsetoinflammatoryprocessesirrespective ofiron stores.
Thisstudywasperformedtodeterminethediagnosticpropertiesofserumferritininthe
diagnosisofirondeficiencyanemiainoldersubjects.
Methods:Thiscase–controlstudyincludedalltheinhabitantsofAmirkolatownwho
partic-ipatedintheAmirkolaHealthandAgingProject.Diagnosisofanemiawasconfirmedbased
onahemoglobinlevel<13g/dLinmenand<12g/dLinwomenandirondeficiencyanemia
bypercenttransferrinsaturation<15%.Areceiveroperatingcharacteristiccurvewas
con-structedtodetermineanoptimalserumferritincutoffvaluetodifferentiatepatientswith
andwithoutirondeficiencyanemiaatthehighestsensitivityandspecificity.
Results:Eighty patients with iron deficiency anemia and160 cases ofanemia without
irondeficiency (meanage:72.9±8and71.6±7.6years,respectively;p-value=0.37)were
analyzed. In iron deficiency anemia, the mean serum ferritin was significantly lower
(p-value=0.036)comparedtopatientswithoutirondeficiencyanemia.Serumferritinwith
acutofflevelof100ng/mLdifferentiatedpatientswithandwithoutirondeficiencyanemia
with a sensitivityof60% andspecificity of59%and areaunderthereceiveroperating
characteristiccurveof0.615±0.040(95%confidenceinterval:0.536–0.694;p-value=0.004).
Conclusion: Thesefindingsindicate thatinelderlysubjects, irondeficiency anemiamay
developwithhigherlevelsofserumferritin.Hence,theconventionalcutoffofserumferritin
forthediagnosisofirondeficiencyanemiainyoungadultsisnotappropriatefortheelderly
population.
©2017Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published
byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
∗ Correspondingauthorat:DepartmentofMedicine,DivisionofRheumatology,RouhaniHospital,ClinicalResearchDevelopmentUnitof
RouhaniHospital,BabolUniversityofMedicalSciences,Babol,Iran.
E-mailaddress:adreess.bheidari6@gmail.com(B.Heidari).
http://dx.doi.org/10.1016/j.bjhh.2017.02.002
1516-8484/©2017Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan
Introduction
Anemia affects one third of the world population with
nearlyhalfofthepatientswithanemiasufferingfrom iron
deficiency.1
In elderly people, even low levels of anemia affect
the quality of life and increase the risk of mortality
resulting in many medical conditions such as
cardio-vascular and cognitive disorders, osteopenia, muscle
weakness, falls and fractures, and depression.2 Several
factors such as inflammatory processes, chronic renal
failure, and gastrointestinal and nutritional disorders
are associated with anemia, in particular iron deficiency
anemia(IDA).Intheaged,theprevalenceofanemiaincreases
withageandrangesfrom8%to25%,nonethelessthecauses
ofanemia,includingthediagnosisoftheirondeficiencystate,
remainundeterminedinmanypatients.3–6 Currently,serum
ferritin(SF)(rangingfrom40to200ng/mL)isameasureofiron
stores in healthy adults. However, its diagnostic capability
variesacrossdifferentstudieswithregardtocutoffpoints.7–9
Inelderlypopulations,changesinSFconcentrationsdonot
alwayscorrelatewith variationsinironstores because
fer-ritinisanacutephaseproteinandisaffectedbyinflammatory
processesirrespectiveoftheironstorestatus.
Manychronicmedicalconditionsinthegeneral
popula-tionsuchasobesity,metabolicsyndrome,chronicobstructive
pulmonary disease and diabetes are also prevalent in the
elderly.10–19 These conditions are usually associated with
inflammation.10,11,20,21Coexistenceofthesecomorbiditiesin
agedpeoplemaybeassociatedwithelevatedlevelsofacute
phaseproteinsincludingSF.Thissituationresultsinthe
devel-opmentof functional IDA (anemiaofinflammation) which
isassociatedwithdisproportionatereleaseofironfromiron
storestocompensatebodydemandswithsubsequentIDA.In
thesecases,incontrasttoabsoluteIDA,SFdoesnotreduce
concomitantlywithironstores.
