1. CHAPTER 64. Hyperbilirubinemia
INTRODUCTION
Hyperbilirubinemiaisacommontransitional findingoccurringin60-70% of term newbornsand
almostall premature infants.Anelevationof serumbilirubinconcentration>2 mg/dLisfoundin
virtuallyall newbornsinthe firstseveral daysof life.Jaundice becomesclinicallyapparentat
serumbilirubinconcentrationof >5mg/dL.
Bilirubinisthe endproductof the catabolismof heme andisproducedprimarilybythe breakdown
of redbloodcell hemoglobin.Othersourcesof heme include heme-containingproteinssuchas
myoglobin,cytochromes,andnitricoxidesynthase.Bilirubinexistsinseveral formsinthe blood
but ispredominantlyboundtoserumalbumin.Free unconjugatedbilirubin,andpossiblyother
forms,can enterthe central nervoussystem(CNS) andbecome toxictocellsif concentrationis
great enough.The precise mechanismisunknown.
Inside livercells,unconjugatedbilirubinisboundtoligandin,Zprotein,andotherbindingproteins;
it isconjugatedbyuridine diphosphoglucuronyltransferase (UDPGT).Conjugatedbilirubinis
water- soluble andcanbe excretedinthe urine,butmostof it israpidlyexcretedasbile intothe
intestine.Conjugatedbilirubinis furthermetabolizedbybacteriainthe intestine andexcretedin
the feces.
Hyperbilirubinemiapresentsinthe neonate aseitherunconjugatedhyperbilirubinemiaor
conjugatedhyperbilirubinemia.The twoformsinvolvedifferentpathophysiologiccauseswith
distinctpotential complications.
UNCONJUGATED(INDIRECT) HYPERBILIRUBINEMIA
I. Definition.Whenthe rate of bilirubinproductionexceedsthe rate of bilirubinelimination,the
endresultisan increase inthe total serumbilirubin(TSB) concentration,resultinginthe clinical
conditionof hyperbilirubinemia,oftencalledjaundice.
II.Classificationandpathophysiology.The causesof unconjugatedhyperbilirubinemiaare listedin
Table 64-1.
A. Physiologicjaundice.Inalmosteverynewborninfant,particularlyprematureinfants,a
physiologicelevationof serumunconjugatedbilirubindevelopsduringthe firstweekof life,
usuallyinthe secondorthird day,and resolvesspontaneously.Jaundice thatdevelopsinthe first
24 h of life istobe consideredpathologicuntil provenotherwise.
1. Exclusioncriteria
a. Unconjugatedbilirubinlevel >12.9 mg/dLin the terminfant.
b. Unconjugatedbilirubinlevel >15mg/dL inthe preterminfant.(Thresholdlevel may vary
dependingonthe gestational age andbirthweightof infant)
c. Bilirubinlevelincreasingata rate >5 mg/dL/day.
2. d. Jaundice inthe first24 h of life.
e.Conjugatedbilirubinlevel >2mg/dL.
f.Clinical jaundice persisting>1weekinfull-terminfantsor>2 weeksinpreterminfants.
2. Physiology
a. Full-terminfant.Serumunconjugatedbilirubinprogressivelyrisestoameanpeakof 5-6
mg/dLby the third dayof life in bothwhite andblackinfantsanda peakof 10 mg/dLat 3-4 days in
Asianbabies.Figure 64-1showshour-specificnomogramwithpredictive valueforsubsequent
hyperbilirubinemia.
b. Pretermneonates.Liverfunctionislessmature,andjaundice ismore frequentand
pronounced.A peakconcentrationof 10-12 mg/dLisreachedby the fifthdayof life.
3. Mechanisms.A numberof mechanismshave beensuggested.
a. Increasedbilirubinloadbecauseof the largerredbloodcell volume,the shorterlifespan
of redbloodcells,andincreasedenterohepaticrecirculationof bilirubininnewborninfants.
b. Defectiveuptake bythe liverasaresultof decreasedconcentrationof bilirubinbinding
proteins,suchasligandin.
c. Defective conjugationbecause of reducedglucuronyl transferase activityinthe term
newborn;evenmore pronouncedinpremature infants.
d. Impairedexcretionintobile.
e.Overall impairment/immaturityof liverfunction.
B. Hemolyticanemia
1. Redbloodcell defects.Hemolyticanemiamayresultfromacongenital redbloodcell defect
such as hereditaryspherocytosis,infantilepyknocytosis,pyruvate kinase deficiency,glucose-6-
phosphate dehydrogenase (G6PD) deficiency,thalassemia,orvitaminK-inducedhemolysis.
2. Acquiredhemolyticanemiamaybe seeninbloodgroupincompatibilities,suchasABO or
Rh incompatibilitybetweeninfantandmother.Itmayalsobe associatedwiththe use of certain
drugs(eg,sulfonamides) orwithinfection.
C. Polycythemia.The livermaynothave the capacityto metabolize the increasedbilirubinload
presentedbythe increasedbloodvolume.
D. Bloodextravasation.Sequestrationof bloodwithinbodycavitiescanresultinincreased
bilirubinandthusoverloadthe bilirubindegradationpathway.Itmaybe seenwith
cephalhematoma,intracranial andpulmonaryhemorrhage,subcapsularhematomaof the liver,
excessiveecchymosesorpetechiae,occultgastrointestinal hemorrhage,andlarge hemangiomas
(ie,Kasabach-Merrittsyndrome).
TABLE 64-1. CAUSES OF UNCONJUGATEDHYPERBILIRUBINEMIA
3. Physiologicjaundice Hemolyticanemia Congenital:redbloodcell defects(hereditary
spherocytosis,infantilepyknocytosis,pyruvatekinasedeficiency,G6PDdeficiency,and
thalassemia) Acquired:bloodgroupincompatibilities(ABOorRhincompatibility),infection,and
drug-inducedhemolysisPolycythemiaBloodextravasationDefectsof conjugation Congenital:
Crigler-Najjarsyndrome(typesIandII),Gilbertsyndrome Acquired:Lucey-Driscollsyndrome
Breast-feedingandbreastmilkjaundice Metabolicdisorders:galactosemia,hypothyroidism
Increasedenterohepaticcirculatonof bilirubinSubstances/disordersaffectingbindingof bilirubin
to albumin:drugs,fattyacidsinnutritional products,asphyxia,acidosis,sepsis,hypothermia,
hyperosmolality,hypoglycemia
G6PD, glucose-6-phosphate dehydrogenase.
