Approach To Evaluation of Cholestasis in Neonates and Young Infants - UpToDate

2017515 ApproachtoevaluationofcholestasisinneonatesandyounginfantsUpToDate
OfficialreprintfromUpToDate
www.uptodate.com2017UpToDate
Approachtoevaluationofcholestasisinneonatesandyounginfants
Authors: KathleenMLoomes,MD,JessiErlichman,MPH
SectionEditors: StevenAAbrams,MD,ElizabethBRand,MD
DeputyEditor: AlisonGHoppin,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Apr2017.|Thistopiclastupdated:Apr10,2017.
INTRODUCTIONNeonatalcholestasisisgenerallydefinedasconjugatedhyperbilirubinemiathatoccursinthe
newbornperiodorshortlythereafter.Cholestasisresultsfromdiminishedbileformationand/orexcretion,which
canbecausedbyanumberofdisorders.Neonatalcholestasislastingmorethantwoweeksaffectsapproximately
1in2500births(excludinginfantswithintestinalfailureassociatedliverdisease),butestimatesvarydepending
onthedefinitionusedtodefinecholestasis[1,2].
Thistopicreviewprovidesanapproachtopatientswithneonatalcholestasis.Thepathogenesisandmanagement
ofneonatalunconjugatedhyperbilirubinemiaandcommoncausesofneonatalcholestasisarediscussed
separately.(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthenewborn"and"Treatment
ofunconjugatedhyperbilirubinemiaintermandlatepreterminfants"and"Causesofcholestasisinneonatesand
younginfants".)
DEFINITIONS
CholestasisCholestasisisdefinedasanimpairmentintheexcretionofbile,whichcanbecausedby
defectsinintrahepaticproductionofbile,transmembranetransportofbile,ormechanicalobstructiontobile
flow.Thebiochemicalfeaturesofcholestasisreflecttheretentionofcomponentsofbileintheserum(eg,
bilirubin,bileacids,and/orcholesterol).Thepatternandseverityofeachoftheseabnormalitiesvarieswith
theunderlyingdisorder.Elevatedconjugatedbilirubinisthepredominantcharacteristicinmostofthecauses
ofneonatalcholestasis.
ConjugatedhyperbilirubinemiaConjugatedhyperbilirubinemiainaneonateisdefinedasaserum
conjugatedbilirubinconcentrationgreaterthan1.0mg/dL(17.1micromol/L)ifthetotalserumbilirubinis<5.0
mg/dL(85.5micromol/L)orgreaterthan20percentofthetotalserumbilirubinifthetotalserumbilirubinis
>5.0mg/dL(85.5micromol/L).Anelevatedconjugatedbilirubinisanabnormalfindingandrequires
additionalevaluation[3].Thethresholdissomewhathigher,usuallyaserumconjugatedbilirubingreaterthan
2.0mg/dL(34.2micromol/L),fordefiningclinicallysignificanthyperbilirubinemiaininfantswithintestinal
failureassociatedliverdisease(whichisalsoknownasparenteralnutritionassociatedliverdisease).(See
"Intestinalfailureassociatedliverdiseaseininfants",sectionon'Definition'.)
Theterms"conjugatedbilirubin"and"directbilirubin"areoftenusedinterchangeablybecauseconjugated
bilirubincanbeestimatedbythe"direct"reactionwithadiazoreagent(vandenBerghreaction).However,
directreactingbilirubinincludesboththeconjugatedbilirubinandthedeltafraction,whichrepresentsbilirubin
covalentlyboundtoalbumin[4].(See"Clinicalaspectsofserumbilirubindetermination",sectionon
'Measurementofserumbilirubin'.)
NeonatalcholestasisTheterm"neonatalcholestasis"isoftenusedtorefertocholestaticliverdisease
thatispresentatbirthand/ordevelopswithinthefirstfewmonthsoflife,ratherthanreferringstrictlytothe
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neonatalperiod(thefirst28daysoflife).Inclinicalpractice,thesedisordersusuallybecomeapparentwithin
thefirstthreemonthsoflife,whichisthecriticalperiodforidentifyinginfantswithbiliaryatresia(table1).
However,similardiagnosticconsiderationsapplyforinfantswhosecholestasisisidentifiedafterthreemonths
ofage.Althoughthecholestasiscausedbythesedisordersispersistent,infantsshouldbeevaluatedassoon
astheconjugatedhyperbilirubinemiaisidentified,toavoiddelayindiagnosis.
