rev bras hematol hemoter. 2014;36(5):319–321
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
w w w . r b h h . o r g
Scientific
comment
An
eye
on
sickle
cell
retinopathy
夽
Mônica
Barbosa
de
Melo
UniversidadeEstadualdeCampinas(UNICAMP),Campinas,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received13July2014 Accepted17July2014
Availableonline12August2014
Sicklecelldisease(SCD)iscausedbyasinglepointmutation atthe sixthposition inthe -globin chainthat substitutes the aminoacid valine forglutamic acid resulting insickle hemoglobin(HbS).Despitebeingcharacterizedbythesame point mutation, the clinical course of SCD is extremely variable,rangingfrommildtoveryseveredependingonthe differentgenotypes.1–4Patientswithsicklecellanemia(SCA),
themostcommonand mostsevereformofSCD,havetwo copiesofthealteredgene,agenotypereferredtoasHbSS. HemoglobinC(HbC)occursfrequentlyincompound heterozy-gositywithHbSwiththeresultingSCdisease(HbSC)being relativelymorebenignthanhomozygousHbSS.However,for reasonsnotwellunderstood,thesepatientsaremorelikelyto beaffectedbythromboemboliccomplications,renalpapillary necrosisandretinopathy.5,6
Boththeanteriorandposteriorsegmentsoftheeyecan becompromised dueto the pathological processes ofSCD but ocularmanifestations inthe retina are considered the mostimportantintermsoffrequencyandvisualimpairment.7
Sickle cell retinopathy develops in up to 42% of individ-uals during the second decade of life.8 It is triggered by
vaso-occlusionoftheocularmicrovasculature,asopposedto diabeticretinopathywhichisassociatedwithoverexposureof
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2014.07.012.
夽
SeepaperbyOliveiraDCAetal.onpages340–4.
Correspondingauthor at:UniversidadeEstadualdeCampinas(Unicamp),CentrodeBiologiaMoleculareEngenhariaGenética,Rua CândidoRondon,400,BarãoGeraldo,13083-875Campinas,SP,Brazil.
E-mailaddress:[email protected](M.B.deMelo).
thevasculartissuestohyperglycemia,andmayleadtovisual impairmentdependingonitslocalizationandaffectedtissue. Sicklecellretinopathycanbeclassifiedasnon-proliferativeor proliferative.Inthenon-proliferativeformthemostcommon clinical findings are salmonpatch hemorrhages, iridescent spots and black sunbursts, which can be observed in the peripheralretina.Moreover,venoustortuosity,enlargement ofthefovealavascularzone,centralretinalarteryobstruction andperi-papillaryandperi-maculararteriolarocclusionshave beenreportedinthecentralpartoftheretina.Angioidstreaks can beobservedinassociationwithsicklecell-thalassemia disease,SCAandSCD.9,10
Proliferative sicklecell retinopathy(PSCR) complications areamajorcontributortovisionloss,leadingtovisual impair-ment in10–20%ofaffected eyes.There isa lowfrequency of visual loss inSCD which may be explained, atleast in part,bythehighfrequencyofspontaneousregression(20–60% of cases) through the development of atrophic lesions or autoinfarction. Spontaneousregression,which occursmost frequentlyabout2yearsafterthedevelopmentofPSCR,isan importantdeterminantinthenaturalhistoryofPSCR.11–13The
highestprevalenceofPSCRinSCApatientsoccursbetween25 and39yearsofageinbothmenandwomen.However,inSCD
http://dx.doi.org/10.1016/j.bjhh.2014.07.020
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revbrashematolhemoter.2014;36(5):319–321patientsitoccursearlier:between15and24yearsinmenand from20 to39years inwomen.13 Peripheralretinal
neovas-cularizationdevelopsaftervaso-occlusion ofthe peripheral retinaand growsanteriorlyfrom perfusedtonon-perfused retina.14Initiallythesenewvesselsareflatanddenominated
sea fan fortheir close resemblancetothe marine inverte-brateGorgoniaflabellum.Neovascularizationinseafans,even smallseafans,iscapableofcausingvitreoushemorrhage.This complicationhappensduetotheconstant leakingofblood componentsinto thevitreousthroughthefragile neovascu-lartissue.Therepetitionofthis hemorrhagic phenomenon leads to worsening of the vitreo-retinal traction, with the potential ofcausing rhegmatogeneous or tractional retinal detachment.12,15