FIGURE 64-1. Hour-specificbilirubinnomogramwiththe predictive abilityof the predischarge
bilirubinvalue forsubsequentseverehyperbilirubinemia,>95thpercentiletract.Reproducedwith
permissionfromBhutani VK,JohnsonLH.Jaundice technologies;predictionof hyperbilirubinemia
interm and neartermnewborns.JPerinatol 2001;21:576
E. Defectsof conjugation
1. Congenital deficiencyof glucuronyl transferase
a. Crigler-Najjarsyndrometype I.A severe formof uridine diphosphate (UPD) glucuronyl
transferase deficiencythatisinheritedasan autosomal recessive disorder.Itisunresponsiveto
phenobarbital therapyandhasa poor prognosis.
b. Crigler-Najjarsyndrome type II.Moderate deficiencyof UDP-glucuronyl transferase.Itis
responsive tophenobarbitaltherapy.
c. Gilbertsyndrome isamildformof UDP-glucuronyl transferase deficiencyandisinherited
as an autosomal dominantcondition,isbenign,andisrelativelycommon.Itisresponsive to
phenobarbital,althoughnospecifictherapyisnecessary.
2. Glucuronyl transferase inhibition
a. Drugs suchas novobiocin.
b. Lucey-Driscollsyndrome.Anunspecifiedmaternal gestationalhormone,foundinthe
infant'sseruminterfereswiththe conjugationof bilirubin.Thisproblemappearstoresolve
spontaneously;however,inextremecases,exchange transfusionsmaybe requiredtoavoid
kernicterus.
F. Breastmilkjaundice (late onset)isaresultof the prolongationof increasedenterohepatic
recirculationof bilirubinbecause of afactor inhumanmilkthat promotesintestinal absorption.It
ischaracterizedbya higherpeak(10- 30 mg/dL,peakingbydays 10-15 of life) andaslowerdecline
inthe serumbilirubinconcentrationthatcanlast forseveral weeks.Itrarelyappearsbeforethe
endof the firstweekof life fortermorpreterminfants.Interruptionof breast-feedingfor24-48 h
at unacceptable bilirubinlevelsresultsinarapiddecline.Resumptionof breast-feedingincreases
bilirubinlevelsslightlybutusuallybelow previouslevels.Breastmilkjaundice mayrecurin70% of
future pregnancies.
4. G. Metabolicdisorders.Galactosemia,hypothyroidism, andmaternal diabetesmaybe
associatedwithunconjugatedhyperbilirubinemia.
H. Increasedenterohepaticrecirculationof unconjugatedbilirubinasa resultof pathologic
conditionssuchascystic fibrosis,gastrointestinal obstruction(ie,pyloricstenosis,duodenal
atresia,annularpancreas),andileusmayresultinexaggeratedjaundice.Bloodswallowedduring
deliveryanddecreasedcaloricintake mayalsobe contributingfactors.
I. Substancesanddisordersaffectingbindingof bilirubintoalbumin.Certaindrugsoccupy
bilirubin-bindingsitesonalbuminandincrease the amountof free unconjugatedbilirubinthatcan
cross the blood-brainbarrier.Drugsinwhichthiseffectmaybe significantinclude aspirinand
sulfonamides.Chloral hydrate isshowntocompete forhepaticglucuronidationwithbilirubinand
thusincrease serumunconjugatedbilirubin.Commondrugsusedinthe neonatessuchaspenicillin
and gentamicinhave alsobeenshowntocompete withbilirubinforalbuminbindingsites.Fatty
acids
innutritional products(eg,Intralipid) mayalsoinfluence bilirubinbindingtoalbumin,asmay
asphyxia,acidosis,sepsis,hypothermia,hyperosmolality,andhypoglycemia.
III.Morbidity
A. General.Unconjugatedbilirubininhighconcentrationcancrossthe blood-brainbarrier,
penetratingthe braincells.Thishasbeenassociatedwithneuronal dysfunctionanddeath.
Bilirubinistoxictothe braininseveral ways.It has beenshowntodepressO2consumptionandat
highconcentrationuncouplesoxidativephosphorylation.Severe hyperbilirubinemiacancause
long-termneurologicsequelae;however,the safetyof moderatedegreeof hyperbilirubinemiahas
beendebated.One studyhasshownthatmoderate hyperbilirubinemia(13.6-26.0 mg/dL) maybe
associatedwithanincrease inminorneurologicdysfunction.
B. Encephalopathy
1. Transient.Earlybilirubin-inducedneurologicdysfunctionistransientandreversible.
Auditorybrainstemevokedresponses(ABRs)show significantprolongationof latencyof specific
wavelengths.These changesmaybe reversedwitheitherexchange transfusionsorwith
spontaneousdecreaseinbilirubinlevels.More recentdatasuggestthat withmarked
hyperbilirubinemia,complete recoveryof the ABRmaybe delayed.The auditorysystemservesas
an objective windowinlookingatthe CNSincases of severe hyperbilirubinemia,whichcanbe
usedas an earlypredictorof bilirubinencephalopathy.
2. Bilirubinencephalopathy.Thisisapreventable lifelongneurologicsequelaeof untreated
hyperbilirubinemia.Itisa clinicallyworseningencephalopathy(over24 h) causedby bilirubin
toxicitytothe basal gangliaand variousbrainstemnuclei.
a. Acute phase.A severelyjaundicedinfantdevelopslethargy,hypotonia,andpoorsucking
response.If leftuntreated,the infantbecomeshypertonicandmaydevelopfeverandahigh-
pitchedcry.Decerebrate posturingcanoccur at the endstage of the disease.
b. Chronicphase.Survivorsusuallydevelopchoreoathetoidcerebralpalsy,hearingloss,
dental dysplasiaandparalysisof upwardgaze,and,lessoften,mental retardation.
5. C. Kernicterus.A postmortemdiagnosisof pathologicfindingsof bilirubintoxicityinthe brain.
1. Stainingandnecrosesof neuronsinthe basal ganglia,hippocampal cortex,subthalamic
nuclei,andcerebellum.Cerebral cortex isusuallyspared.
2. Bilirubintoxicitytothe brainmaybe reversible if bilirubinlevelsfall before saturationof the
CNSnuclei occurs.