OVERVIEWAnyinfantnotedtobejaundicedatthetwoweekwellchildvisitshouldbeevaluatedfor
cholestasis(ie,conjugatedhyperbilirubinemia)[3].Thisisbecausephysiologicjaundice(characterizedby
unconjugatedhyperbilirubinemia)resolvesby14daysofageinatleast85percentofinfants[5,6].Althoughmost
infantswhoarestilljaundicedattwoweeksofagehavebenigncauses(breastfeeding,breastmilk,orhemolytic
jaundice),afewwillhavebiliaryatresiaorotherdiseasesthatrequirepromptdiagnosisandtreatmenttooptimize
outcomes.Initiatingevaluationatthetwoweekvisitisimportantbecausesomeoftheseinfantsmaynothave
anotherhealthcarevisituntiltheyaretwomonthsold.(See"Pathogenesisandetiologyofunconjugated
hyperbilirubinemiainthenewborn"and"Biliaryatresia",sectionon'Diagnosis'.)
Thisapproachresultsinscreeningbetween60and375healthyinfantstodetectonecaseofneonatalcholestasis
[3].Toreducethescreeningburden,theNorthAmericanSocietyforPediatricGastroenterology,Hepatology,and
Nutrition(NASPGHAN)suggeststhefollowingapproachinjaundicedinfantswhoaremostlikelytohavebreast
milkjaundicebecausetheyareexclusivelyornearexclusivelybreastfed:theevaluationforcholestasismaybe
delayeduntilthreeweeksofageinsuchinfantsiftheyhaveanormalphysicalexamination,nohistoryofdark
urineorlightstools,andcanbereliablymonitored[3].
InitialscreeningThefirststepinevaluatingajaundicedinfantforpossiblecholestasisistomeasurethe
serumconcentrationsofbothtotalandconjugatedbilirubin.
Iftheinfanthasunconjugatedhyperbilirubinemia(>2mg/dL[34.2micromol/L]attwoweeksofage),thisis
oftencausedbybreastmilkjaundice,butothercausesalsoshouldbeconsidered,particularlyifthetotal
bilirubinismarkedlyelevated.(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthe
newborn"and"Evaluationofjaundicecausedbyunconjugatedhyperbilirubinemiainchildren".)
Iftheinfanthasconjugatedhyperbilirubinemia,causesofcholestaticjaundiceshouldbeinvestigated
promptly,asdiscussedintheremainderofthistopic.Conjugatedhyperbilirubinemiaisdefinedasaserum
conjugatedbilirubinconcentrationgreaterthan1.0mg/dL(17.1micromol/L)ifthetotalbilirubinis<5.0mg/dL
(85.5micromol/L)orgreaterthan20percentofthetotalbilirubinifthetotalbilirubinis>5.0mg/dL(85.5
micromol/L).
StagesofevaluationTheevaluationofaninfantwithconjugatedhyperbilirubinemiaiscomplexbecause
manydisorderscanpresentwithneonatalcholestasis(table1),anddistinguishingamongthesedisordersis
difficultbecauseofthelackofspecificdiagnostictests.However,relativelyfewdiagnosesaccountforthemajority
ofcases(table2)[7].Interminfants,themostcommoncausesofneonatalcholestasisarebiliaryatresia(25to
40percent)andanarrayofraregeneticdisorders(25percentcollectively)[3].Inprematureinfants,cholestasis
morefrequentlyresultsfromtotalparenteralnutrition(TPN)orsepsis.Thecausesofneonatalcholestasisare
discussedelsewhere.(See"Causesofcholestasisinneonatesandyounginfants"and"Biliaryatresia".)
Evaluationshouldbeundertakeninastagedapproach[8]:
Theinitialstepisrapiddiagnosisandearlyinitiationoftherapyoftreatabledisorders:
Biliaryatresiamustbeidentifiedearlyanddifferentiatedfromothercausesofneonatalcholestasis
becauseearlysurgicalintervention(ie,beforetwomonthsofage)resultsinabetteroutcome.Important
stepsinmakingthisdiagnosisareultrasonographyandliverbiopsy.(See"Biliaryatresia",sectionon
'Diagnosis'.)
Conditionssuchassepsis,hypothyroidism,panhypopituitarism,andinbornerrorsofmetabolism(eg,
galactosemia)mustberecognizedandtreatedpromptlytoavoidsignificantprogressionoftheillness.
Forinfantsinwhomthesedisordersareexcluded,consultationwithapediatricgastroenterologistis
warranted[3].(See'Laboratorystudies'below.)
Additionaltestingisdirectedatthediagnosisofspecificconditions,suchasPitestingforalpha1antitrypsin
deficiency,andsweatand/orgenetestingforcysticfibrosis,andatpotentialcomplicationsofliverdisease
suchascoagulopathy.