Thisissuecreatesdifficultiesinthediagnosticcapability
ofthe ferritintesttodiagnoseIDA.Thus,theclassiccutoff
valueofSFasappliedtoyoungadultsmaybeinappropriate
forthediagnosisofIDAintheelderly.Theseobservations
war-rantfurtherinvestigationstodetermineaSFlevelwithmore
reliablediagnosticproperties.Asystematicreviewof55
stud-iesfoundvariationsinSFtestresultsacrosspopulationswith
andwithoutinflammatoryprocesses,liverdiseaseor
neoplas-ticdiseases.Althoughferritinisnotanexcellentmeasureof
ironstores,itisapracticalandwidelyusedmethodtoassess
ironstores.22
Forthesereasons,thepresentstudywasdesignedto
deter-mineanoptimalSFleveltodifferentiateelderlypatientswith
andwithoutIDAwithgreatersensitivityandspecificity.The
secondarypurposeofthisstudywastodeterminethe
diag-nosticpropertiesofdifferentlevelsofSFinthediagnosisof
IDAinacohortoftheelderlysubjectsaged60yearsandolder.
Methods
Thepatientsofthiscase–controlstudywererecruitedamong
the participants ofthe Amirkola Health and Aging Project
(AHAP).ThisprojectwascarriedoutinAmirkola,Babol,atown
locatedneartheCaspianSea,northernIran.Theprojectwas
fundedbytheVice-ChancelleryofResearchandTechnology,
BabolUniversityofMedicalSciencesfortheinvestigationof
geriatricmedicalproblemssuchasfalling,bonefragilityand
fractures,cognitiveimpairmentanddementia,poormobility
andfunctionaldependence.Thebaselinestageofthisproject
wascarriedoutin2011and2012.Allinhabitantsaged60years
andoverwereinvitedtoparticipateinthisstudywith72.3%
oftheinvitedsubjectsparticipating.12Allpatientswith
ane-mia,definedasahemoglobinlevellowerthan13g/dLinmen
and12g/dLinwomen,wereincludedinthestudy.Participants
withahistoryoftransfusionwithinsixmonthspriortothe
startofthisstudy,thosetakingironsupplements,andpatients
withchronicrenalfailureandonmaintenancehemodialysis
wereexcluded.
All patients gaveinformed consentand the proposalof
thisstudywasapprovedbytheEthicsCommitteeoftheBabol
UniversityofMedicalSciences,Babol,Iran.
Datawerecollectedregardingserumiron,percentof
trans-ferrin saturation and SF and the prevalence of coexistent
chronicmedicalconditionswasrecorded.
Dataregardingchronicdiseaseswereprovidedbyclinical
examination,interviewsandreviewofmedicalrecords.The
diagnosis ofIDA was confirmed basedon transferrin
satu-ration levels of less than 15%.Details ofpatient selection,
datacollectionandlaboratorytestresultshavebeendescribed
elsewhere.12
In the statisticalanalysis, the participantsof this study
were classified as patients with and without IDA. Eighty
patientswithIDAwerecomparedwith160patientswith
ane-miawithoutirondeficiency.Thetwogroupswerecompared
regardingSFandpercentoftransferrinsaturation.
Thediagnostic abilityofSF wasdetermined byreceiver
operatingcharacteristic(ROC)curveanalysis.Theoptimal
cut-offlevelsthatdifferentiatedpatientswithandwithoutIDAat
thehighestsensitivityandspecificityratesweredetermined
usingYouden’sindexcalculatedbysensitivity+specificity–1.
Theaccuracyoftestwasassessedbasedonareaunderthe
ROCcurve(AUC).Thedistributionofallvariableswastested
fornormalityusingtheKolmogorov–Smirnovtest.Parametric
andnon-parametrictestswereusedforanalysesofvariables
withandwithoutnormaldistribution,respectively.The
Sta-tisticalPackagefortheSocialSciences(SPSS)softwareversion
18wasemployedforanalysis.
Results
TheAmirkolaCohortProfileincludedallinhabitantslivingin
the34districtsofAmirkolatown,2234ofwhomwereaged
60yearsorolderwhenthisstudybegan(1158menand1076
women).Thirty-five outof2234participantswere excluded
and114womenand126menoutof1994participants(12.03%)
whohadanemiawerestudied.EightypatientswithIDA,with
ameanageof72.9±8and160patientswithoutIDAwitha
meanageof71.6±7.6yearsold(p-value=0.37)wereanalyzed
(Table1).