3. Controversyexistsoverbilirubinlevelsconsideredatriskforkernicterus.Innonhemolytic
states,andotherwise healthyterminfants,levelsof >25 mg/dLare consideredtoplace the patient
at risk.
4. Kernicterusregistry.Kernicterusisnotareportable conditioninthe UnitedStates;
therefore,itsprevalence isnotknown.A pilotregistryata Pennsylvaniahospital documented90
casesfrom January1984-June 2001.
IV.Clinical presentation
A. History
1. Familyhistory.Familyhistoryof jaundice,anemia,splenectomy,ormetabolicdisordersis
significant.A historyof asiblingwith jaundice maysuggestbloodgroupincompatibility,breast
milkjaundice,orG6PD deficiency.A familial tendencyof neonatalhyperbilirubinemiaispresent
regardlessof breast-feedingandotherriskfactors.
2. Maternal history.Neonatal jaundice isincreasedwithahistoryof maternal diabetesor
infection.Use of oxytocin,sulfonamides,antimalarials,andnitrofurantoinsbythe mothermay
initiate hemolysisinG6PD-deficientinfants.Deliverytrauma,asphyxia,delayedcordclamping,and
prematurityare associatedwithanincreasedriskof hyperbilirubinemiainthe infant.
3. Infant'shistory.
a. Breast-feeding.Poorbreast-feedingmayresultinpoorcaloricintake,leadingto
"starvationjaundice."(See priordiscussionof breastmilkjaundice).
b. Factorsaffectingthe gastrointestinaltract,suchas obstruction,decreasedmotility(ileus),
and delayedpassage of meconium
c. Checkfor clinical symptomssuchasvomitingandlethargy.Metabolicdisorders,infection,
and bowel obstructioncanpresentinthismanner.
B. Signsand symptoms.Clinical jaundice isvisiblewhenthe serumbilirubinlevel approaches5- 7
mg/dL.Jaundice isoftenapparentfirstinthe face,especiallythe nose,andthen descendingtothe
torso andlowerextremitiesasthe degree of jaundice increases.Jaundice canbe demonstratedin
some infantsbypressinglightlyonthe skinwithafinger.The yellow colorisseenmore easilyin
the "fingerprint"areathaninthe surroundingskin.These signsshouldnotappearwithinthe first
24 h afterbirth inotherwise healthyinfants.
Besidesconfirmingthe presence of jaundice,physicalexaminationmayalsobe helpfulin
determiningthe cause of hyperbilirubinemia.Areasof bleedingsuchascephalhematoma,
6. petechiae,orecchymosesindicate bloodextravasation.Hepatosplenomegalymaysignify
hemolyticdisease,liverdisease,orinfection.Physical signsof prematurity,intrauterinegrowth
retardation,andpostmaturitymaybe helpful inelucidatingacause forhyperbilirubinemia.
Plethoraisseenwithpolycythemia,pallorwithhemolyticdisease,andlarge infantswithmaternal
diabetes,all of whichare associatedwithhyperbilirubinemia.Omphalitis,chorioretinitis,
microcephaly,andpetechial andpurpuriclesionssuggestinfectiouscausesof increasedserum
bilirubin.
C. Neurologicexamination.The appearance of abnormal neurologicsignsheraldsthe onsetof
earlybilirubinencephalopathy.Initialsignsinclude lethargy, poorfeeding,vomiting,and
hypotonia.The persistentlyhyperbilirubinemicinfantmaygoon to experience seizures(see
sectionIII,Babove).The progressionof neurologicchangesparallelsthe stagesof bilirubin
encephalopathyfromacute tochronic andirreversible changes.
V. Diagnosis
A. Laboratorystudies.Hyperbilirubinemiashouldbe investigatedwheneverpathologiccauses
are suspected.The presence of aserumbilirubinlevel of ≥13 mg/dL inany infantrequiresinitial
evaluation.
1. Total anddirectbilirubin
a. Directbilirubin=conjugatedfraction.
b. Indirectbilirubin=unconjugatedfraction.Derivedbysubtractingdirectfractionfrom
TSB.
2. Complete bloodcellcountandreticulocyte count.A low hemoglobinorhematocrit
associatedwithahighreticulocyte countandthe presence of nucleatedredbloodcellsishighly
suggestive of hemolyticanemia.Polycythemiaisdefinedasavenousbloodhematocrit>65%.(Use
of capillarybloodsamplesmaycause underestimationof venousbilirubinvalueswhenthe
bilirubinvalue is>10 mg/dL).Total white bloodcell countwithdifferential andplateletcountmay
helpdetectsepsis.The peripheral bloodsmearaidsinthe diagnosisof hereditaryspherocytosis
and otherredbloodcell defects.
3. Bloodtype and Rhstatus inmotherand infant.ABOandRh incompatibilitycanbe easily
diagnosedbycomparinginfantandmaternal bloodtypes.
4. DirectCoombs'test.The testisusuallypositiveininfant'swithisoimmunizationdisorders.
Thistestdoesnot correlate withthe severityof jaundice.
5. Measurementof serumalbuminmayhelptoassesstotal bilirubinbindingsitesavailable
and whetherthere isaneedforan albumininfusion.
6. Otherlaboratorytests.The urine shouldbe testedforreducingsubstances(torule out
galactosemiaif the infantisreceivingagalactose-containingformula) andforinfectiousagents.If
hemolysisispresent,inthe absence of ABOorRh incompatibility,furthertestingbyhemoglobin
electrophoresis,G6PDscreening,orosmoticfragilitytestingmaybe requiredtodiagnosered
bloodcell defects.Persistentjaundice (>2weeksof life) mayrequirethese typesof investigation
7. as well asadditional testsforthyroidandliverfunction,bloodandurine cultures,andmetabolic
screeningworkup,suchasplasmaaminoacidand urine organicacid measurements.
B. Radiologicstudiesforsuspectedintestinal obstructionorbloodextravasationintointernal
organs andultrasonographyof the headto documentintracranial orsubdural hemorrhage might
be indicated.
C. Transcutaneousbilirubinometry(TcB).Measuresthe degree of yellowcolorinthe skinand
subcutaneoustissuesbyselectivewavelengthreflection.Datasuggestthatthismethodologyisan
effectiveadjuncttonursingassessmentinthe terminfant.A TcB value of >13 mg/dL shouldbe
correlatedwithTSB.
