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AlphaandBetaThalassemiaAmericanFamilyPhysician

AlphaandBetaThalassemia
HERBERTL.MUNCIE,JR.,MD,andJAMESS.CAMPBELL,MD,LouisianaStateUniversityHealthSciencesCenter,NewOrleans,Louisiana
AmFamPhysician.2009Aug1580(4):339344.
Thisversionofthearticleincludessupplementalcontent.(afp20090815p339s1.pdf)
Patientinformation:Seerelatedhandoutonthalassemia(http://www.aafp.org/afp/2009/0815/p371.html),writtenbytheauthorsofthisarticle.
Thethalassemiasareagroupofinheritedhematologicdisorderscausedbydefectsinthesynthesisofoneormoreofthehemoglobinchains.Alpha
thalassemiaiscausedbyreducedorabsentsynthesisofalphaglobinchains,andbetathalassemiaiscausedbyreducedorabsentsynthesisofbeta
globinchains.Imbalancesofglobinchainscausehemolysisandimpairerythropoiesis.Silentcarriersofalphathalassemiaandpersonswithalphaor
betathalassemiatraitareasymptomaticandrequirenotreatment.Alphathalassemiaintermedia,orhemoglobinHdisease,causeshemolyticanemia.
AlphathalassemiamajorwithhemoglobinBart'susuallyresultsinfatalhydropsfetalis.Betathalassemiamajorcauseshemolyticanemia,poorgrowth,
andskeletalabnormalitiesduringinfancy.Affectedchildrenwillrequireregularlifelongbloodtransfusions.Betathalassemiaintermediaislesssevere
thanbetathalassemiamajorandmayrequireepisodicbloodtransfusions.Transfusiondependentpatientswilldevelopironoverloadandrequire
chelationtherapytoremovetheexcessiron.Bonemarrowtransplantscanbecurativeforsomechildrenwithbetathalassemiamajor.Personswith
thalassemiashouldbereferredforpreconceptiongeneticcounseling,andpersonswithalphathalassemiatraitshouldconsiderchorionicvillus
samplingtodiagnoseinfantswithhemoglobinBart's,whichincreasestheriskoftoxemiaandpostpartumbleeding.Personswiththethalassemiatrait
haveanormallifeexpectancy.Personswithbetathalassemiamajoroftendiefromcardiaccomplicationsofironoverloadby30yearsofage.
Thethalassemias(namedfromtheGreekwordforsea,thalassa1)areagroupofinheritedautosomalrecessivehematologicdisorders2thatcausehemolytic
anemiabecauseofthedecreasedorabsentsynthesisofaglobinchain.Imbalancesofglobinchainscausehemolysisandimpairerythropoiesis.Familyphysicians
needtoknowhowtodiagnosethalassemias,howtodistinguishthemfromothercausesofamicrocyticanemia,andthetreatmentoptionsforsevereformsof
thalassemia.

Epidemiology
Approximately5percentoftheworld'spopulationhasaglobinvariant,butonly1.7percenthasalphaorbetathalassemiatrait.2Thalassemiaaffectsmenand
womenequallyandoccursinapproximately4.4ofevery10,000livebirths.AlphathalassemiaoccursmostofteninpersonsofAfricanandSoutheastAsian
descent,andbetathalassemiaismostcommoninpersonsofMediterranean,African,andSoutheastAsiandescent.Thalassemiatraitaffects5to30percentof
personsintheseethnicgroups.2
View/PrintTable

SORT:KEYRECOMMENDATIONSFORPRACTICE
CLINICALRECOMMENDATION

EVIDENCE
RATING

REFERENCES

Personswithanemiafromthalassemiatraitshouldnottakeironsupplementsunlesstheyhavecoexistentirondeficiency.

2,6

Personswithbetathalassemiamajorrequireperiodiclifelongbloodtransfusionstomaintainhemoglobinlevelshigherthan9.5gperdL(95g
perL)andsustainnormalgrowth.

2,15

Personswithbetathalassemiamajorrequirechelationtherapyforironoverload.

16

Personsatriskofhavingachildwiththalassemiashouldbeofferedpreconceptiongeneticcounseling.

20,21

A=consistent,goodqualitypatientorientedevidenceB=inconsistentorlimitedqualitypatientorientedevidenceC=consensus,diseaseorientedevidence,usualpractice,expert
opinion,orcaseseries.ForinformationabouttheSORTevidenceratingsystem,gotohttp://www.aafp.org/afpsort.xml(http://www.aafp.org/afpsort.xml).

