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DiagnosisandtreatmentofvitaminB12andfolatedeficiency
OfficialreprintfromUpToDate
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DiagnosisandtreatmentofvitaminB12andfolatedeficiency
Author
StanleyLSchrier,MD

SectionEditor
WilliamCMentzer,MD

DeputyEditor
JenniferSTirnauer,MD

Contributordisclosures
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2016.|Thistopiclastupdated:Apr14,2015.
INTRODUCTIONThediagnosticevaluationandtreatmentofthepatientwithsuspectedvitaminB12(cobalamin,Cbl)
orfolatedeficiencywillbereviewedhere.Thecausesofthesedeficiencies,theirsymptoms,andthemechanismsby
whichthesevitamindeficienciesproduceclinicalabnormalitiesarediscussedseparately.(See"Etiologyandclinical
manifestationsofvitaminB12andfolatedeficiency"and"PhysiologyofvitaminB12andfolatedeficiency".)
Theterms"folate"and"folicacid"aresometimesusedinterchangeablyhowever,thevitaminisfoundinnatureasafolate
whilefolicacid(FA)isthesynthetic,therapeuticformofthevitamin.
INITIALDIAGNOSTICSTRATEGY
ClassicalpresentationInthe"classic"advancedcaseofvitaminB12orfolatedeficiency,thepatientpresentswith
severeanemiaandmacrocyticredcells(meancorpuscularvolume(MCV)>100fL)withorwithoutvaryingneurologic
disturbances.
However,manypatientswithvitaminB12deficiencyexistwhohavenooronlymildanemia,andmacrocytosismaybe
maskedbyaconcurrentdisorder(eg,irondeficiency,thalassemia).Inoneseries,forexample,thediagnosisofvitamin
B12deficiencywasconfirmedinpatientsinwhomonly29percenthadanemia,andonly36percenthadanMCV>100fL
[1].
Hypersegmentationofneutrophils,ifpresent,shouldsuggestthediagnosisofB12orfolatedeficiency,particularlyin
patientswhoalsohaveneurologicsymptoms,evenintheabsenceofanemia.(See"Etiologyandclinicalmanifestationsof
vitaminB12andfolatedeficiency".)
OverviewVitaminB12and/orfolatedeficiencyshouldbesuspectedinpatientswithoneormoreofthefollowing
clinicalorlaboratoryfindings(see"EtiologyandclinicalmanifestationsofvitaminB12andfolatedeficiency",sectionon
'Clinicalmanifestations'):
Ovalmacrocyticredbloodcells(ie,meancorpuscularvolume>100fL)ontheperipheralbloodsmear,withorwithout
anemia(picture1)
Thepresenceofhypersegmentedneutrophilsontheperipheralbloodsmear(ie,>5percentofneutrophilswith5
lobesor1percentofneutrophilswith6lobes)(picture2)
Pancytopenia(ie,thecombinationofanemia,thrombocytopenia,andneutropenia)ofuncertaincause
Unexplainedneurologicsignsandsymptoms,especiallydementiaorweakness,sensoryataxia,andparesthesias
(eg,suspectedsubacutecombineddegeneration)(see"Disordersaffectingthespinalcord",sectionon'Subacute
combineddegeneration')
Specialpopulations,suchasolderadults,alcoholics,andpatientswithmalnutritionareathighriskforthe
developmentoffolateand/orvitaminB12deficiency.StrictvegansareatriskofvitaminB12deficiency.(See
"Vegetariandietsforchildren",sectionon'VitaminB12'.)
PatientswhohaveundergonebariatricsurgeryarealsoatriskofdevelopingfolateandvitaminB12deficiency.Inan
Australianstudyof232patientsanalyzedpreoperativelyand149analyzedpostoperatively,thevitaminB12level
waslowin11percentandRBCfolatewaslowin12percent[2].However,thekindofbariatricsurgeryperformed
makesadifferenceandmostbariatricsurgeryprogramsnowprovidevitaminsupplementspostoperatively.
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VitaminB12andfolatedeficiencyoftencoexistandarenoteasilydifferentiatedonaclinicalbasis.Accordingly,such
patientsshouldbeevaluatedforbothdeficiencies.Thefirststepshouldentailobtainingserumfordeterminationofvitamin
B12andfolateconcentrations.Forhospitalizedpatients,bloodsamplesshouldbeobtainedimmediatelyonadmission,
beforeanymealshavebeentakenandbeforeanybloodtransfusionshavebeengiven,asevenasinglemealor
transfusionmaynormalizeserumconcentrationsofthesevitamins.
SearchingforthecauseIfadiagnosisofvitaminB12and/orfolatedeficiencyhasbeenestablished,itis
reasonabletodetermine,ifpossible,thecauseforthedeficiencyinordertonotoverlookapotentiallytreatableunderlying
condition(eg,sprue,inflammatoryboweldisease,blindloopsyndromes,fishtapeworminfestation,pancreatic
insufficiency,medication).Alistingofthevariouscausesoffolate(table1)andvitaminB12deficiency(table2)indicates
theavenuesthatshouldbeexploredinthisregard.(See"EtiologyandclinicalmanifestationsofvitaminB12andfolate
deficiency".)