HISTORYAwidevarietyofdisordersmaycauseneonatalcholestasis,asoutlinedinthetable(table1)and
detailedinaseparatetopicreview.(See"Causesofcholestasisinneonatesandyounginfants".)
Aspectsofthehistorythatmaybehelpfulinnarrowingthedifferentialdiagnosisaresummarizedinthetable
(table3)[3].
PHYSICALEXAMINATIONSpecificcomponentsofthephysicalexaminationmaybeusefulinnarrowingthe
differentialdiagnosisandareoutlinedinthetable(table4).Keyfeaturesinclude[3]:
Infantswithbiliaryatresiaaregenerallywellappearing,exceptforjaundice,andstoolsareoftenacholic
(examplesofstoolcolorshere).Infantswhopresentlate(>90daysofage)withbiliaryatresiamayhave
featuresofadvancedliverdiseaseincludingfailuretothrive,ascites,andhepatosplenomegaly.
Bycontrast,infantswhoareillappearingorfailingtothrivearemorelikelytohaveinfectionormetabolic
disease.
LABORATORYSTUDIESLaboratorystudiescanhelpassesstheextentofhepatobiliarydysfunctionandmay
identifyanetiology.Stagedlaboratoryevaluationispresentedinthetable(table5).Thesetestsusuallyshouldbe
performedsimultaneouslywiththeimagingevaluationdescribedbelow.
InitialtestsTheinitiallaboratoryevaluationshouldinclude:
Comprehensivemetabolicpanel(CMP)
TotalandconjugatedbilirubinToevaluateforconjugatedhyperbilirubinemia(cholestasis)versus
unconjugatedhyperbilirubinemia.
Serumalanineaminotransferase(ALT)andaspartateaminotransferase(AST)Toassesslivercell
injury.
Serumalkalinephosphataseandgammaglutamyltranspeptidase(GGTP)Thesetestsmayprovide
supportiveevidenceforbiliaryobstruction.Furthermore,severalgenetic/metabolicdisorderscanbe
dividedintohighandlowGGTPcategories.Forexample,GGTPistypicallyelevatedinbiliaryatresia
andAlagillesyndrome,whileanormaltolowGGTPisseeninmostformsofprogressivefamilial
intrahepaticcholestasis(PFIC),bileacidsyntheticdisorders,andarthrogryposisrenaldysfunction
cholestasis(ARC)syndrome.(See"Causesofcholestasisinneonatesandyounginfants".)
Totalproteinandalbumin.
CMPincludeselectrolytes,bicarbonate,andglucose,asaninitialscreenformetabolicdisease.
Completebloodcountwithdifferential.
Prothrombintime(PT)/Internationalnormalizedratio(INR)andpartialthromboplastintime(PTT)Tofurther
evaluatehepatocellularfunctionand/orvitaminKdeficiency.
OtherlaboratorytestsAdditionaltestsmaybeappropriatetoevaluateforsystemicillnessorspecificcauses
ofliverdisease.Selectionofthesetestswillvarybasedontheclinicalpresentation(table5).
IMAGINGSTUDIESSeveralimagingstudiescanassistinestablishingthecauseoftheneonatalcholestasis.
Mostpatientsshouldbeevaluatedwithabdominalultrasonography.Hepatobiliaryscintigraphymaybeofusein
somecases.Itisimportanttocompletethesestudiesexpeditiously,asoutcomesafterKasaiportoenterostomy
areimprovedwithearlierintervention.Manypatientswillalsorequireliverbiopsytoestablishthediagnosis.(See
'Additionaltests'belowand"Biliaryatresia",sectionon'Diagnosis'.)
UltrasonographyWesuggestabdominalultrasonographyastheinitialtestbecauseitisnoninvasive,easily
available,andcanidentifystructuralabnormalitiesofthehepatobiliarytractandabdominalorgans[3].Themain
utilityofthistestistoexcludeotheranatomiccausesofcholestasis(ie,choledochalcyst).However,certain
findingsmaysuggestthediagnosisofbiliaryatresia,includingabsent(ornonvisualized)gallbladderandthe
presenceofthetriangularcordsign(triangularorbandlikeperiportalechogenicdensity>3mminthickness)
[9,10].Ultrasoundmayalsoidentifysitusabnormalities,polysplenia,orvascularanomaliesthatcouldbe
associatedwithbiliaryatresia.
ScintigraphyHepatobiliaryscintigraphy(sometimesknownasa"HIDAscan")isanoptionalsecondstep
performedatinstitutionswherethistestisreadilyavailable,providedthatitdoesnotdelaysubsequentdiagnostic
steps.Itprovidesusefulinformationaboutbiliaryobstruction.However,thetestisassociatedwithsubstantial
numbersoffalsepositiveresultsandoccasionalfalsenegativeresults(ie,excretionoftracerintothebowel
despitebiliaryatresia)[3].Asaresult,scintigraphyshouldbeusedonlyforsupportiveinformationandnotto
independentlyconfirmorexcludethediagnosisofbiliaryatresia.