Itisimportanttonote thatthereisaninverse relation-shipbetweentheseverityofsystemicdiseaseandtheseverity ofretinopathy in homozygousSS individuals compared to compoundheterozygousSCsubjects.Sicklecellpatientshave more systemic complications with multiple vaso-occlusive eventsandsecondaryorgandamage.Heterozygouspatients, ontheotherhand,havefewersystemiccomplications,butan increasedfrequencyandearlyonset retinal neovasculariza-tion.Accordingtoalongitudinalstudydevelopedover20years inJamaica,theprevalenceofPSCRwasgreaterinSCDpatients. TheauthorsreportedthatPSCRhaddevelopedbytheageof24 yearsin43%and14%ofsubjectswithHbSCdiseaseandSCA, respectively.12Thehighprevalenceofretinopathyobservedin
HbSCpatientsmaybetheconsequenceofthismorebenign genotype. The postulated mechanism of action is that an enhancedcirculatorycompetenceofHbSCcellswould pre-servetheretinalcirculationallowingposteriordevelopment ofproliferativelesions.16Ontheotherhand,inSCApatients
thereisanearlyandamorecompleteocclusionofperipheral retinalvesselsandhencefurtherretinalvasculardamageand proliferativelesionsarerare.Thisphenomenonmayexplain whyabenigngenotypesuchasSCdiseasepresentsahigher frequencyofPSCRcomparedwiththeSSgenotype.One possi-bleexplanationproposedbyFabriandKaulisbasedonthree modelswithdifferentvaso-occlusivetendencies.These mod-elsare basedonlow, intermediateandhigh vaso-occlusive indices,withSCdiseasebeingrepresentedbytheintermediate model,thatis,withvaso-occlusionsufficienttoproduce reti-nalischemia,butinsufficienttooccludethedevelopingPSCR lesions.13,17
Thearticleentitled“Sicklecelldiseaseretinopathy: char-acterization among pediatric and teenage patients from northeasternBrazil”byOliveiraetal.andpublishedinthis editionoftheRevistaBrasileiradeHematologiaeHemoterapia describesapopulationofSCDpatientsfromthestateofBahia, accordingtotheirophthalmologiccharacteristics.18Themain
pointofthestudyistheconfirmationthatretinalchangeshave earlyonsetinbothSCAandSCdiseasepatients.Their find-ingscorroboratepreviousreportsindifferentpopulationsand confirmtheneedforophthalmologicalmonitoringofpatients fromearlychildhoodinordertoavoidvisualimpairmentas PSCR isusually asymptomatic untilcomplications such as vitreoushemorrhageorretinaldetachmentoccur.
Inadditiontotheeyeexamination,itisimportanttonote thepresenceoffactorsthatincreasethechanceofdeveloping SCPRashasbeenreportedbyotherresearchgroups.InSCD
patients,paincrisis,malegenderandsplenicsequestration suggesttheneedforearlierophthalmicscreening. Character-isticsofPSCR,suchasneovascularandfibrousproliferations (sea fan),vitreoushemorrhageand retinaldetachment, are associated with older age, pulmonarydisease, deafness or tinnitusandnohistoryofosteomyelitisinpatientswithSC disease.InSCApatients,olderage,malegenderandhistory of acute pyelonephritiswere associated with the develop-ment ofPSCR.19–21 Regarding laboratoryfindings,hightotal
hemoglobininmalesandlowfetalhemoglobininbothmales andfemaleswereobservedinSCApatients.InSCDpatients, increasedmeancellvolumeandlowfetalhemoglobinwere reportedinbothgendersandhightotalhemoglobinandhigh meancorpuscularhemoglobinconcentrationwereobserved
inmen.7,13,14,22
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s
1.SteinbergMH.Pathophysiologyofsicklecelldisease.
BaillieresClinHaematol.1998;11(1):163–84.
2.SteinbergMH,AdewoyeAH.Modifiergenesandsicklecell
anemia.CurrOpinHematol.2006;13(3):131–6.
3.BallasSK,KesenMR,GoldbergMF,LuttyGA,DampierC, OsunkwoI,etal.Beyondthedefinitionsofthephenotypic complicationsofsicklecelldisease:anupdateon management.SciWorldJ.2012:949535,
http://dx.doi.org/10.1100/2012/949535[Epubaheadofprint].