LABORATORYEVALUATION
OverallapproachThediagnosisofvitaminB12orfolatedeficiencycanmostoftenbeestablishedbyacombinationof
thefollowing:
MeasurementoftheserumvitaminB12andtheredbloodcell(orserum)folateconcentrations
Evaluationofspecificmetabolicintermediates(eg,methylmalonateandhomocysteine)whichcanaccumulatein
thesedeficiencies(figure1).
Forthediagnosisofperniciousanemia,thepresenceofantibodiestointrinsicfactorisahelpfulfinding.
MalabsorptionofvitaminB12,anditscorrectionbytheadditionofintrinsicfactor,canbeestablishedthroughuseof
theSchillingtest,whenthistestisavailable(see'Schillingtest'below).
TherapeutictrialsofvitaminB12arewarrantedwhentheabovetestingresultsareinconflictwiththeclinical
diagnosis.
Bonemarrowexaminationtodemonstratemegaloblasticerythropoiesisisusuallyunnecessary(picture3).Evenif
performed,thisexaminationwillnotdistinguishvitaminB12deficiencyfromfolatedeficiency.
RedbloodcellMCVAnelevationoftheredbloodcellmeancorpuscularvolume(MCV)isoneofthehallmarksof
vitaminB12andfolatedeficiency,althoughothercausesarepossible(table3).(See"PhysiologyofvitaminB12andfolate
deficiency",sectionon'Pathophysiologyofmegaloblastosis'and"Macrocytosis/Macrocyticanemia"and
"Microcytosis/Microcyticanemia".)
ThedegreeofelevationoftheMCVisoftenaclueastowhetheravitamindeficiencyispresent.Thus,theprobabilityofa
deficiencyoffolateand/orvitaminB12beingpresentwhentheMCVisnormal(ie,80to100fL)hasbeenestimatedat<25
percent[3].Unlessacombineddeficiency(eg,irondeficiencyplusadeficiencyofvitaminB12orfolate)issuspected,
routinetestingforvitaminB12orfolatedeficiencyinananemicpatientinthepresenceofanMCV<80fLisnotlikelyto
beproductive.
WhileanMCV>110isoftenseeninthemegaloblasticanemias,otherconditionsarecommonlyassociatedwithsuchhigh
values.Asanexample,inastudyof100consecutiveinpatientsinalargeurbanmetropolitanhospitalwhohadanMCV
>110fL,44percenthadbeentreatedwithzidovudine(AZT),19percentwerealcoholics,12percenthadmalignant
neoplasms,4percenthadvitaminB12deficiency,and3percenthadfolatedeficiency[4].(See"Macrocytosis/Macrocytic
anemia",sectionon'Evaluation'.)
FolatelevelsTheserumfolateconcentration,althoughtypicallylowinpatientswithfolatedeficientmegaloblastic
anemia[5],isprimarilyareflectionofshorttermfolatebalance,ascanbeillustratedbythefollowingobservations:
Onehospitalmealcannormalizetheserumfolateinpatientswhoarefolatedeficient
Pregnancy,alcoholintake,certainanticonvulsants,orafewdaysofdecreaseddietaryintakecanlowertheserum
folateconcentration,despitethepresenceofadequatetissuestores.
Theredbloodcellfolateconcentrationistheoreticallyamorereliableindicatoroftissuefolateadequacy,sinceitreflects
atimeaveragedvalueoffolateavailability,andisthereforenotsubjecttotheshorttermfluctuationsnotedabove.The
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lowerlimitofnormalforthistesthasbeenreportedtobeintherangeof283to340nmoles/L.However,thistestisnot
entirelywithoutitsownproblemsofinterpretation[6].
Asaresult,ithasbeensuggestedthatthelessexpensiveserumfolateconcentrationshouldbeobtainedasaninitial
screeningtest[6],andthatthereisnobasisfortheroutinetestingofallsamplesforbothserumfolateandredcellfolate
[7].Thus:
Iftheserumfolateconcentrationis>4ng/mL(9.1nanomol/L),folatedeficiencyiseffectivelyruledout.
Intheabsenceofrecentanorexiaorfasting,aserumconcentration<2nanog/mL(4.5nanomoles/L)isdiagnosticof
folatedeficiency.
Redcellfolatelevelsandthemoreexpensivemetabolitetestingshouldbereservedforpatientswithborderlinevalues
(folateconcentration2to4ng/mL),inthosesuspectedofhavingacombineddeficiencyofbothvitaminB12andfolate,
andforpatientsinwhomtheserumfolatelevelmaynotbeeasilyinterpreted(eg,recenthospitalmealorrecentanorexia)
[6].(See'Methylmalonicacidandhomocysteine'below.)
VitaminB12levelsSeveralcommerciallaboratoriesusedifferentmethods(chemiluminescenceorradioassay)for
measuringvitaminB12.Asaresult,therearedifferentnormalrangesandno"goldstandard"[6,8,9].Accordingly,
therapeutictrialsofvitaminB12arewarrantedwhentestingresultsareinconflictwiththeclinicaldiagnosis.
Thereare,inaddition,importantlimitationsintheabilityofasinglemeasurementofserumvitaminB12todetectB12
sufficiencyordeficiency.Asexamples:
SerumvitaminB12concentrationscommonlyfallduringpregnancy,butthesepatientsdonotnecessarilyexhibit
hematologicevidenceofdeficiency[10].