Thetestisperformedbyadministeringatechnetiumlabelediminodiaceticacidanalogintravenouslyand
monitoringuptakebytheliverandsubsequentexcretionintothebiliarytreeandintestine.Infantswithbiliary
atresiausuallyhavenormaluptakeoftheisotopebutabsentexcretionintothebileandintestine,whereasthose
withneonatalhepatitistypicallyhavedelayeduptakebutappropriateexcretion[8].Thus,ifscintigraphy
demonstratespatencyofthebiliarytract,biliaryatresiaisunlikely,exceptinveryyounginfants[3].However,
nonvisualizationofthegallbladderorlackofexcretioncanoccurinpatientswithoutbiliaryatresia[11].Thetest
dependsuponadequatehepatocellularfunction,andpretreatmentforfivedayswithphenobarbital(5mg/kgper
day)increasestheaccuracyofthistestbyenhancingisotopeexcretion[12].However,inmostcaseswedonot
usephenobarbitalbecauseitwilldelaydiagnosisanddoesnotobviatetheneedforliverbiopsy.(See"Biliary
atresia",sectionon'Hepatobiliaryscintigraphy'.)
Thesensitivityofscintigraphyindetectingbiliaryobstructionisapproximately99percent,andthespecificity
rangesfrom69to72percent[13].Thisrangereflectsvariationsinusebydifferentcenters[3].
ADDITIONALTESTS
LiverbiopsyIftheinitiallaboratoryevaluationandimagingdoesnotidentifyaspecificdiagnosis,we
recommendperformingapercutaneousliverbiopsy,particularlywhenthereisaclinicalsuspicionofbiliaryatresia
orothercausesofbiliarytractobstruction[3].Theresultscanhelptosupportthediagnosisofbiliaryatresia
beforemovingontoanopencholangiogram,orhelptodifferentiatethisdisorderfromintrahepaticcausesof
cholestasisthatmightnotrequiresurgicalexploration[3,14].Thebiopsyshouldbeinterpretedbyapathologist
withexpertiseinpediatricliverdisease.Iftheresultsareequivocalandbiopsywasperformedwhentheinfant
was<6weeksofage,repeatbiopsymaybenecessary.(See"Biliaryatresia",sectionon'Liverbiopsy'.)
Cholangiogram
OpencholangiogramIftheabovestepsintheevaluationsupportthediagnosisofbiliaryatresia,theinfant
shouldbetakentotheoperatingroom.Thefirststepisanintraoperativecholangiogram,whichisthegold
standardinthediagnosisofbiliaryatresia.Iftheintraoperativecholangiogramdemonstratesbiliaryobstruction
(ie,ifthecontrastdoesnotfillthebiliarytreeorreachtheintestine),thesurgeonshouldperforma
hepatoportoenterostomy(Kasaiprocedure).(See"Biliaryatresia",sectionon'Cholangiogram'.)
ERCPEndoscopicretrogradecholangiopancreatography(ERCP)isanalternativetechniqueavailableata
fewselecttertiarycarecenters[3].Itinvolvesendoscopicintubationofthebiliaryandpancreaticductsthrough
theampullaofVaterwithasmallcatheterandinjectionofcontrastmaterialtofacilitateradiologicvisualizationof
theductalsystems.(See"ERCPforbiliarydiseaseinchildren".)
ERCPappearstobeasensitiveandspecificmeansofdetectingbiliaryobstruction[3,1520].However,itsutility
inneonatesislimitedbytheavailabilityofappropriatelysizedendoscopes[20],theneedfordeepsedationor
generalanesthesiainmostcases[3],andthelackofvalidation.Inselectcircumstances,ERCPcanclarifythe
etiologyofneonatalcholestasisandobviatetheneedforlaparotomy.
SUMMARYANDRECOMMENDATIONS
Anyinfantwhoisnotedtobejaundicedattwoweeksofageshouldbeevaluatedforcholestasisby
measuringtotalserumbilirubinandconjugated(direct)bilirubin.Thelaboratoryevaluationofbreastfed
infantswhohaveanormalphysicalexamination,normallycoloredstoolsandurine,andcanbeclosely
monitoredmaybedelayeduntiltheyarethreeweeksofage.(See'Overview'above.)