D. Expiredcarbonmonoxide breathanalyzer.End-tidal carbonmonoxide (CO) correctedfor
ambientCO(ETCO2).An equimolaramountof COisproducedforeverymoleculeof bilirubin
formedfromthe degradationof heme;therefore,measurementof COinend-tidal breathisan
index of total bilirubinproduction.The methodcanalert the attendingphysiciantothe presence
of hemolysisirrespective of the timingof jaundice.
VI.Management.Three methodsof treatmentare commonlyusedtodecrease the levelof
unconjugatedbilirubin:exchange transfusion,phototherapy,andpharmacologictherapy.As
noted,however,controversypersistsastowhatlevelsof serumbilirubinwarranttherapy,
especiallyinotherwise healthyfull-terminfants.
A. Phototherapy(seealsoChapter39)
1. Indication.Mostinfantswithpathologicjaundice are treatedwithphototherapywhenitis
believedthatbilirubinlevelscouldenterthe toxicrange.
a. Practice parameters.The AmericanAcademyof Pediatrics(AAP) iscurrentlyrevisingthe
guidelinesformanagementof hyperbilirubinemia.The concernforkernicterusisbeing
reemphasizedbythe Subcommittee onHyperbilirubinemiapendingthe full assessmentand
analysisof the newapproachestothe jaundicedinfant.Itisimportant torememberthatthe
currentAAPguidelinesare meantforhealthytermnewborninfantswithnoevidence of
hemolysis.Althoughthere iscontinuinguncertaintyaboutwhichTSBlevel warrantsexchange
transfusions,the authorssuggestthatinanotherwise healthytermnewbornaTSBlevel of 20
mg/dLat 48 h of life maybe treatedinitiallywithphototherapy.If the TSBdecreasesby1-2 mg/dL
within4-6 h of startingphototherapy,exchangetransfusionmaynotbe necessary.
b. Inpretermand sick terminfants,amore conservative approachisusuallyadopted.
2. Usingphototherapyeffectively.
a. Lightsource.The mosteffectivelightsource currentlyavailable forphototherapyisthat
providedbyblue fluorescenttubes.Bilirubinabsorbslightmaximallyinthe blue range (420-500
nm).Blue lampswithnarrowspectral range (420-480 nm) are mosteffective.The blue light
reflectiondoesinterfere withskincolorassessmentandhasbeenreportedtocause dizzinessand
nauseain those caring forthese patients.Additionof adaylightfluorescenttube tempersthese
side effects.Energyoutputorirradiance isasecondvariable thatinfluencesthe efficacyof
8. phototherapy.Radiometermeasurementsshouldbe minimally5uW/cm2/nm, withsaturationfor
bilirubindegradationat~11 uW/cm2/nm.
b. Distance fromthe lighttothe infant.Lightintensityisafunctionof the distance fromthe
lightsource;therefore,lightsource shouldbe asclose tothe infantaspossible (12-16inches).
c. Surface area.The largerthe skinsurface area exposed,the more effectiveisthe
phototherapy.The availabilityof fiberopticpads(bili-blankets) make iteasytoincrease exposed
skinarea to the bili-lights.Inpreterminfants,thistype of "double-phototherapy"(overheadlight
plusbili- blanket) isalmosttwice aseffectiveassingle phototherapy.Fiberopticphototherapy
blankets(bili- blankets) canbe wrappedaroundor placedjustbeneaththe infant.
3. Supportive management.The infant'seyesshouldbe coveredwithopaquepatchesfor
overheadlampphototherapy.However,thisisnotnecessarywhenusingonlyfiberopticlight
source.Animal experimentshave shownretinaldamage occurringasa resultof phototherapy.To
maximize exposure,infantsshouldbe nakedinservocontrolledincubators.Phototherapydoes
increase insensible fluidlosses.Forinfantsweighing<1500 g, increase fluidsby0.5mL/kg/h;for
those weighing>1500 g, increase by1 mL/kg/h.Overhydrationdoesnotincrease bilirubin
elimination.
4. Terminationof phototherapy.Phototherapyisstoppedwhenthe followingcriteriaare met:
a. The bilirubinlevelislowenoughtoeliminatethe riskof kernicterus.
b. The infantisoldenoughtohandle the bilirubinload.
5. Complications.Phototherapyissimple,safe,andinexpensive.Complicationsare veryrare
but shouldnotbe overlooked.
a. The retinal effectsof phototherapyonthe exposedinfant'seyesare unknown.However,
animal studiessuggestthatretinal degenerationmayoccur.Thus,eye shieldsmustbe used.
b. Increasedinsensiblefluidlossincreasesfluidrequirementsby25%.In addition,stools
may be looserandmore frequent.Use of fiberopticphototherapyresultsinlowerinsensibleloss.
c. Bronze babysyndrome.Withconjugatedhyperbilirubinemia,phototherapycauses
photodestructionof copperporphyrins,causingurine andskintobecome bronze.
d. Congenital erythropoieticporphyriaisarare syndrome inwhichphototherapyis
contraindicated.Exposure tovisible lightof moderate tohighintensitywill produce severe bullous
lesionsonexposedskinandmayleadtodeath.
B. Exchange transfusion(see alsoChapter21).Exchange transfusionisusedwhenthe riskof
kernicterusforaparticularinfantissignificant.A double-volume exchange replaces85% of the
circulatingredbloodcellsanddecreasesthe bilirubinleveltoabouthalf of the preexchange value.
Besidesremovingbilirubin,anexchange transfusioncanbe usedtocorrect severe anemia.
1. General guidelines.Itappearsthatnospecificlevelof bilirubincanbe consideredsafe or
dangerousforall infantsbecause patient-to-patientvariationsexistforthe permeabilityof the
blood- brainbarrier.The practice parameterspublishedbythe AAPinOctober1994 recommend
9. exchange transfusionsinhealthytermnewbornsatTSB25-30 mg/dL.The debate forupperlimits
of serumbilirubinisdirectedtofull-terminfantswithnoevidence forassociateddisease.
Lowbirthweightinfantsare excludedfromthese considerations.The authorssuggestthat
each institutionanditspracticingphysiciansmustestablishtheircriteriaforphototherapyand
exchange transfusionbygestationalage,weightgroups,postnatal age,andinfant'scondition
consistentwithcurrentstandardof pediatricpractice.