Testresultsarehighlyvariable.Inonereport,themedianintraindividualvariationinmeasuredserumvitaminB12
concentrationswas23percent(range:0to119percent)[11].Absolutedifferences>100pmol/Lonrepeattesting
wereseenin21percentofpatients.
TheserumvitaminB12concentrationmaybenormalinupto5percentofpatientswithdocumentedvitaminB12
deficiency[12].
Inonestudyof84patientswithlowvitaminB12values(<180pg/mL),only16wereconfirmedtobeB12deficient
(positivepredictivevalueof22percent)[13].
SpuriouslyhighvaluesforvitaminB12oncompetitivebindingluminescenceassay(CBLA)testingcanbeseenwhen
highserumlevelsofintrinsicfactorblockingantibodiesarepresent[1416].TestingforthepresenceofIFblocking
antibodiesisthereforesuggestedifCBLAtestresultsareinconflictwiththeclinicaldiagnosis.
SubclinicalvitaminB12deficiency(ie,lowvitaminB12levelsandmildbiochemicalchangesbutwithoutsymptoms,
macrocytosis,neutrophilhypersegmentation,orSchillingtestabnormality)isavexingproblem,especiallyinthe
elderly,whereitmaybepresentin10to25percent[8].Itisourpracticetoinitiatetreatmentinsuchsubjects,
althoughthelongtermbenefitsofsuchtreatmentareunclear.
Ingeneral,however,serumvitaminB12levelscanbeinterpreted,asfollows[6]:
>300pg/mL(>221pmol/L)NormalresultvitaminB12deficiencyunlikely(ie,probabilityof1to5percent)[17]
200to300pg/mL(148to221pmol/L)BorderlineresultvitaminB12deficiencypossible
<200pg/mL(<148pmol/L)LowconsistentwithvitaminB12deficiency(specificityof95to100percent)[13]
NeedformetabolitetestingMetabolitetesting(seebelow)shouldbereservedforthosepatientsinwhomahigh
degreeofsuspicionofvitaminB12orfolatedeficiencyispresent,especiallythosewithborderlineserumvitaminB12or
folatelevels,inthepatientwithotherwiseunexplainedneurologiccomplaintsorunexplainedmacrocytosis,andwhenitis
importanttouncoveratreatablecauseofdementia[9,18].(See"Evaluationofcognitiveimpairmentanddementia",
sectionon'Laboratorytesting'.)
MethylmalonicacidandhomocysteinePatientswithserumvitaminB12valuesatthelowerendofthenormalrange
orintheborderlinerange(asdescribedabove)maybetrulyvitaminB12deficientandrespondtoreplacementtherapy
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[5,6,12,19,20].Measurementoftheserumconcentrationsofthemetabolicintermediarieshomocysteineand
methylmalonicacidappearstobemoresensitiveforthediagnosisofthesedeficienciesthanserumvitaminlevelsalone
[17],andishelpfulinclarifyingthediagnosiswhenserumvitaminB12orfolateconcentrationsareequivocal[12,18,2123],
orarelowinthepregnantsubject[10,2426].
Serumconcentrationsofhomocysteine(HC)aswellasserumandurinaryconcentrationsofmethylmalonicacid(MMA)
areelevatedinvitaminB12deficiency,duetoadecreasedrateofmetabolism[2729].Incomparison,onlyHCiselevated
infolatedeficiency,sincefolatedoesnotparticipateinMMAmetabolism(figure1)[27].
Thismetabolicpatternwasillustratedinastudyof434episodesofdocumentedvitaminB12deficiencyand123episodes
ofdocumentedfolatedeficiency,inwhichthefollowingresultswereobtained[3]:
SerumMMAandHClevelswereelevatedin98and96percent,respectively,oftheepisodesofdocumentedvitamin
B12deficiency.
Intheepisodesofdocumentedfolatedeficiency,serumMMAandHClevelswereelevatedin12and91percent,
respectively.ElevatedMMAinallbutoneofthefolatedeficientsubjectswasattributabletorenalinsufficiency.
AswithmeasurementofserumvitaminB12concentrations,thereareanumberofsituationswhichmayaffectlevelsof
MMAandHC:
HereditaryhomocysteinemiacanraiseserumHClevels[19].(See"Overviewofhomocysteine".)
SerumandurinarylevelsofMMAareelevatedinsubjectswithmethylmalonicaciduria.(See"Organicacidemias",
sectionon'Methylmalonicacidemia'.)
ElevatedlevelsofMMAcanbefoundinpatientswithrenalinsufficiency.
Inonereport,antibiotictreatmentloweredtheserumMMAbutnotthetotalHClevelintwovitaminB12deficient
patients,suggestingthatpropionicacidgeneratedbyanaerobicgutfloramaybeaprecursorofmethylmalonicacidin
vitaminB12deficientpatients[17].
ThereisconsiderablevariabilityinrepeatmeasurementsofMMAandHC[8,11,23].Suspectlevelsshouldbe
repeated.
ElevatedvaluesofMMAandhomocysteinereturntonormalwithvitaminreplacement,providingfurtherevidenceof
vitamindeficiency[12].Inaddition,inaseriesofpatientswithdocumentedperniciousanemiareceivinginadequate
treatment,MMAandtotalhomocysteineconcentrationsrosesoonerthandiddecreasesinserumvitaminB12,establishing
thesuperiorsensitivityofthesemetabolitesindetectingearlyvitaminB12deficiency[17].
