JPediatr(RioJ).2016;92(4):325---327
www.jped.com.br
EDITORIAL
What
is
causing
anemia
in
young
children
and
why
is
it
so
persistent?
夽
,
夽夽
O
que
causa
anemia
em
crianc
¸as
mais
novas
e
por
que
ela
é
tão
persistente?
Alida
Melse-Boonstra
∗,
Martin
Ndegwa
Mwangi
DivisionofHumanNutrition,WageningenUniversity,Wageningen,Netherlands
The worldwideprevalence of anemia in children under 5 yearsofageisestimated tobe42.6%.1Not surprisingly,it
is more often found in low and middle-income countries, withSouth East Asia and Africa beingthe most affected. Theconsequencesofchildhoodanemiarangefromincreased susceptibility to infectious diseases, fatigue, decreased physicalcapacity, and,ifpersistent, lowercognitive func-tion and economic productivity in adulthood.2---5 When a
largepartofthepopulationisaffected,thiscanhave large-scaleconsequencesfortheeconomicproductivity.6
Anemia is rare in newborn babies, since their mother providesthem witha generous supply of ironupon birth, especially in cases of delayed cord clamping. There is evidence that antenatal iron supplementation, as recom-mendedbytheWorldHealthOrganization(WHO),improves neonatalironstores,thus delaying theage atwhich iron-deficiency anemia is likely to develop during infancy.7
Althoughbreastmilkisnotarichsourceofiron,its absorp-tionis enhancedby thepresence of lactoferrin.Formulas usuallycontainahigheramountofirontocompensatefor the lack of lactoferrin. Therefore, anemia often appears aftertheageof6months.Thisroughly coincideswiththe introduction of complementary foods, but also with the
夽
Pleasecitethisarticleas:Melse-BoonstraA,MwangiMN.What
iscausinganemiainyoungchildrenandwhyisitsopersistent?J
Pediatr(RioJ).2016;92:325---7.
夽夽
SeepaperbyZuffoetal.inpages353---60.
∗Correspondingauthor.
E-mail:[email protected](A.Melse-Boonstra).
periodthat children start to explore their world and are frequentlyexposedtocontaminants.Duringschoolage,the riskofanemiaisusuallymuchlower,butitpeaksagain dur-ingpuberty, especiallyin girls after menarche andduring pregnancy,due to thesharp increase in ironrequirement duringthesecondandthirdtrimester.8
The causes ofanemiaare multifactorial,but iron defi-ciencyis themost commoncauseandexplains about half ofthecases.1Meatisanimportantsourceofiron,sinceit
containsheme iron,which is moreefficiently absorbedin comparisontonon-hemeiron,whichistheprimaryformof ironinplantfoods.Non-hemeironisabsorbedintheferrous (Fe2+)formthroughthedivalentmetaltransporter1(DMT1). Theonlytransporterforhemeironthathasbeenobserved upuntilnowistheHCP1carrier,9althoughitisspeculated
thatothercarriersshouldexist.Bioavailabilityofhemeiron rangesfrom15to35%,whereasthatofnon-hemeironis usu-allylowerthan10%.Although darkgreenleafy vegetables arerichiniron,itsabsorptionislowandthesevegetablesare thereforenotverygoodsourcesofthisnutrient.10,11
Like-wise,legumesarerich in phytateandpolyphenols, which hampersironabsorption.12
Iron metabolism and the innate immune response to infectionmayexplaintheinterrelationshipsbetween nutri-tionandanemiainyoungchildren.Duetoitsabilitytoexist inoneoftwooxidationstates,ferrous(Fe2+)orferric(Fe3+), ironisanessentialbutalsotoxicnutrientinthehumanbody. Ironactsasanelectrondonorintheferrousstateandasan electronacceptorintheferricstate.13Theredoxpotential
ofironcanresultinreactiveoxygenspeciesthatultimately leadtogenerationoffreeradicalsthatdamagelipids,DNA,
http://dx.doi.org/10.1016/j.jped.2016.04.001
0021-7557/©2016SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND
326 Melse-BoonstraA,MwangiMN
andprotein,especiallyunderconditionsofironoverload.14
Assuch,ironconcentration anddistributionin thehuman bodyishighlyregulated.