4.GilGP,AnaninaG,OliveiraMB,CostaFF,SilvaMJ,SantosMN,
etal.PolymorphismintheHMOX1geneisassociatedwith
highlevelsoffetalhemoglobininBrazilianpatientswith
sicklecellanemia.Hemoglobin.2013;37(4):315–24.
5.KassimAA,DeBaunMR.Sicklecelldisease,vasculopathy,and
therapeutics.AnnuRevMed.2013;64:451–66.
6.BallasSK,LewisCN,NooneAM,KrasnowSH,Kamarulzaman
E,BurkaER.Clinical,hematological,andbiochemicalfeatures
ofHbSCdisease.AmJHematol.1982;13(1):37–51.
7.FadugbagbeAO,GurgelRQ,Mendonc¸aCQ,CipolottiR,dos
SantosAM,CuevasLE.Ocularmanifestationsofsicklecell
disease.AnnTropPaediatr.2010;30(1):19–26.
8.FribergTR,YoungCM,MilnerPF.Incidenceofocular
abnormalitiesinpatientswithsicklehemoglobinopathies.
AnnOphthalmol.1986;18(4):150–3.
9.PopmaSE.Ocularmanifestationsofsickle
hemoglobinopathies.ClinEyeVisCare.1996;8:111–7.
10.RichetiF,NoronhaRM,WaetgeRT,deVasconcellosJP,de
SouzaOF,KneippB,etal.EvaluationofAC(n)andC(-106)T
polymorphismsofthealdosereductasegeneinBrazilian
patientswithDM1andsusceptibilitytodiabeticretinopathy.
MolVis.2007;13:740–5.
11.CondonPI,SerjeantGR.Behaviourofuntreatedproliferative
sickleretinopathy.BrJOphthalmol.1980;64(6):404–11.
12.DownesSM,HambletonIR,ChuangEL,LoisN,SerjeantGR,
BirdAC.Incidenceandnaturalhistoryofproliferativesickle
cellretinopathy:observationsfromacohortstudy.
Ophthalmology.2005;112(11):1869–75.
13.ElagouzM,JyothiS,GuptaB,SivaprasadS.Sicklecelldisease
andtheeye:oldandnewconcepts.SurvOphthalmol.
revbrashematolhemoter.2014;36(5):319–321
321
14.ScottAW,LuttyGA,GoldbergMF.Hemoglobinopathies:retinal
vasculardiseases.In:RyanSJ,editor.Retina.Philadelphia:
Elsevier;2013.p.1071–82.
15.LuttyGA,McLeodDS.Angiogenesisinsicklecellretinopathy.
In:PennJS,editor.Retinalandchoroidalangiogenesis.
Netherlands:Springer;2008.p.389–405.
16.NagelRL,FabryME,SteinbergMH.Theparadoxof
hemoglobinSCdisease.BloodRev.2003;17(3):167–78.
17.FabryME,KaulDK.Sicklecellvaso-occlusion.HematolOncol
ClinNorthAm.1991;5(3):375–98.
18.OliveiraDC,CarvalhoMO,NascimentoVM,Villas-BôasFS,
Galvão-CastroB,GoncalvesMS.Sicklecelldisease
retinopathy:characterizationamongpediatricandteenage
patientsfromnortheasternBrazil.RevBrasHematol
Hemoter.2014;36(5):340–4.
19.RosenbergJB,HutchesonKA.Pediatricsicklecellretinopathy:
correlationwithclinicalfactors.JAAPOS.2011;15(1):
49–53.
20.LevezielN,Bastuji-GarinS,LalloumF,QuerquesG,BenlianP,
BinaghiM,etal.Clinicalandlaboratoryfactorsassociated
withtheseverityofproliferativesicklecellretinopathyin
patientswithsicklecellhemoglobinC(SC)andhomozygous
sicklecell(SS)disease.Medicine(Baltimore).2011;90(6):
372–8.
21.LimJI.Ophthalmicmanifestationsofsicklecelldisease:
updateofthelatestfindings.CurrOpinOphthalmol.
2012;23(6):533–6.
22.FoxPD,DunnDT,MorrisJS,SerjeantGR.Riskfactorsfor
proliferativesickleretinopathy.BrJOphthalmol.