DiagnosingperniciousanemiaSeveralclinicalandlaboratorystudiescansuggestthediagnosisofperniciousanemia
(PA).(See"EtiologyandclinicalmanifestationsofvitaminB12andfolatedeficiency",sectionon'Clinicalmanifestations'.)
WhilepatientswithPAareachlorhydric,confirmingthisbymeasurementofgastricacidsecretionishighlyinvasiveand
rarelyneeded.Bonemarrowexaminationhelpstoconfirmthediagnosisofmegaloblasticanemia,buttherearenobone
marrowfindingswhicharespecificforPA.
AntibodiestoIFThepresenceofantiintrinsicfactor(IF)antibodiesishighlyconfirmatoryforthediagnosisofPA,
withasensitivityof50to70percentandaspecificityapproaching100percent[8,30].
AntiparietalcellantibodiesareperhapsmoresensitivebutlessspecificforthediagnosisofPAasaresult,theutilityof
antiparietalcellantibodiesindiagnosingPAhasbeencalledintoquestion[8,30,31].
Elevatedserumgastrinlevels,lowpepsinogenIlevels,andalowratioofpepsinogenItopepsinogenIIarehighly
sensitiveforthediagnosisofPA(90to92percent),althoughthesetestslackspecificity[32,33].Additionofthesetests
mayhelptomakethediagnosisofPAinthosepatientswhodonothaveantiIFantibodies[8].(See"Physiologyof
gastrin",sectionon'Causesofhypergastrinemia'and"Classificationanddiagnosisofgastritisandgastropathy",section
on'Stomachspecificbiochemicalmarkers'.)
SchillingtestAclassicprocedurefordiagnosingperniciousanemiaisthetwostageSchillingtest(figure2and
table4).However,vitaminB12deficiency,perniciousanemia,malabsorption,blindloopsyndromes,andilealdiseasecan
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bereliablyandquicklydiagnosedusingmethodsotherthantheSchillingtest.Asanexample,intwostudies,elevated
concentrationsofMMAandtotalhomocysteinewerepresentin15to33percentofpatientswithnormalSchillingtests,
indicatingthesuperiorsensitivityofthesetwometabolitesindiagnosingvitaminB12deficiency[34,35].
DifficultieswiththeradiolabeledreagentusedintheSchillingtest,aswellascertificationissues,makethistestgenerally
unavailableinmanypartsoftheUnitedStates.Accordingly,althoughtheSchillingtesthashistoricalimportancein
understandingabnormalitiesofvitaminB12absorption,itisnotcommonlyemployed,andhaspotentialusefulnessonly
whenmoresimpletests(eg,antiIFantibodies)arenormalandthediagnosisisindoubt.
EvaluationoftestresultsIfserumfolateandvitaminB12concentrationsare>4ng/mL(>9.1nanomoles/L)and>300
pg/mL(>221picomoles/L)respectively,deficienciesofthetwovitaminsareunlikely,andadditionaltestingisunlikelytobe
required[6].
IftheserumfolateandvitaminB12levelsarenotintherangescitedabove,oriftheresultsareborderlineordiscordant
withotherclinicalfeatures,thenextstepshouldbeevaluationofthemetabolitesmethylmalonate(MMA)andtotal
homocysteine:
Ifbothtestresultsarenormal(ie,MMA70to270nanomol/Landtotalhomocysteine5to14micromol/L),deficiency
ofbothvitaminsisextremelyunlikely.Asanexample,bothmetaboliteswerenormalinonly0.2percentof400
patientswithprovenvitaminB12deficiencyand10percentof98patientswithfolatedeficiencythefalsenegative
resultsinthepatientswithfolatedeficiencywerelargelylimitedtopatientswithrenaldisease[3].However,ifa
concernremainsbasedonclinicalfindings,atherapeutictrialofsubcutaneousvitaminB12maybeused1000mcg
weeklyforonetothreeweekscanbeadministeredandthepatientassessedforreticulocyteresponse,hemoglobin
increaseandresolutionofmegaloblasticchanges(eg,macrocytosis,hypersegmentedneutrophils).
Ifconcentrationsofbothmetabolitesareincreased,vitaminB12deficiencyisconfirmed,withasensitivityand
specificityof94and99percent,respectively[3].Becauseoftestandpatientvariability,reassayisadvisableif
marginallyabnormalresultsareobtained[8].Concomitantfolatedeficiencycannotberuledoutwhenthe
concentrationsofbothmetabolitesareincreased.Insuchcases,serumfolatelevelsarehelpful.
IfMMAisnormalandtotalhomocysteineisincreased,folatedeficiencyislikely,withasensitivityandspecificityof
86and99percent,respectively[3].
Forthediagnosisofperniciousanemia(PA),initialtestingshouldbedoneforthepresenceofantibodytointrinsicfactor
(IF)apositivetestisconfirmatoryforPA.
DIAGNOSISOFVITAMINB12ANDFOLATEDEFICIENCYOncethediagnosisofvitaminB12and/orfolate
deficiencyhasbeensuspected,thefollowingtestingisrecommended.Ofimportance,oncethediagnosishasbeenmade,
thecause(s)forthedeficiencyshouldalsobedetermined(table2andtable1).(See'Overview'above.)
