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ApproachtohypoglycemiaininfantsandchildrenUpToDate
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Approachtohypoglycemiaininfantsandchildren
Authors: AgnetaSunehag,MD,PhD,MoreyWHaymond,MD
SectionEditor: JosephIWolfsdorf,MB,BCh
DeputyEditor: AlisonGHoppin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2016.|Thistopiclastupdated:Oct18,2016.
INTRODUCTIONInhealthyindividuals,maintenanceofanormalplasmaglucoseconcentrationdependsupon:
Anormalendocrinesystemforintegratingandmodulatingsubstratemobilization,interconversion,andutilization.
Functionallyintactenzymesforglycogensynthesis,glycogenolysis,glycolysis,gluconeogenesis,andutilizationofothermetabolicfuelsforoxidationandstorage.
Anadequatesupplyofendogenousfat,glycogen,andpotentialgluconeogenicsubstrates(eg,aminoacids,glycerol,andlactate).
Adultsarecapableofmaintaininganearnormalplasmaglucoseconcentration,evenwhenfastingforweeksor,inthecaseofobesesubjects,months[1].Incontrast,
healthyneonatesandyoungchildrenareunabletomaintainnormalplasmaglucoseconcentrationsafterevenashortfast(24to36hours)andexhibitaprogressive
declineinplasmaglucoseconcentrationtohypoglycemicvalues[2,3].
Congenitaloracquiredabnormalitiesinhormonesecretion,substrateinterconversion,andmobilizationofmetabolicfuelscontributetoabnormalitiesinglucoseproduction
andutilizationthatultimatelyresultinhypoglycemiainchildren.Theevaluationandtreatmentofthechildwithhypoglycemiarequireanunderstandingofthefactorsthat
regulateglucosemetabolismandtheuniqueaspectsofglucosemetabolismininfantsandyoungchildren.
Glucosehomeostasisandthediagnosticapproachtohypoglycemiaininfantsandchildrenwillbediscussedhere.Othertopicswithrelatedcontentinclude:
(See"Causesofhypoglycemiaininfantsandchildren".)
(See"Pathogenesis,screening,anddiagnosisofneonatalhypoglycemia".)
(See"Managementandoutcomeofneonatalhypoglycemia".)
(See"Hypoglycemiainchildrenandadolescentswithtype1diabetesmellitus".)
GLUCOSEHOMEOSTASISINNORMALINFANTSANDCHILDRENThroughoutgestation,maternalglucoseistransportedacrosstheplacentatomeetasubstantial
proportionoftheenergyneedsofthefetus.Theenzymesnecessaryforglycogensynthesisandglycogenolysisarepresentinthefetalliverlongbeforetheaccumulationof
glycogencanbedemonstrated.Duringthelastthreetofourweeksofgestation,hepaticglycogenstoresincreasetoreacharound5percentofliverweightatbirth,a
proportionthatishigherthanatanyothertimeinthelifecycle[4].Inanimals,theactivityofoneormoreimportantratelimitingenzymesofgluconeogenesis(pyruvate
carboxylase,phosphoenolpyruvatecarboxykinase,glucose6phosphatase,andfructose1,6diphosphatase)isabsentorverylowinthefetus,doesnotincreaseuntilthe
perinatalperiod,andreachesadultlevelsonlyafterseveralhourstodaysofextrauterinelife[4].Similarly,inhumans,hepaticglucoseproductionandgluconeogenesisare
absentduringfetallife[5],butrapidlyincreasewithinthefirstfewhoursoflife,eveninveryprematureinfants[6].
Atbirth,theinterruptionofplacentalbloodflowasaresultoftheclampingoftheumbilicalcordrequirestheinfanttoutilizehisorherownendogenoussubstratesand
challengesthenewbornwithhisorherfirstfast.Withtheclampingofthecord,thereisanimmediatereleaseofglucagon[7].However,despitetheglucagonsurge,plasma
glucosedecreasesoverthefirsttwohoursoflife.Thisisaccompaniedbyadecreaseininsulinandanincreaseinfreefattyacids(FFAs)andketonebodies[8].Byfourto
sixhoursoflife,theplasmaglucoseconcentrationisstabilizedorisincreasinginmostinfants.Muchofthisearlyglucoseproductionprobablycomesfromthemobilization
ofhepaticglycogen,sincehepaticglycogencontentdecreasesduringthefirstseveraldaysofextrauterinelife.Thisreleaseofhepaticglycogenfacilitatesasmooth
transitionfromthecontinuouslyfed(intrauterine)tothefastedorrelativelyfastedconditionofthefirsthourstodaysofextrauterinelife.However,hepaticglycogenstores
arequicklydepleted,andgluconeogenesismustbeginwithinhoursofbirthtomeetaneverincreasingproportionofendogenousglucoseproduction[6,8].
Intheprematureandterminfant,morethan90percentoftheglucoseisutilizedbythebrain.Thisvaluedecreasestoapproximately40percentofglucoseturnoverin
overnightfastedadults(figure1)[9].Thehigherratesofglucoseturnoverperkilogramofbodyweightininfantsandchildrenwhencomparedwithadultsareconsistentwith
therelativelyhigherproportionofbrainmasstobodysize,whichplacesinfantsandchildrenathigherriskofhypoglycemia[10,11].
Fattyacidmobilizationandoxidationplayacrucialroleinthemaintenanceofglucosehomeostasisininfantsandchildren.PlasmaFFAsandketonebodiescanbeusedby
avarietyofbodytissuesand,thus,decreasethedemandsofthesetissuesforglucoseasanenergysource.Thebrainisuniqueinthatitusesglucoseatarate20times
thatofotherbodytissues(pergram)andcannotuseFFAsdirectlysincetheyarenottransportedacrossthebloodbrainbarrier.However,ketonebodies(beta
hydroxybutyricacidandacetoaceticacid)aretransportedacrossthebloodbrainbarrier,andtheirmetabolismbythebraincanpartiallysupplanttheneedforglucose[1].
Themetabolicresponsetofastinginchildrenissimilartothatinadults,exceptthatchildrenhaveamorerapiddeclineinplasmaglucoseconcentrationandamorerapid
increaseintheplasmaconcentrationofketonebodiesthandoadults.Thesefindingssuggesttherelativelyhighglucoserequirementinchildrenmayacceleratethenormal
adaptivemechanism(s)offastingobservedinadults[3].
Duringthefirst8to10yearsoflife,therateoftotalbodyglucoseutilization(andproduction)increases,followedbyaplateauduringthenextfivetosevenyears,afterwhich
thenormaladultrate(833to944micromol/min[150to170mg/min])isachieved(figure2)[9].Studiesutilizingisotopicallylabeledglucoseindicatethat,byweight,ratesof
glucoseflux(productionandutilization)inadultsareapproximately11to13micromol/kgpermin(2to2.3mg/kgpermin)intheovernightpostabsorptivestate(14hour
fast)anddecreaseto9.8micromol/kgpermin(1.8mg/kgpermin)by30hoursoffasting[10].Therateofglucosefluxininfantsandchildrenafter4to14hoursoffastingis
nearlythreetimeshigher(35micromol/kgpermin[6mg/kgpermin])thanthatofadults,anddecreasesto23micromol/kgpermin(4mg/kgpermin)aftera30to40hour
fast[10,11].
Themobilization,use,andstorageofnutrientsisprimarilyorchestratedbytheclassicalactionsofhormones(eg,insulin,glucagon,catecholamines,cortisol,andgrowth
hormone),althoughmoresubtleinteractionsofotherfactors(eg,cytokines,neuronalinput,ghrelin,leptin,glucagonlikepeptide1[GLP1]postreceptoractivation
mechanism)arenowbeingrecognized.Insulinsecretionplaysacentralroleinglucosehomeostasisandisaffectedbyanumberoffactors,themostimportantofwhichis
theplasmaglucoseconcentration.Amoredetaileddescriptionofthesecretionandactionsofinsulinispresentedseparately.However,weprovideabriefdescriptionhere.
(See"Pancreaticbetacellfunction"and"Insulinaction".)