2. Factors that mayaffectthe decisiontoperformexchange transfusionincludethe infant's
maturity,birthweight,age,rate of rise inbilirubinlevels(>0.5mg/dL/h),andpresence of hypoxia,
acidosis,sepsis,orhypoproteinemia.
3. Albumintransfusionsmaybe usefulif bilirubinlevelsare >20 mg/dLand serumalbumin
levelsare <3 g/dL.Infusionof 1 g of albumin1 h before exchangetransfusionmayimprove the
yieldof bilirubinremoval.Fluidvolume andcardiovascularstatusmustbe carefullyconsidered
before givingalbumin.
C. Pharmacology
1. Phenobarbital therapy
a. Action.Phenobarbital affectsthe metabolismof bilirubinbyincreasingthe concentration
of ligandininlivercells,inducingproductionof glucuronyl transferase,andenhancingbilirubin
excretion.Because ittakes3-7daysto become effective,phenobarbitalisusuallynothelpfulin
treatingunconjugatedhyperbilirubinemiainthe newborninfant.The administrationof
phenobarbital tonewbornsatthe time that jaundice isfirstnotedorevenatbirthis lesseffective
than administrationtomothersduringpregnancyfor≥2 weeksbefore delivery.
b. Indications.Itmaybe useful togive phenobarbital 1-2weeksbefore deliverytoa
pregnantmotherwhose fetushasdocumentedhemolyticdiseasetoaidinreducingbilirubinlevels
inthe affectedneonate.Phenobarbital isalsousedtotreattype IIglucuronyl transferase
deficiencyandGilbertsyndrome inthe infant.
2. Metalloporphyrins.A syntheticheme analog,metalloporphyrinshave beenshownto inhibit
heme oxygenase(HO),the rate-limitingenzyme inthe catabolismof heme.Byactingas a
competitiveinhibitor,the metalloporphyrinsdecrease the productionof bilirubin.Tin-
mesoporphyrin(SnMP)isapotentHO inhibitorthathasbeenextensively studied.Ithasbeen
reportedtobe effective asasingle intramuscularinjection(6mmol/kg) intwopatientswith
hemolyticdisease,resultinginasignificantdropinTSBconcentration,therebyavoidingthe need
for exchange transfusion.Anotherreport hasshownthata single dose of SnMPcan preventthe
developmentof severe hyperbilirubinemiainnewborninfantswithG6PDdeficiency.The only
untowardeffectnotedwasanon-dose-dependent,mild,transienterythemawhenusedin
conjunctionwithphototherapyinapreterminfant.
3. Supportive management.Mostbreast-fedinfantsdonotdevelopbilirubinlevelsof ≥20 mg/
dL in the first8 daysof life.Forinfants6-8 daysold,breast-fedandotherwise well,consider
interruptingbreast-feedingfor48 h and use phototherapyif the bilirubinis>18 mg/dL.
10. CONJUGATED (DIRECT) HYPERBILIRUBINEMIA
I. Definition.Conjugatedhyperbilirubinemiaisasignof hepatobiliarydysfunction.Itusually
appearsinthe newborninfantafterthe firstweekof life,whenthe indirecthyperbilirubinemiaof
physiologicjaundice hasreceded.Whenthe directbilirubin levelis>2.0 mg/dL or is>20% of the
TSB, itis clinicallysignificant.
II. Classification.Conjugatedhyperbilirubinemiaiscausedbyadefector insufficiencyinbile
secretion,biliaryflow,orboth,resultinginaninabilitytoremove conjugatedbilirubinfromthe
body.It isalwayspathologic.The termcholestasisisusedtodescribe the groupof disorders
associatedwithbilirubinexcretionandisassociatedwitharise inserumconjugatedbilirubinlevels
and usuallybile saltsandphospholipids. Causesof conjugatedhyperbilirubinemiaare listedin
Table 64-2.
A. Extrahepaticbiliarydisease
1. Biliaryatresiaisthe single mostcommoncause of neonatal cholestasis,withanestimated
incidence of 1:10,000 live births.Itisthe reasonfor 50-60% of livertransplantationsinchildren
worldwide.Itscause ispoorlyunderstood.Itcanbe associatedwithpolysplenia,cardiovascular
defects,andsitusinversus.
2. Choledochal cystsare dilatationsof extrahepaticbiliarytree. Diagnosisisby
ultrasonographyornuclearmedicinescanning.
3. Otherextrahepaticbiliarydiseasesare bile ductstenosis,spontaneousperforationof bile
duct, cholelithiasis,andneoplasm.These are uncommonconditionsinneonates.Cholelithiasisin
infancyisusuallyrelatedtootherunderlyingconditionssuchashemolysis,anatomic
malformation,use of medications(furosemide),orprolongeduse of parenteral nutrition.
Cholecystectomyisrarelyindicated.
B. Intrahepaticbiliarydisease
1. Intrahepaticbile ductpaucity.Thisconditionmaybe syndromicornonsyndromic.The
syndromicformiscalledAlagille'ssyndrome (arteriohepaticdysplasia).Thisischaracterizedbya
constellationof featuressuchascholestasis,cardiovascularfindings(pulmonaryarterystenosis),
butterflyvertebrae,ocularfindings(posteriorembryotoxon),andcharacteristicfacies.Liverbiopsy
showsa paucityof interlobularbileducts.Transmittedasautosomal dominant,thisdisorderhas
beenassignedtochromosome 20p12, a regionof the chromosome containingthe JAGGED1gene.
2. Progressive intrahepaticcholestasis.These patientshave chronicintrahepaticcholestasis
but withdifferentpathogenesisandprognosis.Clinical featuresinclude chronicpersistent
hepatocellularcholestasis,exclusionof otheridentifiabledisorders,occurrence consistentwith
autosomal recessiveinheritance,andacombinationof clinical,biochemical,andhistologic
features.(See Haber&Lake,1990, fordetailed classificationanddescription.)
3. Inspissatedbile.Infantswithmoderatetosevere hemolyticdisease candevelopbilirubin
overloadandresultingcholestasis.Clinically,hepatosplenomegalyisoftenprominentandliver
enzymesare normal orslightlyelevated.Cholestasismaypersistupto4 weeks;however,if it
persistsbeyond4weeks,itshouldnotbe attributedtobilirubinoverloadalone.