VitaminB12deficiencySerumB12levelscanbeinterpreted,asfollows[6]:
>300pg/mL(>221pmol/L)Normalresultdeficiencyunlikely(sensitivityofapproximately90percenthowever,the
assaymaynotbeassensitiveinindividualswithantiintrinsicfactor(IF)antibodies)[18].
200to300pg/mL(148to221pmol/L)Borderlineresultdeficiencypossible
<200pg/mL(<148pmol/L)Lowconsistentwithdeficiency(specificityof95to100percent)[13]
MetabolitetestingMetabolitetestingshouldbereservedforthosepatientsinwhomahighdegreeofsuspicionof
vitaminB12deficiencyispresent,especiallythosewithborderlineserumvitaminB12levels,inthepatientwithotherwise
unexplainedneurologiccomplaintsorunexplainedmacrocytosis,andwhenitisimportanttouncoveratreatablecauseof
dementia.Serumconcentrationsofhomocysteineaswellasserum(andurinary)concentrationsofmethylmalonicacid
(MMA)areelevatedinvitaminB12deficiencyonlyhomocysteineiselevatedinfolatedeficiency.Normalserumlevelsare
asfollows:
Methylmalonicacid70to270nanomol/L
Homocysteine5to15micromol/L

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PerniciousanemiaThepresenceofantiintrinsicfactor(IF)antibodiesishighlyconfirmatoryforthediagnosisof
perniciousanemia(PA),withasensitivityof50to70percentandaspecificityapproaching100percent.Elevatedserum
gastrinlevels,lowpepsinogenIlevels,andalowratioofpepsinogenItopepsinogenIIarehighlysensitiveforthe
diagnosisofPA(90to92percent),althoughthesetestslackspecificity.Additionofthesetestsmayhelptomakethe
diagnosisofPAinthosepatientswhodonothaveantiIFantibodies.(See'Diagnosingperniciousanemia'above.)
FolatedeficiencySerumfolateconcentrationshouldbeobtainedasaninitialscreeningtest[6]thereisnobasisfor
theroutinetestingofallsamplesforbothserumfolateandredcellfolate[7].
Iftheserumfolateconcentrationis>4ng/mL(9.1nanomol/L),folatedeficiencyiseffectivelyruledout.
Intheabsenceofrecentanorexiaorfasting,aserumconcentration<2nanog/mL(4.5nanomoles/L)isdiagnosticof
folatedeficiency.
AdditionaltestingRedcellfolatelevelsandthemoreexpensivemetabolitetestingshouldbereservedforpatients
withborderlinevalues(folateconcentration2to4ng/mL),forthosesuspectedofhavingacombineddeficiencyofboth
vitaminB12andfolate,andforthoseinwhomtheserumfolatelevelmaynotbeeasilyinterpreted(eg,recenthospital
mealorrecentanorexia)[6].
Serumconcentrationsofhomocysteineaswellasserumandurinaryconcentrationsofmethylmalonicacid(MMA)are
elevatedinvitaminB12deficiencyonlyhomocysteineiselevatedinfolatedeficiency.(See'Methylmalonicacidand
homocysteine'above.)
TREATMENT
FolatedeficiencyFolatedeficiency,nowveryuncommonintheUnitedStates,istreatedwithfolicacid(1to5mg/day
orally)foronetofourmonths,oruntilcompletehematologicrecoveryoccurs.Adoseof1mg/dayisusuallysufficient,
evenifmalabsorptionispresent.Thesedosesareconsiderablyinexcessofthe200mcg/day(0.2mg/day)recommended
fordiseaseprevention(eg,recommendeddailyallowanceinnormaladults,alcoholics,theelderly,preventionofneural
tubedefects).(See"Vitaminsupplementationindiseaseprevention",sectionon'Folicacid'.)
FolicacidcanpartiallyreversesomeofthehematologicabnormalitiesofvitaminB12deficiency,althoughtheneurologic
manifestationswillprogressforreasonsthatarenotentirelyclear[36].Thus,itisimportanttoruleoutvitaminB12
deficiencybeforetreatingapatientwithmegaloblasticanemiawithfolicacid.Ifinitiationoftreatmentisurgentlyrequired,
bloodsamplesshouldbeobtainedfortheappropriateassays(see'Laboratoryevaluation'above),andthepatientshouldbe
treatedwithbothfolicacidandvitaminB12untilthetestresultsareknown.
Folicacidcanbecontinuediftheunderlyingconditioncannotbeeradicated(eg,congenitalhemolyticanemia).Repeat
testingforvitaminB12deficiencymaybewarrantedinpatientsreceivinglongtermfolicacid,especiallyifhematologic
(eg,macrocyticanemia,increasinglevelsofserumlactatedehydrogenase)and/orneurologicworseningoccur[37].
EmpirictherapyforfolatedeficiencyTheclinicalvalueofmeasuringserumfolateisuncertain.Thelimitationsof
thisapproachwereillustratedinastudyinwhichlowvalueswerenotedin2.3percentofalmost3000folatelevelsordered
inagroupofhospitalizedpatients[38].However,thepresenceoflowserumfolatewascommentedoninonly53percent
ofthepatients'recordsandfolicacidwasgivenastreatmentinonly24percent[38].Itwassuggestedthatitwouldbe
morecostefficienttotreatallsuchpatientswithfolicacidratherthantoinitiatetestingforthedeficiency.