Hepcidin,acirculatingpeptidehormone,isnowknownas thekeyregulatorofsystemicironhomeostasisinhumans.13
Hepcidinreducesdietary ironabsorptionby reducing iron transportacrossthegut mucosa;itreducesironexit from macrophages,themainsiteofironstorage;anditreduces ironexitfromtheliver.Inallthreeinstances,thisis accom-plished by reducing the transmembrane iron transporter ferroportin.13Hepcidinsynthesisandsecretionbytheliveris
controlledbyironstoreswithinmacrophages,inflammation, hypoxia,and erythropoiesis.Measuring hepcidin wouldbe ofbenefittoestablishoptimalirondeficiencyanemia treat-ment,butbecausethisis notwidelyavailable, C-reactive protein(CRP)isusedasasurrogatemarker.Inlightof emerg-ingknowledgeregardingirontransportandregulation,there isneedtostudyironmetabolisminrelationtoother physi-ologicalprocessesinhealthanddisease.
The mechanisms of iron homeostasis in human health and disease are largely dependent on the fact that iron is an essential nutrient for both humans and pathogenic microbes.14Nutritionalimmunity(alsoknownas‘‘iron
with-holding’’), a process through which the human immune system limits iron availabilityto invading microbes as an innate immune defense system, may explainwhy anemia in young children is sopersistent. In addition, directand indirectlinksbetweenparasiticinfectionsandhuman iron homeostasisexist.Forexample,hookwormsinfectover700 millionpeopleworldwideandarealeadingcauseof iron-deficiencyanemiainlowerandmiddle-incomecountries.15
Inthisissueofthejournal,Zuffoetal.16describethe
fac-torsassociatedwithanemiaamong334randomlyselected childrenaged6---36monthsattendingMunicipalEarly Child-hood Education Center (Centros Municipais de Educac¸ão Infantil[CMEI])nurseriesinColombo-PR,Brazil.Theyfound a prevalence of anemia of 34.7%, which wassignificantly higheramongyoungermothers(<28years),malechildren, youngerchildren (<24 months),and children who didnot consumeironfood sourcessuchasmeat, beans,and dark greenleafyvegetables.InBrazil,theprevalenceofanemia inchildrenunder5yearsofagehasbeenestimatedat24%.1
Althoughtheprevalenceinthepresentsmallstudyappears tobemuchhigherthanthenationalstatistic,thismightin partbeexplainedbythesmalleragerange(6---36monthsvs. 6---59months).
Ironintakeof the childrenappeared tobe low,witha medianintakeof3mgperday.Thisisfarbelowthe recom-mendedironintakeof7.7mgforchildrenaged6---12months and4.8mgforchildrenaged13---36months.Thepoordietary compositionofthemealsprovidedinthenurseriesmaybe thecause,butthelowironintakecanalsobeduetopoor appetiteofthe childrenfor iron-richfoods.Whateverthe reason, it is clear that low iron intake is a likely expla-nationfor thehighprevalence ofanemiarevealed bythis study.However,itshouldbenotedthatmanyotherpotential causal factors can play a role. In addition to iron, defi-ciencies of vitamin A andB can beimportant, as well as non-nutritionalcauses,suchasparasiticinfestation, infec-tiousdiseases,diarrhea,destructionoferythrocytes(e.g.by malaria),severebloodloss,andgeneticfactors.IntheBrazil
study,almosthalfofthechildrenhadexperiencedfeverand 22%ofthechildrenhaddiarrheainthe15dayspriortothe hemoglobinmeasurement.Thosewithfeverordiarrheahad ahigherprevalenceofanemiathanthosewhodidnot.
Themost commonglobal strategytoaddress iron defi-ciencyanemiaisthefortificationofstaplefoodswithiron. Flourfortificationhas proventobeeffective inimproving ironstatusand,toalesserextent,inreducinganemia.17In
Brazil,fortificationofwheatandmaizeflourwith4.2mgiron and150goffolicacidper100gofflourbecamemandatory
since2004.However,evaluationofthefortificationprogram tenyearsafteritsinceptionbyanationwidesurveyshowed thatflourfortificationaddedlittletothetotalironintake oftheBrazilianpopulation,especiallywhentakingthelow bioavailability of electrolytic iron into consideration.18 In
astudy comparingwholemealmaizeflourfortifiedeither withelectrolyticironorNaEDTA-iron,thelatterwasshown tobe superiorin improving ironstatusand reducing iron-deficiencyanemiainKenyanchildren.19
Despiteglobalprogramstocontrolit,childhoodanemia isstillpresent evenincountrieswithexcellenthealth sys-temsandsufficientironintake,withaprevalenceinNorth America of 7%and inEurope of 19%.1 Itis likelythat the
anemiathatremains afterthecorrectionofironintakeis, toalargeextent,relatedtocommonchildhoodinfections. It isironic thattheseinfections areinevitableinorderto buildupahealthyimmunesystem.Itistherefore question-ablewhetherchildhoodanemiacaneverbefullyeradicated unlesswewouldliveinacompletelysterileenvironment.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
1.World Health Organization (WHO). The global prevalence of anemiain2011.Geneva:WHO;2015.