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Whentheplasmaglucoseconcentrationincreasesafteramealinnormalindividuals,glucoseistransportedintothepancreaticbetacellviathe
glucosetransporter2(GLUT2),isphosphorylatedbyglucokinase,andmetabolizedviatheglycolyticpathway.Thisresultsinanincreaseintheadenosine
triphosphate/adenosinediphosphate(ATP/ADP)ratio,whichclosestheKATPchannels,depolarizesthecellmembrane,openingtheCa++channels,resultinginfusionofthe
insulingranulewiththeplasmamembranecausinginsulinsecretion.Conversely,adecreaseinplasmaglucoseconcentrationresultsindecreasedglucosemetabolismin
thebetacell,whichleadstoareducedATP/ADPratio,openingoftheKATPchannels,hyperpolarizationofthecellmembrane,andclosureofCa++channels,thusblocking
Ca++influxandreducinginsulinsecretion.Fundamentalproblemsintheseprocessescanleadtoprofoundhypoglycemiainchildren[12].(See"Pathogenesis,clinical
features,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy".)
Duringcontrolledinsulininducedhypoglycemia,childrentypicallymountagreatercounterregulatoryhormoneresponse(eg,withcortisol,epinephrine,andglucagon)than
doadults[13,14].However,withrepeatedepisodesofhypoglycemia,secretionofcounterregulatoryhormoneswanes,leadingtodefectivecounterregulationand
"hypoglycemiaunawareness"inanindividualwithdiabetes.Intheabsenceofclassicalsymptomsofhypoglycemia,perhapsasaresultofthisprocess,thediagnosisof
hypoglycemiacanbemissedinsomechildrenformonths.
DEFINITIONOFHYPOGLYCEMIAFordiagnosticpurposes,wedefinehypoglycemiaasaplasmaglucosevalueof40mg/dL(2.22mM)atanyage(exceptduringthe
first48to72hoursoflife).Thisconcentrationshouldtriggeraformalevaluationtoidentifythecauseofthehypoglycemiaandtopreventitsrecurrence.Thisconcentration
shouldnotbeconstruedasidealornecessarilysafeovertime,andshouldonlybeusedinidentifyinganindividualatriskforand/ordiagnosinghypoglycemia.
Innewborns,aplasmaglucosevalueof50mg/dLisanappropriatethresholdtodistinguishinfantswhowarrantfurtherdiagnostictesting.Thisthresholdwassuggestedby
aconsensusconferencethatfocusedprimarilyonthenewbornperiod[15].Thisisarelativelyconservativethreshold,intendedtoavoiddischargingnewbornswhomay
haverisksforrecurrentandseverehypoglycemia.Similarly,whenusingapointofcare(bedside)glucometer,itisreasonabletouseathresholdof50mg/dLtoidentifya
childwhorequiresfurtherevaluation,includinglaboratorymeasurementofplasmaglucose.(See'Criticalsamples'below.)
Bytradition,laboratoriesmeasureplasmaglucose(fromsodiumfluoride,heparin,orethylenediaminetetraaceticacid[EDTA]containingtubes).Evenpointofcareglucose
valuesareadjustedintheircalibrationto"plasmaconcentrations."Alternatively,wholebloodglucosecanbemeasuredonanumberofglucoseanalyzers.However,whole
bloodglucoseconcentrationsareabout15percentlowerthanplasmaglucosemeasurements,andthisdifferenceshouldberecognizedwheninterpretingtheresults
[16,17].
Theprecisedefinitionofhypoglycemiaininfantsandchildrencontinuestobecontroversial.Thisisbecausenormaldistributionsofglucosevaluesdependonconditionsof
feedingandfasting,andalsovarywithclinicalfactorssuchasage,gestation,and/orweight(small,average,orlargeforgestationalage).Despitethisnaturalvariation,we
useasinglethresholdtodefinehypoglycemiafordiagnosticpurposesbecausetheoverallgoalofidentifyingchildrenwithhypoglycemiaistoprotecttheircentralnervous
systemsfromirreparabledamage.Thereisnoapriorireasonthatsomeindividuals(eg,aprematureorlowbirthweightinfant)shouldtoleratealowglucoseconcentration
betterthanothers(eg,anolderchild)infact,quitetheoppositemightbeargued.
ETIOLOGYOFHYPOGLYCEMIAHypoglycemiaoccurswhentherateofappearanceofglucoseintotheplasmaspaceislessthanitsrateofutilization.Thiscanbe
causedbydefectiveglucoseproduction,increasedglucoseutilization,orsomecombinationofthetwo.Formanyhypoglycemicconditions,themechanismisnotentirely
understood.
Ininfantsandchildren,importantcausesofhypoglycemiainclude(table1):
InbornerrorsofmetabolismMostofthedisordersofcarbohydratemetabolismandseveraldisordersofaminoacidandfatmetabolismarecharacterizedbydefective
glucoseproduction.Becauseoftheinteractionsofcarbohydrate,andaminoacidandfatmetabolisminthemaintenanceofnormalfuelhomeostasis,abnormalitiesin
themetabolismofasinglesubstratecanhavesecondaryeffectsonothermetabolicpathways.
Hyperinsulinism
EndogenousPersistenthyperinsulinemichypoglycemiaofinfancy(PHHI)orinsulinoma.Ingestionoforalhypoglycemicagents(sulfonylureas)alsostimulates
insulinsecretion.
ExogenousDuetoinsulinadministration.
OtherMiscellaneouscausesofhypoglycemiaincludeketotichypoglycemia,varioustoxicingestions(includingsulfonylureas,ethanol,andsalicylates),hormone
deficiencies,andmedicalconditionsthateitherincreaseglucoserequirements(eg,sepsis,shock,burns,tumors)oraffecttheliver'sabilitytoproduceglucose(eg,
Reyesyndrome,hepatitis,orothercausesofliverdysfunction).
Theseandothercausesofhypoglycemiainchildrenarediscussedelsewhere.(See"Causesofhypoglycemiaininfantsandchildren".)
CLINICALFEATURES
ChildrenandadultsInchildrenandadults,thesymptomsofhypoglycemiacanbedividedintotwocategories:thosecausedbytheautonomicresponseto
hypoglycemiaandthosecausedbyneuroglycopenia[14].
Neurogenic(autonomic)symptomsTheearlymanifestationsofhypoglycemiaarecausedbytheautonomicresponsetohypoglycemiaandincludesweating,
weakness,tachycardia,tremor,andfeelingsofnervousnessand/orhunger.Thesesymptomsandsignsusuallyoccuratplasmaglucoseconcentrationsbetween40and70
mg/dL(2.2and3.9mM),whicharehigherthantheplasmaglucoseconcentrationsthattriggerneuroglycopenicsignsandsymptoms.Therefore,theautonomicsymptoms
functionasa"warningsystem."However,withrepeatedorprolongedepisodesofhypoglycemia,thethresholdforautonomicsymptomsdecreasestothatfor
neuroglycopenicsymptoms.Thiscanresultintheappearanceofseveresymptomsofhypoglycemiawithlittleornowarning,termed"hypoglycemiaunawareness."(See
'Glucosehomeostasisinnormalinfantsandchildren'above.)
NeuroglycopenicsymptomsSymptomsandsignsthatdevelopwithprolongedorprofoundhypoglycemiaarecausedbyinsufficientsupplyofglucosetothebrain
(neuroglycopenia),andincludelethargy,irritability,confusion,uncharacteristicbehavior,andhypothermia.Inextremehypoglycemia,lossofconsciousness,seizure,or
comamayoccur.Thesesymptomsandsignsoccuratplasmaglucoseconcentrationsbetween10and50mg/dL(0.5to2.8mM).Severeandrepeatedepisodesof
hypoglycemiacanresultinpermanentcentralnervoussystemdamage,andoccasionallyindeath.
InfantsIninfants,thesignsofhypoglycemiaarefrequentlynonspecificandmayincludejitteriness,irritability,feedingproblems,lethargy,cyanosis,tachypnea,and
hypothermia,aswellasthesignsofsevereneuroglycopeniadescribedabove.Thesesymptomsarenotspecificforhypoglycemiaandmaybeearlymanifestationsofa
numberofotherdisorders,includingsepticemia,congenitalheartdisease,ventricularhemorrhage,andrespiratorydistresssyndrome.Infantsareatgreatestriskfor
hypoglycemiaduringthefirstfewdaysoflife.Neonatalhypoglycemiaisdiscussedseparately.(See"Pathogenesis,screening,anddiagnosisofneonatalhypoglycemia".)
IMMEDIATEMANAGEMENTTheimmediatemanagementoftheinfantorchildwithhypoglycemiainvolvesobtainingcriticalsamplesandadministeringparenteral
glucose.Thesestepsaresummarizedinarapidoverview(table2).