11. C. Hepatocellulardisease
TABLE 64-2. CAUSES OF CONJUGATEDHYPERBILIRUBINEMIA
Extrahepaticbiliarydisease BiliaryatresiaCholedochal cystBile ductstenosisSpontaneous
perforationof the bile ductCholelithiasisNeoplasmsIntrahepaticbiliarydisease Intrahepaticbile
duct paucity(syndromicornonsyndromic) Progressiveintrahepaticcholestasis Inspissatedbile
HepatocellulardiseaseMetabolicandgeneticdefectsα1-antitrypsindeficiency,cysticfibrosis,
Zellweger'ssyndrome,Dubin-JohnsonandRotor'ssyndromes,galactosemiaInfectionsTotal
parenteral nutritionIdiopathicneonatal hepatitisNeonatal hemochromatosisMiscellaneousShock
HypoperfusionState,ECMOINTRAHEPATICCHOLESTASISWITHNORMAL BILE DUCTS Infection
Viral:hepatitisBvirus;non-A,non-Bhepatitisvirus;cytomegalovirus;herpessimplex virus;
coxsackie virus;Epstein-Barrvirus;adenovirusBacterial:Treponemapallidum, Escherichiacoli,
groupB streptococcus,Staphylococcusaureus,Listeria;urinarytractinfectioncausedbyE.coli or
Proteusspp,pneumococcusOther:Toxoplasmagondii Geneticdisordersandinbornerrorsof
metabolism:Dubin- Johnsonsyndrome,Rotor'ssyndrome,galactosemia,hereditaryfructose
intolerance,tyrosinemia,α1-antitrypsindeficiency,Bylerdisease,recurrentcholestasiswith
lymphedema,cerebrohepatorenal syndrome,congenital erythropoieticporphyria,Niemann-Pick
disease,Menkes'kinkyhairsyndrome Idiopathicneonatal hepatitis(giantcellhepatitis) Total
parenteral nutrition-inducedcholestasis
1. Metabolicandgeneticdefects.A significantnumberof identifiable metabolicandgenetic
abnormalitiescanpresentwithhepatocellulardysfunction.
a. α1-Antitrypsindeficiency.Thisisanautosomal recessive conditioncharacterizedby
accumulationof α1-antitrypsininthe hepatocyte,resultinginsubsequenthepatocellularnecrosis.
There are several phenotypes;however,onlythe homozygousPi (protease inhibitor) ZZand,
rarely,MZ typeshave beenassociatedwithliverdisease ininfancy.Mostpatientsexperience
jaundice inthe first8 weeksof life.Fiftyto70% of patientswill gointoremissionby6months.
Otherwise,the clinical course ishighlyvariable;some patientsdevelopprogressive liverfailure.
b. Cysticfibrosis.Cholestasiscanbe aninitial presentationof cysticfibrosisininfancy.Most
of these infantswill alsohave meconiumileus.Liverbiopsyof thesepatientswillshow excessive
biliarymucus,inspissatedbile,mildinflammatorychanges,andfibrosis.Patientswhohadresolved
neonatal jaundice are notat greaterriskfor liverdiseaselaterinlifeoverothercysticfibrosis
patients.
c. Zellweger'sorcerebrohepatorenalsyndrome.Thisisaperoxisomal disorderandis
characterizedbythe absence of peroxisomesandderangedmitochondria.Itisinheritedasan
autosomal recessivetraitandpresentsinthe neonatal periodwithcholestasis,hepatomegaly,
profoundhypotonia,anddysmorphicfeatures.Diagnosisisconfirmedbythe presence of
abnormal levelsof very-long-chainfattyacidinthe serum.Prognosisisverypoor.Mostinfantsdie
within1 year.Survivorsbeyond1yearof age have severe mental retardationandseizures.
d. Dubin-JohnsonandRotor'ssyndromes.Thesesyndromesare rarelydiagnosedinthe
neonatal period,althoughtheycaninitiallypresentwithcholestasisduringthatperiod.Dubin-
Johnsonsyndrome isanonhemolyticconjugatedhyperbilirubinemiacausedbydeficiencyinthe
canalicularsecretionof conjugatedbilirubin.Liverbiopsyisnormal exceptforthe presenceof
12. pigmentedgranules.Rotor'ssyndrome isbelievedtobe the resultof a disturbance inthe hepatic
storage of anions,characterizedbylifelongpresence of mildconjugatedhyperbilirubinemia.Liver
biopsyisnormal,butunlike Dubin-Johnsonnopigmentaccumulationisnoted.Bothconditionsare
inheritedasautosomal recessiveandhave anexcellentprognosis.
e.Galactosemia.Thisisan autosomal recessive disorderresultingfromadeficiencyof
galactose-1-phosphate uridyltransferaseactivity.Incidence isabout1:100,000. It is characterized
by presence of cholestasis,hepatomegaly,hypoglycemia,cataracts,vomiting,andfailuretothrive.
Escherichiacoli sepsisisthe mostdevastatingcomplicationinthe newbornperiod.The twoother
enzymes,namelygalactokinase andUDP galactose-4-epimerase,thatare involvedinthe galactose
metabolicpathwayare lesscommoncausesof galactosemia.The pathologicconsequencesare
thoughtto be secondaryto accumulationof toxicmetabolite,galactose-1-phosphate.
Galactosemiamustbe rapidlyexcludedininfantswithearly-onsetcholestasis,withassociated
emesis,acidosis,andgram-negative sepsis(particularlyE.coli).These infants,while onlactose-
containingformula,will have galactose inthe urine,resultinginapositive reducing substancein
the urine (Clinitest)butnegative urinetestforglucose (glucose oxidase).
f.Othermetabolicandgeneticdisorders.Tyrosinemia,fructosemia,Niemann-Pickdisease,
Gaucher's disease,Wolman'sdisease,andglycogenosistype IV are othermetabolicandgenetic
disordersthatmaypresentwithcholestasisasan additional findinginthe neonatal period.
2. Infection.
a. Congenital infection.Congenitallyacquiredinfectionshave aspectrumof manifestations
but are usuallyasymptomatic.Congenitalinfectionusuallypresentswithotherstigmataof the
disease.Vertical transmissionof hepatitisviruses(BandC) is generallyasymptomatic,butclinical
hepatitis,includinghepaticfailure,maydevelopatabout 2 monthsof age.Coxsackievirus,Epstein-
Barr virus,andadenovirusare knowncausesof neonatal hepatitiswithelevatedconjugated
fractions.
b. Sepsis.Directbacterial infectionof the livermayoccur withoverwhelmingsepsis.Toxic
cholestasiswithnodirectinvasionof the liverbymicroorganismsmaybe seenwithurinarytract
infection,particularlywithE.coli urosepsis.