Conjugatedhyperbilirubinemiaisdefinedasconjugatedbilirubinconcentrationgreaterthan1.0mg/dL(17.1
micromol/L)ifthetotalbilirubinis<5.0mg/dL(85.5micromol/L),ormorethan20percentofthetotalbilirubin
ifthetotalbilirubinis>5.0mg/dL(85.5micromol/L).(See'Definitions'above.)
Causesofcholestasisinneonatesandyounginfantsincludeseveraltypesofbiliaryobstruction,hepaticor
systemicinfection,metabolicdiseases,andtoxicoralloimmuneinsults(table1).Biliaryatresiaandneonatal
hepatitisaccountformostcasesofcholestasisinterminfants.Inprematureinfants,cholestasismore
frequentlyresultsfromtotalparenteralnutrition(TPN)orsepsis.(See'Stagesofevaluation'aboveand
"Causesofcholestasisinneonatesandyounginfants".)
Theevaluationofcholestaticjaundiceininfantsaftertwoweeksofageshouldbeundertakeninastaged
approach,guidedbyafocusedhistory(table3),physicalexamination(table4),andlaboratoryevaluation
(table5).(See'Stagesofevaluation'above.)
Theinitialstepisrapiddiagnosisandearlyinitiationoftherapyoftreatabledisorders(eg,sepsis,
hypothyroidism,inbornerrorsofmetabolism).(See'Laboratorystudies'above.)
Thenextstepistodistinguishbiliaryatresiafromothercausesofneonatalcholestasisbecauseearly
surgicalinterventionforbiliaryatresiabefore60daysofageresultsinimprovedoutcome.Keystepsare
ultrasonographyandliverbiopsy.(See'Imagingstudies'aboveand'Liverbiopsy'above.)
Additionaltestingisdirectedatthediagnosisofspecificconditionsandevaluationofassociated
complications(eg,coagulopathy).
Ifjaundicefailstoresolveinaninfantinwhomatreatableconditionisdiagnosed(eg,urinarytractinfection
orgalactosemia)andtreated,furtherevaluationshouldbeperformed.
Intheevaluationofaninfantwithcholestasisofunknownetiology,ultrasonographyoftheliverisalmost
alwaysincludedandliverbiopsyisoftenindicated.(See'Ultrasonography'aboveand'Liverbiopsy'above.)
Hepatobiliaryscintigraphyprovidessupportiveinformationaboutbiliaryobstructionandcanbeperformedif
thetestisreadilyavailableanddoesnotdelaysubsequentdiagnosticsteps.However,thetestisassociated
withsubstantialnumbersofbothfalsepositiveandfalsenegativeresults,soitshouldnotbeusedsolelyto
eitherconfirmorexcludethediagnosisofbiliaryatresia.(See'Scintigraphy'above.)
Endoscopicretrogradecholangiopancreatography(ERCP)isnotroutinelyrecommended.However,if
expertiseinneonatalERCPisavailable,thisprocedurecanbeusedtodetectextrahepaticobstruction,
includingbiliaryatresiaorcholelithiasis.(See'ERCP'above.)
ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgeRobertJShulman,MD,and
StephanieHAbrams,MD,MS,whocontributedtoanearlierversionofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic5941Version27.0
GRAPHICS
Causesofneonatalcholestasis
Extrahepaticobstruction
Extrahepaticbiliaryatresia
Choledochalcyst
Inspissatedbile/mucousplug
Cholelithiasisorbiliarysludge
Tumors/masses(intrinsicandextrinsic)
Neonatalsclerosingcholangitis
Spontaneousperforationofthebileducts
Infection
Viral
Adenovirus,cytomegalovirus(CMV),echovirus,enterovirus,herpessimplexvirus(HSV),humanimmunodeficiency
virus(HIV),parvovirusB19,rubella
Bacterial
Urinarytractinfection,sepsis,syphilis
Protozoal
Toxoplasma
Metabolic/geneticdiseases
Disordersofcarbohydratemetabolism
Galactosemia
Fructosemia
TypeIVglycogenosis
Disordersofaminoacidmetabolism
Tyrosinemia
Disordersoflipidmetabolism
Wolman,NiemannPickC,Gaucher
Disordersofbileacidsynthesis
3betahydroxydelta5C27steroidoxidoreductasedeficiency(BASDtype1)
Delta[4]3oxosteroid5betareductasedeficiency(BASDtype2)
Oxysterol7alphahydroxylasedeficiency(BASDtype3)
AlphamethylacylCoAracemasedeficiency(BASDtype4)
Zellwegersyndrome
SmithLemliOpitzsyndrome
Inheritedcholestaticdisorders
Alagillesyndrome*
ARCsyndrome(arthrogryposisrenaldysfunctioncholestasis)
Cysticfibrosis
NISCHsyndrome(neonatalichthyosissclerosingcholangitis)
Progressivefamilialintrahepaticcholestasis(PFIC),includingBylerdisease
Mitochondrialdisorders
Othermetabolicdefects
Alpha1antitrypsindeficiency
Citrindeficiency
Congenitaldisordersofglycosylation
Endocrine
Hypopituitarism(septoopticdysplasia)
Hypothyroidism
Toxic
Drugs
Parenteralnutrition
Alloimmune
Gestationalalloimmuneliverdisease(Neonatalhemochromatosis)
Miscellaneous
"Idiopathic"neonatalhepatitis
Nonsyndromicpaucityoftheinterlobularbileducts
Shock/hypoperfusion
Intestinalobstruction
*Alagillesyndromeisalsoknownassyndromicpaucityoftheinterlobularbileducts,orarteriohepaticdysplasia.