Wehavenostrongobjectiontothisempiricapproach,providedthattestingforvitaminB12deficiencyiscarriedoutprior
totreatmentwithfolicacid(see'Folatedeficiency'above).
However,inviewofthepossibleassociationoffolicacidtreatmentwithcertainmalignancies,generaladministrationof
folicacidwithoutaspecificindicationhasbeenconsideredunwise,particularlyathigherdoses.(See"Vitamin
supplementationindiseaseprevention",sectionon'Folicacid'.)
VitaminB12deficiency
ParenteralvitaminB12Perniciousanemia(PA)istypicallytreatedwithparenteral(ie,intramuscularordeep
subcutaneous)vitaminB12,inadoseof1000mcg(1mg)everydayforoneweek,followedby1mgeveryweekforfour
weeksandthen,iftheunderlyingdisorderpersists(eg,PA,surgicalremovaloftheterminalileum),1mgeverymonthfor
theremainderofthepatient'slife.IfthecauseoftheCbldeficiencycanbeeliminated(eg,diet,drugs,reversible
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malabsorptionsyndrome[s]),treatmentcanbestoppedwhentheCbldeficiencyhasbeenfullyreversedandthecause
eliminated.
Whiledoseslowerthanthosenotedabovehavebeenrecommended(ie,100mcginplaceof1000mcg),therearefew
adverseconsequencesofthispotential"overtreatment",asparenteralvitaminB12isinexpensive,relativelynontoxic,and
amountsgiveninexcessofneedareexcretedharmlesslyintheurine.Conversely,useofthelowerdosecouldresultina
slowerresponse,whichmightbecriticalwhensevereneurologicdisease(eg,subacutecombineddegeneration)ispresent
andavoidanceofirreversibleneurologicdamageisaconcern[39].
OralandnasalformulationsAnalternativethatappearstobeaseffectiveasparenteraltherapy,butwhich
requiresmuchgreaterpatientcompliance,ishighdoseoralvitaminB12.Therationaleforthisapproachinpatientswith
impairedintrinsicfactorfunctionisthepresenceofasecond,lowerefficiencytransportsystemforvitaminB12thatdoes
notrequireintrinsicfactororafunctioningterminalileum.Thissystemconsistentlyproducesadequatelongtermvitamin
B12replacementatdosesof1000to2000mcg/day.Becauseofvariabilityinabsorption,loweroraldosesarenot
completelyeffectiveinsomepatientswithperniciousanemia[40].Similarly,useof"timedrelease"oralvitaminB12
preparationsshouldbeavoided[41].
Thedosegiveninthissituation(1to2milligrams/day)ismorethan200timeshigherthantheminimumdailyrequirement
fornormalsubjects[42],andsignificantlyhigherthanthatavailableinmoststandardmultivitaminsandB12supplements
(100mcg/day)[43].
Inthefewrandomizedclinicaltrialswhichhavebeenreported,theuseoforalvitaminB12(1000to2000mcg/day)in
newlydiagnosedpatientswasfoundtobeaseffectiveasintramuscularadministrationinobtainingshortterm
hematologicalandneurologicalresponsesinvitaminB12deficientpatients[4446].
Becauseofthepossibilityoferraticabsorption,itismostappropriatetousethisrouteoftreatmentAFTERthepatient's
vitaminB12statushasbeennormalizedwithparenteraltreatmentand/ortomonitortheresponsefrequentlywith
determinationsofserumvitaminB12andmethylmalonateconcentrations.
VitaminB12canbealsobegivensublingually[47],orviaanasalsprayorgel[48].Sublingualandnasalroutesof
treatmenthavenotbeenadequatelystudiedandtheavailableformulationsareexpensive[8].
VitaminB12responsivediseaseNonrandomizedstudiessupporttheexistenceofatleastsomepatientswith
normalvaluesforserumvitaminB12,MMA,and/orHCwhosehematologic,andespeciallyneurologic,impairments
improvedfollowingpharmacologicdosesofvitaminB12[11].Inadditiontothepossibilitythattheseobservationsweredue
toafortuitouscombinationofunrelatedeventsoraplaceboeffect,atleasttwootherexplanationsforthisphenomenonare
possible:
VariabilityinmeasurementofvitaminB12,MMA,andHC,yieldingfalselynormalvaluesinpatientswhoaretruly
B12deficient.
AdirectbenefitofpharmacologicdosesofvitaminB12onalteredneurologicfunction[4951].
PreventivemeasuresThereareanumberofclinicalsettingsinwhichpatientswithmarginalordeficientvitaminB12
statusmaybeatincreasedriskforworseningvitaminB12deficiency[8]:
VegetariansPurevegetariansandpregnantwomenonMediterraneandiets(eg,freshfruitsandvegetableswith
littleinthewayofanimalsourcefoods)areatriskofdevelopmentofvitaminB12deficiencyandrequirevitaminB12
supplementation[52],althoughsomemayrefusesuchtreatment[53].Pregnantwomenwhoplanexclusivebreastfeeding
fortheirinfantsalsoneedsupplementation,astheseinfantsareatmuchgreaterriskofvitaminB12deficiencythantheir
mothers[54,55].(See"Overviewofacquiredperipheralneuropathiesinchildren",sectionon'VitaminB12(cobalamin)
deficiency'.)