2.Haas JD, BrownlieT 4th. Iron deficiency and reduced work capacity:acriticalreviewoftheresearchtodetermineacausal relationship.JNutr.2001;131:676S---88S.
3.BrownlieT 4th,Utermohlen V, Hinton PS,Giordano C, Haas JD. Marginal irondeficiency without anemia impairs aerobic adaptationamongpreviouslyuntrainedwomen.AmJClinNutr. 2002;75:734---42.
4.de Silva A, Atukorala S, Weerasinghe I, Ahluwalia N. Iron supplementationimprovesironstatusandreducesmorbidityin childrenwithorwithoutupperrespiratorytractinfections:a randomizedcontrolledstudyinColombo,SriLanka.AmJClin Nutr.2003;77:234---41.
5.WalkerSP, WachsTD,Gardner JM,Lozoff B,Wasserman GA, Pollitt E, et al. Child development: risk factors for adverse outcomesindevelopingcountries.Lancet.2007;369:145---57.
6.HortonS,RossJ.Theeconomicsofirondeficiency.FoodPolicy. 2003;28:51---75.
7.MwangiMN,RothJM,SmitMR,TrijsburgL,MwangiAM,Demir AY,etal.Effectofdailyantenatalironsupplementationon plas-modiuminfectioninKenyanwomen:arandomizedclinicaltrial. JAMA.2015;314:1009---20.
Anemiainyoungchildren 327
9.ShayeghiM,Latunde-DadaGO,OakhillJS,LaftahAH,Takeuchi K,HallidayN,etal.Identificationofanintestinalheme trans-porter.Cell.2005;122:789---801.
10.CercamondiCI,Icard-Vernière C,EgliIM, VernayM,Hama F, BrouwerID,etal.Ahigherproportionofiron-richleafy veg-etablesina typicalBurkinabe maizemealdoes notincrease the amount of iron absorbed in young women. J Nutr. 2014;144:1394---400.
11.van der Hoeven M, Faber M, Osei J, Kruger A, Smuts CM. Effect ofAfrican leafyvegetables on the micronutrient sta-tusof mildly deficient farm-school children in SouthAfrica: a randomizedcontrolled study.Public Health Nutr. 2016;19: 935---45.
12.PetryN,EgliI,ZederC,WalczykT,HurrellR.Polyphenolsand phyticacidcontributetothelowironbioavailabilityfrom com-monbeansinyoungwomen.JNutr.2010;140:1977---82.
13.AndrewsNC,SchmidtPJ.Ironhomeostasis.AnnuRevPhysiol. 2007;69:69---85.
14.CassatJE,SkaarEP.Ironininfectionandimmunity.CellHost Microbe.2013;13:509---19.
15.Long SS, Pickering LK, Prober CG, editors. Principles and practiceofpediatricinfectiousdiseases,vol.100.NewYork: ChurchillLivingstone;2003.
16.Zuffo CR, Osório MM, Taconeli CA,Schmidt ST, da SilvaBH, AlmeidaCC.Prevalenceandriskfactorsofanemiainchildren. JPediatr(RioJ).2016;92:353---60.
17.Pachón H, Spohrer R, Mei Z, Serdula MK. Evidence of the effectivenessofflourfortificationprogramsonironstatusand anemia:asystematicreview.NutrRev.2015;73:780---95.
18.dosSantosQ,NilsonEA,VerlyJuniorE,SichieriR.Anevaluation oftheeffectivenessoftheflourironfortificationprogrammein Brazil.PublicHealthNutr.2015;18:1670---4.