Pathophysiology
Hemoglobinconsistsofanironcontaininghemeringandfourglobinchains:twoalphaandtwononalpha.Thecompositionofthefourglobinchainsdeterminesthe
hemoglobintype.Fetalhemoglobin(HbF)hastwoalphaandtwogammachains(alpha2gamma2).AdulthemoglobinA(HbA)hastwoalphaandtwobetachains
(alpha2beta2),whereashemoglobinA2(HbA2)hastwoalphaandtwodeltachains(alpha2delta2).Atbirth,HbFaccountsforapproximately80percentof

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hemoglobinandHbAaccountsfor20percent.3Thetransitionfromgammaglobinsynthesis(HbF)tobetaglobinsynthesis(HbA)beginsbeforebirth.By
approximatelysixmonthsofage,healthyinfantswillhavetransitionedtomostlyHbA,asmallamountofHbA2,andnegligibleHbF.Figure1showsnormaland
abnormalhemoglobins.
View/PrintFigure

Figure1.
Normal(hemoglobinF,A,andA2)andabnormal(hemoglobinHandBart's)hemoglobins.Hemoglobinconsistsofanironcontaininghemeringandfourglobinchains:twoalphaand
twononalpha.Thecompositionofthefourglobinchainsdeterminesthehemoglobintype.

ALPHATHALASSEMIA
Alphathalassemiaistheresultofdeficientorabsentsynthesisofalphaglobinchains,leadingtoexcessbetaglobinchains.Alphaglobinchainproductionis
controlledbytwogenesoneachchromosome16(Table14,5).Deficientproductionisusuallycausedbyadeletionofoneormoreofthesegenes.Asinglegene
deletionresultsinalphathalassemiasilentcarrierstatus,whichisasymptomaticwithnormalhematologicfindings.Thetwogenedeletioncausesalphathalassemia
trait(minor)withmicrocytosisandusuallynoanemia.ThethreegenedeletionresultsinsignificantproductionofhemoglobinH(HbH),whichhasfourbetachains
(beta4).Alphathalassemiaintermedia,orHbHdisease,causesmicrocyticanemia,hemolysis,andsplenomegaly.Thefourgenedeletionresultsinsignificant
productionofhemoglobinBart's(HbBart's),whichhasfourgammachains(gamma4).AlphathalassemiamajorwithHbBart'susuallyresultsinfatalhydropsfetalis.
View/PrintTable

Table1.
PrototypicalFormsofAlphaThalassemia
VARIANT

CHROMOSOME16

SIGNSANDSYMPTOMS

Alphathalassemiasilentcarrier

Oneoffourgene
deletions

Asymptomatic

Alphathalassemiatrait

Twooffourgene
deletions

Asymptomatic

HemoglobinConstantSpring

Reducedoutputof
alphaglobin

Silentormildlysymptomatic

Alphathalassemiaintermediawithsignificanthemoglobin
H(hemoglobinHdisease)

Threeoffourgene
deletions

Moderatetoseverehemolyticanemia,modestdegreeofineffectiveerythropoiesis,
splenomegaly,variablebonechanges4

Alphathalassemiamajorwithsignificanthemoglobin
Bart's

Fouroffourgene
deletions

Causesnonimmunehydropsfetalis,usuallyfatal5

Informationfromreferences4and5.

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BETATHALASSEMIA
Betathalassemiaistheresultofdeficientorabsentsynthesisofbetaglobinchains,leadingtoexcessalphachains.Betaglobinsynthesisiscontrolledbyonegene
oneachchromosome11.Betathalassemiaoccursfromanyofmorethan200pointmutationsand(rarely)deletionsofthetwogenes.Betaglobinchainproduction
canrangefromnearnormaltocompletelyabsent,leadingtovaryingdegreesofexcessalphaglobintobetaglobinchainproduction.Theonegenedefect,beta
thalassemiatrait(minor),isasymptomaticandresultsinmicrocytosisandmildanemia.Ifthesynthesisfrombothgenesisseverelyreducedorabsent,theperson
hasbetathalassemiamajor,alsoknownasCooleyanemia.Personswithbetathalassemiamajorarealmostneversymptomaticatbirthbecauseofthepresenceof
HbF,butsymptomsbegintodevelopbysixmonthsofage.Ifthesynthesisofbetachainsislessseverelyreduced,thepersonhasbetathalassemiaintermedia.
Thesepersonsexperiencesymptomsthatarelesssevereanddonotrequirelifelongtransfusionstosurvivepast20yearsofage(Table2).6
View/PrintTable

Table2.
PrototypicalFormsofBetaThalassemia
VARIANT

CHROMOSOME11

SIGNSANDSYMPTOMS

Betathalassemia
trait

Onegenedefect

Asymptomatic

Betathalassemia
intermedia

Twogenesdefective(mildtomoderatedecrease
inbetaglobinsynthesis)

Variabledegreesofseverityofsymptomsofthalassemiamajor

Betathalassemia
major

Twogenesdefective(severedecreaseinbeta
globinsynthesis)

Abdominalswelling,growthretardation,irritability,jaundice,pallor,skeletalabnormalities,
splenomegalyrequireslifelongbloodtransfusions6

Informationfromreference6.