GastricsurgeryTheriskofmalabsorptionoffoodboundvitaminB12isincreasedaftergastricsurgery(eg,subtotal
gastrectomy,bariatricsurgery).PreventivesupplementationwithlargedosesoforalvitaminB12,preferablyonanempty
stomach,iswarranted.(See"EtiologyandclinicalmanifestationsofvitaminB12andfolatedeficiency",sectionon'Older
adults'.)
NitrousoxideexposureNitrousoxide(N2O)inactivatesvitaminB12anditsuseinanesthesiamayprecipitate
rapidneuropsychiatricdeteriorationinvitaminB12deficientindividuals[5659].PatientscontemplatingN2Oanesthesia
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shouldbecheckedforvitaminB12deficiencyandtreatedpriortosuchexposure.
Similarly,inhalantabuseofN2Omaycauseneuropsychiatricproblems,eveninvitaminB12sufficientsubjects.(See
"Disordersaffectingthespinalcord",sectionon'Subacutecombineddegeneration'.)
ResponsetotreatmentLaboratorystudiesshouldbemonitoredaftervitaminB12therapytodocumentahematologic
andmetabolicresponse:
Elevatedlevelsofserumiron,indirectbilirubin,andLDHfallrapidlywithinthefirstonetotwodaysfollowing
treatmentwithparenteralvitaminB12bonemarrowerythropoiesisalsochangesfrommegaloblastictonormoblastic
duringthisperiod.Inaddition,thepatientmightnoteanimprovedfeelingofwellbeing,longbeforethereareany
changesinthedegreeofanemia.
Hypokalemiaduringtheearlyresponseisduetothemarkedincreaseinpotassiumutilizationduringproductionof
newhematopoieticcells.Itmaybeprofoundinthosewhoareseverelyanemicatthetimeoftreatment,butits
clinicalrelevanceisuncertain[60].Suchpatientsshouldbemonitoredduringtheirinitialresponse,andsevere
hypokalemiatreatedwithpotassiumsupplementation.(See"Causesofhypokalemiainadults",sectionon'Increased
bloodcellproduction'.)
Ifthepatientisanemic,therewillbeareticulocytosisinthreetofourdays,peakingatoneweek,followedbyarise
inhemoglobinandafallinredbloodcellmeancorpuscularvolume.Thehemoglobinconcentrationbeginstorise
within10daysandusuallyreturnstonormalwithineightweeks.Adelayedorincompleteresponsesuggeststhe
presenceofanadditionalabnormalityoranincorrectdiagnosis(eg,concomitantirondeficiency,infection,
hypothyroidism,malignancy).
Hypersegmentedneutrophilsdisappearat10to14days.
Neurologicabnormalities,ifpresent,improveovertheensuing3months,withmaximumimprovementattainedat6to
12months.Thedegreeofimprovementisinverselyrelatedtotheextentanddurationofdisease[1,6,61].
BloodtransfusionPatientswithvitaminB12deficiencydevelopanemiaslowly,andthusareabletodevelop
compensatoryincreasesinoxygendelivery.Evenelderlypatientsmaytoleratesevereanemia,oftentohemoglobinlevels
aslowas5g/dL[8,62].
Thedecisiontotransfusecanbeadifficultone,particularlyinelderlypatientsatriskforcongestivefailureduetoan
alreadyexpandedplasmavolumefromthechronicanemia,thepresenceofcomorbiddisease(eg,coronaryartery
disease),aswellastheassociationbetweenheartfailureandelevatedlevelsofhomocysteine.(See"Overviewof
homocysteine",sectionon'Roleinvasculardisease'.)
Ifanemiaissevere,thepatientiscriticallyill,andfluidstatusisaconcern,oneunitcanbegiveninitiallyataveryslow
rateofinfusion,incombinationwithadiuretic.Inextremecircumstances,isovolemicexchangecanbeperformed,in
whichoneunitofthepatient'sblood(withalowhematocrit)isremovedatthesametimeasaunitofpackedcells(witha
hematocritof60to80percent)isinfusing.(See"Transfusionassociatedcirculatoryoverload(TACO)",sectionon
'Prevention'.)
MonitoringformalignancyPatientswithPAappeartohaveanincreasedriskofdevelopingmalignanciesofthe
gastrointestinaltract,butthedataarenotentirelyconclusiveforsitesotherthanthestomach[1,63,64].Ametaanalysisof
27studiesfrommultiplecountriesreportedincidenceratesforgastriccancervaryingfromzeroto1.2percentperpatient
year,withapooledincidencerateof0.27percentperpatientyearandanoverallgastriccancerrelativeriskinPAof6.8
(95%CI2.618.1)[65].
Itisprudenttoperiodicallymonitorstoolsinthesepatientsforthepresenceofblood.Asingleendoscopyshouldbe
consideredatthetimeofdiagnosistoidentifyearly,treatablelesions(gastriccancer,neuroendocrinetumors,metaplasia
ordysplasia)inpatientswithPA[8,65],butthereareinsufficientdatatosupportroutinesubsequentendoscopic
surveillanceforthesepatients.(See"Gastriccancerscreening".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"Beyond
theBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
th

th

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piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthe
keyword(s)ofinterest.)