3. Total parenteral nutrition(TPN) cholestasis.The frequency,notnecessarilythe severity,of
cholestasisispartlyafunctionof the degree of prematurity.Cholestasisdevelopsin>50% of
infantswithbirthweightof <1000 g and <10% of terminfantsafterprolongedhyperalimentation.
No precise cause hasbeenfound;however,the mostsignificantcontributingfactorwasthoughtto
be the lackof enteral feeding.The resumptionof normal enteral feedshasbeenassociatedwith
improvementof cholestasisin1-3months,withnoor little residual fibrosisandnormal hepatic
function.
4. Idiopathicneonatal hepatitis(Table 64-3).Thisdiagnosisapplieswhenknowninfectious,
metabolic,andgeneticcauseshave beenruledout.Jaundiceandhepatosplenomegalyare major
physical findings.Liverbiopsydemonstratesgiantcell transformation,increasedextramedullary
hematopoiesis,andinflammation.Prognosisisfair.
5. Miscellaneous.
13. a. Neonatal hemochromatosis(NH).Alsoknownasneonatal ironstorage disease,this
conditionresultsfromliverdisease of intrauterineonset.Itisassociatedwithextrahepatic
depositsof stainable iron.Patientspresentwithhepatocellularsyntheticinsufficiency
(hypoalbuminemia,coagulopathy,andlow fibrinogen) withend-stage liverdisease.Prognosisis
verypoor andis almostalwaysfatal.
b. Shockor hypoperfusion.Multiorganinvolvementisnotuncommonincasesof perinatal
asphyxiaorshock/hypoperfusionstate.
c. Extracorporeal membrane oxygenation(ECMO).InfantsonECMOmay show an increase
inthe prevalence andseverityof cholestasis.
III.Clinical presentation.The classicclinical manifestationsof neonatalcholestasisinclude
jaundice,acholicstools,anddarkurine.Otherfindingsmayincludehepatomegaly,splenomegaly,
pruritus,failure tothrive,decreasedfeeding/appetite,ascites,andportal hypertension.
Unfortunately,individualsignsandsymptomscannotdifferentiate betweenintra- versus
extrahepaticdisease.The combinationof clinical andhistorical findingscanleadtopossible
causes.The presence of nonhepaticfindingswillprovidehelpfulcluestospecificdiagnosis,suchas
the following:
A. Alagille'ssyndrome.Cardiovascularfindings(peripheral pulmonicstenosis),vertebral
anomalies,ocularfindings(posteriorembryotoxon),andpeculiarfacies.
B. Zellweger'ssyndrome orcerebrohepatorenal syndrome.Profoundhypotonia,seizures,and
dysmorphicfeatures.
C. Congenital infections.Microcephaly,intracranial calcifications,intrauterine growth
retardation.
D. Galactosemia.Failure tothrive,vomiting,cataracts,andGram-negative bacterial sepsis(E.
coli).
E. TPN-inducedcholestasis.Historyof prematurityandprolongeduse of hyperalimentation.
IV.Diagnosis
A. Laboratorystudies
1. Bilirubinlevels(total anddirect).
2. Liverfunctiontests.Serumglutamicoxaloacetictransaminase(SGOT[aspartate
transaminase,orAST]),serumglutamicpyruvictransaminase (SGPT[alanine transaminase,or
ALT]),and alkaline phosphatasemaybe helpfulinmonitoringthe course of the disease.
3. Prothrombintime andpartial thromboplastintimemaybe reliableindicatorsof liver
function.
4. γ-Glutamyl transpeptidase,5′-nucleotidase,andserumbile acidsare alsousuallyelevated
incholestasis.Once the diagnosisof cholestasisismade,measurementof these markersof
cholestasismaynotaddany furtherinformation.
14. 5. A complete bloodcell countandreticulocyte countmaybe helpful if hepatitisisa
possibilitybecausehemolysismaybe found.
6. Serumcholesterol,triglycerides,andalbuminlevels.Triglyceride andcholesterollevelsmay
aidin nutritional managementandassessmentof liverfailure.Albuminisalong-termindicatorof
hepaticfunction.
7. Ammonialevelsshouldbe checkedif liverfailure issuspected.
8. Serumglucose levelsshouldbe checkedif the infantappearsill.
9. Urine testingforreducingsubstancesisasimple screeningtestthatshouldalwaysbe
performedtodetectformetabolicdisease.
10. TORCH (toxoplasmosis,rubella,cytomegalovirus[CMV],andherpessimplexvirus) titers
and urine culturesforCMV.The use of TORCH titersshouldbe guidedbythe clinical presentation,
keepinginmindthatCMV infectionmaybe asymptomaticandcongenital syphilisistreatable.
CMV immunoglobulinsMand G (IgMand IgG),Venereal Disease ResearchLaboratory(VDRL),and
IgM-specifictitersforherpessimplex,rubella,andtoxoplasmosismaybe useful insome cases.
11. Alpha-fetoprotein(AFP).
12. Other tests.More specifictestsare indicatedinthe investigationof the specificcausesof
conjugatedhyperbilirubinemia.
a. Hepatitis.The maternal hepatitisBsurface antigen(HBsAg) statusshouldbe known,and
the infantshouldalsobe tested.
b. Sepsis.If bacterial sepsisorurinarytract infectionis suspected,appropriatecultures
shouldbe obtained.
c. Metabolicdisorders
i.Galactosemiaandhereditaryfructose intolerance.The urine shouldbe testedfornon-
glucose-reducingsubstances.Enzymesinvolvedinthesedisorderscanalsobe assayedinthe
blood.
ii.Tyrosinemia.Highconcentrationsof tyrosineandmethionine,andtheirmetabolic
derivatives,will be seeninthe urine.
iii.α1-Antitrypsindeficiency.Decreasedserumα1-antitrypsinconcentrationandliver
biopsyshowingperiodicacid-Schiff (PAS)-positivecytoplasmicgranuleswithvariabledegreesof
hepaticnecrosisandfibrosis.
iv.Cysticfibrosis.A sweattestmaydiagnose cysticfibrosis.