Coexistent common chronic medical diseases such as,
Table1–Comparisonofironparametersinelderlysubjectsaged60yearsandolderwithandwithoutirondeficiency anemia.
Variables IDApresent
n=80
IDAabsenta n=160
p-Valuec
Age(Mean±SD)–years 72.9±8 71.6±7.6 0.37
Hemoglobinlevel–g/dL 9.7±1.3 10.1±1.2 0.018
Serumiron–g/dL 35.8±8.3 95.3±26.4 0.001
Transferrin–g/dL 333.1±26.7 269±28.8 0.001
Transferrinsaturationlevel–mean,% 10.85±2.2 31.1±8.2 0.001
Serumferritin–ng/mL 148.5±147.7 188.4±134 0.036
IDA:irondeficiencyanemia.
a Confirmedbytransferrinsaturation<15%.
b Non-IDAanemia.
c Student’st-testwasusedforcomparison.
disease,hypothyroidism and congestive heart failure were
foundin41.6%,24.5%,34.1%,7.5%,4.1%and2.5%ofthetotal
patientswithanemia,respectively.Prevalenceof
comorbidi-tiesinpatientswithandwithoutIDAarepresentedinTable2.
Theprevalenceofdiabetes,chroniclungdiseaseand
hypothy-roidismwassignificantlyhigherinpatientswithIDAbutthe
prevalences of incontinency and hypertension were lower
comparedtothosewithoutIDA.
In iron deficient patients, serum iron concentration
wassignificantly lower,serum transferrin was significantly
higher,and bothtransferrinsaturationand SFwere
signifi-cantlylowercomparedwithpatientswithoutirondeficiency
(Table1).
SF at cutoff level of 100ng/mL differentiated patients
withand without IDA withasensitivity of60%and
speci-ficity of 59% with the area under the ROC curve of
0.615±0.040[95%Confidence interval(95% CI):0.536–0.694;
p-value=0.004].
Thiscutofflevelyieldedpositiveand negativepredictive
valuesof45% and 74%,respectively. Furtheranalyseswere
performedtodeterminethediagnosticperformanceforother
levelsofSF(Table3).SFlevelslowerthan18ng/mLyieldedthe
highestlikelihoodratioof3.71(95%CI:1.5–8.4),sensitivityof
16%andspecificityof96%forthediagnosisofIDA(Table3).
Serumcutofflevelsof45ng/mLand60ng/mLyielded
posi-tivelikelihoodratios of2.54(95%CI:1.4–4.4)and 2.33(95%
CI:1.4–3.73),respectively.InpatientswithSFlevelslessthan
100ng/mL,the likelihood ofIDAdecreased to1.61(95% CI:
1.18–2.2)withnegativepredictivevalueof72%andlikelihood
negativeratioof0.76.
Discussion
Theresultsofthisstudyindicatethat,inelderlysubjects,SF
testshaveadifferentdiagnosticabilityaccordingtothe
cut-offlevels.Inthepresentstudy,theoptimalSFwithacutoff
pointof100ng/mLyieldedthehighestsensitivityand
speci-ficityforthediagnosisofIDAinsubjectsaged60yearsand
older.Basedonthisstudy,SFoflessthan100ng/mLidentified
51%ofpatientswhohadtransferrinsaturation<15%,whereas
SF>100ng/mLidentified74%ofsubjectswithoutIDA
indicat-ingahighernegativepredictivevaluecomparedtothepositive
predictivevalue.ThissuggeststhatinelderlysubjectsSF
lev-els>100ng/mLcomparedwith<100ng/mLyieldgreaterability
toexcluderatherthanconfirmIDA.
Thisstudyfounddifferentdiagnosticpropertiesacross
var-ious SF levels. Compared to the cutoff level of 100ng/mL,
cutoffsof18ng/mL, 45ng/mLand 60ng/mLyieldedgreater
positivepredictivevaluesaswellaspositivelikelihoodratios
butlowersensitivityforthediagnosisofIDA(Table3).
On theother hand,whileserum cutofflevels of45 and
60ng/mL yielded comparable diagnostic properties, levels
≤18ng/mLcomparedwithothercutoffpointsexhibitedhigher
specificityandlikelihoodratiobutlowersensitivity.