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CriticalsamplesWhenthediagnosisofhypoglycemiaissuspectedandsupportedbyarapidmeasurementoftheplasmaglucoseconcentration(andbeta
hydroxybutyrate,ifavailableasapointofcaremeasurement),asampleofbloodshouldbeobtainedbeforetherapeuticintervention.Thissampleisusedtoconfirmthe
diagnosisofhypoglycemiaandassessforrelatedelectrolyteabnormalities.Ifthecauseofthehypoglycemiaisunknown,thiscriticalsampleisusedforadditional
biochemicalteststoinvestigateitscause,asdiscussedbelow.(See'Laboratorytesting'below.)
BloodDuringtheperiodofhypoglycemia,collecta5to10mLsampleofbloodbeforetherapeuticintervention.Thebloodshouldbedrawnintheappropriatetubes
accordingtotherequirementsofindividualclinicallaboratories.However,mostofthestudiescanbeperformedonbloodtreatedwithheparinorethylenediaminetetraacetic
acid(EDTA).Bloodsamplesshouldbetransportedonicetothelaboratory.Excessplasmashouldbestoredat70Cuntilalltheorderedresultsareavailable.
UrineIfthecauseofhypoglycemiaisunknown,thenthefirsturinevoidedduringorafterthehypoglycemicepisodeshouldbecollected.Aurinesampleshouldbe
testedforketones(ifplasmabetahydroxybutyrateisnotavailable)andreducingsubstances.Thepresenceofnonglucosereducingsubstancesintheurinesuggests
galactosemiaorhereditaryfructoseintoleranceifotherreducingsubstances(eg,streptomycin)areexcluded.(See"Galactosemia:Clinicalfeaturesanddiagnosis"and
"Causesofhypoglycemiaininfantsandchildren".)
Theremainingurineshouldbefrozenandsavedfortoxicologystudies,organicacids,dicarboxylicacids,and/oracylglycines,ifindicatedbysubsequentevaluation.(See
'Evaluationforthecauseofhypoglycemia'belowand"Approachtothechildwithocculttoxicexposure".)
Treatment
Glucosetherapy
ConsciouspatientIfthepatientisconsciousandabletodrinkandswallowsafely,arapidlyabsorbedcarbohydrate(eg,glucosetablets,glucosegel,tablesugar,
fruitjuice,orhoney)shouldbegivenbymouth.Anappropriatedoseforachildis10to20grams(or0.3grams/kg).Fifteengramscanbesuppliedby3glucosetablets,a
tubeofdextrosegelwith15grams4oz(120mL)fruitjuice6ouncesofnondietsodaoratablespoon(15mL)ofhoneyortablesugar.Thisprocessmayberepeatedin
10to15minutes.However,ifthehypoglycemiadoesnotimprovewithin15to30minutes,parenteralglucoseisrecommended.
PatientwithalteredconsciousnessInfantsandchildrenwithalteredconsciousnessand/orwhoareunabletosafelyswallowrapidlyabsorbedcarbohydrates
shouldbetreatedwithintravenous(IV)dextrose.IfIVaccessisnotreadilyavailable,thensubcutaneousorintramuscularglucagonshouldbegiven.(See'Glucagon'
below.)
InitialbolusGivedextrose,0.20to0.25grams/kgofbodyweight(maximumsingledose,25grams).Thisisusuallyachievedwith2.5mL/kgof10percentdextrose
solution,sinceextravasationofhigherconcentrationsofglucosewillleadtoseveretissuedamage.Thebolusshouldbeadministeredslowly(2to3mL/min),
regardlessofthepatient'sage.Thedextroseisgivenslowlytoavoidacutehyperglycemia,whichcancausereboundhypoglycemia.Somewhatlowerconcentrationof
dextrosesolutionisoftenusedformanagementofhypoglycemiainneonates.(See"Pathogenesis,screening,anddiagnosisofneonatalhypoglycemia".)
SubsequentinfusionAfterthebolus,plasmaglucoseshouldbemaintainedbyaninfusionofdextroseat6to9mg/kgperminute.Therateofglucoseinfusion
(mg/kgperminute)canbecalculatedasfollows:
Rateofinfusion(mg/kgpermin)=(Percentdextroseinsolutionx10xrateofinfusion[mLperhr])(60xweight[kg])
Thus,foraninfusionof10percentdextrosesolution:
3mL/kg/hourprovides5mg/kgperminute
5mL/kg/hourprovidesapproximately8mg/kgperminute
Higherdosesofdextrose(eg,0.5to1.0g/kg)aresometimesrecommendedfortheinitialbolus.However,ourclinicalexperienceinchildrenandinfants,andstudiesin
adults,suggestthatsuchdosesareexcessiveandarelikelytocausehyperosmolarityandhyperglycemia,whichcanresultinreboundhyperinsulinemiaandrecurrenceof
hypoglycemia[18,19].
Symptomatichypoglycemiacausedbysulfonylureaoverdoseismanagedwithbolusesofdextroseasdescribedabove,withclosemonitoringforrecurrenthypoglycemia.If
hypoglycemiarecursorbecomesmoresevere,octreotidehasbeenused[20]butuseofglucagonasaninfusionorminidoseglucagonmightalsobeconsidered[21].(See
"Sulfonylureaagentpoisoning".)
GlucagonIfIVaccessisnotreadilyavailableandthepatientisunabletosafelyswallowarapidlyabsorbedcarbohydrate,hypoglycemiamaybetreatedwith
glucagon,givenintramuscularlyorsubcutaneously(0.03mg/kguptoamaximumof1mg).
Glucagonisgenerallyeffectiveforinitialtreatmentofhypoglycemiacausedbyhyperinsulinemia(eg,inapatientwithdiabetestreatedwithexogenousinsulin),butmaynot
beeffectiveforothercausesofhypoglycemia.Moreover,theresponseisfrequentlytransient.Thus,ifthehyperinsulinemiapersists,repeatedadministrationofglucose
and/orglucagonmayberequired.Theresponsetoglucagonalsomayprovidediagnosticinformationforpatientsinwhomtheetiologyofhypoglycemiaisunknown.(See
'Glucagonstimulationtest'below.)
MonitoringDuringtheinitialtreatmentphase,theplasmaglucoseshouldbemonitoredevery30to60minutesandthedextroseinfusionadjustedaccordingly,untila
stableplasmaglucoseconcentrationbetween70and120mg/dL(3.9to6.7mmol/L)isattained[15].Thereafter,plasmaglucoseshouldbemonitoredeverytwotofour
hours.Ifratesofglucoseinfusiongreaterthan6to10mg/kgperminutearenecessarytomaintainnormalplasmaglucoseconcentrations,thepatient'shypoglycemiais
likelytobecausedbyhyperinsulinemia(eg,duetopersistenthyperinsulinemichypoglycemiaofinfancy[PHHI],alsoknownascongenitalhyperinsulinism[CHI]).(See
"Pathogenesis,clinicalfeatures,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy".)
EVALUATIONFORTHECAUSEOFHYPOGLYCEMIATheresultsobtainedfromthehistory,physicalexamination,andinitialplasmasamplesshouldguidefurther
testing.
HistoryThehistoryinahypoglycemicchildshouldincludeathoroughexplorationofthepastmedicalhistory(includingperinatalhistory),detailsoftheacuteeventas
wellaspreviousepisodes,andfamilyhistory[22].
AgeatonsetAlthoughthereisconsiderableoverlap,theageofonsetofsymptomssuggestsdiagnosticcategories:
NeonatalperiodorthefirsttwoyearsoflifeMostinbornerrorsofmetabolism(includingcausesofhyperinsulinism)andcongenitalhormonedeficiencies.(See
"Pathogenesis,clinicalfeatures,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy"and"Overviewofinheriteddisordersofglucoseandglycogen
metabolism".)
OneyeartoearlychildhoodKetotichypoglycemia,isolatedgrowthhormonedeficiency,andcortisoldeficiency.(See"Causesofhypoglycemiaininfantsandchildren",
sectionon'Ketotichypoglycemia'and"Causesofhypoglycemiaininfantsandchildren",sectionon'Hormonedeficiencies'.)

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ToddlersandyoungchildrenIngestionshouldalwaysbeconsideredinthisagegroup.(See"Approachtothechildwithocculttoxicexposure"and"Causesof
hypoglycemiaininfantsandchildren",sectionon'Ingestions'.)
TriggersThedetailsoftheacuteeventshouldincludeinformationaboutthechild'sdietaryintakebeforetheeventandhelpstonarrowthedifferentialdiagnosis[23].
(See"Causesofhypoglycemiaininfantsandchildren".)
FastingstateDeterminewhetherthechildwasinthefedorfastingconditionatthetimeofhypoglycemia,orwhetheranacuteillnesspreventedthechildfrom
achievingadequatecarbohydrateintake.Thedegreeoffastingthatistoleratedbeforehypoglycemiadevelopsvarieswithageinhealthyinfantsandchildren,and
variesamongdifferentinbornerrorsofmetabolism.Patientswithcriticalillnesses,especiallysepsis,liverfailure,orrenalfailure,areatgreaterriskfordeveloping
hypoglycemia.
IngestionSpecificallyinquireaboutthepossibilitythatthechildmighthaveingestedsubstancesthatcancausehypoglycemia,includingalcohol,oralhypoglycemic
agents(sulfonylureasormeglitinides),aspirin,betablockers,quinine,orunripeackeefruit(astapleinJamaicandiets).(See"Approachtothechildwithocculttoxic
exposure".)
Specificfoods
Symptomsafteringestionofmilkproductsorfructosemayindicategalactosemiaorhereditaryfructoseintolerance,respectively.
Childrenwhohavehereditarydefectsofaminoacidororganicacidmetabolismmaydevelophypoglycemiashortlyaftertheingestionofprotein.(See"Organic
acidemias".)
PastmedicalhistoryTheperinatalhistoryshouldincludethebirthweight,gestationalage,andwhetherthechildhadhypoglycemicsymptomsatbirthorinthe
neonatalperiod.Itisimportanttoexplorethechild'spastmedicalhistoryandtoreviewavailablemedicalrecords,todeterminewhetherthechildhadotherepisodes
suggestiveofhypoglycemiathatmayhavebeenmissedordiagnosedasotherconditions(eg,seizuredisorder,etc).
FamilyhistoryAfamilyhistoryofReyesyndrome,unexplainedinfantdeaths,orotheraffectedfamilymemberssuggestsaninbornerrorofmetabolism,particularlya
fattyacidoxidationdefect[4,12,13].Hormonaldeficienciesandhyperinsulinismalsomayruninfamilies[24].(See"Causesofhypoglycemiaininfantsandchildren",section
on'Disordersoffattyacidmetabolism'.)
PhysicalexaminationTheexaminationmayprovideimportantcluestothediagnosis[15].
Thechild'sweightandlengthorheightshouldbemeasuredandplottedonanappropriategrowthchart,andthechild'sgrowthtrajectoryshouldbeevaluated.Short
staturemayindicatehypopituitarismorgrowthhormonedeficiency.Disordersofaminoacid,organicacid,andcarbohydratemetabolismareusuallyassociatedwith
failuretothrive,whereaschildrenwithfattyacidoxidationdisorderstypicallyhavenormalgrowth.Childrenwhoareunderweightforagemaybeatriskforketotic
hypoglycemia.Poorweightgainalsomaybecausedbyhypopituitarismandadrenocorticotropichormone(ACTH)deficiencyorunresponsiveness,andprimaryadrenal
insufficiency[25,26].
Feversuggestssepsisoranotherinfectioustrigger,whilehypothermiaisconsistentwithprolongedhypoglycemia(neuroglycopenia),sepsis,alcoholtoxicity,andsome
inbornerrorsofmetabolismthatimpairenergyutilization.
Midlinefacialdefects(eg,asinglecentralincisor,opticnervehypoplasia,cleftliporpalate)andmicrophallusorsmallnormalpenisorundescendedtesticlesinboys
mayindicatehypopituitarismand/orgrowthhormonedeficiency.(See"Diagnosisofgrowthhormonedeficiencyinchildren".)
Hepatomegalyand/orhypotoniasuggestaninbornerrorofmetabolism,suchasaglycogenstoragedisease,defectsingluconeogenesis,galactosemia,orhereditary
fructoseintolerance[25].(See"Overviewofinheriteddisordersofglucoseandglycogenmetabolism".)
Macrosomia,hepatosplenomegaly,andumbilicalherniamayindicateBeckwithWiedemannsyndrome.Hypoglycemiainaffectedpatientsusuallyislimitedtothe
neonatalperiod(ie,thefirstmonthoflife).(See"BeckwithWiedemannsyndrome".)
Hyperventilationmaybeacluetometabolicacidosisfromaninbornerrorofmetabolism.(See"Inbornerrorsofmetabolism:Epidemiology,pathogenesis,andclinical
features"and"Inbornerrorsofmetabolism:Metabolicemergencies".)
Hyperpigmentationmaybeacluetoadrenalinsufficiency.(See"Causesandclinicalmanifestationsofprimaryadrenalinsufficiencyinchildren".)
LaboratorytestingForpatientswithunexplainedhypoglycemia,thehistoryandphysicalexaminationareusedtodevelopclinicalsuspicionsandtheevaluationis
tailoredaccordingly(algorithm1).Asexamples,clinicalfeaturessuggestinganaccidentalortoxicingestionoraspecificinbornerrorofmetabolismshouldpromptspecific
testingforthesuspecteddisorder.
Ifthecauseofthehypoglycemiaisunknown,thefollowingtestsshouldbeperformedon"criticalsamples"collectedduringaperiodofhypoglycemia(eitherattheinitial
presentationorduringanelectivefast)[15]:
Plasmaglucose
Insulin
Cpeptide
Betahydroxybutyrate
Freefattyacids(FFAs)
Acylcarnitineprofile
Lactate
Ammonia
Urineorganicacids
Alsomeasurebloodelectrolytes,bloodureanitrogen(BUN),creatinine,aspartateaminotransferase(AST),andalanineaminotransferase(ALT),ifnotalreadydone.
Measurementsofbothgrowthhormoneandcortisolatthetimeofhypoglycemiaseldomprovidediagnosticinformation.However,shouldthechildhaveanyindicationsof
hypopituitarism(microphallus,centralfacialanomalies,growthfailure)orifthediagnosisremainsunclearfollowingtheinitialevaluation,considerationshouldbegivento
evaluatingthechildforhypothalamicorpituitarydeficiencies.Evaluationwouldincludebrainmagneticresonanceimaging(MRI)andlaboratorytestingforgrowthhormone,
cortisol,andthyroidfunction(T4andTSH)(algorithm1).