HEMOGLOBINOPATHIESWITHTHALASSEMIA
Ahemoglobinopathyisageneticdefectthatresultsinanabnormalstructureofaglobinchain.Athalassemiaresultsinanabnormallylowquantityofaglobinchain.
Rarely,personswillhavecoexistinghemoglobinopathyandthalassemia(OnlineTableA)(afp20090815p339s1.pdf).

Diagnosis
Mostpersonswiththalassemiatraitarefoundincidentallywhentheircompletebloodcountshowsamildmicrocyticanemia.Microcyticanemiacanbecausedby
irondeficiency,thalassemia,leadpoisoning,sideroblasticanemia,oranemiaofchronicdisease.Themeancorpuscularvolume(MCV),redbloodcelldistribution
width(RDW),andthepatient'shistorycanexcludesomeoftheseetiologies.TheMCVisusuallylessthan75flwiththalassemiaandrarelylessthan80fliniron
deficiencyuntilthehematocritislessthan30percent.Forchildren,theMentzerindex(MCV/redbloodcellcount)canhelpdistinguishbetweenirondeficiencyand
thalassemia.Inirondeficiency,theratioisusuallygreaterthan13,whereasthalassemiayieldsvalueslessthan13.Aratioof13wouldbeconsidereduncertain.7
TheRDWmayassistindifferentiatingirondeficiencyandsideroblasticanemiafromthalassemia(Table3).TheRDWwillbeelevatedinmorethan90percentof
personswithirondeficiency,butinonly50percentofpersonswiththalassemia.8TheRDWisusuallyelevatedinsideroblasticanemia.Therefore,althougha
microcyticanemiawithanormalRDWwillalmostalwaysbebecauseofthalassemia,personswithanelevatedRDWwillrequireadditionaltesting(Figure2).9
View/PrintTable

Table3.
HematologicIndicesofIronDeficiencyandAlphaandBetaThalassemia
TEST

IRONDEFICIENCY

BETATHALASSEMIA

ALPHATHALASSEMIA

MCV(abnormalif<80flinadults<70flinchildrensixmonthstosixyears
ofageand<76flinchildrensevento12yearsofage)

Low

Low

Low

Redbloodcelldistributionwidth

High

Normaloccasionallyhigh

Normal

Ferritin

Low

Normal

Normal

Mentzerindexforchildren(MCV/redbloodcellcount)

>13

<13

<13

Hbelectrophoresis

Normal(may
havereduced
HbA2)

IncreasedHbA2,reducedHbA,
andprobablyincreasedHbF

Adults:normalNewborns:
mayhaveHbHorHbBart's

Hb=hemoglobinHbF=fetalhemoglobinMCV=meancorpuscularvolume.

View/PrintFigure

UseofRDWValuesintheDiagnosisofThalassemia

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Figure2.
AlgorithmoftheuseofRDWvaluestoassistindiagnosingthalassemia.(MCV=meancorpuscularvalueRDW=redbloodcelldistributionwidth.)
Informationfromreference9.

Supplementaltestsincludeserumferritin,theperipheralsmear,hemoglobinelectrophoresis,serumleadlevel,andrarelybonemarrowaspirate.Serumferritinis
thebesttesttoscreenforirondeficiencyanemia.10Intheabsenceofinflammation,anormalferritinlevelgenerallyexcludesirondeficiency.Serumiron,totaliron
bindingcapacity,andtransferrinsaturationarerarelyneeded.Sideroblasticanemiacanbeexcludedwithanexaminationoftheperipheralsmearorthebone
marrowaspirate.Anormalserumleadlevelexcludesleadpoisoning.Anemiaofchronicdiseaseismostoftenanormocyticnormochromicmildanemia.If
thalassemiaisstillsuspected,ahemoglobinelectrophoresismayhelpdiagnosethecondition.
ThehemoglobinelectrophoresiswithbetathalassemiatraitusuallyhasreducedorabsentHbA,elevatedlevelsofHbA2,andincreasedHbF.2However,anormal
concentrationofHbA2doesnotruleoutbetathalassemiatrait,especiallyiftherewascoexistentirondeficiency,whichcanlowerHbA2levelsintothenormalrange.
Inthenewbornperiod,iftheelectrophoresisshowsHbBart'sorHbH,theinfanthasalphathalassemia.Thehemoglobinelectrophoresisisusuallynormalinadults
withalphathalassemiatrait.
Personswithbetathalassemiamajorarediagnosedduringinfancy.Pallor,irritability,growthretardation,abdominalswelling,andjaundiceappearduringthesecond
sixmonthsoflife.6
Personswithamicrocyticanemiabutmildersymptomsthatstartlaterinlifehavebetathalassemiaintermedia.