Overall,byincreasingSFcutofflevels,thesensitivityand
thenegativepredictivevalueofthistestinthediagnosisof
IDAincreasesattheexpenseofdecreasingspecificityandthe
positivepredictivevalue.
In the present study,the mean SFin patientswith IDA
washigherthan100ng/mL,whereasinastudyofapparently
Table2–Prevalenceofchronicmedicalconditionsinpatientswithandwithoutirondeficiencyanemiainelderly subjectsaged60yearsandmore.
Chronicmedicalconditions Irondeficiencyanemia N=80
n(%)
Anemiawithoutirondeficiency N=160
n(%)
p-Value
Chroniclungdisease 13(16.2) 5(8) 0.001
Diabetes 48(60) 34(21.25) 0.001
Urinaryincompetence 8(5) 51(63.7) 0.001
Hypertension 57(35.6) 43(53.7) 0.001
Congestiveheartfailure 2(2.5) 4(2.5) 0.64
Table3–Diagnosticpropertiesfordifferentcutofflevelsofserumferritinindiagnosisofirondeficiencyanemiain elderlypatientsaged>60yearsold.
18ng/mL 45ng/mL 60ng/mL 100ng/mL
Sensitivity(95%CI) 16(8–24) 29(19–30) 35(25–45) 51(40–62) Specificity(95%CI) 96(92–99) 89(84–94) 85(79–91) 68(61–75) PPV(95%CI) 66(44–86) 56(41–71) 53(40–67) 44.3(34–55) NPV(95%CI) 69(63–70) 71(65–78) 72(66–79) 73.4(67–81) LR+(95%CI) 4(1.5–8.4) 2.64(1.4–4.4) 2.3(1.4.3.75) 1.6(1.18–2.20) LR−(95%CI) 0.87(0.79–0.97) 0.8(0.69–0.93) 0.76(0.64–0.91) 0.72(0.56–0.92)
95%CI:95%confidenceinterval;PPV:positivepredictivevalue;NPV:negativepredictivevalue;LR+:likelihoodratiopositive;LR−:likelihood rationegative.
healthy80-year-oldDanishmenandwomen,themedianSF
valuewas100ng/mLinmenand78ng/mLinwomen.In9%of thesesubjects,theSFlevelswere>300ng/mL.23Inastudyof73
patientswithanemiaandchronicdiseasesbyCoenenetal.,SF
concentrationsoflessthan70ng/mLwerealwaysindicativeof
IDA.24Inpatientswithinflammatorydiseasesuchas
rheuma-toidarthritis,irondeficiencyanemiamaydevelopathigher
levelsofSFandsothecutoffpointisexpectedtobehigher.25
Theresultsofasystematicreviewsuggestthatfurther
investi-gationsareneededonthediagnosisofIDAinconditionswith
SFconcentrationslowerthan100ng/mL.26
Theresultsofanotherstudyofanemicveteranswithawide
varietyofgeneralmedicalcomorbiditieswerepartlysimilar
tothisstudy.Thestudyfoundasensitivityof64.9%withSF
≤100ng/mLandaspecificityof96.1%todetectpatientswith
IDA.27
The cutoffpoints forSF in patients with IDA in
previ-ousstudiesvaryfrom12to100ng/mL.7,23,24,27Inarandomly
selectedsampleof38-year-oldwomen,SF<16ng/mLwasthe
bestcutoffleveltodifferentiatepatientswithandwithoutiron
deficiency withasensitivity of75% and specificity of98%;
the ironstores beganto disappear atSFlevels from 25 to
40ng/mL.7 However,comparedtothecurrentstudytheage
ofpatientswaslower.
Inanotherstudyofelderlypatients,SFmeasurementwas
the best diagnostic test todiscriminate patients with and
withoutIDA.Inthisstudy,thelikelihoodofdiagnosisofIDAin
caseswithSFfrom18to45ng/mLwas3.12andinthosewith
lessthan 18ng/mL,it was41.47, withanegativepredictive
valueof72%.22
Thisstudyindicatesthat,inelderlypeople,SFhasless
diag-nosticabilitycomparedtopercentoftransferrinsaturation.In
astudyof49consecutivesubjectsaged80yearsormorewith
IDAasconfirmedbybonemarrowaspiration,correct
diagno-sisbySF,serumironandpercentoftransferrinsaturationwas
possibleinonly16.3%.28
VariationsinthediagnosticabilityofSFtodiagnoseIDA
acrossvariousstudies maybeattributedtofactors suchas
thediagnosticcriteriaappliedforIDA,characteristicsofthe
study patients, and the prevalenceofcomorbidities inthe
studypatients.6,7,22,24–32Thepresenceofcomorbiditiesinthe
studypopulation,particularlyinoldersubjects,isassociated
withelevatedlevelsofacutephaseproteinsincludingferritin
andthusmayaffectthecutofflevelandchangetheresults.