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SubsequenttestingforunexplainedhypoglycemiaIfthecauseofthehypoglycemiaremainsunclearafterreviewingthecriticalsampleresults,weperformfurther
testingtonarrowthediagnosticpossibilities.Thesestepsmustbeperformedduringaperiodofhypoglycemia,eitherarisingspontaneouslyorinducedbyadiagnosticfast
undercarefullyestablishedconditions.Ifthefastinducesahypoglycemicepisode,thecriticalsamplesmustbeobtainedpriortotherapeuticinterventionandaglucagon
stimulationcarriedoutasdescribedbelow(algorithm1).Theglucagonstimulationtestwillnarrowthediagnosticpossibilitiesbyidentifyingorexcludinghyperinsulinemia.
ElectivefastIfthecauseofthehypoglycemiaremainsunclearandthecriticaldiagnosticsampleswerenotobtainedduringaspontaneousepisodeofhypoglycemia
(see'Criticalsamples'above),thenanelectivefastusuallyshouldbeperformedtodeterminethecauseofthehypoglycemia.Priortoperforminganelectivefast,the
plasmacarnitineandacylcarnitineconcentrationsshouldbeproventobenormal,toexcludethepossibilityofadefectinfattyacidorcarnitinemetabolism.Thisisbecause
hypoglycemiacancausesevereencephalopathyinchildrenwiththesedisorders.(See"Causesofhypoglycemiaininfantsandchildren",sectionon'Disordersoffattyacid
metabolism'and"Metabolicmyopathiescausedbydisordersoflipidandpurinemetabolism".)
Thedurationofthefastdependsuponthechild'sageandnormalfeedingpattern.Forinfantsandveryyoungchildrenwhoarenormallyfedeverythreetosixhours,the
fastmayconsistofomittingoneormorefeedings[27].Foranolderchild,whobyhistorytypicallyfastsovernight,a24to30hourfastshouldbeinitiatedaftertheevening
meal(ie,startingaround6PM).Childrenwhofastedaccordingtosuchaprotocoltendtodevelophypoglycemiaafter16to24hoursoffasting(ie,between10:00AMand
6:00PM),atimeduringwhichtheyshouldbeawakeandalert,andtheavailabilityofthephysicianandlaboratorystaffisoptimal.
Duringthefast,plasmaconcentrationsofglucose,insulin,betahydroxybutyrate,andlactateshouldbeseriallymonitoredandcomparedwithpublishedvaluesforafasting
study.Thetimingofsamplingisdependentontheplasmaglucosevalue.Wetypicallysampleeverytwotothreehourswhiletheplasmaglucoseremainsabove70mg/dL.
Astheplasmaglucosedecreasesbelowthisthreshold,wesamplemorefrequently(eg,hourly)toavoidprolongedhypoglycemia.
Ifhypoglycemiadevelops(plasmaglucose<40mg/dL[2.2mM]forchildrenandinfantsotherthannewborns):
Repeatmeasurementofglucose,insulin,Cpeptide,betahydroxybutyrate,andlactateconcentrations.
Measurefreefattyacids,ammonia,acylcarnitineprofile,andurineorganicacids
Measureplasmagrowthhormone,cortisol,andinsulinlikegrowthfactorbindingprotein1(IGFBP1)(althoughtheirinterpretationisnotalwaysclear).
Performaglucagonstimulationtest,asdescribedbelow.
Ifketotichypoglycemiaissuspected,theclinicianmayconsiderobtainingaplasmaalanineconcentrationatthetimeofhypoglycemiathisdisorderischaracterizedbylow
plasmaalaninewithnormallactateconcentration.
Ifhypoglycemiacannotbeinducedwithafastofreasonableduration,thechildshouldbedischargedafterthefamilyisinstructedinhomeglucosemonitoring,toensure
safetyandtoprovidefurtherdiagnosticinformation.Shouldthechildexperienceanadditionalepisodeofhypoglycemia,itisimperativethatthecriticalsamplesbeobtained
immediatelytoconfirmthehypoglycemiaandalsotoobtainthecriticalsamplesasdescribedabove.
GlucagonstimulationtestInthecaseofachildwithhypoglycemiaofunknowncause,aglucagonstimulationtest(orglucagonchallengetest)atthetimeof
hypoglycemiacanprovideveryusefuldiagnosticinformationaboutglycogenstores.
Thetestisperformedasfollows:Whilethechildishypoglycemic,glucagon(0.03mgperkg)isinfusedorgivenbyintramuscularinjection.Itiscriticallyimportantthat
plasmaglucoseconcentrationismeasuredwithinminutespriortogivingtheglucagon.Subsequently,wemeasureplasmaglucoseat10,20,and30minutes.Theinitial
samplesareprimarilytomakesurethattheplasmaglucoseconcentrationisnotcontinuingtodecrease.Aclearglycemicresponse(plasmaglucoserisesby>30mg/dL[2
mmol/L]withinthefirst30minutesafterglucagonadministration)inahypoglycemicchildsuggestshyperinsulinemia.Hyperinsulinemiacausesinappropriatesequestration
ofhepaticglycogenatthetimeofhypoglycemia,whichisthenreleasedinresponsetothepharmacologicdoseofglucagon.(See'Hyperinsulinism'below.)
InterpretationofresultsForpatientswithunexplainedhypoglycemia,thetestsonthe"criticalsamples"obtainedduringanepisodeofhypoglycemia(eitheratthe
timeofinitialpresentationorduringanelectivefast)andglucagonstimulationtestareusedtoidentifythetypeofdisordercausinghypoglycemia.
Wenarrowthediagnosticpossibilitiesinthefollowingsequence,assummarizedinthealgorithm(algorithm1).
Hyperinsulinism
Fattyacidoxidationdisorders
Disordersofgluconeogenesisand/orglycogenmetabolism
Wethenconfirmorrefinethediagnosticcategoryestablishedbythesetestsbyconsideringthedegreeofketosis.
HyperinsulinismFirst,wedeterminewhetheroneorbothofthefollowingcharacteristicsofhyperinsulinismarepresent(algorithm1):
PositiveglucagonstimulationtestAglycemicresponse(plasmaglucoserises>30mg/dL)toglucagonstimulationiscausedbyinappropriatehepaticglycogenstores,
andsuggestshyperinsulinemia.
InappropriatelyelevatedlevelsofinsulinPlasmainsulinconcentrationforanormalchildwhohasbecomehypoglycemicduetofastingisusually<15pmol/L(2
microIU/mL)andrarelygreaterthan35pmol/L(5microIU/mL),exceptinmarkedlyobesechildren.Plasmainsulinconcentrationsgreaterthan35pmol/L(5
microIU/mL)withconcomitantplasmaglucosevaluelessthan2.8mM(50mg/dL)aredistinctlyabnormal,regardlessoftheperiodoffasting.
Ifhyperinsulinemiaissuggestedbyoneorbothoftheabovemeasures,thenextstepistodetermineifitisofendogenousorexogenousorigin.AlowCpeptide
concentrationinapatientwithapositiveglycemicresponsetoaglucagonstimulationtestindicatesthatthesourceoftheinsulinisexogenousbecausethebetacell
cosecretesCpeptideinequimolaramountswithinsulin.
Iftheglucagonstimulationtestisclearlypositivebuttheplasmainsulinconcentrationsarelow(andtheCpeptidelevelisalsolow),thepossibilityofexogenousinsulin
administrationshouldbefurtherinvestigated[28].Thisisbecauserecombinantmodifiedhumaninsulinsmaynotbedetectedinthenewmonoclonalsandwichassaysused
bymanycommerciallaboratoriestomeasurespecificallyunmodifiedhumaninsulin.Inthiscase,polyclonalinsulinassaysmustbesoughttodetectexogenousinsulin.(See
"Causesofhypoglycemiaininfantsandchildren",sectionon'Hyperinsulinism'.)
Inaddition,lowconcentrationsofIGFBP1(ifmeasured),providessupportiveevidenceofinappropriatehyperinsulinemiabecauseinsulinpotentlyinhibitsIGFBP1
production[29].(See"Pathogenesis,clinicalfeatures,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy",sectionon'Biochemicaltests'.)
FattyacidoxidationdisordersIfhyperinsulinemiaisexcluded,wedeterminewhetherthefollowingcharacteristicsarepresent,whichsuggestafattyacid
oxidationdisorder(algorithm1):
ElevatedFFAandacylcarnitineconcentrations.FFAconcentrationsmaybeveryhigh(>1.8mmol/L)infattyacidoxidationdisorders,butalsomaybemoderately
elevatedindisordersofgluconeogenesisorglycogenmetabolism.Thespecificacylcarnitineprofilehelpstoidentifythespecificfattyacidoxidationdisorder(table3).