Complications
Thecomplicationsthatoccurwithbetathalassemiamajororintermediaarerelatedtooverstimulationofthebonemarrow,ineffectiveerythropoiesis,andiron
overloadfromregularbloodtransfusions.Untreatedinfantshavepoorgrowth,skeletalabnormalities,andjaundice.Alphathalassemiaintermedia,orHbHdisease,
causeshemolysisandsevereanemia.AlphathalassemiamajorwithHbBart'scausesnonimmunehydropsfetalisinutero,whichisalmostalwaysfatal.
Withmultiplebloodtransfusionsandcontinuedabsorptionofintestinaliron,ironoverloaddevelops.Ironisdepositedinvisceralorgans(mainlytheheart,liver,and
endocrineglands),andmostpatientdeathsarecausedbycardiaccomplications.11Endocrinopathies,particularlyhypogonadismanddiabetesmellitus,mayoccur
inadolescentsandadults.2
Splenomegalyinvariablydevelopsinthesymptomaticthalassemias.Splenomegalycanworsentheanemiaandoccasionallycauseneutropeniaand
thrombocytopenia.
Thromboembolicevents,venousandarterial,arenotuncommon.Personswithbetathalassemiamajororintermediamaydevelopachronichypercoagulable
state,12especiallyaftersplenectomy.13
Osteopeniaandosteoporosisarebeingfoundmoreoftenaspersonswiththalassemiamajorlivelonger.Onestudyfoundosteoporosisin51percentofpersons
olderthan12yearswiththalassemiamajor.14

GeneralManagementIssues
Personswiththalassemiatraitrequirenotreatmentorlongtermmonitoring.Theyusuallydonothaveirondeficiency,soironsupplementswillnotimprovetheir
anemia.Accordingly,irontherapyshouldonlybeadministeredifirondeficiencyoccurs.2,6

BLOODTRANSFUSIONS
Personswithbetathalassemiamajorrequireperiodicandlifelongbloodtransfusionstomaintainahemoglobinlevelhigherthan9.5gperdL(95gperL)and
sustainnormalgrowth.2,15Theneedforbloodtransfusionsmaybeginasearlyassixmonthsofage.Forpersonswithbetathalassemiaintermedia,thedecisionto
transfuseisamoresubjectiveclinicalassessment.Transfusionrequirementsareepisodicandbecomenecessarywhentheperson'shemoglobinisinadequatefor
anormallifeorwhentheanemiaimpairsgrowthanddevelopment.
Alphathalassemiaintermedia,orHbHdisease,causesmildtomoderatehemolysis.Transfusionswilloccasionallybenecessarydependingupontheseverityofthe
clinicalcondition.

CHELATION

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Transfusiondependentpatientsdevelopironoverloadbecausetheyhavenophysiologicprocesstoremoveexcessironfrommultipletransfusions.Therefore,they
requiretreatmentwithanironchelatorstartingbetweenfiveandeightyearsofage.16Deferoxamine(Desferal),subcutaneouslyorintravenously,hasbeenthe
treatmentofchoice.Althoughthistherapyisrelativelynontoxic,itiscumbersomeandexpensive.TheU.S.FoodandDrugAdministrationrecentlyapprovedoral
deferasirox(Exjade)asanalternativetreatment.17Adverseeffectsofdeferasiroxweretransientandgastrointestinalinnature,andnocasesofagranulocytosis
werereported.