In a study of patients in the general practice aged 65
years and older, 23% suffered from at least one chronic
disease with 15% suffering from more than one chronic
diseasesuchosteoarthritis,diabetes,chronicobstructive
pul-monary disease,coronary arterydisease,hypertension and
diabetes.18 In another study,82% ofaged Medicare
benefi-ciaries had one or more chronic conditions and 65% had
multiplechronicconditions.17About82%oftheparticipants
aged 65–84 years of the 2003 National Sleep Foundation
study reported one or moreof 11 medicalconditions and
nearly 25% of respondents had four or more conditions
such as obesity, arthritis, diabetes, lung disease, stroke
and osteoporosis.19 In thepresent study hypertension,
uri-nary incontinency,diabetes and chronic lung disease were
foundinsignificantproportionsofpatientsinbothgroups.
Most chronic medicalconditions particularly diabetes,
uri-nary incontinencyand chronic lungdisease are associated
withinflammatoryprocesses.10,11,13–16,20,21Theprevalenceof
bothgeneralandabdominalobesityincreaseswithaging.13,14
Obesity is associated with inflammation and there is a
positive correlation between the body mass index and
SF.33
Thelimitations ofthisstudy shouldbeconsidered.One
major limitation is the lack of bone marrow aspiration
fordefinitivediagnosis ofirondeficiencyanemia.Although
absence ofironinthe bonemarrowisconsidered thegold
standarddiagnostictestfordiagnosisofIDA,thelackofiron
stores in the bonemarrow aspirate isnot necessarily
pre-dictiveofIDA.34Inaretrospectivestudyof12patientswith
depleted ironstores,irondeficiency wasthe cause of
ane-miaonly in50% ofthe patients.34 However,Klantar-Zadeh
et al. reported high sensitivity and specificity of the
per-cent of transferrin saturation test in the diagnosis of IDA
in chronic renal disease with inflammatory conditions.35
Another limitationisrelatedtolackofdataconcerningthe
assessmentofserumC-reactiveproteinandothermeasures
ofinflammationtoshowtheexistenceofinflammatory
pro-cesses. However, the high prevalence of diabetes, chronic
lung disease and urinary incontinenceeven inthe control
groupindicatesthattherewerechroniccomorbiditiesinthe
elderlypeople,andconsequentlyinflammatoryprocessesare
common.
Thestrengthofthisstudyisrelatedtothestudysample
whichincludedallparticipantsoftheAlmirkolaCohortStudy
thatenrolledalltheinhabitantsofAmirkola,asmalltownin
northernIran.Anotherstrengthisrelatedtothehomogeneity
ofthestudy populationinrespecttodemographicfeatures,
Theclinicalsignificanceofthesefindingsisrelatedtothe
incapabilityof theSF testas a measuretoidentify IDA in
elderlypeople.ThesefindingssuggestthatSFlevelsinmany
elderlysubjectswithIDAmaybenormalorhigherthan
nor-mal,and thus SFusing conventional cutoff levelsis not a
reliablemeasureinthediagnosisofabsoluteIDA.
Conclusion
Inconclusion,theresultsofthisstudyindicatethatSFisnot
anappropriate testfor the diagnosis of IDA inthe elderly
subjects aged 60 years and older.Based on these findings
the SF cutoff level of 100ng/mL can predict half of the
patients with absoluteIDA, whereas SF>100 yieldsa 74%
negativepredictive value, indicating that in elderly people
higherlevelsofSFarebettertoexcludeIDAratherthanlow
levels of SF to confirm IDA. This context requires further
studies.
Conflict
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgement
WethanktheClinicalResearchDevelopmentUnitOfRouhani
Hospitalforassistanceinmanuscriptsubmissionand
refer-encesarrangement.
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