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Mildormoderateketosis(betahydroxybutyrate<2.5mmol/L)becauseFFAscannotbeusedforketonebodyformation(table4)thislowlevelofketosisissometimes
termed"inappropriate"forthedegreeofhypoglycemia.
Incontrasttohyperinsulinism,thereisminimalglycemicresponsetoglucagonstimulation,andplasmaconcentrationsofinsulinandCpeptidearenormal.An
exceptionisthatsomedisordersoffattyacidoxidation(eg,hydroxyacylcoenzymeAdehydrogenase,HADH,previouslyknownasshortchainL3hydroxyacylCoA
dehydrogenasedeficiency,SCHAD)cancausedisturbanceofadenosinetriphosphate/adenosinediphosphate(ATP/ADP)ratiosinthebetacellandhavebeen
associatedwithhyperinsulinemia[30].Asaresult,thisdisorderisgroupedwiththemutationscausingpersistenthyperinsulinemichypoglycemiaofinfancy(PHHI).
(See"Pathogenesis,clinicalfeatures,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy".)
DefectsingluconeogenesisorglycogenmetabolismNext,wedeterminewhetherthefollowingcharacteristicsarepresent,whichsuggestdefective
gluconeogenesisorglycogenmetabolism(algorithm1):
Normalacylcarnitineprofile,usuallywithmildormoderatelyelevatedFFAconcentrations.
Inchildrenwithsevereglucose6phosphatasedeficiency,thebaselineplasmalactateconcentrationwillbesignificantlyelevatedandmayincreasefurtherduringa
glucagonstimulationtest,withnoconcomitantriseinglucose.Forchildrenwithmilderdisease,thebaselinelactateconcentrationmaybeonlymildlyelevatedbutcould
increasedramaticallyduringaglucagonstimulationtest.
Mildormoderateketosis(betahydroxybutyrate<2.5mmol/L)becauseketonesarenotbeingsynthesizedappropriatelyinglycogenstoragediseasetype1(vonGierke
disease)andotherconditionsinwhichdefectivegluconeogenesisexist(table5).(See"Overviewofinheriteddisordersofglucoseandglycogenmetabolism".)
Incontrasttohyperinsulinism,thereisminimalglycemicresponsetoglucagonstimulation,andplasmaconcentrationsofinsulinandCpeptidearenormalorlow.
Mostbutnotallofthedisordersofglycogenolysisandgluconeogenesisareassociatedwithhepatomegalytheycanbefurtherdistinguishedbytheirclinicalfeatures(table
6andtable7),andbyspecificgenetictesting.(See"Causesofhypoglycemiaininfantsandchildren",sectionon'Disordersofcarbohydratemetabolism'.)
KetosisLast,wedeterminewhetherthepatienthadarobust("appropriate")ketoticresponsetotheepisodeofhypoglycemia,ideallymeasuredbyplasmabeta
hydroxybutyrateconcentration(algorithm1).Thisservestoconfirmorrefinethediagnosticcategoryestablishedbytheothertests:
MinimalketosisConsistentwithhyperinsulinemia.Becausethislackofaketoticresponsetohypoglycemiaisabnormal,itissometimestermed"inappropriate."
Mildormoderateketosis(betahydroxybutyrate<2.5mmol/L)Consistentwithdisordersofgluconeogenesisorglycogenmetabolismincludingglycogenstorage
diseasetypeI[31,32],andwithmostfattyacidoxidationdisorders.Themildketosisseeninthesedisordersisalsoconsideredabnormalor"inappropriate"forthe
degreeofhypoglycemia.
Markedketosis(betahydroxybutyrate>2.5mmol/L)Thisfindingisanormal(appropriate)responsetofasting,andisconsistentwithstarvationorprolongedfastingin
anindividualwithoutaninbornerrorofmetabolism.Thisdegreeofketosisisalsoconsistentwithketotichypoglycemia,adisorderofunknowncause,certainglycogen
storagediseases(types0,III,VI,andIX),orwithdeficienciesofgrowthhormoneorcortisol[33].(See"Causesofhypoglycemiaininfantsandchildren",sectionon
'Ketotichypoglycemia'and"Overviewofinheriteddisordersofglucoseandglycogenmetabolism".)
Disordersofaminoacidororganicacidmetabolismalsotendtohaveketosisduringhypoglycemia.Thepresenceorabsenceofhepatomegalyandmeasurementof
qualitativeurineorganicacidscanhelptodistinguishamongthesepossibilities.(See"Organicacidemias".)
Markedlyelevatedketoneswithrelativelymildhypoglycemiamaybeseenindisordersofketolysis.Thesedisordersarerareandcanbescreenedforbythefindingof
elevatedbetahydroxybutyrateafteranovernightfastandindeedeveninthefedstate(>0.2mmol/L).TheyincludesuccinylCoA:3ketoacidCoAtransferase(SCOT)
deficiency(MIM#245050),alphamethylacetoaceticaciduria(MIM#203750),andmonocarboxylasetransporter1(MCT1)deficiency(MIM#616095)[34].
AdditionaltestingOncethegeneralcategoryofdisorderisidentified,furtherdiagnostictestingcanbeperformedtoidentifythespecificdisorder.Avarietyofdisorders
arediagnosedwithDNAanalyses(eg,defectsinglycogenandfattyacidmetabolism,hyperinsulinemia,defectsingluconeogenesisorglycogenolysis).(See"Inbornerrors
ofmetabolism:Identifyingthespecificdisorder".)
Furtherinformationaboutidentifyingthespecificorderwithineachcategoryisavailableinseparatetopicreviews:
Endogenoushyperinsulinism(See"Pathogenesis,clinicalfeatures,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy"and"Insulinoma".)
Fattyacidoxidationdisorders(See"Causesofhypoglycemiaininfantsandchildren",sectionon'Disordersoffattyacidmetabolism'and"Metabolicmyopathies
causedbydisordersoflipidandpurinemetabolism".)
Disordersofgluconeogenesisorglycogenmetabolism(See"Causesofhypoglycemiaininfantsandchildren",sectionon'Disordersofcarbohydratemetabolism'.)
Appropriateketosis(See"Causesofhypoglycemiaininfantsandchildren",sectionon'Ketotichypoglycemia'and"Causesofhypoglycemiaininfantsandchildren",
sectionon'Hormonedeficiencies'.)
Ifsuchtargetedtestingdoesnotestablishthediagnosis,thenotherprovocativetestsmaybeconsidered.Asexamples,galactose,fructose,andalaninetolerancetests
maybeperformedinchildrenwithsuspecteddefectsingluconeogenesis(see"Causesofhypoglycemiaininfantsandchildren"),orleucinetolerancetestsforsuspected
hyperinsulinismhyperammonemia(HIHA)syndrome(see"Pathogenesis,clinicalfeatures,anddiagnosisofpersistenthyperinsulinemichypoglycemiaofinfancy",section
on'Glutamatedehydrogenasedefects').However,asageneralrule,thesetestsshouldbeperformedonlyinselectedcircumstancesandbyindividualswhoare
experiencedintheirperformanceandinterpretation.
Ifthediagnosisandappropriatetherapycannotbereasonablydetermined,thechildshouldbetransferredtoacenterpreparedandexperiencedtomakeanevenmore
thoroughevaluationofthechild'sorfamilies'deoxyribonucleicacid(DNA).Usingtotalexomesequencingnewandpreviouslyunrecognizeddisordersmaybeidentified.
Rarely,aliverbiopsymaybenecessarytomeasuredeficienciesofhepaticenzymeswhenallelsehasbeenexhausted.(See"Inbornerrorsofmetabolism:Identifyingthe
specificdisorder".)
SUMMARYANDRECOMMENDATIONSHypoglycemiaininfantsandchildrenrequirespromptrecognitionandtreatmenttopreventpermanentneurologicsequelae.
Clinicalpresentationanddiagnosis
Symptomsofhypoglycemiaincludeneurogenic(autonomic)symptomsandneuroglycopenicsymptoms.Theseverityofsymptomsmayormaynotpredicttheseverity
ofthehypoglycemia.Neuroglycopenicsymptomstypicallyoccuratlowerplasmaglucoselevelsthanautonomicsymptoms.However,withrepeatedepisodesof