Graphic64995Version8.0
Mostcommoncausesofneonatalcholestasis
Proportionofyounginfantswith
Diagnosis
conjugatedhyperbilirubinemia
Extrahepaticbiliaryatresia 25percent(range2to55percent)
Idiopathicneonatalhepatitis 25percent(range4to45percent)
Infectioushepatitis(eg,CMV) 11percent(range3to38percent)
Parenteralnutritionassociated 6percent(range7to30percent)
Metabolicdisease(eg,galactosemia) 4percent
Alpha1antitrypsindeficiency 4percent
Alagillesyndrome 1percent
Progressivefamilialintrahepaticcholestasis 1percent
Thepercentagesshownherearebaseduponasystematicreviewof17studiesencompassing1692infants. Mostbut
notallofthestudieswerefromresourcerichcountries.Theproportionofinfantsineachcategoryvariedsubstantially
acrossthestudies,likelyduetodifferencesininfectiousdiseasesinthepopulationaswellasthemethodsusesto
makethediagnoses.
CMV:cytomegalovirus.
Datafrom:GottesmanLE,DelVecchioMT,AronoffSC.Etiologiesofconjugatedhyperbilirubinemiaininfancy:Asystematic
reviewof1692subjects.BMCPediatrics201515:192.
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Importantelementsoftheclinicalhistoryforevaluatinganeonateoryounginfant
withcholestaticliverdisease
Finding Implications
Birthhistory
Prenatalultrasonography Evaluateforcholedochalcystorbowelanomalies.
andresults
Birthweightand Infantswithbiliaryatresiatypicallyhavenormalprenatalhistoryandnormalbirth
gestationalage weight.Manygeneticandmetaboliccausesofneonatalliverdiseaseareassociatedwith
poorfetalgrowth.
Newbornscreenresults Disordersonthenewbornscreenthatcanpresentwithcholestasisincludecystic
fibrosisgalactosemiatyrosinemiaorotherdisordersofaminoacidmetabolismand
disordersoffattyacidoxidationororganicacidmetabolism.*
Isoimmunehemolysis IninfantswithsevereABOincompatibility,conjugatedhyperbilirubinemiaoccasionally
persistsuntiltwoweeksofage.
Maternalinfections AmongtheTORCHinfections,herpessimplexvirusinfectionandsyphilisareparticularly
(TORCH) likelytobeassociatedwithliverinjuryintheneonate.
Complicationsof Intrahepaticcholestasisofpregnancyinthemother(whichmaymanifestaspruritus
pregnancy withoutjaundice)suggeststhepossibilityofPFICintheinfant.
Acutefattyliverofpregnancyinthemothersuggeststhepossibilityofafattyacid
oxidationdefectintheinfant.
Familyhistory
Consanguinity Increasestheriskofanautosomalrecessivedisorder.
Historyofsimilar Suggestsaheritabledisorder,particularlythosewithdominantorcodominant
problemsinthefamily inheritance.
Stoolcharacteristics
Stoolcolor Persistentacholic(claycolored)stoolsareasignofcholestasis,whichcouldbethe
resultofbiliaryobstruction(eg,biliaryatresia)orothercauses.
Stoolingpattern Delayedstoolingmayoccurincysticfibrosisorhypothyroidismdiarrheamayoccurin
infection,metabolicdisease,orPFIC.
Dietandgastrointestinalsymptoms
Dietaryhistory Galactosemiaisonlyexpressediftheinfantistakingbreastmilkoracow'smilkbased
formula(containslactose,whichishydrolyzedtogalactose).
Weightgain Severecholestasis,geneticdisease,ormetabolicdiseasemaycausefailuretothrive.
Vomiting Mayoccurinmetabolicdisease,bowelobstruction,andpyloricstenosis.
Othersymptoms
Urinecolor Darkurinesuggestsconjugatedhyperbilirubinemia.