Basicstopics(see"Patientinformation:VitaminB12deficiencyandfolate(folicacid)deficiency(TheBasics)"and
"Patientinformation:Perniciousanemia(TheBasics)")
SUMMARYANDRECOMMENDATIONS
SuspectingthediagnosisVitaminB12and/orfolatedeficiencyshouldbesuspectedinpatientswithoneormoreof
thefollowingclinicalsettings.(See'Overview'above.):

Thepresenceofovalmacrocyticredcells,withorwithoutanemia
Thepresenceofhypersegmentedneutrophils
Pancytopenia(anemia,thrombocytopenia,neutropenia)ofuncertaincause
Unexplainedneurologicsignsandsymptoms(eg,dementia,progressiveweakness,ataxia,paresthesias)

Suspicionforthesediagnosesshouldbegreaterinthosepopulationsathigherriskfordevelopmentofthesedeficiencies,
suchasolderadults,alcoholics,purevegans,andthosewithmalnutrition.
ConfirmingthediagnosisAsafirststep,serumfordeterminationofbothvitaminB12andfolateconcentrations
shouldbeobtained.IfserumfolateandvitaminB12concentrationsare>4ng/mLand>300pg/mL,respectively,
deficienciesofthetwovitaminsareunlikely,andadditionaltestingisnotrequired.(See'Laboratoryevaluation'above.)
Iftheabovetwotestsarenotintherangescitedabove,oriftheresultsareborderlineordiscordantwithotherclinical
features,thenextstepshouldbeevaluationoftheserumlevelsofthemetabolitesmethylmalonate(MMA)andtotal
homocysteine.(See'Needformetabolitetesting'above.)
Ifbothtestresultsarewithinthenormalrange(ie,MMA70to270nmol/Landtotalhomocysteine5to15
micromol/L),deficiencyofbothvitaminsisextremelyunlikely.However,aconcernremainsbasedonclinical
findings,atherapeutictrialofsubcutaneousvitaminB12maybeused1000mcgweeklyforonetothreeweekscan
beadministeredandthepatientassessedforreticulocyteresponse,hemoglobinincreaseandresolutionof
megaloblasticchanges(eg,macrocytosis,hypersegmentedneutrophils).
Ifconcentrationsofbothmetabolitesareincreased,vitaminB12deficiencyisconfirmed,withasensitivityand
specificityof94and99percent,respectively.
IfMMAisnormalandtotalhomocysteineisincreased,folatedeficiencyislikely,withasensitivityandspecificityof
86and99percent,respectively.
Forthediagnosisofperniciousanemia,initialtestingshouldbedoneforthepresenceofantibodytointrinsicfactor.
ApositivetestisconfirmatoryforthediagnosisofPA,withasensitivityof50to70percentandaspecificity
approaching100percent.(See'Perniciousanemia'above.)
IfadiagnosisofvitaminB12and/orfolatedeficiencyhasbeenestablished,itisreasonabletodetermine,ifpossible,the
causeforthedeficiencyinordertonotoverlookapotentiallytreatableunderlyingcondition(eg,sprue,inflammatorybowel
disease,pancreaticinsufficiency,medication).Alistingofthevariouscausesoffolate(table1)andvitaminB12deficiency
(table2)indicatestheavenueswhichshouldbeexploredinthisregard.(See"Etiologyandclinicalmanifestationsof
vitaminB12andfolatedeficiency".)
Treatment
FolatedeficiencyPatientswithdocumentedfolatedeficiencyshouldbetreatedwithoralfolicacid.Standarddosing
oforalfolicacidis1to5mg/dayorallyforonetofourmonths,oruntilcompletehematologicrecoveryoccurs.Theoral
routeissufficienteveninthosewithmalabsorption.
VitaminB12deficiencymustberuledout,andtreatedifpresent,beforegivingfolicacidtoapatientwithmegaloblastic
anemia,sinceadministrationoffolicacidmayworsenneurologiccomplicationsofuntreatedvitaminB12deficiency.(See
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'Folatedeficiency'above.)
VitaminB12deficiencyAllpatientswithdocumentedvitaminB12deficiencyshouldbetreated.Treatmentcanbe
givenviaparenteralororalroutes.ForpatientswithpermanentlydecreasedabilitytoabsorbdietaryvitaminB12(eg,
perniciousanemia,totalgastrectomy,surgicalremovaloftheterminalileum),lifelongtreatmentisnecessary.Ifthecause
ofthevitaminB12deficiencycanbeeneliminated(eg,diet,drugs,reversiblemalabsorptionsyndrome(s)),treatmentcan
bestoppedwhenthevitaminB12deficiencyhasbeenfullyreversedandthecauseeliminated.(See'VitaminB12
deficiency'above.)
WesuggestthatpatientsbetreatedinitiallywithparenteralB12(Grade2B).Weconsiderthisparticularlyimportant
inpatientswithneurologiccomplaints,whereagoalistomaximizetheprobabilityoffullneurologicrecovery.
AlthoughoralB12appearstobeatleastaseffectiveasparenteralB12,concernsaboutpatientcomplianceleadus
topreferthemorecertainparenteralroute.(See'ParenteralvitaminB12'above.)
Oncethepatient'svitaminB12statushasbeennormalized,maintenancetherapycanbeperformedwithparenteral
ororalB12.(See'Oralandnasalformulations'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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