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hypoglycemia,thethresholdglucoseconcentrationforadrenergicsymptomsdecreases,suchthattheymaynotappearbeforetheonsetofneuroglycopenicsymptoms.
(See'Clinicalfeatures'above.)
Autonomicsymptomsofhypoglycemiainchildrenandadultsareduetoincreasedadrenergicactivity,andincludesweating,weakness,tachycardia,tremor,and
feelingsofnervousness,and/orhunger.(See'Neurogenic(autonomic)symptoms'above.)
Neuroglycopenicsymptomsincludelethargy,irritability,confusion,behaviorthatisoutofcharacter,andhypothermia.Inextremehypoglycemia,seizureandcoma
mayoccur.(See'Neuroglycopenicsymptoms'above.)
Ininfants,symptomsofhypoglycemiaarenonspecificandincludejitteriness,irritability,feedingproblems,lethargy,cyanosis,andtachypnea.(See'Infants'above.)
Whenhypoglycemiaissuspected,arapid(bedside)plasmaglucosedeterminationshouldbeperformed.Ifitislow(50mg/dL[2.7mmol/L]forthisinitialbedside
measurement),criticalsamplesshouldbeobtainedbeforetreatment,ifthiscanbedonewithoutdelayingtreatment.Obtainingcriticalsamplesbeforetheinitiationof
therapy,andcollectingthefirstvoidedurinesample,candramaticallyimprovetheabilitytodiagnosetheetiologyofthehypoglycemiaandsimplifythesubsequent
diagnosticevaluation.(See'Criticalsamples'above.)
TreatmentTreatmentofhypoglycemiavarieswiththedegreeofhypoglycemiaandassociatedsymptoms.Thekeystepsfordiagnosisandtreatmentaresummarizedin
arapidoverview(table2).(See'Immediatemanagement'above.)
Ifthepatientisfullyconsciousandabletodrinkandswallowsafely,arapidlyabsorbedcarbohydrate(eg,glucosetablets,glucosegel,tablesugar,orfruitjuice)should
begivenbymouth.Ifthehypoglycemiadoesnotimprovewithin10to15minutes,parenteralglucosemustbeadministered.(See'Glucosetherapy'above.)
Individualswithalteredconsciousnessand/orwhoareunabletosafelyswallowarapidlyabsorbedcarbohydrateshouldbetreatedwithintravenous(IV)dextrose,ata
doseof0.2to0.25g/kgofbodyweight(maximumsingledose,25grams).Thisisusuallyachievedwith2.5mL/kgof10percentdextrosesolution,givenslowly(2to3
mL/min).(See'Glucosetherapy'above.)
SubsequentmanagementTheIVbolusdescribedaboveshouldbefollowedbyaninfusionofdextrose.Plasmaglucoseshouldbemonitoredevery30to60minutes
andthedextroseinfusionadjustedaccordingly,untilstableplasmaglucoseconcentrationbetween70and120mg/dL(3.9to6.7mmol/L)isattained.Thereafter,
frequencyofglucosemonitoringshouldbedecreasedaccordingtothepatient'sclinicalandbiochemicalresponses.(See'Glucosetherapy'above.)
SulfonylureaoverdoseSymptomatichypoglycemiacausedbysulfonylureaoverdoseismanagedwithbolusesofdextroseandsometimesalsowithoctreotide.(See
"Sulfonylureaagentpoisoning".)
Evaluationforthecause
Causesofhypoglycemiaincludeavarietyofinbornerrorsofmetabolism,hyperinsulinemia,toxicingestions,andavarietyofunderlyingillnesses(table1).The
evaluationtodeterminethecauseisguidedbythefindingsofthehistory,examination,andpreliminarylaboratoryresults.Asexamples,clinicalfeaturestosuggesting
anaccidentalortoxicingestionoraspecificinbornerrorofmetabolismshouldpromptspecifictestingforthesuspecteddisorder.(See'Evaluationforthecauseof
hypoglycemia'above.)
Ifthecauseofthehypoglycemiaisunclear,thecriticalsamplesobtainedduringanepisodeofhypoglycemiaareusedtoidentifythetypeofdisordercausing
hypoglycemia.Acontrolledelectivefastmaybenecessarytocollectthecriticalsamples,butshouldbeperformedonlyafterdisordersoffattyacidoxidationhavebeen
excludedbyperforminganacylcarnitineprofileandurineorganicacidsinthewellstate.Wenarrowthediagnosticpossibilitiesintocategoriesinastepwisesequence,
assummarizedinthealgorithm(algorithm1).(See'Subsequenttestingforunexplainedhypoglycemia'aboveand'Interpretationofresults'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Glucoseusebythebrainversusothertissues

Estimatedpercentageofglucoserateofdisappearance(Rd)usedbybrainandnonbraintissue
frominfancytoadulthood(n=141).Thetissuedatapointsrepresentthemeanvaluesfor
subjectswithbodyweights,inkg,of0.51.0,1.12.0,2.13.0,3.14.0,4.15.0,5.110,10.115,
15.120.0,20.130.0,30.140.0,40.150.0,50.160.0,60.170,and70.195.0,respectively.
DatafromHaymond,MW,Sunehag,A,EndocrinolMetabClinNorthAm199928:663.
Graphic76157Version1.0

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Glucoserateofdisappearance(Rd)

Totalglucoserateofdisappearance(Rd)(mmol/min)asafunctionofbodyweightfrominfancyto
adulthood(n=141bodyweightsrangefrom0.6to94kg).
DatafromHaymond,MW,Sunehag,A.Controllingthesugarbowl.Regulationofglucosehomeostasis
inchildren.EndocrinolMetabClinNorthAm199928:663.
Graphic64790Version1.0

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Causesofhypoglycemiaininfantsandchildren

Othernames

OMIM#

Disordersofcarbohydratemetabolism
Disordersofglycogenolysis

Glycogensynthetasedeficiency

GSDtype0a

240600

Glucose6phosphatasedeficiency

GSDtypeIa(vonGierkedisase)orIb

232200or232220

Debrancherdeficiency

GSDtypeIII

232400

Hepaticphosphorylasedeficiency

GSDtypeVI

232700

HepaticphosphorylaseBkinasedeficiency

GSDIXa1,IXbd

306000

Phosphoglucomutase1deficiency

CongenitaldisorderofglycosylationtypeIt

614921

Phosphomannomutase2deficiency

CongenitaldisorderofglycosylationtypeIa

212065

Mannosephosphateisomerasedeficiency

CongenitaldisorderofglycosylationtypeIb

602579

Fructose1,6bisphosphatasedeficiency

229700

Pyruvatecarboxylasedeficiency

266150

PEPCKdeficiency

261650

Galactosemia

230400others

Hereditaryfructoseintolerance

229600

Propionicacidemia

606054

Methylmalonicaciduria

277400others

Glutaricaciduriatype1

231670

201450,others

Persistenthyperinsulinemichypoglycemiaofinfancy
(PHHI)

Familialhyperinsulinemichypoglycemiacongenital
hyperinsulinism

256450601820others

Insulinoma(includinginassociationwithMEN1)

Exogenousadministrationofinsulin(eg,in
Munchausen'ssyndromebyproxyordiabetes
mellitus)

Growthhormonedeficiency

Cortisoldeficiency

Hypothyroidism

Oralhypoglycemics(eg,sulfonylureassuchas
glipizideorglyburide)causeshyperinsulinemia

Ethanol

Salicylates

Betablockers

Pentamidine

Heartdisease

Surgery

Criticalillness(eg,sepsis)

Hepaticfailure

Disordersofglycosylation

Disordersofgluconeogenesis

Disordersofaminoacidmetabolism

Disordersoffattyacidmetabolism
MediumchainacylCoAdehydrogenase(MCAD)and
others
Increasedutilizationofglucose
Hyperinsulinemia

Miscellaneous
Ketotichypoglycemia
Hormonedeficiencies

Ingestions

Other

OMIM:onlineMendelianinheritanceinmandatabaseGSD:glycogenstoragediseasePEPCK:phosphoenolpyruvatecarboxykinasePHHI:persistenthyperinsulinemichypoglycemiaof
infancyMEN1:multipleendocrineneoplasiatype1MCAD:mediumchainacylCoAdehydrogenase.
CourtesyofDrs.MoreyHaymondandAgnetaSunehag.
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Rapidoverviewforhypoglycemiainadolescentsandchildren,otherthanneonates
Clinicalfeatures
Anypatientwithacutelethargyorcomashouldhaveanimmediatemeasurementofbloodglucosetodetermineifhypoglycemiaisapossiblecause
Otherfindingsofhypoglycemiaarenonspecific*andvarybyage:
Infants
Irritability
Lethargy
Jitteriness
Feedingproblems
Hypothermia
Hypotonia
Tachypnea
Cyanosis
Apnea
Seizures
Olderchildrenandadolescents
Autonomicresponse(tendstooccurwithbloodglucose<50to65mg/dL)
Sweating
Tachycardia
Palpitations
Tremor
Nervousness
Hunger
Paresthesias
Pallor

Neuroglycopenia
Irritability
Confusion
Uncharacteristicbehavior
Weakness
Seizures
Coma
Occasionally,transientfocalneurologicdeficits

Diagnosis
Obtainrapidbedsidebloodglucoseconcentration(andhydroxybutyrate,ifavailableasapointofcaremeasurement)
Confirmthepresenceofhypoglycemiawithasimultaneouslydrawnplasmaglucose
Treat,asoutlinedbelow,ifthebedsidevalueislow(<70mg/dL[3.89mmol/L])insymptomaticpatients
Obtainabloodsampleforadditionaldiagnosticstudiespriortoglucoseadministration,ifpossible,andcollectthefirstvoidedurineafterthehypoglycemiceventinallinfantsand
youngchildrenwhoarenotbeingtreatedfordiabetesmellitusordonothaveaknowncauseforhypoglycemia

Treatment
Donotdelaytreatmentifsymptomatichypoglycemiaissuspected.However,everyreasonableeffortshouldbemadetoobtainarapidbloodglucosemeasurementpriorto
administeringglucose.
Giveglucosebaseduponthepatientslevelofconsciousnessandabilitytoswallowsafely(ie,alertenoughtodosoandwithintactgagreflex)asfollows:
Consciousandabletodrinkandswallowsafely:
Administer0.3g/kg(10to20g)ofarapidlyabsorbedcarbohydrate.15gissuppliedby3glucosetablets,atubeofgelwith15g,4oz(120mL)sweetenedfruitjuice,6oznondietsoda,or
atablespoon(15mL)ofhoneyortablesugar.Mayrepeatin10to15minutes.