Excessivebleeding(eg, Mayindicatecoagulopathy(eg,duetovitaminKdeficiencyorpoorhepatocellular
aftercircumcision) function).
Infant'sbehavior Irritabilitymayindicatemetabolicdiseaseorsepsislethargymayindicatemetabolic
disease,sepsis,hypothyroidism,orpanhypopituitarism.
Neonatalinfection Infections,particularlyurinarytractinfections,maybeassociatedwithtransient
cholestasis.
PFIC:progressivefamilialintrahepaticcholestasisTORCH:toxoplasmosis,other(syphilis),rubella,cytomegalovirus,herpes
simplexvirus.
*AllUSstatesroutinelyperformnewbornscreeningforcysticfibrosis,galactosemia,andseveralfattyacidandorganicacid
disorders.Moststatesalsoincludescreeningfortyrosinemia.DetailsareavailableattheNationalNewbornScreeningand
GlobalResourceCenter(http://genesrus.uthscsa.edu/).
Isoimmunehemolysiscausesahyperbilirubinemiathatispredominantlyunconjugated,butmayhaveasignificant
conjugatedcomponent,duetoimmaturityoftheliverandenterohepaticcirculation.
Disorderswithanautosomalrecessivepatternofinheritanceincludecysticfibrosis,alpha1antitrypsindeficiency,
galactosemia,tyrosinemia,andprogressivefamilialintrahepaticcholestasis(PFIC).
DisorderswithdominantorcodominantinheritanceincludeAlagillesyndrome.
Stoolcolorcardsprovideexamplesofnormalandabnormalinfantstoolcolors.Anexampleisavailableat:
http://www.perinatalservicesbc.ca/Documents/Screening/BiliaryAtresia/StoolColourCard_English.pdf.
Importantelementsofthephysicalexaminationforevaluatinganeonateoryoung
infantwithcholestaticliverdisease
Vitalsigns Infantswithbiliaryatresiatypicallyhavenormalvitalsigns.Abnormalvitalsigns
aremorelikelyininfantswithanunderlyinginfectiousormetabolicdisease.
Generalhealthandvigor Infantswithbiliaryatresiatypicallyappearwellillappearancemayindicate
infectionormetabolicdisease.
Growthparameters Infantswithbiliaryatresiatypicallyhavenormalgrowthinitially,butpoorweight
gainafterbecomingcholestatic.
Faciesandappearance InfantswithAlagillesyndromemayhaveacharacteristicfacialappearancewitha
broadnasalbridge,triangularfacies,anddeepseteyes.Thisandotherfacial
malformationsordysmorphismshouldpromptfurtherevaluationforgenetic
disorders,suchascleftliporpalate(Hardikarsyndrome),orothersyndromic
features.
Ophthalmologicexamination Cataractssuggestcongenitalinfectionorgalactosemiamacularcherryredspot
suggestsNiemannPickposteriorembryotoxonsuggestsAlagillesyndromeoptic
nervehypoplasiasuggestsseptoopticdysplasia.
Cardiacexamination CongenitalheartdiseasemaybepresentinpatientswithbiliaryatresiaorAlagille
syndrome.
Abdominalexamination
Ascites Suggestsportalhypertension.*
Abdominalwallveins Prominentabdominalwallveinssuggestportalhypertension.*
Liversize Hepatomegalysuggestsastoragedisorder.Hepatomegalymayalsobepresentin
biliaryatresiaorothercholestaticdisorders.
Liverconsistency Firmlivertexturesuggestsfibrosisandmaybepresentinbiliaryatresia.
Spleen Splenomegalysuggestsportalhypertensionorstoragedisorder.*
Skin Bruisingorpetechiaesuggestcoagulopathyorthrombocytopenia.Jaundice
confirmshyperbilirubinemia(whichmaybeeitherconjugatedorunconjugated).
Urine Darkurinesuggestsconjugatedhyperbilirubinemia.
Stool Acholic(verypale)stoolssuggestabsentbileflow.
*Portalhypertensionisunusualatthetimeofdiagnosisinbiliaryatresia,unlessthepresentationislate.
Stoolcolorcardsprovideexamplesofnormalandabnormalinfantstoolcolors.Anexampleisavailableat:
http://www.perinatalservicesbc.ca/Documents/Screening/BiliaryAtresia/StoolColourCard_English.pdf.
Laboratorytestingforevaluatinganeonateoryounginfantwithsuspected
cholestaticliverdisease
Initialtestsforallinfants
Comprehensivemetabolicpanel
Totalandconjugated Toevaluateforconjugatedhyperbilirubinemia(cholestasis)versusunconjugated
bilirubin hyperbilirubinemia.