BONEMARROWTRANSPLANT
Bonemarrowtransplantationinchildhoodistheonlycurativetherapyforbetathalassemiamajor.Hematopoieticstemcelltransplantationgenerallyresultsinan
excellentoutcomeinlowriskpersons,definedasthosewithnohepatomegaly,noportalfibrosisonliverbiopsy,andregularchelationtherapy,oratmost,twoof
theseabnormalities.2

ManagementofSpecificConditions
HYPERSPLENISM
Ifhypersplenismcausesamarkedincreaseintransfusionrequirements,splenectomymaybeneeded.Surgeryisusuallydelayeduntilatleastfouryearsofage
becauseofthespleen'sroleinclearingbacteriaandpreventingsepsis.Atleastonemonthbeforesurgery,patientsshouldreceivethepneumococcal
polysaccharidevaccine.Childrenshouldalsoreceivethepneumococcalconjugatevaccineseries.Antibioticprophylaxiswithpenicillin,250mgorallytwiceaday,is
recommendedforallpersonsduringthefirsttwoyearsaftersurgeryandforchildrenyoungerthan16years.18

ENDOCRINOPATHIES
Growthhormonetherapyforbetathalassemiaintermediaandmajorhashadvariablesuccessandisnotgenerallyrecommended.Hormonetherapyiseffectivefor
hypogonadism.19

PREGNANCY
Preconceptiongeneticcounselingisstronglyadvisedforallpersonswiththalassemia.20Twoparents,eachwithbetathalassemiatrait,haveaoneinfourchanceof
conceivingachildwithbetathalassemiamajorandathreeinfourchancethechildwillhavethalassemiatraitorbenormal(OnlineFigureA)(afp20090815p339s1.pdf).
Personswithalphathalassemiatraithaveamorecomplexpatternofinheritance.Whetherbothdefectivegenesareonthesameordifferentchromosomeswill
altertheoutcome(OnlineFigureB)(afp20090815p339s1.pdf).
Chorionicvillussamplingusingpolymerasechainreactiontechnologytodetectpointmutationsordeletionscanidentifyinfantsaffectedwithbetathalassemia.
PersonswithalphathalassemiatraitshouldconsiderprenataldiagnosisbecauseHbBart'sincreasestheriskoftoxemiaandpostpartumbleeding.Preimplantation
geneticdiagnosisisbecomingavailableinconjunctionwithinvitrofertilization.21

CARDIAC
Serumferritinhasbeenusedasamarkerofironstoragetopredictcardiaccomplications.Ferritinlevelslessthan2,500ngpermL(2,500mcgperL)are
associatedwithimprovedsurvival.22However,ferritinlevelsareunreliablewhenliverdiseaseispresent.23

HYPERCOAGULOPATHY
Norandomizedorobservationalstudiesregardinganticoagulation,antiplatelettherapy,orbothhavebeenreportedforpersonsatgreaterriskofthromboembolic
events.Therefore,nospecifictreatmentcanberecommended.Personswithahistoryofthrombosismaybetreatedwithlowmolecularweightheparin.
Anticoagulationtherapyiswarrantedbeforesurgeryandduringpregnancyforatriskpersons.Alternativestoestrogencontainingcontraceptionshouldbeoffered
towomenofreproductiveage.

PSYCHOSOCIAL
Betathalassemiamajororintermediaisachronicdiseasewithasignificantimpactonthepatientandthepatient'sfamilyandoffspring.Educationaboutthe
geneticsofthedisease,prenataldiagnosisoptions,andpsychologicaltherapytohelpmanagethecomplicationsisappropriate.However,neitherthetypeof
educationnorthedurationoftherapycanbespecifiedbasedoncurrentevidence.24

VITAMINDEFICIENCIES
Folicaciddeficiencyhasbeenreportedinthalassemiamajorandintermediaasaresultofincreasederythropoiesis.Therefore,dailyoralsupplementationwith1
mgoffolicacidisrecommendedforpersonswithevidenceoffolatedeficiency.18
Becausesomecomplicationsseemtoberelatedtocellularoxidativestress,treatmentwithantioxidantshasbeenthoughttobebeneficial.18However,no
improvementsinanemiaorreductionsinmorbidityormortalityhavebeendemonstrated.VitaminCisnotrecommendedexceptintransfusiondependentpatients
withaprovendeficiency.

Prognosis
Personswiththalassemiatraithaveanormallifeexpectancy.Personswithbetathalassemiamajorliveanaverageof17yearsandusuallydieby30yearsofage.
Mostdeathsarecausedbythecardiaccomplicationsofironoverload.11

TheAuthors showallauthorinfo
HERBERTL.MUNCIE,JR.,MD,isdirectorofpredoctoraleducationandaprofessorintheDepartmentofFamilyMedicineatLouisianaStateUniversityHealth
SciencesCenter,NewOrleans....

REFERENCES showallreferences
1.WhippleGH,BradfordWL.Mediterraneandisease:thalassemia(erythroblasticanemiaofCooley).JPediatr.19369:279311....

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