Alteredmentalstatus,unabletoswallow,ordoesnotrespondtooralglucoseadministrationwithin15minutes:
GiveaninitialIVbolusofglucoseof0.25g/kgofdextrose(maximumsingledose25g). Thevolumeandconcentrationofglucosebolusisinfusedslowlyat2to3mLperminuteandbasedupon
age:
2.5mL/kgof10%dextrosesolution(D10W)ininfantsandchildrenupto12yearsofage(10%dextroseis100mg/mL)
1mL/kgof25%dextrose(D25W)or0.5mL/kgof50%dextrose(D50W)inadolescents(25%dextroseis250mg/mL50%dextroseis500mg/mL)

UnabletoreceiveoralglucoseandunabletoobtainIVaccess:
Giveglucagon0.03mg/kgIMorSQ(maximumdose1mg) :
Performbloodglucosemonitoringevery10to15minutesastheeffectsofglucagonmaybetransient
Establishvascularaccessassoonaspossible

Afterinitialhypoglycemiaisreversed,provideadditionalglucoseandtreatmentbaseduponsuspectedetiology:
GivechildrenandadolescentswithtypeIdiabetesmellitusanormaldiet
Givepatientswithanunknowncauseofhypoglycemiaintravenousinfusionofdextrose10%(6to9mg/kgperminute)titratedtomaintainbloodglucoseinasafeand
appropriaterange(70to150mg/dL[3.89to8.33mmol/L])
Givepatients,whohaveingestedasulfonylureaandhaverecurrenthypoglycemia,octreotide(dose:1to1.5mcg/kgIMorSQ,maximumdose150mcgevery6hours)in
additiontoglucose.(RefertoUpToDatetopiconsulfonylureapoisoning).
Measurearapidbloodandplasmaglucose15to30minutesaftertheinitialIVglucosebolusandthenmonitorevery30to60minutesuntilstable(minimumoffourhours)toensure
thatplasmaglucoseconcentrationismaintainedinthenormalrange(>70to100mg/dL[>3.89to5.55mmol/L])
Obtainpediatricendocrinologyconsultationforpatientswithhypoglycemiaofunknowncause
ObtainmedicaltoxicologyconsultationforpatientswithingestionoforalhypoglycemicagentsbycallingtheUnitedStatesPoisonControlNetworkat18002221222

oraccessthe

WorldHealthOrganization'slistofinternationalpoisoncenters(www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html)

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Admitthefollowingpatients:
Cannotmaintainnormoglycemiawithoralintake
Hypoglycemiaofunknowncause
Ingestionoflongactinghypoglycemicagents
Recurrenthypoglycemiaduringtheperiodofobservation
IV:intravenousIM:intramuscularSQ:subcutaneousD10W:10%dextroseinwaterD25W:25%dextroseinwaterD50W:50%dextroseinwater.
*Thesefindingsmayalsooccurininfantswithsepsis,congenitalheartdisease,respiratorydistresssyndrome,intraventricularhemorrhage,othermetabolicdisorders,andinchildrenand
adolescentswithavarietyofunderlyingconditions.
Specificlaboratorystudiestoobtaininchildrenincludebloodsamplesforglucose,insulin,Cpeptide,betahydroxybutyrate,lactate(freeflowingbloodmustbeobtainedwithouta
tourniquet),plasmaacylcarnitines,freefattyacids,growthhormone,andcortisol.
Higherdosesofglucose(eg,0.5to1g/kg[5to10mL/kgof10%dextroseinwateror2to4mL/kgof25%dextroseinwater])maybeneededtocorrecthypoglycemiacausedby

sulfonylureaingestion.(Formoredetail,refertoUpToDatetopiconsulfonylureaagentpoisoning).
Glucagonwillreversehypoglycemiacausedbyexcessendogenousorexogenousinsulinandwillnotbeeffectiveinpatientswithinadequateglycogenstores(prolongedfasting),ketotic
hypoglycemia,orareunabletomobilizeglycogen(glycogenstoragediseases).Ofnote,childrenmayexhausttheirglycogenstoresinaslittleas12hours.Otherconditionsinwhichglycogen
cannotbeeffectivelymobilizedincludeethanolintoxicationinchildren,adrenalinsufficiency,andcertaininbornerrorsofmetabolism(eg,adisorderofglycogensynthesisandglycogen
storagediseases).
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Algorithmforevaluationofaninfantorchildwithhypoglycemia

BUN:bloodureanitrogenAST:aspartateaminotransferaseALT:alanineaminotransferaseFFA:freefattyacidsPG:plasmaglucose:elevated:decreasedACTH:adrenocorticotropichormoneNH3:
ammoniaIGFI:insulinlikegrowthfactorIIGFBP3:insulinlikegrowthfactorbindingprotein3T4:thyroxineTSH:thyroidstimulatinghormone(thyrotropin).
*Plasmainsulinlevelsmaybeeitherloworhighifexogenousinsulinhasbeengiven(eg,inMunchausensyndromebyproxy).Thisisbecauserecombinantmodifiedhumaninsulinsmaynotbedetectedin
themonoclonal"sandwich"assaysusedbymanycommerciallaboratoriestomeasureunmodifiedhumaninsulin.Thus,iftheglucagonchallengetestispositive(riseinBG),butmeasuredplasmainsulin
concentrationsarelow(andtheCpeptidelevelisalsolow),polyclonalinsulinassaysmustbesoughttodetectexogenousinsulin.
Acylcarnitineelevationswillbeforaspecificfattyacidoxidationdisorder.
Whenthelactateiselevatedwithouthepatomegaly,considerorganicacidemia,ketolysisdefect,ormitochondrialrespiratorychaindisorder.Ifthelactateispresentwithisolatedhepatomegaly,glycogen
storagediseaseorgluconeogenesisdefectsaresuspected.
Defectsofketolysismaycausemarkedlyelevatedketonesinthesettingofmildhypoglycemia.Thesedisordersarerare,andincludeSCOTdeficiency(MIM#245050),alphamethylacetoaceticaciduria(MIM

#203750),andmonocarboxylasetransporter1deficiency(MIM#616095).
Thyroidfunctiontestsaremeasuredaspartoftheevaluationforpanhypopituitarism.Itisunlikelythatisolatedhypothyroidismcauseshypoglycemia.
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Disordersoffattyacidoxidation
Disorders

Acylcarnitineprofileabnormalities

Carnitineuptakedefect

Free(C0)carnitine

ShortchainacylCoAdehydrogenase(SCAD)deficiency

Butyryl(C4)carnitine

ShortchainhydroxyacylCoAdehydrogenase(SCHAD)deficiency

3hydroxybutyryl(C4OH)carnitine

MediumchainacylCoAdehydrogenase(MCAD)deficiency

Octanoyl(C8)carnitine
Decanoyl(C10)carnitine
Decenoyl(C10:1)carnitine

VerylongchainacylCoAdehydrogenase(VLCAD)deficiency

Tetradecenoyl(C14:1)carnitine
Tetradecanoyl(C14)carnitine
Tetradecendioyl(C14:2)carnitine
Dodecanoyl(C12)carnitine
Dodecenoyl(C12:1)carnitine
Hexadecanoyl(C16)carnitine

LongchainhydroxyacylCoAdehydrogenase(LCHAD)deficiency

Hydroxypalmitoyl(C16OH)carnitine
Hydroxyhexadecenoyl(C16:1OH)carnitine

Trifunctionalprotein(TFP)deficiency

Hydroxysteryl(C18OH)carnitine
Hydroxyoleyl(C18:1OH)carnitine

CarnitinepalmitoyltransferaseII(CPTII)deficiency
Carnitineacylcarnitinetranslocase(CACT)deficiency

Palmitoyl(C16)carnitine
Steryl(C18)carnitine
Oleyl(C18:1)carnitine

CarnitinepalmitoyltransferaseI(CPTI)deficiency

Free(C0)carnitine

MultipleacylCoAdehydrogenasedeficiency(glutaricacidemiatypeII)

Inmultiplenonhydroxylatedacylcarnitines

Listofcommonfattyacidoxidationdisordersandassociatedacylcarnitineabnormalities.Notethatthefirstnewbornscreenismostusefulfordiagnosisandthatacylcarnitineprofiles
maybenormalformilderphenotypeswhennotacutelyill.Additionally,forsomeofthelongerchaindisorders(eg,VLCADandCPTII),furthertestingsuchasDNAmutationanalysis
mayberequiredtoestablishadiagnosisdefinitively.
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Distinguishingbiochemicalfindingsofinbornerrorsofmetabolism

Findings

Maplesyrup
urinedisease

Urea
cycle
defects

Organic
acidemias

Disordersof
carbohydrate
metabolism

Fattyacid
oxidation
disorders

Mitochondrial
disorders

Peroxisomal
disorders

Lysosomal
storage
disorders

Metabolic
acidosis

++

Respiratory
alkalosis

Hyperammonemia

++

Hypoglycemia

Ketones

A/H

A/H

A/L

A/H

Lacticacidosis

++

:usuallyabsent:sometimespresent+:usuallypresent++:alwayspresentA:appropriateH:inappropriatelyhighL:inappropriatelylow.
*Withindiseasecategories,notalldiseaseshaveallfindingsfordisorderswithepisodicdecompensationclinicalandlaboratoryfindingsmaybepresentonlyduringacutecrisisfor
progressivedisorders,findingsmaynotbepresentearlyinthecourseofdisease.
Adaptedfrom:WeinerDL.MetabolicEmergencies.In:TextbookofPediatricEmergencyMedicine,5thed,FleisherGR,LudwigS,HenretigFM(Eds),Lippincott,Williams&Wilkins,Philadelphia
2006.p.1193.
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Disordersofglycogen/glucosemetabolism
Classification