ALTandAST Toassessforhepatocyteinjury.
Alkalinephosphataseand Toassessforbiliaryinjury.Furthermore,severalgenetic/metabolicdisorderscan
GGTP bedividedintohighandlowGGTPcategories.*
Totalproteinandalbumin Toassesshepatocytefunction.Lowalbuminsuggestspoornutrition,renallosses
orpoorhepaticsyntheticfunction.
Electrolytes,bicarbonate, Toassessformetabolicdisease.Abnormalitiesintheseresultsareoftenseenin
glucose infantswithmetabolicdisease.
CBCwithdifferential Toassessforinfectionand/orsplenicsequestration.ElevatedWBCissuggestive
ofinfection.LowWBCandplateletcountcouldindicateportalhypertension(with
splenicsequestration).
PT/INRandPTT Toassesshepatocytefunctionand/orvitaminKdeficiency.Abnormalresults
indicateimpairedliversyntheticfunctionand/orvitaminKdeficiency.
Additionalteststoevaluateforsystemicillnessofspecificliverdiseases
Urinalysisandurineculture Appropriateformostinfantswithcholestasis,toexcludeurinarytractinfection
andtoevaluatepossiblerenalinvolvement.
Bloodculture Ifclinicalpresentationsuggestssepsis.
Urinereducingsubstances Screenforgalactosemia(ininfantsingestinglactose).
Serumbileacids Elevationsarediagnosticofcholestasis.
Alpha1antitrypsin LowlevelssuggestAATdeficiency.NormallevelsdonotexcludeAATdeficiency
concentration becausethisisanacutephasereactant.
Andproteaseinhibitor TheprimaryallelesassociatedwithliverdiseasearePI*ZZhomozygosityorPI*SZ
phenotype(PItype) heterozygosity.
TSH,T4 Screenforcongenitalhypothyroidism(primaryorcentral).
Urinebileacidanalysisby Usedtodiagnosebileacidsyntheticdisorders(BASD),whichmaypresentwith
FABMS lowGGTcholestasis.
Metabolictesting Ifametabolicdisorderissuspected,initialscreeningincludesplasmaaminoacids,
urineorganicacids,acylcarnitineprofile,ammonia,lactate/pyruvateratio.
Genetictesting Genetictestingisrapidlyevolvingwiththeavailabilityofnewtechnologies.
ALT:alanineaminotransferaseAST:aspartateaminotransferaseGGTP:gammaglutamyltranspeptidaseCBC:complete
bloodcountWBC:whitebloodcellcountPT:prothrombintimeINR:internationalnormalizedratioPTT:partial
thromboplastintimeAAT:alpha1antitrypsinTSH:thyroidstimulatinghormone(thyrotropin)T4:thyroxineFABMS:fast
atombombardmentmassspectrometryGGT:gammaglutamyltransferase.
*GGTPisdisproportionatelyelevated(comparedwithASTandALT)inthemostcommontypesofneonatalcholestasis,
includingbiliaryatresiaandAlagillesyndrome,whileanormalorlowGGTPisseeninmostformsofprogressivefamilial
intrahepaticcholestasis(PFIC),BASD,andarthrogryposisrenaldysfunctioncholestasis(ARC)syndrome.
Thesetestsareselectedbasedupontheclinicalpresentationandresultsofinitialtests.
Urinereducingsubstancesisonlyvalidasascreenforgalactosemiaiftheinfantisfedbreastmilkoracow'smilkbased
formula(whichcontainslactose,thenhydrolyzedtogalactose).
Infantsmustbeoffofursodeoxycholicacidforatleastfivedayspriortourinecollectionforbileacidanalysis,becausethe
FABMSsignatureofthedrugoverlapswithsomeoftheabnormalbileacidmetabolitesseeninBASD.
Individualgenesequencingcanbedoneiftheclinicalpresentationsuggestsaspecificdiagnosis,suchasAlagille
syndrome.Forscreeningofmultiplegenesassociatedwithinheritedcholestasis,nextgenerationsequencingpanelsare
available.Eachpanelinterrogatesabout20to50genes.Uptodateinformationisavailableathttp://www.GeneTests.org.
ContributorDisclosures
KathleenMLoomes,MD Nothingtodisclose JessiErlichman,MPH Nothingtodisclose StevenAAbrams,
MD Consultant/AdvisoryBoards:MilkPep[Childhoodnutrition(Diary)]NestleNutrition[Infantnutrition(Preterm
infantformulas)]. ElizabethBRand,MD Nothingtodisclose AlisonGHoppin,MD Nothingtodisclose
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconformto
UpToDatestandardsofevidence.
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