B. Radiologicstudies.Diagnosisof biliaryatresiaandotherformsof extrahepaticbiliary
obstructionby8 weeksof age isrequiredtopreventprogressionof the disease.
1. Ultrasonography.Thisisusedtoview the liverparenchymaandtodiagnose dilatationof
the biliarytree;inextrahepaticobstruction,halfof the infantswillhave dilatedproximal ducts
withinthe liver.Choledochal cystsare seen.Aninabilitytoidentifythe gallbladderon
15. ultrasonographymayresultfromobliterationof itslumeninbiliaryatresia.However,the presence
of a gallbladderdoesnotrule outbiliaryatresia.Because thistestissimple andnoninvasive and
because of the reportedcoexistence of certaincholestaticdiseases,we highlyrecommendthatall
infantswithcholestasishave thisdiagnostictestdone.
2. Hepatobiliaryimaging.Contrastagentsare takenupbythe liverandexcretedintothe bile.
HIDA (hepatobiliaryiminodiaceticacid),EHIDA (ethyl hepatobiliaryiminodiaceticacid),andPIPIDA
(p-isopropylacetanilide-iminodiaceticacid) are technetiumlabeledandprovide aclearimage of
the biliarytree afterintravenousinjection.Neonatalhepatitis,hyperalimentation,andsepto- optic
dysplasiaare reportedcausesof absentgastrointestinal contrastexcretionandmustbe
consideredinthe diagnosisof biliaryatresia.Administrationof phenobarbital,5mg/kg/dayfor5
days,inconjunctionwithhepatobiliaryscanningmaybe helpful indistinguishinginfantswhodo
not have biliaryatresia.Excretionof the contrastmediummayimprove afterphenobarbital
treatment.
C. Otherstudies
1. Percutaneousliverbiopsy.Thisisasafe procedure inexperiencedhands.Biopsyfindings
mustbe correlatedwithclinical andlaboratorydata.
2. Exploratorylaparotomywithoperative cholangiogramissometimesindicatedtocorrect
biliaryatresia,especiallyif the just-mentionedtestsare notdiagnostic.
V.Management(see alsoChapter38)
A. Medical management
1. General plan.Incholestaticjaundice,promotionof bile flowandpreventionof
malnutrition,vitamindeficiencies,andbleedingare goalsof treatment.
2. Pharmacologicmanagement.Phenobarbital andcholestyramine will promotebileflow and
decrease serumbilirubinandbilesaltlevels.Cholestyramineisanonabsorbable anionexchange
resinthatirreversiblybindssaltsinthe intestine.Thisleadstoincreasedfecal excretionof bile
saltsand increasedhepaticsynthesisof bile saltsfromcholesterol,whichmaylowerserum
cholesterol levels.Actigall (ursodeoxycholicacid) hasalsobeensuccessfullyusedinconjunction
withphenobarbital andcholestyramine.
B. Dietarymanagement
1. Medium-chaintriglycerides(MCT).Long-chaintriglyceridesare poorlyabsorbedinthe
absence of sufficientbilesalts.Therefore,infantswithcholestasisoftenrequire adietthat
includesMCTs,whichcan be absorbedwithoutthe actionof bile salts.FormulascontainingMCTs
include PortagenandPregestimil.Breast-fedcholestaticinfantsshouldbe givensupplemental
MCT.
2. Vitaminsupplementation.Fatmalabsorptionwill alsointerfere withmaintenance of
adequate levelsof fat-soluble vitaminsinthese infants.Supplementationof vitaminsA,D,E,and K
issuggested.ExtravitaminKsupplementationmaybe necessaryif ableedingtendencydevelops.
16. 3. Dietaryrestrictions.Removal of galactose pluslactose andfructose plussucrose may
preventthe developmentof cirrhosisandothermanifestationsof galactosemiaandhereditary
fructose intolerance,respectively.Dietaryrestrictionsmayalsobe usedtotreat tyrosinemiabut
usuallyare lesssuccessful.Mostothermetaboliccausesof cholestaticjaundice have nospecific
therapy.
C. Surgical management
1. Laparotomywithbiopsy.If extrahepaticbiliaryobstructionisstronglysuspectedafter
completionof anappropriate evaluation,exploratorylaparotomyshouldbe performedwith
operative cholangiographyandliverbiopsy.Operative examinationshouldbe performedby
surgeonspreparedtoproceedwithcorrective proceduresif necessary.Othercausesof
extrahepaticbiliaryobstructionthatmaybe diagnosedandtreatedduringexploratorylaparotomy
include choledochal cyst,spontaneousrupture of the bile duct,lymphnodeenlargement,tumors,
annularpancreas,pancreaticandhepaticcysts,and hemangioendotheliomaof the pancreasor
liver.Inspissatedbile syndrome causedbycysticfibrosisalsorequiressurgical removalof
tenaciousbile fromthe bile ducts.
2. Kasai procedure.Surgical procedure suchasKasai portoenterostomyshouldbe done to
establishbiliarydrainage inpatientsdiagnosedwithbiliaryatresia.Optimal resultsare obtainedif
the
procedure isdone before 8weeksof age.If the Kasai procedure issuccessful,mostinfantswill
have deteriorationof liverfunctionovertime andeventuallyneedalivertransplant.The
procedure isusedas a bridge totransplantation.
3. Livertransplantation.Whenend-stageliverdisease isinevitable,livertransplantationis
considered.Biliaryatresiaisthe mostcommonindicationforlivertransplantationinthe United
States.Overall,the successof livertransplantationhasimprovedsignificantly,withreportsof 5-
yearsurvival rate of >80%. Some centersreporta 1-year survival rate close to90%.
D. Othertreatments
1. Infectiousdiseases.Some of the infectiouscausesof hepatitis,suchashepatitisBvirus,
herpessimplex virus,congenital syphilis,andbacterial infections,have specifictherapeutic
regimens.Mostotherformsof infectioushepatitisresolve withnospecifictherapy.
2. TPN-inducedconjugatedhyperbilirubinemiawillusuallyresolve once TPN isstopped.The
decisiontocontinue TPN (withorwithouttrace elements) inaninfantwithcholestasismustbe
carefullyconsidered.Resumptionof normal enteral feedsisassociatedwithclearingof cholestasis
in4-12 weeks.