Keyclinicalfindings

Diagnosis

Therapy

GSD0a(MIM#240600,glycogensynthase2deficiencyinliver)

Ketotichypoglycemia,no
hepatomegaly

Liverbiopsyandenzymetesting
DNAtesting

Uncookedcornstarch,
commercialglucosepolymers(eg,
Glycosade),livertransplantation

GSD0b(MIM#611556,muscleglycogensynthasedeficiency)

Cardiomyopathy,exercise
intolerance,weakness

Musclebiopsy(glycogen
depletion),enzymeassay,DNA
testing

Nospecifictreatment

GSDI(MIM#232200GSDIa,vonGierkedisease,glucose6
phosphatasedeficiencyGSDIbduetoqtransportdefect)

Ketotichypoglycemia,
hepatomegaly

DNAtesting,liverbiopsy,and
enzymeassay

Cornstarch,allopurinol,
granulocytecolonystimulating
factor(GCSF),commercial
glucosepolymers(eg,Glycosade),
livertransplantation

Lysosomalacidmaltasedeficiency(MIM#232300,Pompedisease,GSD
II*)

Hypotonia,muscleweakness,
hypertrophiccardiomyopathy,
rhabdomyolysis

Fibroblast,leukocyte,muscle,or
liverenzymeassayDNAtesting

Enzymereplacementtherapy,
commercialglucosepolymers(eg,
Glycosade),livertransplantation

Lysosomeassociatedmembraneprotein2(LAMP2)deficiency(MIM
#300257,Danondisease,GSDIIb *)

Hypotonia,hypertrophic
cardiomyopathy,rhabdomyolysis

Musclebiopsy,DNAtesting

Nospecifictreatment

GSDIII(MIM#232400,glycogendebrancherdeficiency)

Ketotichypoglycemia,
hepatomegaly

Fibroblastorliverenzymeassay
DNAtesting

Uncookedcornstarch,
commercialglucosepolymers(eg,
Glycosade),livertransplantation

GSDIV(MIM#232500,glycogenbranchingenzymedeficiency)

Hepatomegaly,cirrhosis,rare
neuromuscularpresentations,such
asfetalakinesiasequence,
myopathy,axonalneuropathy,adult
polyglucosanbodydisease

Fibroblast,muscle,orliverbiopsy
DNAtesting

Commercialglucosepolymers(eg,
Glycosade),livertransplantation

GSDV(MIM#232600,McArdledisease,musclephosphorylase
deficiency)

Fatigability,myoglobinuria,
rhabdomyolysis

Musclebiopsy,muscleenzyme
assay,DNAtesting

Sucrosepriortoexercise

GSDVI(MIM#232700,Hersdisease,liverphosphorylasedeficiency)

Hepatomegaly,mildhypoglycemia

Liverbiopsyandenzymeassay
DNAtesting

Commercialglucosepolymers(eg,
Glycosade),livertransplantation

GSDVII(MIM#232800,Taruidisease,phosphofructokinasedeficiency
inmuscle)

Fatigability,myoglobinuria,
rhabdomyolysis

Muscleenzymeassay,DNAtesting

Nospecifictreatment

Phosphoglyceratekinasedeficiency(MIM#311800)

Hemolysis,fatigability,
myoglobinuria,CNSdysfunction,
rhabdomyolysis

Muscle/RBCenzymeassayDNA
testing

Bonemarrowtransplantation

GSDIX(phosphorylasekinasedeficiencyIXa1,MIM#306000,formerly
GSDVIII,alpha2subunitdefectinliverIXb,MIM#261750,beta
subunitdefectinliverIXc,MIM#613027,gammasubunitdefectinliver
andmuscleIXd,MIM#300559,alphasubunitdefectinmuscle)

Hepatomegaly,mildhypoglycemia,
fatigability,exerciseintolerance

Liver/musclebiopsyenzyme
assayDNAtesting

Commercialglucosepolymers(eg,
Glycosade),livertransplantation

GSDX(MIM#261670,phosphoglyceratemutasedeficiency)

Fatigability,myoglobinuria,exercise
intolerance,rhabdomyolysis

Musclebiopsyandenzymeassay
DNAtesting

Nospecifictreatment

GSDXI(MIM#612933lactatedehydrogenaseA[LDHA,MIM#150000]
deficiencyandlactatedehydrogenaseBdeficiency[LDHB,MIM
#150100])

Fatigability,myoglobinuria,
rhabdomyolysis

MuscleorRBCenzymeassayDNA
testing

Nospecifictreatment

GLUT2deficiency(MIM#138160FanconiBickelsyndrome)

Growthretardation,renalFanconi
syndrome,galactosemia

Clinicalfeatures,DNAtesting

Smallmeals,cornstarch,
electrolytesasneeded

GSDXII(MIM#611881,aldolaseAdeficiency)

Hemolysis,jaundice,
myoglobinuria,muscleweakness,
fatigability,rhabdomyolysis

MuscleorRBCenzymeassayDNA
testing

Nospecifictreatment

GSDXIII(MIM#612932,betaenolasedeficiencyinmuscle)

Exerciseintolerance,increased
CPK,rhabdomyolysis

Musclebiopsy,enzymeassay,DNA
testing

Nospecifictreatment

GSDXIV(MIM#612934,phosphoglucomutase1deficiencyinmuscle)

Exerciseintolerance,
myoglobinuria,increasedCPK,
rhabdomyolysis,myoglobinuria

Musclebiopsy,enzymeassay,DNA
testing

Nospecifictreatment

GSDXV(MIM#613507,glycogenin1deficiencyinmuscle)

Muscleweakness,arrhythmias

Musclebiopsy(glycogen
depletion),DNAtesting

Nospecifictreatment

GSD:glycogenstoragediseaseMIM:MendelianinheritanceinmanDNA:deoxyribonucleicacidCNS:centralnervoussystemRBC:redbloodcellGLUT2:glucosetransporter2CPK:
creatininephosphokinase.
*Thesediseaseswereoriginallyclassifiedasglycogenstoragesdiseases.Itwassubsequentlyrecognizedthattheaccumulationofglycogeninlysosomesseeninthesediseasesisdueto
defectivelysosomalmetabolismratherthanenergydeficiencyfromglycogen/glucosemetabolism.Thus,theyareconsideredbothglycogenstoragediseasesandlysosomalstoragediseases.
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Clinicalandlaboratoryfeaturesofhepaticenzymedeficienciesofglycogenmetabolisminchildren
Enzyme
deficiency
Glycogen
synthase(GSD
0)

Lacticacid
*

Uricacid

Ketosis
+

Serumlipids

Response
toglucagon

Clinicalfeatures
Normalliversize
Neonatalonset
Severefastinghypoglycemia,butpostprandialhyperglycemiaandlactic
acidosis

Glucose6
phosphatase
(GSDI)

Hepatomegaly
Neonatalonset
Severefastinghypoglycemia
Somepatientshaveneutropenia,plateletdysfunction,renaldiseaseor
hypertension

Glycogen
debrancher
(GSDIII)

Normalor

Normal

Normalor

Normaltwo
hoursafter
glucosemeal,
butabsentafter
fast

Hepatomegaly
Onsetininfancy
Mildfastinghypoglycemia
Mayhavecardiacorskeletalmusclemanifestations(eg,elevatedCK)
MayhaveelevatedRBCglycogen

Hepatic
phosphorylase
(GSDVI)

Normal

Hepatic
phosphorylaseb
kinase

Normal

Normal

Normalor

Usuallynormal,
butvariable

Hepatomegaly
Onsetinearlychildhood
Mildfastinghypoglycemia

Normalor

Normalor

Normal

Hepatomegaly
Onsetinearlychildhood
Mildfastinghypoglycemia
Xlinkedinheritance

GSD:glycogenstoragediseaseCK:creatinekinaseRBC:redbloodcell+:present.
*Postprandial.
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Clinicalandlaboratoryfeaturesofhepaticenzymedeficienciesofgluconeogenesisinchildren
Enzyme
deficiency
G6P

Lactic
acid

Uric
acid

Serum
lipids

Ketosis

Responseto
glucagon

Comment
Hepatomegaly
Neonatalonset
Severefastinghypoglycemia
Somepatientshaveneutropenia,plateletdysfunction,renaldiseaseor
hypertension

F16DP

(whenfed,notwhen
fasted)

Mild/moderatehepatomegaly
Moderatehypoglycemia
Onsetininfancy
Muscularweakness
Failuretothrive
Hyperalaninemia

PEPCK

Normal

Onsetininfancy
Severehypoglycemia
Elevatedtransaminases
Coagulationabnormalities
Fattyliver,fattykidneys

PC

Normal

Normalor

Onsetininfancy,withearlydeath
Mildhypoglycemia
Severementalretardation
Subacutenecrotizingencephalopathy

G6P:glucose6phosphataseF16DP:fructose1,6,diphosphatasePEPCK:phospholenolpyruvatecarboxykinasePC:pyruvatecarboxylase:increased:decreased+:present:may
ormaynotbepresent.
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ContributorDisclosures
AgnetaSunehag,MD,PhD Nothingtodisclose MoreyWHaymond,MD Consultant/AdvisoryBoards:AegerionPharmaceuticalsInc[Reviewaregistry(Metreleptin)]
AstraZeneca[diabetes(Exenatide)]DaiichiSankyo[WellkidsStudy(Colesevelamhydrochloride)]NationalInstitutesofHealth[Dataandsafetymonitoringboards(Life
Momstudy)]NovoNordisk[Obesity]XerisPharmaceuticals,Inc[Glucagonandhypoglycemia(nonaqueousglucagonformulation)]. JosephIWolfsdorf,MB,
BCh Nothingtodisclose AlisonGHoppin,MD Nothingtodisclose
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,and
throughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDate
standardsofevidence.
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